U

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(8:37 a.m.)

ADMINISTRATIVE MATTERS

MEMBER FREAS: Mr. Chairman, members of

the Committee, invited speakers, and members of the

public, I would like to welcome all of you to this,

our 97th meeting of the Vaccines and Related

Biological Products Advisory Committee meeting.

I am Bill Freas. I am the Acting

Executive Secretary for today. At this time, before

the meeting, begins, I would like to go around and

introduce to the public the members seated at the head

table.

We will start on the right side of the

table. That is the audience's right‑hand side. And

I will read the names of the people at the table.

Would the members please raise their hands as I call

their names?

David Markovitz, Professor, Division of

Infectious Diseases, University of Michigan Medical

Center.

Next is Dr. Walter Dowdle, Senior Public

Health Consultant, The Task Force for Child Survival

and Development.

Next is Dr. Judith Goldberg, Director,

Division of Biostatistics, New York University School

of Medicine.

Next is Dr. Ruth Karron, Associate

Professor, Johns Hopkins School of Hygiene and Public

Health.

Next is Dr. Walter Royal, Associate

Professor of Medicine, Morehouse School of Medicine.

Next is Dr. Monica Farley, Professor of

Medicine, Emory University School of Medicine.

Next is Dr. Pamela McInnes, Deputy

Director, Division of Microbiology and Infectious

Diseases, NIH.

Next is Ms. Cindy Lyn Province, Associate

Director, Bioethics Center of St. Louis.

Next is Dr. Bruce Gellin, Director,

National Vaccine Program.

In the empty chair, we will soon be joined

by Dr. Stephen Phillips, Director, Deployment Medicine

and Surveillance, Office of Assistant Secretary of

Defense.

Next I would like to introduce you to the

Chair of this Committee, Dr. Gary Overturf, Professor

of Medicine, University of New Mexico School of

Medicine.

Coming around the table, we have Dr.

Philip LaRussa, Professor of Clinical Pediatrics,

Columbia‑Presbyterian Hospital.

Next we have Dr. Martin Myers,

Co‑Director, Public Health Policy and Education,

University of Texas Medical Branch.

Next we have Dr. Bonnie Word, Assistant

Professor of Pediatrics, Baylor College of Medicine.

Next we have Dr. Peter Palese, Chairman

and Professor, Department of Microbiology, Mt. Sinai

School of Medicine.

Next we have Dr. Arnold Monto, Professor,

The University of Michigan.

Next we have Dr. Ted Eickhoff, Professor

of Medicine, University of Colorado Health Sciences

Center.

Next we have our nonvoting industry

representative, Dr. Michael Decker, Vice President,

Scientific and Medical Affairs of Aventis Pasteur.

Next we have a nonvoting participant, Dr.

Nancy Cox, Chief of the Influenza Branch, Centers for

Disease Control and Prevention.

Next we have Dr. Roland Levandowski from

the FDA.

Dr. Richard Whitley, University of

Alabama, member of this Committee, has recused himself

from today's participation.

I would like to thank the members for

attending. There is one other person I would like to

introduce at this time. Many people have asked me,

"When are you going to get a real executive secretary

for this Advisory Committee?" I would like to

introduce this morning Christine Walsh, who will be

the next Executive Secretary for this Committee at the

next meeting, which will be announced later. It will

be either in March or May. We have a teleconference

scheduled for March the 17th at this time.

I would now like to read the conflict of

interest statement into the record. Before I do that,

I would like to ask the members of the public if they

could put their cell phones on silence mode, it would

be appreciated.

"The following announcement addresses the

conflict of interest issues associated with the

Vaccines and Related Biological Products Advisory

Committee meeting on February 18th and 19th, 2004.

The Director of the Center of Biologics Evaluation and

Research has appointed Drs. Walter Dowdle, Ted

Eickhoff, Bruce Gellin, Judith Goldberg, Pamela

McInnes, Arnold Monto, Martin Myers, and Stephen

Phillips as temporary voting members for this meeting.

"Based on the agenda, it has been

determined that there are no specific products being

approved at this meeting. The Committee participants

have been screened for their financial interests. To

determine if any conflicts of interest existed, the

agency reviewed the agenda and all relevant financial

interests reported by the meeting participants.

"The Food and Drug Administration prepared

general matters waivers for participants who required

a waiver under 18 U.S. Code 208. Because general

topics impact on many entities, it is not prudent to

recite all potential conflicts of interest as they

apply to each member. FDA acknowledges that there may

be potential conflicts of interest, but because of the

general nature of the discussions before the

Committee, these potential conflicts of interest are

mitigated.

"We would like to note for the record that

Dr. Michael Decker is a nonvoting industry

representative for this Committee acting on behalf of

a regulated industry. Dr. Decker's appointment is not

subject to 18 U.S. Code 208. He is employed by

Aventis and, thus, has a financial interest in his

employer. In addition, in the interest of fairness,

FDA is disclosing that his employer, Aventis, is a

manufacturer of a product that could be affected by

today's discussions.

"With regards to FDA's invited guest

speakers, the agency has determined that the services

of these speakers are essential. The following

interests are being made public to allow meeting

participants to objectively evaluate any presentation

and/or comment made by the speakers.

"Dr. Antoine Flahault is employed by the

World Health Organization Collaborating Center for

Electronic Disease Surveillance in France. He has

associations with firms that could be affected by the

Committee discussion.

"Dr. Maria Zambon is employed by the

Respiratory Virus Unit, Health Protection Agency in

England. Her agency's laboratory conducts tests on

licensed influenza vaccines. Her employers

collaborates with firms that could be affected by the

Committee discussions.

"In addition, there are vaccine

manufacturers making industry presentations. These

speakers have financial interests associated with

their employer and with other regulated firms. They

were not screened for conflict of interest.

"Members and consultants are aware of the

need to exclude themselves from the discussions

involving specific products or firms for which they

have not been screened for conflict of interest.

Their exclusion will be noted in the public record.

"With respect to all other meeting

participants, we ask in the interest of fairness that

you address any current or previous financial

involvement with any firm or product you wish to

comment upon. Waivers are available by written

request under the Freedom of Information Act."

So ends the reading of the conflicts of

interest statement. Dr. Overturf, I turn the meeting

over to you.

CALL TO ORDER

CHAIRMAN OVERTURF: Good morning. I would

like to welcome everybody to this meeting of the

VRBPAC Advisory Committee February 18th and 19th.

Dr. Midthun, would you like to make

presentations to retiring members?

PRESENTATION OF PLAQUES TO RETIRING MEMBERS

DR. MIDTHUN: Good morning. I would like

to ask Dr. Judith Goldberg to please come up to the

podium. I would like to thank her for her many years

of service on this Advisory Committee. She has always

been here with great dedication, always has prepared

extremely well, and provided excellent input to us.

We are really going to miss her and really appreciate

all that she has given to us.

I think I am supposed to stand over here

so we can get with the picture of the plaque. Thank

you. And we also have a letter here for you from Mr.

Peter Pitts, who is our Associate Commissioner for

External Relations. So thank you so much.

(Applause.)

DR. GOLDBERG: I just want to thank all of

you because it has really been a privilege to serve on

this Committee. I have enjoyed every minute of it,

and I have learned a tremendous amount.

DR. MIDTHUN: Thank you so much.

CHAIRMAN OVERTURF: I think we will

proceed. As you know, there has been a great deal of

interest in influenza, for those of you who forgot

about last winter. So this year I think will be a

striking update of last year. So that I think we will

begin with the data that is going to be presented by

Dr. Roland Levandowski and his associates. Thank you.

DR. LEVANDOWSKI: Great. Thanks very

much, Dr. Overturf.

OPEN SESSION

STRAIN SELECTION FOR INFLUENZA VIRUS VACCINE

FOR THE 2004‑2005 SEASON

INTRODUCTION

DR. LEVANDOWSKI: I am going to try to

give a somewhat extended review of what has been

happening this last season. Generally I do give a

fairly brief review, but today I am going to be going

into a little bit more detail.

There is an awful lot that is going on.

What we would like to try to cover, just as a

reminder, the real business for today is what is first

on this list of topics for us to take a look at. We

are really here today to make the recommendations for

the strains that should be used in next year's

trivalent vaccine, for the 2004‑2005 trivalent vaccine

for the H1N1, H3N2, and Influenza B viruses.

We do also on this program, as you will

see from the agenda, have some other items that we

wanted to bring to the attention of the Committee. In

particular, there are some items that we have that we

would like to bring to the attention of the Committee

just mainly for information for things that are

happening.

There has been a lot of interest this year

about the effectiveness of vaccines. This has been a

discussion point at this Committee on many occasions

in the past. In fact, I can't remember one when it

hasn't been discussed in recent memory of mine.

So we have several speakers: Dr. Carolyn

Bridges from CDC, Col. James Neville from the

Department of Defense, and Dr. Antoine Flahault from

the Institut National de la Sante et de la Recherche

Medicale, who will be talking about some studies that

they have ongoing to look at vaccine effectiveness.

Some of these are still in progress, but we will at

least get to hear what is happening to try to look at

this in an ongoing manner.

I also wanted to bring to the attention of

the Committee what is happening with H5 avian

influenza in Asia. At this time last year, you might

remember we were talking about what is happening with

SARS. So we know that the Committee will be very

interested to hear this information. We also want to

bring it to the attention of the Committee because

there may need to be some activities that go on at a

later date. We just wanted to have them informed as

much as we can at this point.

Finally, on the agenda, we have something

that we would like to have some discussion with the

Committee. This relates to a point that was brought

up last year about use of tissue culture isolates from

field laboratories for preparation of influenza

vaccines.

You will see on the agenda that tomorrow

toward the conclusion of the meeting we have a couple

of presentations by one of my colleagues, Zhiping Ye,

Center for Biologics, and also Dr. Phil Minor from

NIBSC, to talk about our perspectives on what the

issues might be with issue of tissue culture isolates.

So this is the main business. Again, this

is the question that we are asking the Committee to

give us recommendations today. We are asking for a

vote on this. This is the abbreviated version of the

question, what strain should be recommended for the

antigenic composition of the 2004‑2005 influenza virus

vaccine for use in the United States?

Just by way of review, this was the

recommendation that was made by the Committee last

year at this time. It was for a trivalent vaccine

that would contain an A/New Caledonia/20/99 H1N1‑like

strain. Actually, it was A/New Caledonia/20/99.

It would also contain a B/Hong

Kong/330/01‑like strain. And in our case, the strains

that were used for vaccine preparation were the actual

strain, B/Hong Kong/330/2001 or B/Hong Kong/1434/2002.

The H3N2 component that was recommended based on all

of the information was for an A/Panama/2007/99‑like

strain.

Why do we change strains for influenza

vaccines? Well, we do it because the vaccine efficacy

is really related to two things. One is how much

antigen is present in the vaccine and then, very

importantly, what the match of the vaccine,

hemagglutinin and neuraminidase, are with the wild

type circulating strains. This has been very clear to

us since the earliest days of influenza vaccine use.

You might remember that influenza viruses

were first isolated in the mid '30s, human influenza

viruses, mid '30s to early '40s. And it was very

quickly that some vaccines were prepared as whole

virus vaccines.

The first vaccine was licensed in the

United States in 1945. And within two years, by 1947,

it was pretty clear that when there were antigenic

changes occurring by way of mutation in the viruses,

that there was reduced vaccine effectiveness. That

led to setting up the global surveillance system.

What we know from that period of time

onward is that there have been continuous antigenic

changes in the hemagglutinin and neuraminidase of both

influenza A and influenza B viruses.

These are the questions that are asked in

order to answer the question for recommendations. I

will just go over these a little bit with you. First

of all, we want to know, are there new either drifted

or shifted antigen influenza viruses present? Drift

is point mutation occurring in the viruses. And shift

would be exchange of an entire gene segment.

I guess I should remind you that influenza

viruses have a segmented genome. There are eight gene

segments for either influenza A or influenza B. These

can reassort in nature to put new hemagglutinin and

neuraminidases into human influenza viruses. That

usually results in a pandemic. But, anyway, the

question is, are there new influenza viruses present?

This is the purpose that surveillance

serves. It provides us with that information as to

whether there are new viruses that are occurring.

Mainly we are interested in, are they new in terms of

their antigenic properties, mainly for the

hemagglutinin but also for the neuraminidase?

It is also from surveillance that we get

the viruses that are used for vaccine preparation. So

without that underpinning, there really isn't anything

that we would be able to accomplish.

The question to be answered if there are

new viruses, ‑‑ and they almost always are new viruses

that are being identified because of the continuity of

evolution of the viruses ‑‑ are they spreading in

people?

It is not unusual to see that there are

influenza viruses that are really wildly different,

but it turns out they are one off. So that occurs

from time to time. And it takes a while, in fact, to

have an understanding as to whether these new viruses

really have any significance or a potential impact

that we need to take into consideration for vaccine

preparation.

If there are new viruses spreading, then

we also want to know whether our current vaccines are

going to have any likelihood of having effectiveness

against these new strains. And, for that purpose, we

look at responses from people who have been immunized

with the current vaccines. Often the case is that

although there are some new viruses that are

spreading, the current vaccines actually make

antibodies that cross‑react fairly well.

And while the differences you will see for

these two different activities are somewhat

complementary, there are thousands of influenza

viruses that are examined with a relatively small

number ‑‑ it is not entirely small, but it is a

relatively small number of sera that are used to

categorize them. With the human serologies, we are

looking at the reverse, where we have several hundred

different sera from people who have been infected or

immunized and looking at a relatively small, select

group of these viruses that have been identified in

surveillance.

And then, last but not least, if it is

true that there are new viruses, they are spreading,

the current vaccines don't look like they produce very

good antibody responses to those new strains, then we

still need to know, "Can we do something about it?

And are there any strains that are suitable for use in

vaccines?"

And so, to answer the questions, last

year, just to review what we did, were there new

influenza A, H1N1, viruses? No. The answer was no.

The HA of all of the strains was very similar to the

vaccine strain.

For H3N2, the answer, however, was yes.

There were quite a few strains that were identified.

Although most of these strains were originally very

much like the current vaccine strain, there were some

strains that were identified early in 2003 that were

antigenically distinguishable. And it was a

relatively small proportion to begin with, but that is

not unusual either that it starts out small and

quickly snowballs.

However, after collecting information and

analyzing, it wasn't really until February of last

year that it was clear that there was a cluster that

were antigenically and genetically related that seemed

to be the ones that were most likely to spread

further.

For influenza B viruses, again, the answer

was really no. There weren't really any new viruses

that were found. The majority of the strains were

very similar to what was in the vaccine, but there

were a small number of strains that are different.

There actually have been two hemagglutinin

lineages for influenza B viruses co‑circulating for at

least the past 15 years. One or the other of these

hemagglutinin lineages has tended to be the

predominant strain. We had just left a period of time

where for about ten years, the strains in the

so‑called B/Yamagata/16/88 lineage were the ones that

were predominant, particularly outside of Asia.

For the last two years, however, the

strains that have been predominating are on the other

HA lineage. They are in the B/Victoria/2/87

hemagglutinin lineage. And that is what we have

currently in our vaccine. But there was a small

proportion of viruses last year that were identified

that were in the B/Yamagata/16/88 lineage. That was

being paid attention to, but it was not sufficient to

think that there was something really happening there.

Were these viruses spreading? For the

H3N2, as I mentioned, the answer was yes. By the time

the Committee was meeting in February or March, it was

pretty clear that there were some of these viruses

found on several continents, including Asia, Europe,

and North America. Were these viruses inhibited by

the current vaccines? And the answer to that was

partially no.

There were a number of strains that were

very much like the Panama/2007/99 vaccine strain.

Those were very well‑inhibited. But for the group

that we are now calling A/Fujian‑like strains, some of

these were relatively well‑inhibited by current

vaccines and some were not. It was not a very

homogeneous situation.

Then, to answer the question, were strains

suitable for manufacturing available? The answer was

actually no. And it related to the fact that all of

this information was coming out just at the time that

decisions need to be made in order to prepare a

vaccine. I will give a little bit of explanation

shortly about why that is true, why the timing was

off.

Sort of in a nutshell here, the

manufacturing does depend on having an egg‑adapted

strain that will grow well. It could be either

wild‑type or a high growth reassortant for the

influenza A viruses. Generally it needs to be a high

growth reassortment.

The fact that these first Fujian‑like

strains were first identified in February made this

difficult. The first egg isolate of an A Fujian‑like

strain wasn't until April. The first high growth

reassortant wasn't prepared until toward the end of

June. That timing also is fairly typical for dealing

with new influenza viruses as they are appearing.

So the implications of the strain

selection from last year were that the preparation of

vaccines this current year was very much on schedule.

I will provide some information about that. And the

supply of vaccine matched the demand that was expected

by the previous year's experiences.

There were some other implications. One,

this year there was an early widespread appearance of

drift variant of A Fujian‑like viruses in the United

States. There were reports of mortality in children.

Now, that significantly increased vaccine demand.

And although there were several million

doses of vaccine, both of inactivated and live

vaccine, that were still available in mid November.

And it appeared that we were headed toward a situation

where a lot of vaccine would not be used again, which

has frequently been the case in the past, not just the

year before but for many years running. The amount of

vaccine that was available was not sufficient to avoid

some spot shortages that occurred after the

Thanksgiving holiday in the United States.

And then again, the effectiveness of the

vaccines against this drift variant has been

questioned. So there are some studies that are

ongoing. We are going to be hearing about those.

So for the United States, we have three

licensed influenza vaccine manufacturers. Two of them

produce inactivated vaccine: Aventis Pasteur and

Evans Vaccines. Evans is now part of Chiron. So I

have to be careful. It is hard for me to keep up with

the changes that occur business‑wise, but these two

companies have been licensed in the United States for

quite some time, as you can see here.

And last year, between the two companies,

there was production of about 83 million doses of

vaccine. Put that into a little bit of perspective.

Inactivated vaccines around 1990, there were

approximately 25 to 30 million doses produced per

year. So over the decade of the '90s, vaccine

production had increased substantially.

And our license manufacturer for live

attenuated vaccine is MedImmune. They were licensed,

as you might recall, in June of 2003. And they

produced about four million doses of vaccine for use.

The timelines for vaccine production are

shown here. And it is a little bit of a pyramid

scheme. What most everybody is interested in or what

gets the most visibility is vaccine use, which occurs

in the fall through the early winter. But supporting

that, underneath that, is all the work that the

manufacturers have to do to prepare the vaccine. And,

even before that, surveillance and other activities

are required. We are right here in February to March.

So we are right down here in this period of time. It

is early days for vaccine preparation, and it is

months away from vaccine use.

As I mentioned, without surveillance, we

would not have strains for use in vaccine production

in the first place. And there is a lot of work that

goes on between surveillance and trying to develop new

strains throughout the year, although there may be

periods of time when there is more activity than

others. But there is some activity going on pretty

much all the time.

Recommendations are generally made by the

WHO for the Northern Hemisphere and for the winter

months here and for the Southern Hemisphere and for

the winter months there. But these recommendations

are important so that the manufacturers know what they

should do.

Too, as there are reference strains that

are getting worked, the manufacturers throughout the

year are working on their seed viruses, which were

proprietary to them. They worked with the virus to

make sure that it is going to be appropriate for the

manufacturing conditions. And although there may be

some early seed viruses that are used in production,

there is some continuous work that goes on to try to

make that better so that manufacturing can be smoothed

out. I will show a little bit of information about

that, too.

Production of the monovalent components of

the vaccine takes many, many months. And, really, it

starts maybe earlier than January. Manufacturers may

be working at risk before recommendations are made to

produce monovalent components. They don't do this

without some education. They are paying close

attention to the surveillance that is being reported

throughout the year by WHO and our colleagues at CDC.

Once all three of the components are

present, trivalent vaccine can be produced, but you

will see that there is still overlap. There is still

for quite a long time, actually, many years, work

being done with the monovalent vaccines. And so there

is some vaccine that starts to come out, but it

doesn't all come out at one time. And that vaccine

uses the desired goal at the top again.

So to try to also give some understanding

about how long it takes, when there is a new strain

that is recommended, when there is a new reference

virus that is identified, for the point of time that

that new reference is identified to the time that that

is available for sending out to manufacturers to

develop their seed viruses, for the period of several

weeks, part of this is trying to understand, is this

the best strain that is available or are these the

best strains that are available for producing the

vaccine? It takes some analysis. It takes some

collaboration between the WHO centers to come to that

understanding.

Part of the time for influenza A viruses

and probably for influenza B viruses in the future is

preparing the high growth reassortants that make it

more expeditious for producing the vaccine. At the

same time that that is happening, reference reagents

for standardization of the vaccine need to be

prepared. And this is true not only for inactivated

vaccines, but it may be necessary for the live

vaccines also.

Potency testing for these is dependent

upon having antisera that can be used for the tests

that are done to try to standardize in terms of

potency.

Once the manufacturer has a seed virus

prepared, then they can start to manufacture. As I

mentioned, there may be manufacturing at risk when the

strains are not changed. Those strains can be

prepared in advance of this meeting if the

manufacturers so desire, but they really can't do

anything until they have in their hand something that

is appropriate for making a seed virus. And they

can't manufacture all the strains without having those

available.

So this just shows manufacturing three

different strains. And I am showing down here vaccine

release. There are activities that go on between the

manufacturer and regulatory authorities to try to make

sure that these seed viruses: first, are appropriate

for use, that they maintain their antigenic

characteristics; and, second, that other kinds of

qualities are maintained.

Now, this bar is about three weeks long

for each of the monovalents. That is an

approximation. Most of that time I think you will

hear from our colleagues from industry relates to

quality control, not necessarily interaction with

regulatory authorities but just needing to meet their

own good manufacturing practices and be sure that the

vaccines are going to meet all of the specifications

that are set for them.

Once the three strains are produced, then

it is possible to go ahead and formulate vaccine and

to fill it and to send it out. You see, each of these

points have bars that are about three weeks long as

well. And there are some release activities that go

on for the trivalent vaccines.

This duration of time here again is not so

much the actual physical manipulation of the vaccine.

It has to do with the quality control measures that

need to be met and some very important ones, like

sterility for inactivated vaccines, for example.

So once that has all happened, then, of

course, the vaccine can be distributed. But, you see,

this time line up here, for a new strain, I am

indicating about 20 weeks. I think that is a

reasonable estimate. If you put that in months, that

is about five months from the time of the first

appearance of the new strain until there is really the

possibility of having a product in hand that can be

used.

That is just the first. Once the first

comes out, then, of course, it just keeps rolling.

Again, to try to put this into some more perspective,

it seems to be cut off a little bit on the boundaries.

That is okay.

I went back and reviewed monovalent

vaccines that were produced for inactivated vaccine

over the last several years. What I am trying to show

you here is that when strains are changed and those

are shown across the bottom, the relative proportion

‑‑ this should add up to 100 percent for all 3 strains

‑‑ of the strains that are produced really tends to

favor the new strains that are added. So you can see

between 1998 and 1999, there was a new influenza B

virus. And although 38 percent of all of the

monovalent concentrates produced in 1998 were

influenza B, over half of them, about 55 percent, were

influenza B.

You see that with other changes. In 2000,

we added a new H1N1 and H3N2. And you can see in both

instances, the amount of effort, the relative amount

of effort, in terms of the number of monovalent

concentrates that had to be produced was mostly

devoted toward the new strains. You can see that all

the way across here, that when new strains were added,

that there needs to be an adjustment that it is the

early work that has to be done by the manufacturers to

figure out how best to get things growing.

Once they get it organized, you can see

that it is possible that things may even out a little

bit more between the three strains, but the strain

that has changed, the strains that are changed are the

ones that are the most difficult in terms of overall

production, at least for the first year.

In terms of timing of these things, this

is what we see in terms of submission to the Center

for Biologics for Release. I am showing the number of

lots here against the month for both the monovalent

vaccine and the trivalent.

What I really want to point out to you on

this slide, the numbers aren't so important. It is

the overall pattern. You see that there is kind of

this buildup of more and more monovalent concentrates

coming in up until about August‑September. And then

it starts to wane.

And this relates to the point at which

manufacturers when they are trying to meet the need

for vaccine in October and November have already

planned out how they are going to be putting together

how they are going to be manufacturing the vaccine

components, when they need to have them on tap and so

on. And so they come to a decision point about August

or September where they have to decide whether it is

worthwhile for them to continue manufacturing or not.

There is a lot of effort and money that

goes into that continuation. And it is possible for

them to do so. They could keep going if they knew

that there would be demand, for example, within our

current system. It is possible to make more vaccine.

It doesn't have to stop right here, but it does

because there is a target that has been developed from

sales and demand. And it is really kind of a

practical decision.

You see that there still is overlap

between the preparation of the trivalent vaccine and

preparation of the monovalent right on out to the end

of the overall campaign for the year.

For this year, because the strains were

the same as the previous year and the demand was

fairly well‑understood at the beginning of the year,

it was possible to get everything ready.

This curve shows cumulative percent of all

the lots that are submitted to us for release from

June to December. Two thousand was the year that we

had the shortages or delays that were concerning. And

this was an atypical year in that the point at which

50 percent of the vaccine that was available was

shifted out substantially from where it normally is.

These curves over here are more typical of

what we would be seeing. And generally 100 percent of

the vaccine in the past has been out by about October.

And that is where we are here. This is the red color

here, the diamonds. The red diamonds are this year,

2003.

So you can see that vaccine was being

produced fairly consistently throughout this period of

time and very expeditiously met the overall goal for

this production campaign without any delays.

So why are influenza vaccines important?

Well, they are important because influenza has a lot

of economic consequences, the lost work, school time,

and so on. We know that morbidity is high,

particularly in the very young.

Pneumonia and Influenza, that is the only

category that is in the top ten causes of death in the

United States, the only infectious diseases category

that is in the top ten causes of death in the United

States. And this is for ages overall. It is not for

a specific age group but for the ages overall.

We know from other statistics that we can

expect somewhere between 20,000 and 40,000 deaths in

a typical year related to influenza. That is

generally in the elderly. And we know that pandemics

cause even more.

I just wanted to read a couple of things

that were from some publications that sort of put this

into perspective. So I am quoting here. It says,

"Early apprehension was increased by the fact that

when the first indications of the outbreak were

observed in the country, the influenza had already

attained epidemic proportions in England.

The sharp rise in influenza deaths,

however, was found not to be due to virulence of the

causative organism but to a high case incidence. The

term "lightening influenza" was used in newspaper

reports.

Also, the epidemic caused by influenza A

viruses was unusually severe for the inner pandemic

period. The attack rate in children was much higher

than for adults. At least 30 percent of children

under 5 years of age were ill. And most were taken to

medical care facilities.

Over 320 children per day crowded into the

pediatric outpatient clinic at Ben Taub Hospital. So

you might think that was this year, but the first one

is from 1943 and the second one is from 1975.

I just wanted to try to remind everybody

that what we are dealing with here is something that

maybe has been a little bit forgotten but that we

should remember that influenza is a very serious

disease.

And to try to highlight that more, I have

got some other slides here that I have taken from some

of the older literature. This is data from

door‑to‑door surveillance activities in Baltimore that

were undertaken during and after the pandemic of 1918

to try to get some information about what was

happening. Unfortunately, my legend is cut off over

here. The red one is 1918. The purplish one down

here is 1919. The green one is 1928 to '29. And the

black one down here is '40 to '41. This is 1943 to

1944.

That quote that I was reading partly

related to this. There was what was seen as a

relatively large incidence of case attack rate in

children predominantly during that period of time.

There was a large fear that this was the return of the

1918 pandemic strain. So you can see, by comparison,

it wasn't quite as high an attack rate, but it was

much higher than what had been seen in some of these

intervening years. So there was a lot of concern

about that.

I think what it indicates to us is that

attack rates can be higher or lower. It is sort of

interesting that in the case of both of these years,

there is sort of a relative disproportionality in

terms of younger children and then sort of young

adults. It caught my attention because I think that

may relate a little bit to what we are seeing this

year as well. I think we are seeing more activity,

and I think we will hear more about that.

So in terms of pneumonia ‑‑ and these were

cases per 10,000 shown on the other slide, and it is

the same scale here, but the numbers are drastically

different. So this is the pneumonia cases in those

same surveys.

You can see from 1918 to 1919, this very

much parallels the mortality curve, where there was a

kind of instead of a U‑shape, where it is very high at

both ends in the very young and the very old, there

was this extra peak occurring in young otherwise

healthy adults. And there is a small echo of that in

the year following 1918, during 1919 and 1920.

What I am showing here is that this blue

down here again is 1943, where there is a huge number

of cases occurring, but the amount of pneumonia that

was being identified in Baltimore was relatively low,

particularly in young healthy adults. There was a

little bit of an increase more in elderly than in

children, but the young children were affected as

well.

These are some data from 1975‑1976 in

Houston during an A/Victoria/3/75 epidemic of

influenza. I am showing this. Again, I am trying to

use that same scale. This is hospitalizations per

10,000. These are the ages of the individuals.

I guess what I should have said in my

previous two slides is that a lot of this, of course,

1918, some of this could have been something other

than flu. We didn't really have virologic

capabilities until later, but it is based on the

sharpness of the peak of the epidemic. And it is

probably true a little bit here for these data as

well.

These are not all virus isolates. These

are clinical studies that were done to try to define

what was happening in the epidemic. But this is

during an epidemic in Houston. Again, you see this

U‑shaped curve, where the hospitalizations are most

marked for the very young and the very old. In fact,

the number of hospitalizations in this particular

instance appear to be probably more than in the

elderly. But you see some level of hospitalization

during this relatively severe influenza season in all

age groups.

Different from that, however, is what has

been seen for mortality in some of these epidemics.

This is a different age 3 and 2 epidemic in Houston,

encompassing Harris County, Texas, the statistics,

health statistics, from there. Again, these are

deaths per 10,000 at different ages.

Here you can see that, really, it is the

elderly who are most markedly affected. They are the

ones who die when they become ill and develop

pneumonia. But there are deaths that are reported in

all ages. It is kind of a small number here in the

young adults. And there are quite a few more seen in

young children but not nearly what we see in the

elderly.

So from this information, the effects

here, we know that influenza attack rates are often

highest in children who are less than ten years ago.

There is serious illness in all of the age brackets,

with the young and the old most affected. And the

mortality is generally highest in the elderly,

although it is also seen in young children. And in

some instances, it seems to parallel the incidence of

pneumonia during the period of time that the influenza

epidemic is occurring.

So a brief history of influenza vaccine

efficacy. In 1941, there was a request to license the

first inactivated vaccine in the United States, but

the regulatory authorities at the time, who were part

of NIH under the Public Health Service Act, thought

that it was best to get efficacy. That wasn't really

required, I believe. It was mainly safety data that

were needed. But there was a request to show that the

vaccine would actually be efficacious.

They were set to do the study. They had

all of the materials in place and the desire to do the

study in 1942, but this often happens to those people

who are trying to study influenza. There was no

epidemic that year. So it was not possible to do the

studies. Instead, there were some challenge studies

that were done at the time, which demonstrated that

these vaccines were effective against influenza A and

Those studies were published as well as

the information from the studies that were done later

from large‑scale field studies. Those were done in

1943 through 1945. And they were done with bivalent

vaccine using influenza A and B viruses.

The first vaccine was licensed in the

United States in 1945. And, as I mentioned before, it

was very shortly after that that it was recognized

that antigenic drift could reduce the effectiveness of

vaccines and the Global Surveillance System was

inaugurated to try to identify changes that were

occurring and to be able to make alterations in

influenza vaccine as necessary.

So the first studies that were done by

Tommy Francis and Jonas Salk and others with the armed

forces and a special commission that was set up to

investigate influenza, the studies that I am going to

be talking about were done as randomized

placebo‑controlled field efficacy studies between 1943

and 1945. The vaccines that were used at that time

were whole virus, formal and inactivated. They were

highly formalin‑inactivated reactogenic.

A large percentage of the people who got

the vaccines felt ill for a couple of days. Some of

them went to infirmary. The antigens that were

contained in the vaccine, it was actually trivalent

vaccine. It had two H1N1 components: A/Puerto

Rico/8/34 and A/Weiss/43. There was an influenza B

component. It was B/Lee/40.

The studies were done at the Army

specialized training program centers around the

country at the time. These were located in a number

of universities and medical schools. In these

particular studies, there were more than 10,000

participants.

What they were looking at, mainly they

were looking at the clinical endpoint. It was

influenza illness. It was most important. They did

have the capability. And they were using it during

the studies to identify infection by culture. They

also could look for serologies. But, really, the

endpoint here was the illness.

Illness was supposed to be characterized

by symptoms that included abrupt onset fever,

myalgias, cough, sore throat, and nasal symptoms. And

the cases were further categorized by illness

severity. Those who had a temperature over 100 by

whatever the going criteria were, they were sent to

the infirmary for hospitalization to get them away

from the rest of the men in the barracks where they

were staying. They also, of course, did X‑rays when

they wanted to look for pneumonia.

There were some differences between the

multiple centers in terms of the way the actual study

was run. So that in some instances, hospitalization

could have been for lesser fever, but generally this

is what was followed.

I am showing the two different studies

that were done here looking at influenza A and

influenza B. Again, this was a clinical measurement.

It was clinical influenza that resulted in febrile

illness that needed hospitalization. There were

approximately 12,000 individuals who were randomized

to get either the vaccine, the trivalent vaccine, or

somewhat identical placebo.

The number of cases that occurred was

substantially higher in those who got the placebo than

those who got the vaccine. If you calculate

protective effectiveness from that, it works out to be

about 69 percent protective effectiveness against the

clinical febrile illness requiring hospitalization.

A similar study was done for influenza B.

The numbers here are approximations because the people

involved in these programs at the time were sort of

going in and out. There was a lot of personnel

transfer in motion. So they did the best they could

to try to determine what the denominators were here,

but it really is kind of an estimate.

The number of cases, it is firmer. Again,

you can see that for the vaccine, there were

substantially fewer cases than in the placebo group.

Translated, it would be a protective effectiveness,

around 88 percent.

There were some subanalyses that were done

in this set of studies that have been published also.

In one subset at the University of Michigan, they

tried to look at the effect on illness, different

levels of severity. They looked at people who had any

kind of respiratory illness. This included the common

cold or what they called the common cold. It was

illness that was obvious, but it wasn't severe enough

to result in hospitalization. And it didn't have

other symptoms that they thought would be more typical

of the syndrome that we call influenza with all of

those symptoms that I listed early on.

We know very clearly that influenza

infection can cause what seems to be a common cold in

some people, and we know just as well that other viral

infections can cause what seems to be influenza by its

clinical manifestations with fever, myalgias, and so

on. So it is a very nonspecific indicator.

For those that they thought were more

likely to have influenza based on the symptomatology,

again, that is based on the clinical symptoms but

being more typical for influenza syndrome. These

inpatients had fever. Then, of course, they were also

looking at pneumonia.

What you see across the bottom here if you

try to figure out a protective effectiveness, you can

see that there is increasing effectiveness of the

vaccine against the more severe forms of illness.

It is very difficult to show vaccine

effectiveness when it is diluted by many different

types of respiratory viruses, none of which were known

at the time. They were identified specifically at the

time these studies were being done, but they were, the

giants whose shoulders we stand on were, very much

aware of the fact that there were other etiologic

agents out there that needed to be categorized. You

can see that it is very difficult to show that.

If you go to the most severe forms of

illness, it is a lot easier to try to show that there

is some effect. They commented that throughout the

study, there were no cases of pneumonia in anybody who

got the vaccine. There were ‑‑ this is a relatively

small number ‑‑ only four cases of pneumonia in the

recruits who got the placebo. That does fit, however.

These studies were done in 1943 and 1944, when I

showed that there was very low incidence of pneumonia,

even though there was a high attack rate for

influenza.

So there were some other observations they

made from this. One of them was that in these kinds

of studies, the placebo group was actually diluted by

having an immunized cohort that may have been able to

reduce transmission in the placebo group. This was in

one of the first thoughts about herd immunity.

The differences in the attack rates

between vaccine and placebo were really greatest at

the peak of the epidemic. And as the epidemic

receded, it was harder and harder to be able to show

anything.

One corollary to this part was that there

was at least one center where there was an attempt to

immunize in the face of what seemed to be the

developing epidemic. And they noted that it was very

clear‑cut that during the first week, they couldn't

really show any difference in the attack rate in the

placebo or the vaccinated individuals, but after one

week, it was very clear who had been immunized. There

seemed to be a big difference, even after that

one‑week period of time.

I mention this just because we often talk

about needing two weeks after immunization, somebody

who is immunologically primed. Of course, these

individuals all were immunologically prime by previous

exposures. But there may be protective effects that

are kicking in, even in an earlier period of time.

So, to add a little bit of information

about some of the other studies that had been done, I

wanted to concentrate on a few studies. These are

selected by me to make some points about the effect of

vaccine when there is antigenic drift that is

occurring.

This first study that I want to talk a

little bit about was done in Texas in 1976. It was

the Houston family study for this particular

publication. There were 37 families who had 155

members of different ages, ranging from infants up to

about mid '40s.

The A/Port Chalmers/1/73‑like viruses had

caused an epidemic in 1975. And so these individuals

who were not immunized specifically had antibodies

that were directed against or should have had some

possibility of having antibodies directed against Port

Chalmers, but then the following year, A

Victoria/3/75‑like viruses caused an epidemic. These

viruses, the A Victoria/3/75 viruses, are really drift

variants of the previous strains.

At the time, it was noted that this was a

very dramatic difference in terms of antigenic

characteristics between these two viruses. I don't

know whether it is fair to say so, but it probably was

at least as different as what we are seeing this past

year with the Panama‑like strains and the Fujian‑like

strains and possibly more because, actually, it was

remarkable and there was a lot of comment about how

different those strains were.

They were able to use virus isolation and

serologies to try to document infection. As I

mentioned, there was no vaccine used. Now, what I am

showing here are the preexposure hemagglutination

inhibition titers from the people who were in the

study. They were able to get blood from 154. They

tested them for antibodies to both Port Chalmers 73

and Victoria 75 strains.

What you can see here, I think, is that

there was some proportion who had, really, very low

antibodies in both of these groups. These are the

same people, of course. So you see that some higher

frequency of those who they tested for antibodies to

Victoria were more likely. They were more likely not

to have antibodies is what I am trying to say.

If you look at the distribution from low

antibody to high antibody, you can see that in

comparison to Port Chalmers, there is a shift toward

lower antibody titers for Victoria strains. And that

is what we are usually dealing with when we are

looking at our serology. So this is very similar.

They were able to do some other things to

look at infection and illness. I think that what you

can see is that there is a relation between antibody

presence and protection. As you get higher antibody

titers, there are fewer and fewer people who are

infected. The same thing is true if you look at

clinical illness. Those who have higher antibody

titers are less likely to be clinically ill.

What this also says is that the number of

people who are infected who are relatively

asymptomatic is fairly high compared to the numbers

that we would recognize as having had influenza. So

it is something else to keep in mind in terms of

trying to make sense out of what is there.

So another study done by the same group in

1986. Again, it was the family study, Houston family

study. They had 98 families enrolled with 192

children who are between 3 and 18 years old.

These children were randomized. I am not

sure that is quite the right word. They were groups

that got either placebo or inactivated trivalent

vaccine or a live attenuated bivalent vaccine.

Each of those vaccines contained an

A/Chile/1/83‑like H1N1 virus. These children all got

a single dose of vaccine. That particular year, the

H1N1 virus was a new one that had appeared only in

March, was first identified in March.

And you might remember that that was the

year that there was a supplemental vaccine that was

produced for A/Taiwan/1/86. It was not used in this

study, but it was recognized that the Taiwan/1/86

virus was substantially different from Chile so much

so that it was thought that for younger people, that

an A/Taiwan vaccine would be a good idea.

Again, they had virus isolation and

serology to try to document infection. What they

showed was both of these vaccines had protective

effect against infection with A/Taiwan/1/86. And this

is infection and not illness that we are looking at

now. So it is the measurement that would pick up more

individuals.

Anyway, you see this is fairly similar.

It was about 52 percent protective effect on this

drift variant from the live attenuated vaccine in use

at that time and about 61 percent for the inactivated

vaccine.

The authors commented that they thought,

actually, in the younger age group, the live

attenuated vaccine performed better than the

inactivated vaccine and vice versa for the inactivated

vaccine, which you can see here. Nevertheless, both

of these vaccines were substantially better than no

vaccine in terms of what happened to the placebo

group.

So, finally, one more drift variant story,

a nursing home in Colorado in 1987 during an outbreak.

There was an outbreak that was caused by an H3N2 drift

variant.

The vaccine strain at the time was

A/Leningrad/6/86. The viruses that were being

isolated have names. They are Colorado, of course.

They were all similar to this reference strain, the

Sichuan/2/87 strain. And that strain was different

enough that the following year, it was included in the

vaccine for use. So that there was some difference.

I am not sure that the difference between

Sichuan/2/87 and Leningrad/6/86 is the same as the

Victoria/Port Chalmers difference, but there was still

enough that it was thought a good idea to change the

vaccine after those had appeared.

Not everybody in this nursing home was

immunized, but they immunized a very high percentage

of them after the outbreak started. The outbreak

itself had a peak that occurred about two weeks after

the immunization campaign.

This analysis was done retrospectively,

but they were able to get pretty good documentation

from the nursing home records about who had fever; as

measured by thermometer, who had illnesses, what kind

of illnesses they were. Of course, pneumonia and

death were pretty obvious because the residents needed

for the treatments. In a subset, they were able to

confirm that infection had occurred because of H3N2.

But generally this again was a clinical observation.

This just shows the epidemic, how it

occurred. When it was first recognized, it was a

fairly sharp epidemic. There were about five of the

residents of the nursing home who were infected. The

following week, vaccine was given to all who wanted it

or could receive it. There were a number of

individuals who refused the vaccine, and there were a

number of individuals who had other ongoing illnesses

that were thought to be contraindications to getting

the vaccine.

So the numbers peaked around week four

here on the epidemic. And then it kind of quickly

tapered off afterward. What you can see is that

although there are quite a few cases in both the

immunized and the unimmunized populations, looking at

vaccine effectiveness, as calculated by the authors,

they mainly were looking at febrile upper respiratory

illness.

They excluded a number of individuals who

had been immunized in that two‑week interval. From

the time they immunized until two weeks, they excluded

those from their true analysis. And that was true for

both vaccinees and non‑vaccinees. There were some

other exclusions as well.

Looking at the incidence, these are

numbers and not percents here. Looking at the number

of febrile upper respiratory illnesses that occurred,

the proportion was significantly less in those who

received vaccine. And protective effectiveness

against febrile upper respiratory illness in that

group was calculated to be about 65 percent.

There were no pneumonias in those who got

vaccine and there were no deaths in those who got

vaccine; whereas, there were pneumonias and deaths in

those who did not. This isn't really randomized

prospectively. So there may be some other reasons for

that. But if you look at all of the residents all

together, you can see that all together, the residents

who got vaccine, there were no pneumonias and no

deaths; whereas, there was a substantial number of

both incidence of pneumonia and death in the residents

who were not immunized.

Some facts that I guess we could take from

those studies are that the vaccine protective effect

is a lot more obvious for severe forms of illness and

for complications that are related to influenza and

infection.

The vaccine shifts the spectrum of disease

toward the less severe consequences and milder

illness. Whatever you are looking at, they have to

keep that in mind. And higher antibody titers are

more likely to result in protection from clinical

illness.

Also, for infection, this is not an

absolute. There is in my own mind not an absolute

number to use for this, but it is pretty clear that

the more antibody you have, the better.

The vaccine administered in an ongoing

epidemic still may reduce illness, pneumonia, and

death, even when there is antigenic drift that has

occurred.

Turning away from that at the moment,

these are the recommendations that were made by the

World Health Organization for influenza vaccine

composition for the Northern Hemisphere for 2004‑2005.

The recommendations from there that are

based on the information that was available to WHO

last week were to continue to use an A/New

Caledonia/20/99 H1N1‑like virus, to use an

A/Fujian/411/2002 H3N2‑like virus, and to use a

B/Shanghai/361/2002‑like virus for the B strain.

Again, the question for the Committee,

"What strain should be recommended for the antigenic

composition of the 2004‑2005 influenza virus vaccine?

Should it be based on the epidemiology and antigenic

characteristics of the viruses, the serologic

responses, and availability of candidate strains?"

All the information that we are going to

be presenting apart from the vaccine effectiveness

studies this morning will relate directly to answering

this set of questions by the Committee. And I think

I can stop there and ask if there are any questions.

CHAIRMAN OVERTURF: Were there any

questions for Dr. Levandowski? Yes? Please identify

yourself.

DR. MARKOVITZ: David Markovitz. I am

speaking from the somewhat claustrophobic right

corridor of the table, where it is difficult to see or

breathe. So if you will excuse me, I am not

articulate.

My question is this. You showed a graph

that implied that the vaccine manufacturing process

was quite effective this year but, yet, also alluded

to some early gaps, early in the season, which we all

noticed just in our hospitals or reading the

newspaper. What is your overall assessment of how the

manufacturing process kicked in this year?

DR. LEVANDOWSKI: Well, I am not sure what

gaps you are referring to, but from the point of view

of production and vaccine release this year, it went

about as smoothly as it ever goes, which means that

manufacturers were busy producing monovalent vaccines

and busy producing trivalent vaccines and having those

released and being able to get them into distribution.

I don't know that I have any other

information. From our perspective, things went

extremely well.

DR. MARKOVITZ: I guess at our hospital,

in the fall, for example, people were not able to get

vaccine. I don't know what the cause of that was.

Was that just too early in the year? Did they strike

too soon or what? Is that just an anecdotal

observation from what I have seen? I believe I read

about that nationally, too, I thought.

DR. LEVANDOWSKI: Again, from our

perspective, I don't understand it. I don't have any

information that relates directly to distribution. We

don't get involved with distribution per se at FDA.

It is more understanding that the vaccines meet their

specifications and that they are okay to go out.

What we saw was a steady stream of vaccine

preparation release. And maybe this is a question for

the manufacturers and not for me because I don't know

what issues there might have been for them in terms of

distribution.

DR. MARKOVITZ: I wasn't really thinking

of distribution. I was thinking more of manufacture.

DR. LEVANDOWSKI: Well, that is an

important part of manufacturing: getting the vaccine

out to where it is supposed to be used. But, again,

that is not a part that FDA really interacts with

directly as the vaccine is being prepared. It is more

of the release specifications being met for the

vaccine and that all of the good manufacturing

practices have been met to make sure that the vaccine

is ready to go.

Again, I would have to say that this year

‑‑ and the graph I showed I think is an indication of

that ‑‑ all the vaccine that came through FDA came

through at a very early time point.

CHAIRMAN OVERTURF: Dr. Myers?

DR. MYERS: Roland, the data sometimes is

presented for children less than five and sometimes

broken down by a year or less than five. The data you

showed is striking for the morbidity being for

children less than a year of age. Is there any

protective effectiveness data for that population?

DR. LEVANDOWSKI: There is relatively

little direct information. Again, I would have to ask

some of our other colleagues out there what they know.

I don't know that there has been a specific study to

look at vaccine effectiveness in children who are less

than one year of age.

I think we do have some understanding that

immunogenicity may be decreased in the very young

children as well. I think that is partly reflected in

the setting, the cutoff at six months for use of

vaccines, if there is an understanding that maybe the

vaccines won't be so immunogenic in those children and

maybe the reactogenicity is a bigger concern than any

clinical benefit that they might get.

There is, however, relatively little for

inactivated vaccines. There is more recently for live

attenuated vaccines. In children 15 to 72 months of

age, the studies that were done by MedImmune show a

very high level of vaccine effectiveness, efficacy

actually, in those children.

CHAIRMAN OVERTURF: Dr. Gellin?

DR. GELLIN: Well, two questions. The

first is you made a comment in 1986 that there was a

supplemental vaccine produced. Could you give us a

little more insight into what that was?

DR. LEVANDOWSKI: Right. The vaccine was

made for the A/Taiwan/1/86 strain. That virus was

first identified, I believe, in March of that year.

It was at a very late point in time. There was a

recommendation that a supplemental vaccine be

prepared. And the manufacturers did that, but the

timing for it was not available until late November

anyplace.

And because of the way it came out, there

was a lot of confusion, part of the confusion because

I was in clinical practice at the time trying to

figure out what to do with the vaccine late November

and early December. There was a lot of confusion on

the part of practitioners about what to do with it.

Not much of it got used. Most of it was subsequently

discarded. It had to be thrown away, basically. That

strain was what was used in the vaccine, then, the

following year for the trivalent vaccine.

DR. GELLIN: So it was a monovalent

product?

DR. LEVANDOWSKI: Yes. Sorry. It was a

monovalent supplemental vaccine, right, that one year.

DR. GELLIN: The second question was, in

your chart about the efforts, intensive efforts, that

go into when they are changed each year and then the

subsequent graph about the delay in production.

In 1992 to 2000, there were two changes.

And that was the year that there was a delay in the

release of the vaccine that was used. I was wondering

if they were related.

DR. LEVANDOWSKI: It is partly related.

Some manufacturers had some difficulty with

replication of the H3 strain early on, but that was

worked out, as it usually is. Manufacturers are

actually quite resourceful at making things work.

If you will look at that chart that you

are talking about ‑‑ I am not sure I can get to it

because of the touch pad here on the computer. It is

not that friendly. If you look at that graph that you

are referring to, you can see that most of the effort

actually goes into producing the H1 strain. And

although the H3 is the one that got all the notoriety

for being difficult to work with, at least initially,

the H1 strain took up more manufacturing time in terms

of number of monovalents.

The way I presented that information, you

can't directly equate that with the overall amount of

vaccine that is being produced because their

variability, lot sizes are variable from manufacturer

to manufacturer and even within a manufacturer. So it

is not like you have one box that has 100 units in it.

You have a box that might have ten units. You have a

box that might have 150 units. It is not that direct.

But I just tried to give some impression

as to the overall effort. It is actually the H1

strains that have been more difficult the last few

years in terms of overall manufacturing effort.

CHAIRMAN OVERTURF: Dr. Monto?

DR. MONTO: I would comment about the

nursing home and how to interpret drift in terms of

nursing home outbreaks. We have had a surveillance

going on in a number of Michigan nursing homes for a

number of years now. Two years ago, with a rather

wimpy A/H3N2 outbreak with a non‑drifted variant, we

had confirmed transmission in 26 percent of our homes.

This year it is going to be higher. And

we had an outbreak in December. It is going to be in

the 30 percent range, we think, once we finish the

analysis.

What I am saying is that you really have

to look at what happens in nursing homes, even in a

non‑drifted year, in terms of putting things into

context because the vaccine really does not protect

all that well against just influenza‑like illness,

even laboratory‑confirmed, even in a non‑drifted year,

in this population. Our nursing homes were typically

80 percent and many of them 90 percent vaccinated.

CHAIRMAN OVERTURF: Dr. Farley?

MEMBER FARLEY: To me, one of the most

striking features of this year's influenza profile was

the early onset of disease. Given the manufacturing

timetable that you presented, if there were any

indication to attempt to begin immunizations earlier

in the fall or late summer even, is it even possible

within the constraints of the timetable?

DR. LEVANDOWSKI: I think the answer, is

it possible, yes, I think it is. I mean, I think that

this year the vaccine was prepared at a very early

point. If you have that graph? Again, I am not sure

I can get to it easily here because of the computer

system.

There was a substantial amount of vaccine

in trivalent form. That graph that I was showing was

for trivalent vaccine. There was a substantial amount

that had been released for distribution, even in the

summer months. So it is possible that it could have

been.

This year, although there was an early

epidemic of influenza, although it started early,

there was a substantial amount of vaccine that could

have been available around the country at that point

based on the manufacturing timelines for this past

year.

If we had made a strain change this last

year, I don't know that that would have been true. I

am not sure that there would have been further delays.

Given the timelines for preparation of seed viruses

and so on this past year, I would assume that we would

not have been seeing vaccine early in the summer but

probably the first vaccines might have been available

September, rather than in July.

So, again, from my perspective, I think

manufacturing went very efficiently and was early and

on time with a total amount that was intended for

production for this year based on what the demand

parameters were that the manufacturers understood for

all of the vaccines.

CHAIRMAN OVERTURF: Dr. LaRussa?

MEMBER LaRUSSA: Just to carry that a

little further, can you just sort of estimate?

According to one of your slides, the high growth

reassortants were available in June for the Fujian

strain. If you had decided to go ahead and make a

monovalent vaccine, what would be the earliest that

would have been available?

DR. LEVANDOWSKI: Well, that is what I was

trying to get to with that other slide that I had

about manufacturing timelines, the 20 weeks. If you

take about six weeks for development of the reference

virus at that point, what would that be? That is

about three and a half months.

So from June until sometime late September

probably by the time we would be seeing any vaccine

produced that was trivalent; whereas, with the

manufacturing system as it was, the first trivalent

vaccines were actually coming in end of June,

beginning of July.

CHAIRMAN OVERTURF: We have time for about

one more question. Any other questions?

(No response.)

CHAIRMAN OVERTURF: I think we will go

ahead and proceed, then, with the discussion regarding

vaccine effectiveness. I guess Dr. Carolyn Bridges is

going to make that presentation.

VACCINE EFFECTIVENESS

DR. BRIDGES: Good morning. Today I am

going to be discussing some studies that have been

done on vaccine effectiveness of the inactivated

influenza vaccine this year that CDC collaborated on.

I will be discussing a little bit of

background about the flu season, most of which Roland

has already covered. Then I will be describing two of

those studies, where we have preliminary results; and

then listing some other studies that are currently in

progress; and then end with some final remarks.

As Roland stated, influenza activity

started earlier than usual this year. And children

appeared to be disproportionately affected compared

with recent years. There were widely publicized

reports of pediatric deaths that received quite a bit

of attention.

There is also unprecedented demand for

vaccine more than in some recent years. And there was

discussion at the HHS level about additional vaccine

purchase. Although, as Roland says, the amount of

vaccine that was purchased or was manufactured was

equal to the demand from the previous year.

In addition to these pediatric deaths,

there is also a drifted variant of influenza H3N2,

which predominated, which was different from the

vaccine strain. And influenza vaccine effectiveness

was questioned.

In order to assess the effectiveness of

this year's inactivated vaccine, several studies were

initiated simultaneously using various age groups and

looking at different outcomes.

Preliminary results are available from two

of those studies, which were conducted in the State of

Colorado. One of those studies was a retrospective

cohort study among health care workers. The principal

investigator for that study is Dr. Nidhi Jain.

The other one is a case cohort and

subsequent case control study among persons aged 50 to

64 years who have laboratory‑confirmed influenza. And

the co‑PIs for that study are Drs. Marika Iwane and

Guillermo Herrera.

This is some surveillance data from the

Children's Hospital in Denver, Colorado. And, as you

will look at the left scale, it goes from zero to 400.

This is a scale for influenza A viruses. On the

right‑hand of the graph, it is a scale for RSV and

influenza B, which goes from zero to 40. So there is

a tenfold difference in the scales.

As you can see, influenza A activity began

early in November. It peaked towards the end of

November and then started on this decline. There were

very few influenza B viruses and very few cases of RSV

that were identified at the Children's Hospital among

hospitalized as well as outpatients.

This is the remainder of their

surveillance data. Again notice the scale, zero to

20. So there also was very little in the way of

paraflu, adeno, rhinovirus, or pertussis that was

identified.

Incidentally, of the respiratory specimens

that were tested in the hospital laboratory, the

percent of specimens that tested positive for

influenza at the peak was around 60 to 70 percent. So

this is a very high percent positive rate from

respiratory specimens.

We decided to conduct a study among health

care workers at the Children's Hospital because the

staff provided a large cohort for rapid analysis. And

we knew that a large number was needed if we were

going to look at nonspecific outcome.

Also, this cohort has substantial

opportunities for exposure to influenza as they had

many hospitalized patients who were influenza‑positive

and they had conducted the bulk of their inactivated

influenza vaccine campaign in the month of October.

Influenza‑like illness was the outcome.

This has been used, as Roland has described, in many

prior studies, although we clearly understand that

this underestimates the vaccine effectiveness that

could be seen looking at more specific outcomes, such

as laboratory‑confirmed influenza.

We thought that this may provide us with

a reasonable estimate or reasonable chance of finding

vaccine effectiveness because influenza was so

predominant as the cause of flu‑like illness in the

population based on the Children's Hospital

surveillance data. Preliminary results of this study

were published in the January 16th MMWR.

The objective of this study was to

estimate the effectiveness of the 2003‑04 inactivated

influenza vaccine in preventing influenza‑like

illness, or ILI, among adults working at the

Children's Hospital in Denver, Colorado.

This is a retrospective cohort study. A

questionnaire was distributed via e‑mail and also

paper surveys to approximately 3,100 employees. This

is an anonymous survey, and very limited demographic

information could be collected. Information was

collected on age group, sex, whether they had patient

contact, whether they had one or more high‑risk

conditions, whether they are vaccinated, and the

timing of their vaccination, illness onset and

symptoms, and whether they had physician visits or

were influenza‑tested. We also asked about missed

workdays from flu‑like illness. The questionnaire was

distributed from December 11th through December 17th.

The ILI definition used was self‑reported

fever plus either cough or sore throat, which is

similar to the CDC surveillance case definition.

Illnesses were counted if they began on or after

November 1st or through the date of survey completion.

We conducted two different types of

analysis, one a categorical analysis and the other a

person‑time analysis. For the categorical analysis,

we estimated vaccine effectiveness against ILI only

among persons who were vaccinated before November 1st

and compared those with those who were never

vaccinated.

We looked at two different vaccination

definitions for persons who became ill less than two

weeks after being vaccinated. In one instance, we

categorized those persons as being unvaccinated. In

the second analysis, we excluded them from the

analysis.

For the person‑time analysis, again, the

person‑time began November 1st and ended on the date

of survey completion. We did not exclude persons who

were vaccinated during the illness period for this

analysis, but an individual could contribute both

vaccinated and unvaccinated time if they got

vaccinated during the period of interest of November

1 through survey completion date.

The outcome for this study was ILI

incidence density rate. And, similar to the first

study for those who became ill one to 13 days after

vaccination, we either counted that time as being

unvaccinated time in one analysis or we excluded those

person‑days from the analysis.

This graph shows the number of

influenza‑like illness cases among staff. Those are

in the short light blue bars; the number of

laboratory‑confirmed influenza cases among patients at

the Children's Hospital, which are the tall purple

bars; and the line graph shows the percentage of the

cohort that was included in the study, the percent of

the cohort that was vaccinated by time.

So as of November 1st, 54 percent of the

persons who answered the questionnaire were

vaccinated. An additional 24 percent were vaccinated

during the outbreak period of November 1 and later.

So of 3,100 persons to whom the

questionnaire was distributed, 1,886, or 61 percent,

completed the survey. Half of those completed it

online and half of those completed it by paper.

Persons were excluded if they did not

report their vaccination status as being yes or no or

if they did not report date of vaccination. We also

excluded persons who did not report whether or not

they had an illness or if they did not report date of

illness onset.

This is the demographic information from

the persons who completed the questionnaire. It

includes all persons vaccinated or unvaccinated,

regardless of the timing of their vaccination.

Persons who were vaccinated tended to be

in the older age group. And a higher proportion of

them, though not statistically significant, were

female.

In addition, physicians and nurses were

more likely to be vaccinated than persons in neither

of those occupation categories. And people who had

patient contact also were more likely to be

vaccinated. There is a considerable correlation

between these two variables.

As I mentioned, we asked people if they

had been tested for influenza and also what the

results of that testing were. Twenty‑eight people who

had influenza‑like illness reported being tested for

influenza. And of those, 13, or 46 percent, reported

that they were positive.

Now let's skip to the results. This is

for the categorical analysis, where persons were

counted as unvaccinated if they became ill in the less

than 14 days prior to vaccination.

So of the vaccinated persons, about 15

percent of them developed influenza‑like illness

compared to almost 17 percent among the unvaccinated.

The vaccine effectiveness adjusted for age group,

high‑risk condition, and patient contact was

approximately 14 percent with confidence intervals

that included zero.

If we looked at the additional vaccination

definition, where we excluded persons who became ill

in the 14 days after vaccination, that eliminated 9

people from the analysis. This analysis, then, again,

15 percent of vaccinated were ill and approximately 15

percent of unvaccinated were ill, with an adjusted

vaccine effectiveness estimate of approximately 3

percent, again, with confidence intervals that

included zero.

In addition to the categorical analysis,

we conducted a person‑time or survival analysis. In

this analysis, again, people were not excluded if they

got vaccinated during the outbreak period.

Again, looking at the two different

definitions for vaccination, vaccine effectiveness for

both of these, the point estimates were negative, but

the confidence intervals were very wide and were not

statistically significant from zero.

There are a number of limitations to this

study. One, the response rate was only 61 percent.

And there was certainly a possibility for responses by

us. Secondly, vaccination and influenza‑like illness

status were self‑reported. And vaccination was

self‑selected. So there may have been some

confounding by indication for those two who were

vaccinated.

In addition, there was a high vaccination

rate among the respondents. And this decreased our

power to detect a lower vaccine effectiveness

estimate. However, the vaccination rate that we found

in this cohort was very similar to what the hospital

estimated for their entire population. They estimated

that they had approximately 75 to 80 percent of their

employees vaccinated.

In addition, because the influenza season

was early, some persons were vaccinated during the

peak influenza activity. In addition, we used a

nonspecific case definition, which likely

underestimated true vaccine effectiveness if one were

to look at laboratory‑confirmed flu.

The conclusions from this study are that

we were unable to demonstrate vaccine effectiveness

against ILI and this study when it drifted, influenza

H3N2 virus predominated. However, vaccine

effectiveness is likely to be higher against

laboratory‑confirmed influenza and against

influenza‑related hospitalizations and deaths.

The recommendations that were published in

the MMWR were to continue vaccination, particularly of

high‑risk persons, their contacts and health care

workers because H1N1 and influenza B may circulate

later in the flu season and because based on

historical information, vaccine is expected to protect

against influenza‑related complications and

laboratory‑confirmed influenza.

The study pointed out that retrospective

analyses and sort of on‑the‑fly analyses are very

difficult to do during the middle of flu season and

that prospective annual vaccine effectiveness studies

against laboratory‑confirmed influenza are needed for

more accurate yearly assessment of vaccine

effectiveness and to assess the impact of the vaccine

program.

I am now going to move on to the case

cohort analysis for persons 50 to 64 years of age.

This study was initiated to estimate the effectiveness

of the inactivated vaccine against

laboratory‑confirmed influenza in persons 50 to 64

years of age. And this was initiated at the same time

as the health care worker study.

For the cases, these all were

laboratory‑confirmed cases that were identified

through the surveillance system in the Colorado

Department of Health. Colorado requires that persons

with laboratory‑confirmed influenza are reported to

the state Health Department. However, they are not

required to report contact information. They report

age, gender, and name but not phone number or address

or county many of the times.

Over 10,000 cases were reported to

Colorado by the end of December. And over 500 of

those cases were in persons 50 to 64 years of age.

However, more serious cases of influenza were more

likely to be reported.

The cases were interviewed by phone. And

they were excluded if they did not recall being tested

for influenza or they denied being ill. In that case,

we may have had the wrong person when we tried to hunt

down a phone number based on name only.

Information was collected on demographics,

illness onset, and duration, vaccination, and timing

of vaccination, health care provider visits, and

hospitalization.

For the cohort, the cohort was considered

the Colorado population aged 50 to 64 years. To

estimate the coverage in Colorado among persons 50 to

64 years, we looked at the Colorado behavior risk

factor surveillance survey. This is an annually

conducted survey that is state‑based. And for a

number of years, the question has been asked, "Have

you had a flu shot in the past 12 months?"

We looked at data from 2001 through 2003

for the limited 2003 data that was available. We used

a screening method or case cohort method to estimate

vaccine effectiveness, which was estimate to be

approximately equal to one minus the relative risk.

The confidence intervals calculation included the

variance of the various aspects and coverage

estimates. So the confidence intervals were

considerably wider.

Again, similar to the other study, we used

two different classifications of vaccination for

persons who were ill in the two weeks following

vaccination. In one sense, they were counted as

unvaccinated. And then they were also in a second

analysis excluded.

Vaccine effectiveness was calculated for

the different possible cohort coverage rates in a

sensitivity analysis. Because of the difficulty in

determining the vaccination rate of the cohort,

because the outbreak happened during the typical time

where vaccine is administered, we have also initiated

a case control study.

So controls are being recruited that will

be age group frequency matched. We are attempting to

recruit three controls per case. And they are being

recruited through random digit dialing. Hopefully

this will provide a more accurate assessment of

vaccine effectiveness.

So among the cases, there were

approximately 574 cases reported to the Colorado

Department of Health. Of those, interviews were

completed on 56 percent. Among those where there was

not an interview completed, for most of those persons,

it was an inability to contract the person or for most

of those inability to identify a telephone number. If

there were 1,200 John Smiths in Colorado, it was

difficult to identify who that name and age may have

belonged to. However, those who were interviewed and

those non‑interviewed did not differ by gender or age.

So this graph shows the number of cases by

week of their illness onset. As you can see, most of

these started again in early November and a cumulative

percentage of these cases that were vaccinated, which

is represented by the red line.

Of the cases, approximately 329 were

included. As you may have noticed from the slide

earlier, there were 330, but the vaccination status on

one of those persons couldn't be confirmed.

Of the 329, approximately 50 percent were

high‑risk and 50 percent were not high‑risk using our

vaccination definition of counting them as

unvaccinated if they became ill less than 2 weeks

after the vaccination date.

Among all persons in this category, 42

percent were vaccinated, 52 percent of those were

high‑risk, and 32 percent were non‑high‑risk who were

vaccinated. A high proportion was hospitalized.

Forty‑eight percent of high‑risk people were

hospitalized, and 17 percent of those classified as

non‑high‑risk were hospitalized.

We found very similar numbers when we did

a second analysis and excluded people if they were

vaccinated one to 13 days before illness onset.

Again, about 50 percent were high‑risk. And

vaccination rate was about 56 percent among

non‑high‑risk and 36 percent among non‑high‑risk

persons. And, again, high rates of hospitalization,

about a third.

I would like to look at the results of the

cohort. So this is the overall Colorado population 50

to 64. We had a number of different estimates. The

middle estimate was using the 2002 BRFSS final

weighted data. And the estimate, vaccine estimate, is

45 percent.

The high estimate may be the 2003

unweighted monthly data from BRFSS. So this is

preliminary data. And the December estimate was 52

percent.

A low estimate would be the 2002 Western

regional national health interview survey data for

persons 50 to 64. That data would suggest that the

vaccination for high‑risk be 40 percent and

non‑high‑risk 32 percent.

However, we know that Colorado generally

has substantially higher vaccination rates in all age

groups compared to most of the other Western region,

particularly California, which tends to weight that

estimate down quite a bit.

This is some preliminary results from the

controls that have been recruited from the case

control study. Of 304 persons who have interviews

completed and data entered, 26 percent of those have

high‑risk conditions. And vaccination rate for those

for this flu seasons, for 2003‑04, was 58 percent

among non‑high‑risk and 61 percent among high‑risk, so

considerably higher than the previous behavioral risk

factor surveillance survey estimates. We hope to have

recruitment through about 1,100 persons completed by

early March.

So if one considers this range of vaccine

coverage estimates in the cohort, we then use the

screening method to estimate what the vaccine

effectiveness may be in the overall cohort of 50 to

64‑year‑olds.

If you look at the non‑high‑risk group,

where among the cases, the vaccination rate was 32.5

percent, assuming the vaccination coverage for the

cohort ranges somewhere between 40 and 60 percent,

then the overall vaccine effectiveness may range

somewhere between 28 percent and 68 percent.

When you look at the high‑risk group,

there is substantially more content by indication. I

think it is very difficult to assess these results.

In general, it looks like vaccine effectiveness is

lower. I think that is very difficult to assess.

Again, looking at the second definition

for vaccination for cases being excluded if they

became ill in that two‑week period after vaccination,

the estimates are somewhat lower, but the

non‑high‑risk, the estimate is somewhere between 16

and 63 percent, and for the high‑risk, again, most of

the estimates are negative. That I think is very,

very difficult to assess.

The limitation of this study is that these

lab‑reportable cases over‑represent sicker and

hospitalized patients and certainly over‑represent

high‑risk persons. The case cohort method provided

for a very wide confidence intervals of the vaccine

effectiveness estimate, which gives us quite a bit of

degree of uncertainty.

However, overall the vaccination rate at

the time of onset of cases of illness is unknown due

to the early season. So we don't really know what the

vaccination rate is, really, for the controls at the

time of the outbreak. So use of the historical

vaccine coverage estimates would overestimate overall

vaccine effectiveness.

So the case control study will help us in

determining what the vaccination rate was during the

time of the outbreak. So that should give us a little

bit more confidence.

The conclusions from our case cohort study

are that vaccine effectiveness among the non‑high‑risk

is likely somewhere between 16 and 68 percent. It is

a very wide estimate.

The vaccine effectiveness among high‑risk

persons is difficult to interpret because of content

by indication. And further analysis is pending for

the case control study.

I would like to acknowledge our

collaborators at the Children's Hospital, the

University of Colorado, the Colorado Department of

Public Health and Environment, and colleagues at CDC.

I just wanted to show you some other

studies that are currently in progress on which CDC is

collaborating. As I mentioned, the Colorado case

control study, we hope to have some results from that

by the summer.

There is also a cohort study being done

among children 6 to 23 months using Colorado HMO

database, which will look at ILI as an outcome. In

addition, the vaccine safety datalink sites are going

to be looking at vaccine effectiveness among 6 to

23‑month‑olds with outcome of hospitalized

influenza‑like illness.

And in Georgia, a study is ongoing to look

at the effectiveness in children 6 months to 4 years

with laboratory‑confirmed influenza as outpatients.

The new vaccine surveillance network in

Rochester, Cincinnati, and Vanderbilt will be using

the case cohort method to look at vaccine

effectiveness for influenza, hospitalization, and ED

and outpatient visits.

There is an ongoing study in Iowa among

college students, which is a cohort study to estimate

effectiveness against influenza in outpatients.

Among all of these studies, one of the

issues has been for persons who are tested for

influenza. What is the bias in terms of who gets

tested? And are people being tested based on their

vaccination status.

The new vaccine surveillance network is an

active prospective surveillance system. And children

who come into that system who are enrolled, there is

no bias in terms of their vaccination status. So this

may provide us with one of the more accurate

estimates.

So our results, we feel, are compatible

with many prior studies and years with the suboptimal

vaccine match, where low or no vaccine effectiveness

against ILI can be demonstrated. However, there is

likely to be vaccine effectiveness against

laboratory‑confirmed influenza as our case cohort

study suggests. These studies also illustrate the

difficulty in estimating vaccine effectiveness in

retrospective studies.

Our resources should be devoted to annual

assessment of vaccine effectiveness and to the

vaccine's health impact. We hope to have a pediatric

assessment using the new vaccine surveillance network.

And we would like to be able to use that system for

yearly estimates in children.

I will stop there.

CHAIRMAN OVERTURF: Yes, Dr. Myers?

DR. MYERS: Carolyn, I guess my conclusion

is it is hard to do studies with vaccine effectiveness

in the midst of the epidemic. So I think it is great

that the CDC is trying to do that.

On the first study, I am not so troubled

by your using ILI in association with a lot of

clinical isolates of influenza as your endpoint, but

I am troubled by the apples and oranges of the groups

that you evaluated.

You showed a statistical likelihood for

people who are likely to be exposed to get vaccine.

So the doctors and the nurses or people who had

patient contact were more likely to get the vaccine.

So I would have liked to have seen and

maybe you have available of that subgroup looking at

vaccine effectiveness for the people who had patient

contact during that interval.

DR. BRIDGES: You know, we really thought

a lot about asking questions about exposure, more

exposure, variables. But because there was so much

influenza circulating in the community, we thought

that that was extremely difficult to do, particularly

given that many people affected with influenza may

shed virus but are clinically asymptomatic.

We did adjust in our analysis for patient

contact. We adjusted for occupation in one analysis,

which I didn't present. And it didn't make any

difference.

We did a subgroup analysis. Also, it

didn't make any difference in terms of being able to

find vaccine effectiveness.

CHAIRMAN OVERTURF: Dr. Palese?

DR. PALESE: In terms of your first study,

where influenza‑like illness is being used as an

endpoint and there was no vaccine effectiveness

demonstrated, is it known what percentage the Fujian

strain made up in terms of influenza activity?

In other words, what is the reason for the

ineffectiveness of the vaccine? Do we know that 80

percent was Fujian there? You said it was

predominantly Fujian, but do we know? Do we have

precise values in terms of how much Fujian was and how

much H3 basically was occurring at the time in that

location?

DR. BRIDGES: Very few isolates were

antigenically characterized from Colorado by CDC.

They obviously characterized a huge number of isolates

but relatively few isolates from every state. Some of

those isolates have overworked Fujian. I think it is

very difficult to assess what the proportion of H3N2

viruses in Colorado were Fujian based on the small

number of isolates that were characterized.

DR. PHILLIPS: Wouldn't they be interested

to know why the vaccine was not effective?

DR. BRIDGES: Nationally I think Ann Moen

will present this. About 80 percent. Is that right?

Seventy‑five or 80 percent of the H3N2 viruses were

Fujian‑like.

CHAIRMAN OVERTURF: Dr. Monto?

DR. MONTO: I want to congratulate you all

for putting together the case cohort study in

Colorado. I know how difficult it is in the midst of

an outbreak trying to identify the places where you

can get useful data, which may have important public

health impact.

I just want to recall that the multiple

studies that were put together during the period when

HCFA questioned the use of influenza vaccine for older

individuals, the 65‑plus, that there the endpoint was

hospitalization for pneumonia, influenza indications

in the course of an influenza season and not

laboratory‑confirmed influenza.

I would assume that many of your

confirmations here are in the more severe individuals.

And controlling for confounding because we all know

that the people with undermined conditions are both

more likely to get vaccinated and more likely to be

hospitalized, the effectiveness there was from 31 to

maybe 50‑55 percent, fairly wide.

And these were all non‑drifted years. So

this really is not all that incompatible. You would

have a better endpoint here in terms of laboratory

confirmation. So it is all in the same ballpark and,

thus, suggests that there was some degree of vaccine

effectiveness in the past year.

In terms of the other study, I want to ask

you a question and make a comment, namely since the

outbreak was so abrupt and you have a fairly large

population group, could you look at the peak couple of

weeks of the outbreak in terms of the reported illness

and also in terms of the ILI case definition?

We have done some studies which we are

going to be publishing suggesting that sore throat

actually is a negative predictor in a febrile

individual of the isolation of an influenza virus,

which suggests that it may be appropriate to change

the very long used ILI case definition, but this has

been present in two very large studies of antivirals

in which laboratory confirmation was made before

treatment began. Sore throat clearly predicts against

the presence of influenza virus.

DR. BRIDGES: Thanks, Arnold.

We also looked at analysis from just

November 15th on, which was more of the peak week. We

didn't look at a two‑week interval, but we did narrow

it down to about a four‑week interval and still didn't

find effectiveness.

In addition, we looked at several other

outcomes that I didn't present today. One of those

was looking at a definition where persons had fever

for three days, plus two or more respiratory symptoms.

In addition, we looked at influenza

associated with loss of work, physician visits, and we

also looked at days in bed to try and find a more

severe outcome. And with none of those were we able

to demonstrate effectiveness.

CHAIRMAN OVERTURF: I will take just two

more questions: Dr. Karron and Dr. Goldberg.

MEMBER KARRON: Given information that has

been available in the past about potential increased

efficacy of live attenuated vaccine in children

against drifted strains, do you know of any studies

that are currently being conducted, either

head‑to‑head comparisons to look this year at the

efficacies or just live attenuated vaccine versus

non‑vaccinated children?

DR. BRIDGES: I don't know if there is

someone from the manufacturers that could address that

question, I think. I see Kathy Coelingh in the back.

Kathy Coelingh?

MS. COELINGH: I am Kathy Coelingh from

MedImmune Vaccines. There are some ongoing studies

that are being conducted. None of those data will be

available for several months, head‑to‑head comparisons

during the first year.

MEMBER KARRON: Did you do some studies to

assess the effective coverage probabilities in one of

these studies? Did you look at different models to

try and assess the different levels of

non‑responsiveness in the different groups and whether

you can model this out just to get an idea of whether

that is what is causing the problem?

The definition problem you addressed in

several ways, but there is a whole other piece about

what happened to the non‑responsiveness. You made

different classes of assumptions about them. Have you

done that?

MS. COELINGH: We haven't done that, but

that is something that we easily can do.

CHAIRMAN OVERTURF: Carolyn, if you could

just stay there? I am going to have Col. Neville come

forward and go ahead and set up his presentation. We

can take one more.

DR. DOWDLE: Thank you very much. I will

congratulate you for some remarkable analysis in a

very short period of time.

On the first study, in the 28 staff

members, as I recall, that reported being tested for

influenza, which was considerably less than the

percentage among the patients, if I recall correctly,

the question is, did you go further, do any further

analysis, of those who had reported influenza‑like

illness and were tested?

By the way, was this serology? Was this

isolation?

DR. BRIDGES: These were all rapid tests.

As far as we know, it is anecdotal. We didn't ask

people to specifically to antidote. The hospital

epidemiologists and laboratories were testing some of

the staff in the lab. And also physically they used

the staff for the advantage of testing.

We did look to see if we could find

something very different in terms of the vaccine

effectiveness point estimate among those 20 people.

And in looking at that, we have estimates of zero,

point estimates.

DR. DOWDLE: Thank you.

CHAIRMAN OVERTURF: You get the last

question.

MEMBER DECKER: And a couple of segues, I

think. First, I don't find your presentation and the

handouts. Will it be made available to the Committee?

DR. BRIDGES: The case cohort, the

information on the health care workers study was

published in the MMWR. And that is in the handout.

MEMBER DECKER: Right. The other one.

DR. BRIDGES: The other one is very

preliminary. So at some point, when we have more

analysis, we will be able to provide that.

MEMBER DECKER: All right. And the second

question is, if I understood your table correctly, the

first availability of the data that looks at

hospitalization or mortality is by vaccination status,

which I think is the real outcome of interest because

I think that is why the country hires the vaccines, to

prevent hospitalization and death and not

influenza‑like illness.

The first data on that will be available

at the end of this year at the sites? Is that right?

DR. BRIDGES: Right. The NVSN sites, we

want to have some data, hopefully by the end of the

year. For the case control data, because we have such

a high proportion of those persons who were

hospitalized, maybe also we are able to look at

hospitalization outcomes for the 50 to 64‑year‑olds.

CHAIRMAN OVERTURF: I think we will

proceed at this time. Thank you very much.

Dr. Neville is going to make a

presentation from DOD.

COL. NEVILLE: Thank you very much. I

appreciate the invitation.

I am here because the Air Force is the

executive agency in the DOD for influenza

surveillance. And the Air Force has been conducting

systematic influenza surveillance since the late

1970s. In 1999, it became the DOD program.

My organization is the Air Force Institute

for Operational Health, Brooks City, based in San

Antonio. We collaborate with the Naval Health

Research Center you see here in San Diego. In

addition the Army, this here, you will see in a minute

conducts clinical and virology services at the medical

centers. And the DOD oversees labs participating in

febrile respiratory illness projects.

The overall program is conducted under the

auspices and guidance of the DOD global emerging

infections surveillance and response system, or

DOD‑GEIS.

Later you will hear from Linda Canas this

afternoon, who will present her annual summary of the

data from the DOD lab‑based surveillance program. I

won't present her data here, but, rather, my intention

is to describe other aspects of the DOD's involvement

in influenza surveillance with an emphasis on tests to

meet vaccine effectiveness, which, of course, received

attention this year.

DOD typically does not conduct influenza

vaccine effectiveness research, although this year

several efforts were made, as I will describe.

I will briefly overview the surveillance

programs that exist in the DOD and describe some of

the data that was available for estimating vaccine

effectiveness. Those include a Navy estimate, an Army

estimate, and Air Force estimate. These are the three

that I am aware of in DOD.

All three medical services and also the

Coast Guard contributed to influenza surveillance in

the Department of Defense. The Air Force program is

laboratory‑based, radiology‑focused, its main purpose

being the collection of respiratory pathogens from

military populations around the world that are

considered good sentinel sites. Don't worry about the

map details here. You will see it again this

afternoon from Linda Canas.

Selection factors for several sites

include overseas location, major ports of entry, and

the history of participation in the program. There

are 27 sites from all 3 services and the Coast Guard.

In addition, the overseas laboratory

network supplies specimens from various countries

where those programs are active. Some of the overseas

labs sends isolates to us in San Diego. Some of them

process their own or ship to the regional health

organization labs.

AFIOH in San Antonio has the only

full‑service clinical virology laboratory in the Air

Force. The Navy's febrile respiratory illness

surveillance program is managed by the Naval Health

Research Center. It focuses on eight military

training centers.

On‑site investigators at FRI visits,

febrile respiratory illness visits, they all take the

denominator data and collect specimens of

systematically health care‑seeking trainees who meet

an FRI case definition, which is a temperature greater

than 100.4 and a cough or a sore throat. we may have

to change that maybe. We will see.

Since these trainee populations are

well‑characterized and monitored, attack rates can be

established with a high degree of confidence. NHRC

has the name "Respiratory Virology Lab."

U.S. Army has six regional medical

centers, each with clinical diagnostic virology

capability. While there is no systematic influenza

surveillance program per se in the Army, clinical

results are characterized as needed. And local and

regional preventative medicine staff track FRI rates

and etiologies as needed.

Special operating investigations also are

conducted as needed, more of which I will describe

briefly here in a minute. I should mention that all

three services have agreements or a plan in place for

sharing laboratory services in situations where demand

outstrips capacity, such as how major febrile

respiratory illness operates.

I will briefly describe some of the

relevant data sources that have been identified from

the DOD. Certainly these are not all unique data

sources, but in the context of an urgent public health

effort to estimate the effectiveness of the vaccine in

the face of this nationally occurring disease, these

are the data sources that we used both to monitor

disease activity and to attempt the evaluation of

vaccine effectiveness.

The first is the local public health

officer reports, which is a surprising part of the

report. The primary responsibility for response and

monitoring rests at the local level in DOD. Reports

include routine reports of reportable diseases and

evidence of unusual patterns of disease or outbreaks

which might require special responses or assistance.

Our medical surveillance currently takes

advantage of data collection systems, largely not

designed specifically for surveillance activities.

Among this existing data sources is familiar IC‑9

coding for ambulatory visits.

Many of you may be familiar with the

electronic surveillance system for the early

notification of community‑based epidemics, or ESSENCE,

which monitors ambulatory visits at every DOD health

care facility.

These data can be manipulated or used in

several ways. Here this chart may be hard to see.

This data accumulates all of the Pacific Rim DOD

medical care facilities and the percent of visits for

ILI, influenza‑like illness, which is comprised of

about 30 different codes, IC‑9 codes, that make this

ILI family. So this can be monitored on a daily

basis.

Facility‑specific data can also be

monitored. And a similar approach is used to monitor

diseases and non‑battle injuries for deployed

locations. Data collection at those locations is

often more lacking for a variety of reasons.

Laboratory specimens, submissions, and the

results can also be used to identify surges in

activity generally or at specific sites. This is an

example from last year where an outbreak occurred in

the Tidewater region of Virginia. Percent of total

commissions gives a good indication of pathogen

activity as well as illness occurrence. This is

similar to data displayed by CDC.

Officers. This tracks vaccination

delivery. These here just show the Air Force's data

because that is what it was most able to meet.

Annual influenza vaccination is mandatory

for military members, barring contraindications, of

course. High vaccination rates are achieved fairly

quickly.

Again, this may be a little difficult to

see from the back reading from the handouts. Eighty

percent coverage was achieved by the 2nd of December

in this past year, 2003 and by the 6th of December,

2002.

Because influenza vaccination is mandatory

and it is a command program, it is not a medical

service program, it is a commend program, analyzing

vaccine effectiveness among active duty personnel

during this time period would be a fairly complex

undertaking.

Because such a small portion of service

members remain unvaccinated comparing attack rates

between vaccinated and unvaccinated groups is not very

efficient.

Now to the vaccine effectiveness data.

First, the Navy's. As I described earlier, the Naval

Health Research Center in San Diego monitors FRI

illness, febrile respiratory illness, on basic

trainees of all three services. They have used

existing data here to estimate influenza vaccine

effectiveness.

Their calculation is based on data for

four representative centers, training bases: Fort

Leonardwood, Fort Jackson, Marine Corps Recruit Depot

in San Diego, and Lackland Air Force Base in Texas.

For the month of December 2003,

influenza‑specific attack rates were calculated based

on culture‑proven influenza cases identified in the

ongoing surveillance program.

All trainees are routinely vaccinated upon

arrival of basic training, especially during this

time, the early fall. For this analysis, they were

considered unvaccinated or non‑immune for the first

two weeks after vaccination. So for an 8‑week

training course, for example, 75 percent of the

person‑time, they are considered immune or vaccinated.

So just to display the data that NHRC

worked with, these numbers are for their overall

surveillance program, not just for the sites that they

focused on.

Only influenza A has been identified so

far this season as a ton of data, which was about a

week and a half ago. All of the isolates that they

sequenced were of the Fujian strain.

The dark red segments are influenza

isolates from trainees who had been vaccinated at

least two weeks prior to the onset of illness. As you

can see, the number of influenza cases is dreadfully

small, but there were no isolates segmented away.

This is the size of the calculation.

Because of the specific calculations they are showing,

viewing the vaccine effectiveness estimate of 9.9

percent, it is basic trainees. These data are not yet

published. I don't have other parameters, like age

ranges and gender and so forth, at this time.

The Army's Fort Lee is an Army post,

design post, in southeast of Richmond, Virginia. It

is home of the Army's quartermaster center and school.

It is not a basic training base, but it is a basic.

And that is specialty training.

At any one time, there are a little over

3,000 students present. And courses at that school

are of varying length, from 4 to 12 weeks. Students

arrive weekly for different courses. They are

organized into companies of 200 or so trainees. They

are housed in dormitory rooms of three to four people

each. And so it is a fairly complex model of exposure

in populations at risk.

An influenza outbreak began on the 31st of

October to find out it was in the students and staff

of the 23rd quartermaster brigade, which was a

training. Also, that epidemic occurred here. So the

31st of October, that is when that outbreak began.

Massive vaccination campaign began.

EPICON is the term for epidemiology

consulting team, the Army's Center for Health

Promotion. So the next outside team came and did some

work here. A team came back later in December to get

more information to try to evaluate this vaccine

effectiveness.

Fort Lee had just done their routine

annual influenza immunization campaign. And few were

immunized when the outbreak started. So the medical

personnel on the post responded with a rigorous case

isolation protocol and mass immunization campaign that

reportedly reached about 95 percent of the target

population, which in this case is the trainees.

Data for two different cohorts were

analyzed, primarily based on data availability. One

cohort arrived early November, and the other cohort

arrived later in November. These two different case

definitions now that we see, in a minute we will see

four different analyses.

There are two case definitions. The loose

case definition and any ILI‑related IC‑9 code, a

visit, a health care visit, with a diagnosis of an ILI

code, and also a tight case definition that documented

febrile illness with sore throat or cough or

lab‑confirmed influenza infection.

There are few limitations here for us.

One of those is that it occurred right after an

epidemic, an influenza epidemic, in that training

post, which means that the threat of a subsequent

outbreak may have been modified somewhat by the

population on the study, being surrounded by people

who had achieved the natural immunity grasp.

So two different cohorts are listed,

population size for each, 67 and 463 there. The

vaccine effectiveness point estimates range from 40.5

to 100. And here there were no cases among the group

considered to be immune. Obviously those confidence

intervals are pretty well. And we put zero. So it's

hard to reach any conclusions of effectiveness

evaluation.

Now, the Air Force is here. The Services

Branch of AFIOH has a retrospective force underway

using telephone surveys to collect data on household

contacts of influenza‑infected index cases. They

identify influenza‑exposed cohort by identifying index

cases, who are persons whose cultures have tested

positive for influenza in our own lab.

We included only Air Force personnel for

simplicity and excluded persons from the Air Force

Academy and those who are deployed, in deployed

locations, because our real target is household

members.

We contacted the sponsor of each positive

culture, which may be the person with the culture or

in post housing, and sought voluntary participation in

the survey and took some surveillance within two weeks

of the index case as well as vaccination status.

The secondary attack rate among vaccinated

and unvaccinated is used to estimate vaccine

effectiveness or is being used to estimate vaccine

effectiveness.

There are almost 2,500 specimens in our

lab this year as of a couple of weeks ago. Of those,

859 were positive for influenza. And of those, 114

were considered eligible for this. Among those

eligible, there should be about 400 family members of

those.

So as of February 12th, last Thursday, we

had collected data on 219 of these family members.

And the preliminary estimate of vaccine effectiveness

is 40.1 percent. We feel this could be a greatly

recurring annual study because it is relatively

efficient to do.

Plan B, we would like to do the same study

with a little more effort to validate some of hte

data, like looking at medical records, linking the Air

Force's immunization tracking, electronic tracking,

system to validate vaccine delivery and so on.

So, to summarize, NHRC had a vaccine

effectiveness of 91 percent. CHPPM's vaccine

effectiveness was 40.1 percent, although our concern

was pretty wide. It included zero. Our vaccine point

estimate in the Air Force was preliminary point

estimate is 40 percent, but that it gave us

collections that were none.

With that, I will be happy to answer any

questions.

CHAIRMAN OVERTURF: You didn't mention,

out of those 240 isolates, what the type was.

COL. NEVILLE: Every isolate we got was an

A, an influenza A. And every one that we have

sequenced is consistent with Fujian strain. I don't

know that we sequenced, but it might be something like

20‑30 percent.

CHAIRMAN OVERTURF: Are there any more

questions?

DR. MYERS: I missed it, the NHRC Fujian

portion.

COL. NEVILLE: Every one that they

sequenced as well as those after the first isolate

that they sequenced ‑‑

PARTICIPANT: They have sequenced about 20

percent, sir.

COL. NEVILLE: Pardon me?

PARTICIPANT: They sequenced about 20

percent.

COL. NEVILLE: About 20 percent.

DR. GELLIN: Can you comment about the

regularly recurring annual study?

COL. NEVILLE: Well, competing interests,

I suppose, supplies and manpower and stuff like that.

We were able to achieve pretty rapid IRB permission to

do this next year. It's on the chart. We will do it

again. And it is relatively easy and cheap.

But there is another operator, another war

somewhere and competing priorities, then yes. We plan

to, sir.

CHAIRMAN OVERTURF: Dr. LaRussa?

MEMBER LaRUSSA: Would you just remind me?

The Air Force study, was it everyone who had the

influenza culture?

COL. NEVILLE: The sampling is designed

primarily for collecting pathogens. So not every

person who shows up at a clinic, even if the symptoms

are right, is sampled. It's just the clinician in the

local public health system.

We try to get them to send us six a week,

but that is the target. So if they have not much

disease, they don't get that many out of these. And

we may get a lot more than that.

So I don't know what portion of people

presenting to a clinic with febrile respiratory

illness is sampled. It is variable.

CHAIRMAN OVERTURF: Any other questions?

(No response.)

CHAIRMAN OVERTURF: We are on time. We

will hear the INSERM presentation.

DR. FLAHAULT: Ladies and gentlemen, first

of all, I would like to thank the adviser very much

for inviting me to present this work. This work is

followed by INSERM in France, which is the national

institute, the French NIH, I will say, and by the

Universite Pierre et Marie Curie, which is a

university of Paris.

Of course, I will not come back too long

to the strain selection for the influenza vaccine,

just to say that in Europe, that was, of course, the

same recommendation. And vaccine which was not

created in Europe also used Panama strain, rather than

the Moscow, and used several other strains of the B

virus for the epidemic current season. Eventually it

is a main circulating strain. As you say, it was also

in Europe, the Fujian strain.

So it is a question of which of those is

during, at the beginning of the epidemic, and not

after the epidemic was, how effective was the vaccine

against clinical disease? So it was nearly impossible

to try to provide some answer due to certain

difficulties but also to measure it for sure during

that time in Europe as well as in the U.S.A.

Also in Europe, we had a very early

epidemic. It was just above the man, the average,

epidemic, but as an early epidemic, it was not so easy

to determine.

The question you had in the previous talk

was about the particular rates you found in your

revised studies and also in the comprehensive review,

which was done by Roland at the first talk.

So what is an appropriate protective rate

is difficult to answer. It has been proposed by the

weekly epidemiological record of the WHO that against

ILI, clinical disease, at least, that should be

between 15 and 80 vaccines.

How can we measure vaccine effectiveness

in the flu season? We have seen several methods also,

of course, particular efficacy, which is mainly used

for trial vaccines. And the clinical effectiveness is

usually observed by the so‑called screening methods in

the cohorts that are the case controls and the case

cohorts and all of these kinds of models, which, in

fact, try to compare attack rates in vaccinated versus

unvaccinated.

The vaccine effectiveness with the

so‑called screening methods is this formula, which is

1 minus the ratio of attack rate in vaccinated

population and of the attack rate in unvaccinated

population.

To assess vaccine effectiveness in real

time in France, we used the screening methods because

they are efficient, because cases are drawn from our

sentinel system, which is a very clinic surveillance

system, which provides some figures in real time or

close to a real‑time basis. I say "closely" because

we have all of the consolidated figures each week.

We chose the controls of the cohort from

a regular poll which had been collected by the French

Social Security using a private company specializing

in these kinds of polls for studying and estimating

the vaccine coverage in France for years.

It had been set up in our communities 20

years ago in November '84. It continues on the clinic

surveillance of 12 conditions: ID, of course, but

also acute diarrhea, measles, mumps, chicken pox,

spinal meningitis, viral hepatitis, and also other

infectious conditions, such as asthma.

It can hold a network of 1,200 sentinel

GPs, which are virtually unpaid and all private

practitioners, as they provide information on a

numbering basis. As I told you, we have re‑created a

ton of information which is widely available on the

internet, including the vaccine effectiveness.

So cases are ILI reporting ID cases, which

are only clinical cases with high fever and myalgia,

upper respiratory symptoms, as you mentioned. What is

at work is in each case is individually described with

the age in year, either in months for children;

gender; vaccine status. That is the trademark, only

the vaccine or not, during the preceding four; and

also hospitalization, the case of and with many

details of hospitalization, such as condition dates

and so on, in the case of. It is a mix for France.

Controls. As I told you, we conducted a

poll, which has been done annually for estimating in

terms of vaccine compliance. This is a national

survey. It was a representative sample of the French

population. We obtained data until ten years ago

conducted by a private organization.

As I told you, we have to make

assumptions. These are the figures which were 65

years or less, between 60 persons and 70 persons now.

Of course, we did not have the level of the

cooperation of the current season. So we assume it

was constant, it was the same as the year before.

For the others, the illness in 50 and 64,

there is a rate of conditions being low in France. It

is assumed to be 11 percent for the current season as

it was for the preceding season.

This slide is just to show you some

existing tools for monitoring that we have in France.

We have an early warning system based on accepting

what it takes to detect epidemic in time and to

measure the excess morbidity of influenza.

Also, we have a set of predictors. The

size of influenza epidemics prior to its occurrence

has been presented in our application 5. It predicted

fairly well the level of influenza activity in last

September for the current system. We predicted a

sweep on two million cases. And eventually the size

was Sweden in person‑time, which is a country of 16

million persons.

We also have set up a forecasting

time‑space dynamic of influenza epidemics broadcasted

on French TV, which was for broadcasting three weeks

ahead the times of influenza. These maps are

broadcast on the French TV each week now during the

epidemic, of course. It was actually this content in

France.

As I told you, we have now set up a field

vaccine effectiveness, which is run for years for

measles. It has been published in 1993 and which is

on the routine basis since 1998 in France for

influenza and clinical disease. We also have some

maps showing the current evolution of the epidemic

week after week in the country.

So the available material for influenza

effectiveness assessment is to have this contingency

table for each age strata and each age group strata.

We need to have the number of vaccinated ID cases,

vaccinated ID cases, and say which coverage in the age

strata.

In fact, we did not choose the screening

methods as it was presented because it is too

simplistic. If we want to adjust an age group, we

need to use this for vaccine efficacy which has been

proposed by Greenland in statistics medicine in '86

and which also is used to compute the 95 confidence

interval, which is very easy to meet demands in our

system.

The results of these measures, the ongoing

measurements, are this one. You have here the figure

of this year, which is vaccine efficacy/effectiveness

of 60 percent, which computes along with the score to

77.

Of course, the confidence interval may be

large. And if the point estimate, the confidence

interval, which is very important, which was very

important to our public health authority, is to see

that in 2003‑2004, the level of vaccine effectiveness

was pretty similar to that of the other years with the

exception of the year '97‑'98 where when the H3N2

Sydney strain was circulating and it was very

well‑known that this strain was not included in the

vaccine and the vaccine was clearly not protective

against this strain and the vaccine effectiveness

using the same methods was 26 persons developed, 13 to

39.

We presented this measure on the first

week of the epidemic. And we completed this series

during the whole epidemic using two relative figures,

but it did not vary a lot. Of course, the confidence

interval was much larger at the beginning of the

epidemic, but the vaccine effectiveness was about the

same.

We put all of the data each week on the

Web site, which is now available also available. Many

things are in French. We have set up for WHO since we

have been designated five years or six years ago as a

collaborating center for epidemic disease

surveillance. We have set up for them the FluNet

System, which is still based in Paris, our unit, but

we put the move, really, in 2004 for Geneva. It was

set up in 1997 trying to connect all of the network of

412 centers and also the center between WHO, which was

very important.

Because of that, it is possible to have

some very interesting findings. The first thing is

that there are similar patterns in the Northern

Hemisphere in terms of morbidity. It really begins in

the U.S. early. It begins also in Europe very early.

The duration of epidemics was the same in '98 and '99

presenting the figures, but also for the four

following winters.

The virus circulation with the FluNet,

which is reported in FluNet, you can see that in the

Southern Hemisphere, not for Hong Kong, which is more

a subtropical area, but in the temperate zone of the

Southern Hemisphere, you have a very good coherence of

time occurrence of isolates reported in the

hemisphere. Of course, in the Southern Hemisphere,

there is a lag of six months, which is also very, very

good evidence.

We have tried to study the mortality in

France, in the U.S., and in Australia. We have seen

that the average duration of activity with the same

kind of model organization using a periodic regression

model for estimating the size of epidemics to show

that the average is really very, very similar in

France and in the U.S. It is a little shorter in

Australia.

Excess mortality is highly correlated

between France. So we can say between Europe and the

U.S. It is not correlated between the South and the

North Hemisphere as in Europe or in the U.S. The

correlation between France and hte U.S. was open to 60

to 66.

To understand if the peak is happening

here the same date in France and in the U.S. and also

in Australia, we can see this is a way to get the

analysis. We show very, very high coincidence in the

phase of rapidity.

And we can see also a high correlation

between the peak date in the U.S. and the peak date in

France, showing that the peak occurred at the same

time in both countries. So we see a peak between the

U.S. and France in the last 20 years. It was opened

five weeks, so very, very short.

There is a strong coherence in Northern

Hemisphere, the temperate zone at least. It may

suggest the starting date, date of peak, duration of

influenza epidemic are similar in the U.S. and Europe.

Also size and severity of influenza incidence are

proportionally similar in the U.S. and as for Europe.

So we can probably assume that virus circulation and

probably also vaccine effectiveness among clinical

disease as we see in France is probably similar. And

this is going to be around 60 persons in the U.S. as

well as Europe. That was around 60 persons using the

method reviews, the general practitioners, the

clinical nurse, and so on.

So I want to take this opportunity to

thank all of my team, which worked with us on this

thing. Tank you very much for your attention.

(Applause.)

CHAIRMAN OVERTURF: Are there any

questions? Yes, Michael?

MEMBER DECKER: I just wanted the same

question I had for Dr. Bridges. Will you make a copy

of your presentation? Will it be available?

DR. FLAHAULT: Yes, of course. I just did

not provide that. In fact, I was a little embarrassed

because we wanted to publish the material. And we

know that FDA will publish it on the Web site. So we

will wait for the presentation to provide all of the

figures and charts with that.

CHAIRMAN OVERTURF: Dr. Farley?

MEMBER FARLEY: Yes. I am wondering what

predicts an early onset of a flu season.

DR. FLAHAULT: In fact, we did not try to

predict. We did not include that in our predictions.

So we only predicted the size in terms of morbidity

and mortality of the epidemic in France.

We did not predict the onset. We only

predict the onset with the other model, which has been

very recently published in the American Journal of

Epidemiology by Cecile Viboud, a nurse, which is

predictions three weeks ahead. So that is providing

a very big warning for the beginning. And after we

predict three weeks.

CHAIRMAN OVERTURF: Yes, Dr. Monto?

DR. MONTO: I think your studies show the

idea of long‑term ability to study influenza vaccine

effectiveness from year to year because then you

really can put what you observe into context.

What I would like to ask you about is the

variation in peak time in influenza incidence in

various countries in Europe. I had better be careful

what I say. France is a relatively small country.

And the peak occurs over a reasonably short time

period in the entire country.

I understand there were different times,

just as there were different times of peak occurrence

in Europe. And we have the same situation in the

United States. How well does your model predict

occurrence of peaks in western and central Europe, for

example?

DR. FLAHAULT: It is not so easy to have

precise data and available data on that. In fact, we

felt that the distribution of the peak was much wider

than it was, effectively, either in France, within

France. We used to say that the peak was moving from

a region to another one. The reasons were so that, in

fact, there is a good coincidence everything is done

within ten weeks.

So ten weeks may be not exactly

coincident, but all activity is done in ten weeks.

And all of the peaks are done within three weeks, so

very, very short. So within Europe, we need to have

the same kind of system or at least the same kind, not

the same system but to know what we know, if anything,

about the peak.

And in terms of mortality data, when we

have them, we can say that the peak of mortality is

really, really coincidental. And so I don't know what

is your experience in the United States between the

states of the United States, but I am not so sure it

is a very wide distribution of peak in your country,

too.

CHAIRMAN OVERTURF: I assume that the

reason for no breakdown in the age group from 15 to 60

or 65 is because there is no recommendation for

vaccine routinely to be given. I assume that the

rates of immunization in 50‑year‑olds is the same as

it is in 15‑year‑olds, which is 10 percent. Is that

true or not?

DR. FLAHAULT: Yes, not completely true

but approximately true. That is right. In France, it

is free of charge to be immunized after 65 and plus,

and it is not reimbursed before. It is not completely

exact because in several companies, you may have free

of charge vaccination. And because of that, in the

same age group, in some particular situation, you may

have some higher figures, but in children at least,

the figure ‑‑ not in children. It is very low, but

between 15 and 30 is very low, too.

CHAIRMAN OVERTURF: There are no European

countries that are considering immunization of

children that you know?

DR. FLAHAULT: All of us are considering

immunization of children, but we are still waiting for

the product, which is still not yet marketed, also to

have some recommendation of regulatory authority with

work on that in the future, we are sure.

CHAIRMAN OVERTURF: Dr. Gellin?

DR. GELLIN: We are enlightened by this

series of vaccine‑effective studies. Do you or does

anybody know if there are similar studies in the

Southern Hemisphere?

DR. FLAHAULT: I am sorry. Can you repeat

that?

DR. GELLIN: Does anyone know if there are

vaccine‑effectiveness studies in the Southern

Hemisphere?

DR. FLAHAULT: No, I am not aware of that.

CHAIRMAN OVERTURF: Yes, Dr. LaRussa?

MEMBER LaRUSSA: Do you plan to have any

data on the importance of influenza‑like illness in

children?

DR. FLAHAULT: We collect influenza‑like

illness in children. In France, general practitioners

are taking main charge of the presence of the children

in terms of immunization, in terms of like illness.

So we have these down. They are not immunized at all.

So we did not compute any vaccine effectiveness. So

the measurement of the coverage, vaccine coverage,

only concerns age 15‑plus.

CHAIRMAN OVERTURF: Any further questions?

(No response.)

CHAIRMAN OVERTURF: Well, I would like to

thank all of the presenters thus far. We have a

little extra time for a break. We are to be back here

by 11:30. And we will hear about U.S. surveillance.

(Whereupon, the foregoing matter went off

the record at 11:15 a.m. and went back on

the record at 11:36 a.m.)

CHAIRMAN OVERTURF: Ann Moen is going to

present the data on the U.S. influenza surveillance.

U.S. SURVEILLANCE

MS. MOEN: Good morning. I am going to

spend about the next 20 minutes giving you an overview

of the U.S. influenza surveillance data for the

current 2003‑2004 season.

This first slide depicts the general

schematic of the U.S. influenza surveillance season

and the major components of that under which CDC

collects data on a weekly basis from October to May

each year.

There are four major components that we

collect data on weekly. The first is virologic data,

which we collect from the system of laboratories in

all 50 states. And then there are sentinel providers

that we collect influenza‑like illness on throughout

the 50 states. That is data reported weekly to CDC.

Each week, the state and territorial

epidemiologists in each state report to CDC the level

of influenza activity in their state based on defined

criteria. And then the 122 cities' mortality system

we receive vital statistics, registrars' reports to

CDC on a weekly basis, reporting influenza mortality

due to P and I.

There are some other various forms of data

that come in sporadically, such as institutional

outbreaks and sometimes cruise ships. This year we

had some extra data we collected on pediatric

mortality, which I will talk about later.

All of this information flows into CDC

through the state health departments. And we work

very closely with our partners in the states. Then

the data is analyzed weekly at CDC and then published

in reports that go back out to public health

officials, physicians, the medics, and the public.

This slide shows the virologic data that

is collected through the WHO and national respiratory

and enteric virus surveillance system collaborating

laboratories. There are approximately 120

laboratories throughout the United States that collect

virologic data. They report to us weekly the number

of respiratory specimens that they tested and the

percent that were positive for influenza.

This graph shows just the positive

samples, and the yellow bar shows the influenza A

viruses, which were unsubtyped. And that smaller

subset, which were subtyped, the influenza A(H3N2)

viruses, are shown in red. There is a smattering of

B viruses down here, just a small handful, shown in

green that you may or may not be able to see. And

then the blue line shows the percent of overall

respiratory specimens that tested positive for

influenza.

To give you an idea of the magnitude of

the data collected through that system, of the

viruses, the total specimens tested by the WHO in

NREVSS laboratories in the U.S. for the week ending

February 7th, there were over 92,000 respiratory

specimens tested for influenza. And of these, 22,419

were positive for flu.

All of the laboratories in this

surveillance system type the influenza viruses. Of

those positive for influenza, 22,286, or 99.4 percent,

were influenza A viruses. And then there was a small

handful of influenza B viruses, just 133.

Now, a smaller subset of these 120 or so

labs also do subtyping of influenza viruses. And of

the 22,000‑some viruses positive for influenza A,

5,862 were subtyped. Of those, 99.9 percent were

influenza A, H3N2, viruses with just one influenza A,

H1 virus, which was detected from a military base in

Virginia, I believe, and was probably associated with

travel.

So of all of these viruses collected

through this system, a subset is sent to CDC for

further characterization. This afternoon, you will

hear about the antigenic and genetic characterization

in detail.

In reference to an earlier question about

the percentage of Fujian‑like viruses, I believe for

the week ending February 7th, approximately 82 percent

of them were antigenically similar to Fujian viruses.

And 18 percent were Panama‑like. You will hear those

details later.

So this slide shows the percentage of

estimates testing positive for influenza. The red

line shows this year's data. You can see that it

peaked at about 36 percent positive around week 51‑52.

For comparison here, I have shown the data

from the 1999‑2000 season in green, which is the most

recent moderately severe influenza AH2 H3N2 season

that we have had. And then, for further comparison,

the purple line shows the percent of positive

specimens tested through this system of labs for the

2002‑2003 season.

What this slide does a very good job of

showing is that the season did come earlier this year

and started very early and peaked earlier than most of

the previous seasons. The 1999‑2000 season was

considered early at the time. And this season was

even earlier than that.

This slide showed the percentage of visits

for influenza‑like illness reported by sentinel

providers through our national system of sentinel

providers. Each week, a series of sentinel providers

in the U.S. report the total number of patients seen

in their practice and then the total number of patient

visits for influenza‑like illness using a case

definition of fever of greater than or equal to 100

and cough or sore throat with no other known cause of

illness.

The smooth white line across the center at

2.5 percent is a national baseline. And you can see

that this season that started early peaked around

eight percent. And it has currently come back down

under the baseline. We are currently at the end of

last week around 1.5 percent.

Again, for comparison, the 1999

season‑2000 season is shown in green. And then the

much milder season that we had last year is shown in

purple, where there wasn't that much time spent above

the national baseline.

Just to give you an idea of the numbers of

sentinel physicians in this program, we currently have

1,931 sentinel providers that are enrolled in this

program. And they voluntarily report this information

to CDC on a weekly basis. Of the providers enrolled

in this program this year, 1,141 of them have been

regularly reporting so far, which is considered

reporting more than half of the weeks.

From these sentinel physicians, we

received almost 20,000 reports to the end of last

week, which was for over 5 and a half million patient

visits. And of these, about 170,000 of them were for

reports of influenza‑like illness.

This slide shows the third major component

of the influenza surveillance data collected at CDC.

It represents the pneumonia and influenza mortality

data for the 122 cities. Each week the vital

registrars in the 122 cities report the total number

of death certificates filed and then the number of

death certificates that have either pneumonia or

influenza listed somewhere on them so that we can get

a percentage of deaths due to P and I.

This data represents about a third of the

mortality data for the U.S. The 122 cities represent

about a third of all deaths in the U.S. On this

slide, you can see the bottom smooth line is the

seasonal baseline that is calculated using a

mathematical modeling method. And the upper smooth

line is the epidemic threshold, which is 1.645

standard deviations above the seasonal baseline. Then

the red jagged line shows the influenza mortality due

to pneumonia and influenza.

You can see for the current season that we

have peaked at about 10.3 percent and just for the

week ending 2‑7 came down to about 8.7 percent is

still above the epidemic threshold. Any time the red

line crosses the epidemic threshold, then we consider

that there is excess death due to influenza and

pneumonia.

For comparison on this graph, you can also

see last season, which was much milder and barely up

above the epidemic threshold. Then you can also see

the 1999‑2000 H3N2 season, which peaked at 11.2

percent over here. So it would sort of show that this

season wasn't greater in magnitude in terms of

mortality than previous H3N2 seasons.

This slide shows the fourth major

component of our influenza surveillance system, where

we have received weekly influenza activity estimates

reported, as assessed and reported, by state and

territorial epidemiologists.

The white color shows no report. The

yellow color is no activity. Green represents

sporadic activity. Purple or the light purple

represents local activity. Blue is the regional. And

red represents widespread.

This is the very first week that we have

started reporting data for this season. And you can

see that already in Texas, local activity was being

shown.

The next series of slides is going to take

you on a quick trip through the weekly reports as

reported and assessed by the state and territorial

epidemiologists. You will see how the season

progressed.

By the middle of November, there was quite

a bit of activity reported, especially in the western

half of the United States. And by the beginning of

December, there was widespread, lots of influenza

activity throughout the United States, where we peaked

about the middle of December or towards the end of

December.

Then you can see the activity continued to

decline, and there is still as of the week ending

February 7th some activity or relatively a bit more

activity in the East, where the outbreaks and the

epidemics started just a bit later.

This year we made some changes in the

activity reports from the state and territorial

epidemiologists. In previous years, the activity

levels were assessed at four levels: none, sporadic,

regional, or widespread. These were based on a

percentage of the population and counties. And then

the criteria used was either outbreaks of

culture‑confirmed influenza or influenza‑like illness.

In response to some comments from states,

we worked closely with our partners in the states to

make the criteria by which reporting was done more

defined so that it could be more uniform from state to

state.

So for this current year, five levels of

activity reported: none, sporadic, local, regional,

or widespread. And this was based on state‑defined

regions within the states. The defined criteria used

a combination of influenza‑like illness and outbreaks

and laboratory data. There were specified time frames

for which the lab confirmation needed to take place,

though hopefully we will be able to assess this at the

end of the season and see if states are happier with

this local new definition for providing activity

reports.

So, just to take you back to the peak

week, though, for the week ending December 20th, 351,

there were 49 states reporting either regional or

widespread activity in contrast to the previous

1999‑2000 H3N2 season, when there were 45 states

reporting either regional or widespread activity.

You can see that that season peaked about

three and a half weeks later than the current season.

This is in contrast to last year, where at the peak of

the epidemic, there were 34 states reporting regional

or widespread activity. And that peaked at the

beginning of March.

I also want to spend a couple of minutes

talking about influenza‑associated death among

children less than 18 years of age. Because of the

early attention that pediatric mortality received, CDC

requested reports of influenza death in children by

sending out health alert networks, publishing in the

MMWR and Epi‑X.

As of the end of last week, we had 134

influenza‑associated deaths that were lab‑confirmed

reported to CDC. The median age was 3.36 years with

the range of 2 weeks to 17 years.

Of these, 82 children were less than 5

years of age, 36 children were 6 to 23 months of age.

And of the 134 children, 32 of these children had

underlying medical conditions.

Of the available vaccination histories, it

is shown that 76 children were unvaccinated, 38 had

missing or unknown vaccination histories, 20 had some

sort of vaccination, but only 3 of these were

vaccinated according to the recommendations. It was

pretty much equal opportunity with about half and half

male and female.

This slide shows the epidemic curve by day

and week of the influenza impact in children. You can

see or you will see that the peak here correlates with

the peak of the nationwide aggregate data.

So the question is, is the 2003‑2004

different in impact among children? Well, this has

not been a normal part of our regular surveillance

systems. The influenza‑associated deaths are not

reportable conditions in the U.S. So the average

annual number of influenza death is unknown. There is

no baseline data.

There was a study that looked at ten

years, from 1990 to 1999, and estimated the annual

average of 92 deaths, respiratory and circulated

deaths, occurring among children less than 5 years of

age. This estimate is based on mathematical modeling,

and it is not counting laboratory‑confirmed

fatalities.

Studies to determine if hospitalization

increased in children are ongoing. And discussions

are underway with our state partners to consider

making laboratory‑confirmed deaths in children or

reportable conditions.

This slide, in summary, shows some of the

main components of our influenza surveillance system

overlay so you can see how they correlate. The red

line shows the percent of visits for influenza‑like

illness. The blue line shows the number of states

reporting widespread or regional influenza activity.

The yellow line shows the pediatric deaths. And the

green line shows the percent of positive isolates as

tested by the WHO collaborating and NREVSS

laboratories.

You can see that the ILI, the state

reports, and the influenza mortality, pediatric

mortality all nicely correlate and peak around week

51. The virologic data seems to precede the other

indicators a bit. And it may be due to some early and

very heavy reporting by some of the states who tested

a lot of respiratory specimens in the West and

submitted a lot of specimens that were positive.

I think I will stop there and take any

questions.

CHAIRMAN OVERTURF: Are there any

questions? Dr. Myers?

DR. MYERS: Ann, in those pediatric

deaths, particularly the ones in young children, were

there risk factors other than age? And did you look

specifically under one year of age?

MS. MOEN: They have got age data on all

of the children. The data are being analyzed. The

form that they used is to collect as much information

as they could on children.

But some of the information was hard to

collect because we had reporting of a lot of death

before they decided to collect certain information.

They are going back and trying to fill in some of that

information. Hopefully more full information will be

published.

CHAIRMAN OVERTURF: I believe from the

published data already, about 50 percent of the

children did have underlying illness, though. Isn't

that correct?

MS. MOEN: That was through a few weeks

ago. This is the most current data as of the end of

last week. So the underlying illness for this is a

bit lower.

CHAIRMAN OVERTURF: Dr. Monto?

DR. MONTO: One of the questions we are

always asked is whether the deaths in children that

have been in the newspapers, et cetera, and locally is

something new or is something that has been around for

a while that we haven't recognized.

One thing that was striking to us in

southeastern Michigan is that we had several deaths of

children last year. And some of them were type A H1.

And some of them were type B. And none of them were

A H3N2, which is the subtype we generally associate

with severity.

My question is, how much is the use of

rapid testing to identify influenza virus associated

with the correlation between children's deaths during

an influenza outbreak and identification of influenza

as the etiologic agent?

MS. MOEN: I am not sure how many of these

children were tested by rapid test or influenza

culture. So I can't answer that question.

CHAIRMAN OVERTURF: There is a question

from the audience. Yes?

DR. RUBEN: Fred Ruben of Aventis Pasteur.

I just wondered, Ann. We would normally

think of deaths during influenza periods as associated

with pneumonia and influenza. My understanding from

a presentation by Tim Uyeki was that these weren't all

pneumonia and influenza‑like type deaths, that there

were other attributes, like neurologic conditions and

so forth. Could you comment on that?

MS. MOEN: I think that is true. Some of

them were sudden. It runs the gamut. There were some

that were quite rapid and not associated with

long‑term pneumonia illness.

And there were definitely some excess or

additional cases of pediatric encephalopathies

associated with some of these cases. And we

additionally have been collecting information on other

severe cases of influenza associated with

encephalopathies that may not have resulted in death.

CHAIRMAN OVERTURF: Dr. Gellin?

DR. GELLIN: Ann, you commented early on

about the surveillance, the virologic surveillance,

system. I don't have a context for how many samples

normally go through that system. I guess the question

is akin to the rapid diagnostics. With the increasing

availability of rapid diagnostics, is there a problem

in the system with getting enough viral cultures?

MS. MOEN: I think right now it is

something we remain concerned about. We know there is

a good useful rapid test on occasion, but we also need

to maintain viral isolation so that we can

characterize the viruses.

I don't know what percentage of these

tests were rapid positives, but those are also

reported. An in some cases, say in a year like this

year, when there weren't very many B's, if we're just

getting mostly rapid test reports of B's, that doesn't

leave us very many isolates.

But so far, I mean, the 92,000 that have

been year to date this year is almost equivalent to

the total number of respiratory specimens that were

looked at last year. So I think we are getting more

isolates so far this year.

CHAIRMAN OVERTURF: Dr. Myers?

DR. MYERS: I guess after the presentation

we had just before the break, the obvious question is

to ask, as the numerator data, the case selection

method that France is using, is available to us

through our sentinel physician system, has CDC

considered the possibility of doing an electronic

surveillance analogous to what is done in France,

which, really, I was impressed by the fact that it

gives real‑time data?

MS. MOEN: Yes, their system is

impressive. Right now our sentinel physicians don't

collect vaccination data or patient‑level data. We

get only age data on the sentinel physicians. So we

can't look at vaccination right now.

And on a wide scale, I don't know how well

we would be able to convince all of these providers to

report that level of detail gratis, as they are doing

now.

But it would be great if the U.S. could

implement some way to have annual estimates of vaccine

effectiveness based on surveillance data.

CHAIRMAN OVERTURF: Yes?

DR. ROYAL: Are you able to comment more

specifically on what is known about some of the

neurologic complications these children have

developed, either pathologic findings or other autopsy

abnormalities?

MS. MOEN: No. I wouldn't be the best

person to comment on that.

CHAIRMAN OVERTURF: Is there anyone

present who can comment on that?

(No response.)

CHAIRMAN OVERTURF: Are there any further

questions for Dr. Moen?

(No response.)

CHAIRMAN OVERTURF: We only have three

minutes left before the scheduled break for lunch. I

think Dr. Cox was going to go early, but I don't think

we have time for Dr. Cox. So I think we will just

wait until after that time.

We are scheduled to reconvene at 1:00

o'clock. So I will adjourn the meeting until that

time.

(Whereupon, at 11:59 a.m., the foregoing

matter was recessed for lunch, to

reconvene at 1:00 p.m. the same day.)

DR. FREAS: I think we're ready to resume

the meeting.

CHAIRMAN OVERTURF: At this time of the

meeting, there's time set aside for public comment.

We've heard of nobody who wants to make public

comment, but at this time I would encourage members in

the audience or others who want to make public comment

to step forward to a microphone, identify themselves.

Before you comment, I need to make one

statement which I need to read for the FDA. "Both the

Food and Drug Administration and the public believe in

a transparent process for information gathering and

decision making. To ensure such transparency at the

open public hearing session of the Advisory Committee

Meeting, FDA believes that it's important to

understand the context of an individual's

presentation. For this reason, the FDA encourages

you, the open public hearing speaker at the beginning

of your written or oral statement to advise Committee

of any financial relationship that you may have with

any company or any group that is likely to be impacted

by the topic of this meeting. For example, the

financial information may include the company's or

group's payment of your travel, lodging or other

expenses in connection with your attendance at the

meeting. Likewise, the FDA encourages you at the

beginning of your statement to advise the Committee if

you do not have any such financial relationships. If

you choose not to address this issue of financial

relationships at the beginning of your statement, it

will not preclude you from speaking."

MS. BARR: Thank you. My name is Geeta

Barr. I'm with the National Vaccine Information

Center. And I have no financial conflicts of

interest.

And this question is addressed to Ann

Moen. During the question and answer period after

your presentation, something came up regarding flu

related deaths in children, especially in regards to

neurological complications, encephalopathy and you

mentioned encephalopathy has been associated as a

cause of complication with these flu related deaths.

Is there or will there be available data

on how many of these children were vaccinated?

MS. MOEN: I gave the vaccination data for

the kids that were vaccinated. I believe it was 76 or

78 of the children were unvaccinated and then there

was missing data on I believe it was 38 of the

children and vaccinated children were approximately 20

with three of them vaccinated according to the

recommendations.

MS. BARR: Thank you. And I had one other

comment.

Dr. Levandowski mentioned in his

introduction that protection from being vaccinated has

been noted as early as one week following vaccination

and considering this point, is it really appropriate

in many of the effectiveness studies since they have

considered subjects as unvaccinated for the two weeks

following vaccination?

CHAIRMAN OVERTURF: Dr. Levandowski, would

you like to address that issue?

DR. LEVANDOWSKI: All right, I'll try. I

was just ‑‑ I think I was trying to point out in that

early study in 1943, it was commented that they could

tell the difference between the people who were

vaccinated and unvaccinated as early as one week

later.

Traditionally, we think about protection

as taking two weeks, mainly because it takes at least

that long for peak antibody titers to be achieved

after immunization and somebody who has been

immunologically primed and we believe strongly, at

least for the inactivated influence of vaccines, it's

the antibodies' direction against hemagglutinin and

that they are the most important of the protection.

I'm sorry if that seems a little confusing, but I

don't think we actually know exactly when protection

kicks in for any one person and on a population basis,

we would, I think, normally be expecting it should be

at least within about two weeks, but there may be some

effect earlier or it might be later in some

individuals.

MS. BARR: Thank you.

DR. FREAS: Mr. Chairman, just for

clarification, I would like to say that the open

public hearing, it really is to address the Committee

and make comments before the Committee. We would

appreciate you holding questions until the end of the

discussion or the end of all presentations just in

case those questions may be answered in subsequent

presentations.

Thank you.

CHAIRMAN OVERTURF: Are there any

additional public comments?

(Pause.)

I think we will proceed then. Dr. Cox

will present the information on the world surveillance

of strain characterization.

DR. COX: Okay, I want to start out my

presentation by reminding you that CDC houses one of

four WHO collaborating centers for influenza and one

of our responsibilities that we fulfill for WHO is to

receive influenza viruses from the National Influenza

Centers located around the world and we characterize

those viruses both genetically and antigenically in

order to provide data for vaccine strain selection to

WHO.

We have a number of additional

responsibilities, but that's the main responsibility

that is relevant to my presentation today.

So I'll be talking about influenza H1

viruses first. Hopefully, the blood hasn't all gone

to your stomachs and you'll be able to go through some

of this rather dense laboratory data with me.

Influenza A (H1N1) and (H1N2) viruses have

continued to circulate globally although at very low

levels during this past six months. Here is the

first hemagglutination inhibition table which I'll

show you and I'll walk you through this first one

fairly slowly and fairly carefully. I know there are

new members on the Committee and some of these data

presentations may not be totally familiar to you.

When we're looking at the antigenic

characterization of influenza viruses, we do so by

developing a post‑infection ferret serum against

viruses that are part of our reference battery. So we

have our reference antigens listed across here and we

have the corresponding reference ferret antisera

listed across here. And so the homologous titers,

that is the titer, the inhibition titer for the

Beijing/262 antiserum against the Beijing/262 antigen

is 640.

Now when we are looking for differences,

we're looking for at least fourfold reductions in

titer compared to this homologous titer. What we

tried to do is to develop post‑infection ferret sera

to viruses isolated over time and with a reasonable

geographic distribution and in particular, if we find

a virus that is reduced in titer to the vaccine

strain, for example, the Peru/3135 here show where the

vaccine strain, New Caledonia/20/99 has a homologous

titer of 1280, we have a titer against the Peru virus

of 80.

Whenever we see a virus with a low titer,

we retest that virus in order to make sure that it is

actually reproducibly low in an HI test.

For any viruses that are put into ferrets

and for a selection of other viruses that have a good

geographic distribution, a good temporal distribution,

we also sequence the hemagglutinin. As Roland pointed

out, antibodies directed against the hemagglutinin are

the most important determinants of protection against

influenza and then we also look at a subset of the

viruses for which we sequence hemagglutinins and

characterized their neuraminidase as genetically.

We also do some neuraminidase inhibition

tests to characterize the neuraminidase.

Okay, having said that, what I can say and

you can see very clearly is that there are a couple of

viruses which are variants from the vaccine strain,

New Caledonia. One of them is the Peru/3135 shown

here and the other is the Hawaii/15/01 shown here.

Those are really outliers. We have seen them, seen

viruses like these viruses relatively rarely.

What you have here are the test antigens

8 through 14. They have been isolated from a variety

of continents including Europe, Asia and North

America. And you can see very clearly here that all

of the titers for these viruses are within twofold, at

least within twofold of the homologous titer for the

New Caledonia.

Although we haven't determined the

neuraminidase subtype for these viruses shown here,

what I can tell you from past experience is that it

doesn't matter if the virus is an H1N1 virus or an

H1N2 virus. The HA pattern looks very similar.

So the hemagglutination inhibition pattern

looks very similar for H1N1 and H1N2 viruses. You

really can't distinguish them by doing an HI test.

You have to look at neuraminidase specifically.

So in summary then, what I'm showing here

is the antigenic characteristics of viruses, H1

viruses that were isolated between October 2003 and

February 2004, rather ‑‑ yes, their isolation dates

were between October and February. We only have 10

viruses that were H1 viruses and only one of the 10

was low to the New Caledonia vaccine strain.

If we look back at the previous period,

April to September during the time when influenza

viruses were circulating in the Southern Hemisphere,

we have a larger number of viruses to look at, a total

of 130. And likewise, for that period we had

relatively few, 5 percent or so which were low

reactors to the New Caledonia serum.

Just to amplify a bit with data on the

subtype of neuraminidase, we have 126 viruses for

which we had determined the neuraminidase subtype

isolated between April and September of 2003. And you

can see that roughly half of them were H1N2 viruses.

And for this current interval, we're also

talking about co‑circulation of both H1N1 and H1N2

viruses, although our numbers are very small.

When we look at the sequence of the

hemagglutinins and I've got a much simplified

dendogram on the screen, you can see that there are

two subgroups; one, which represents the H1N1

hemagglutinins and the second of which represents the

hemagglutinins of H1N2 viruses. I mentioned before

that we could not distinguished these two subgroups

antigenically. We can tell them apart genetically,

but not antigenically.

Here is the N1 neuraminidase gene tree and

you can see that here's our vaccine strain down here

and there's really relatively little change in the N1

neuraminidase since 1999. So I can point out that the

Peru viruses that had a bit of antigenic difference

among them also have a few changes on the

neuraminidase and I should also point out that I had

pointed out the Peru 3135 virus on the HI table and

this virus was a low reactor and like other low

reactors it has a K144E change. But those viruses are

really in the minority.

So in summary, I can say that relatively

few H1N1 viruses have been isolated during the past

six months and relatively little influenza activity

has been associated with circulation of these viruses.

No new antigenic or genetic variance of H1HA have been

detected.

And in HI tests using post‑infection

antiserum to the A New Caledonia vaccine strain, these

recently isolated H1 viruses are well inhibited. The

NA genes of both N1 and N2 subtype viruses are similar

to those of viruses circulating a year ago.

That was the easy one.

(Laughter.)

Now we'll go into influenza A H3N2

viruses.

On the screen you'll see a simplified

table and I'll lead you through the simplified table

which was developed for last year's meeting. And I

just wanted to remind you what we were actually seeing

last year at this time for H3N2 viruses.

We have on this particular HI table, the

old Moscow/10/99 reference strain as well as the

Panama/2007/99 vaccine strain. We also have antisera

and antigens representing Fujian/140, Chile/6416, Hong

Kong/1550 and a number of other viruses.

What you can see is that last year at this

time we were seeing a number of viruses isolated from

different continents which were well inhibited by

antiserum to the Panama strain. There were some

viruses which had reductions fourfold or greater

reductions in titer against the Panama, but the

majority of strains really were well inhibited.

We did, however, have antiserum to this

Fujian strain which we can see if we look at this

table carefully we can see that there was at least a

fourfold reduction between Moscow homologous titer and

the Fujian titer and in this particular case there was

only a twofold reduction, but in some other tests

there was a greater reduction. And there were some

other similar strains that gave a difference that was

at least fourfold in both directions.

And that's really what we're looking for

when we're looking for a variant. We're looking for

a variant that has a fourfold reduction in both

directions.

So basically, we were seeing a pattern

where there were viruses with reduced titers, but for

many of the strains, for example, this one, you didn't

see the reduction with the Panama and Moscow older

strains, neither did we for the New York/55 nor for

this particular strain from Asia which had somewhat

reduced titers with Moscow and Panama.

This is a simplified table that was

developed for this year's meeting and what you'll see

here is that in contrast to what we were seeing last

year, we have many more viruses that have a fourfold

or greater reduction in titer compared to the

homologous Panama titer. We have our Fujian 411

reference strain here and you can see that in spite of

the fact that all of these viruses are Fujian, when

you look at their genetic characteristics there are

some viruses which are not as well inhibited by this

antiserum and actually we were seeing that last winter

as well.

Here's another Fujian‑like virus, the

Korean/770 and we have a homologous titer of 1280 and

there are a few viruses down here at the bottom that

have a fourfold or greater reduction in titer compared

to the homologous.

What we have tried to do here is to

represent different genetic groups that we have

observed through our sequencing data by developing

ferret antisera to these viruses and then looking to

see what kind of patterns we get. So we have this

recent virus from Texas. This was from the Texas

outbreak. This is actually a virus that was isolated

in October and you can see that there really aren't

significant differences in the patterns that we get.

If we have a virus that tends to be a low reactor, it

tends to react rather low to all of the different

ferret antisera, indicating that we may have low avid

viruses.

So I think in summary what I'd like to say

here is that we have a lot ‑‑ we've analyzed a

tremendous number of viruses during this current

influenza season from a number of different continents

and antigenically they are somewhat heterogeneous.

There still have been quite a number of viruses that

were very well inhibited by antiserum to the Panama

strain and this is not like the pattern that we had

when the Sydney virus emerged back in 1997. We very

clearly had two‑way fourfold or greater differences

when we looked at HI tests. So every virus that was

Sydney‑like genetically was also Sydney‑like

antigenically. There were very, very clear cut

differences. For the Fujian variant, we haven't seen

that kind of clear‑cut antigenic difference. And so

we've really tried extremely hard to understand what

is going on with these particular viruses and why are

they slightly different from other ‑‑ why is the

emergence of this variant slightly different from the

other variants we've seen over the past few years.

Here is a summary slide for the antigenic

characterization of the H3N2 viruses that were

isolated between October and March, October 2002 and

March 2003, last influenza season. You can see that

there were some Fujian‑like viruses, I think it adds

up to a total of about 28 percent that were Panama‑

like (low) of Fujian‑like.

Likewise, during the summer months that

there were actually increasing numbers or increasing

proportions of Fujian‑like viruses. If we look at the

data for the current influenza season, we see that of

a total of 720 viruses that we've analyzed in this

extensive reference battery, a lot of different post‑

infection ferret antisera that we have about 70 or 80

percent, close to 80 percent being Fujian‑like and a

proportion of those are low to Fujian, give lower

titers with the Fujian antiserum and that's what we

would expect as well. We always see a proportion of

viruses that are low.

Once again, I've simplified the dendograms

so that I could walk you through it more efficiently.

If you look at the dendogram in your package, you'll

see that viruses that have been isolated in eggs are

shown in blue color, if you have color ‑‑ no, sorry.

But you'll notice that we have more egg isolates this

year than we did last year because we put a tremendous

amount of effort into this endeavor.

Last year at this time we were seeing

quite a number of viruses in this the Fujian part of

the graph, but we were also seeing quite a few viruses

down in what we call the Chili genetic group and it

wasn't entirely clear which of these two genetic

groups would win, so to speak. In Europe, they were

actually seeing a higher proportion of viruses at

about this time last year in this particular group

than in this particular group. We all know that the

Fujian‑like viruses won out and we then, as I

mentioned, were monitoring the changes in this group

of viruses very closely.

And you can see that there's a subgroup of

viruses that have changes, these viruses have changes

of amino acids 193 and 227; a separate subgroup that

has a change in amino acid 140; and then this group up

top which really constituted the majority of the

strains that circulated in the United States which has

a change in amino 126. In that previous slide with

the H1 table I had represented viruses from this

genetic group and this genetic group and we really

can't see distinct antigenic differences for these

groups, but we've been looking actually very carefully

to make sure that if we choose a virus that's a little

bit older like the Wyoming/03 virus and the Kumomoto

virus which have been actually ‑‑ actually, the

Wyoming strain was used to prepare vaccine for the

Southern Hemisphere season that's upcoming, so we

wanted to be sure that we didn't need to go even

beyond these strains.

The neuraminidase genes of the N2 subtype

are really quite heterogeneous. The Panama

neuraminidase gene is represented back here and

there's been a lot of genetic change in the N2

neuraminidase since Panama. And we've really got a

couple of different groups that I'll tell you about.

The N2 genes of the H1N2 viruses all

cluster together right here. The N2 gene of the

Chili‑like strains that I pointed out that had been

circulating in Europe last year cluster down here.

The N2 genes of the majority of the viruses that had

been circulating were clustering up here.

Many of the new viruses that we ‑‑ the

neuraminidase genes of the most recent viruses, for

example, some of the Texas viruses that we had looked

at cluster down here and this indicates that there's

been genetic reassortment between H3N2 viruses in the

Chili and the Fujian genetic group, so this is fairly

interesting and it just shows how promiscuous

influenza viruses are. They're out circulating in

populations and reassorting all the time.

Now I'm only going to show one slide with

data about the H1N antibody response to the 2003‑2004

vaccine, maybe two slides. But I wanted, in

particular, to show this slide because this Committee

has asked for data on children who had been vaccinated

and we had been able with Chris Turley and Marty Myers

to do a study that would allow us to look at the

immune responses in children 6 to 23 months of age.

And here we have the immune responses to the Panama

vaccine strain and then to some representative strains

that were circulating this year.

And you can see that there was, from a

pre‑vaccination, geometric mean titer of 5. We went

up to a post‑vaccine, geometric mean titer of 50 in

this population of children, and we also were able to

detect antibodies to the Texas/40/2003 and other

representative viruses that had been circulating this

winter. And of course, we can see that there are

lower titers, but still there has been an immune

response to these other viruses.

I mentioned that we had been looking very

carefully at our HI tables and really wonder whether

we had something slightly different going on this year

and perhaps our hemagglutination inhibition tests

weren't telling us the whole story. So if you'll look

at the bottom half of this particular slide, you'll

see that we have done microneutralization tests using

a variety of different antigens and again using post‑

infection ferret antisera.

So this is more of a functional assay

where we're looking at the ability of antibody against

the Panama virus to neutralize these other strains and

we can see a bit more of a clearcut differentiation

between the Panama and these Fujian‑like reference

viruses. But you can see there is quite a bit of

cross reactivity and you get some inhibition in both

ways.

We also used microneutralization tests to

look at the antibody responses among students who were

vaccinated with the 2003/2004 influenza vaccine and

these sera were collected by Arnold Monto and I'd like

to thank him for those sera. So we were looking at

the neutralizing antibody titer rises to Panama,

Fujian/411 and Fujian/455 and Fujian/444‑like virus

and the Christ Church/28 strain.

And you can see that although the post‑

vaccination geometric mean titers were reduced, we

still did have neutralizing antibody to these other

strains.

So in summary, H3N2 viruses have

circulated really quite widely during the past year

and have been responsible for most reported outbreaks

of influenza in Europe and North America during this

past season.

A Fujian/411/2002‑like viruses have

predominated. Viruses that are well inhibited by

post‑infection antiserum to the A Panama vaccine

strain do continue to circulate, however.

Genetic heterogeneity among current H3N2

viruses has been observed, but we haven't found a

correlate when we look at the antigenic properties of

these viruses and I'd also like to mention that

reassortment has occurred among H3N2 viruses so that

some of the viruses with Fujian‑lineage HA have a

Chile‑lineage neuraminidase.

So now I'll move on to Influenza B virus

characterization and I'd like to remind you there are

two very distinct sublineages of Influenza B viruses

that have circulated, as Roland mentioned, for at

least the past 15 years. One lineage is called the

B/Victoria lineage. The other is called the

B/Yamagata lineage and I'll try to point out so that

you don't get too confused which viruses belong to

which lineage.

Here's a slide which shows two B/Yamagata

lineage viruses, the B/Sichuan/379/99 strain which was

the prior vaccine strain before we moved to a Victoria

lineage strain. And then we also have

B/Shizuoka/15/2001 which was a referenced strain which

was an updated virus, but was in the same genetic and

antigenic group with Sichuan.

These viruses from reference antigen

number 3 down to 9 are B/Victoria lineage viruses and

what I'd like to point out right away is that you

really see very little cross reactivity between the

Yamagata lineage and the Victoria lineage viruses.

Likewise, these Victoria lineage viruses induce

antisera that do not inhibit the B/Yamagata lineage

viruses at all well. And remember, we're working with

ferret antisera. We make sure that the ferrets are

clean of any antibodies to influenza so the ferrets

behave more like a naive human, like a child, for

example, who has never experienced influenza before,

but you do get these very clear, clean reactions.

We had been seeing viruses that were on

the B/Victoria lineage. Last year we had a lot of

Influenza B activity, a lot of school closings caused

by Influenza B viruses. There were some Influenza B‑

related pediatric deaths and all of those viruses

would have looked similar to these Hawaii viruses down

here at the bottom.

We had relatively few Influenza B viruses

and really had to beat the bushes to get viruses sent

to us. There were relatively few, only somewhat over

a hundred that were isolated in the United States and

so we have been very actively soliciting those

viruses. Most people were concerned about the H3N2

vaccine component and were concerned about the large

outbreaks that were occurring due to H3N2, so we

really haven't had as many viruses as ‑‑ Influenza B

viruses as we would like. But of those that we've

had, the majority have been represented by the

B/Yamagata lineage and we noticed that the majority of

the viruses had reduced titers to the old Sichuan/379

vaccine strain.

So in response to those findings, we very

aggressively pushed ahead to develop some additional

ferret antisera to newer strains. So here on this

slide we have some new strains. Once again, these

viruses here at the top are the B/Yamagata lineage

viruses. These two are the B/Victoria lineage viruses

and you can see that we developed ferret antiserum to

Shanghai/361/2002, to this Jilin 2003 and Ulan Ude

2003 viruses.

And in this particular test we've put in

viruses from North America, primarily, but we also

have some viruses from the Middle East and from Asia.

We can see that the antiserum to the Shanghai 361

virus does inhibit these viruses quite well and as

does the antiserum to the Jilin, although we have a

fairly low homologous titer, a little bit lower than

we normally like.

So in summary, what we can say is for this

last most recent time interval, we have 17 Influenza

B viruses that we've analyzed. Of those, 15 are in

the Yamagata lineage and the majority of those are low

to the Sichuan antiserum, that is, the older

B/Yamagata lineage vaccine strain.

We only have two viruses that are in the

B/Victoria lineage and data developed in Japan and

also in Europe very much reflect what we found in our

WHO collaborating center, that is that the majority of

the viruses that they have received are likewise of

the B/Yamagata lineage.

So I haven't actually put the HA sequence

data for both the Yamagata and the Victoria lineage

viruses on the same dendogram. I have an old slide

that I had hoped to put into my presentation last

evening, but my computer had an encounter with some

water and so it really wasn't very happy about that.

So you'll just have to take my word for it that these

two lineages, HA lineages are very distinct and so if

we were to have them on the same slide, we'd have

very, very small tip branches and we'd have a long

line and then it would be connected to the other

lineage.

So first of all, we'll look at the

Yamagata HA gene relationships. Here is the old

Sichuan/379 vaccine strain that was used previously as

a representative of the Yamagata lineage and the

viruses that are currently circulating are primarily

related to an older reference strain that some of you

will remember, Harbin/7/94. And that is the lineage

that's really taken off and has become predominant.

I'd like to point out here up at the top,

the Jilin/20/2003 reference virus. We had developed

antiserum to that virus. There's the Shanghai/361

virus right there. It was a low reactor and that was

one of the other reference viruses. So we have a

number of egg isolates. We have Jilin/20/2003,

Shangdong/22, Jiangsu/10, and then of course, the

Shanghai/361.

Just for reference, we'll go back and look

at the B/Victoria HA gene relationships. Here's our

reference virus here, Hong Kong/330/2001 and the

current vaccines are B/Hong Kong/330‑like.

And the majority of the viruses that have

been circulating actually have HAs that are up here.

The viruses that have HAs up here are not

antigenically distinguishable from those that have

their HAs fall on this part of the tree.

And now we'll move on to the genetic

relationships among the neuraminidase genes of the

currently circulating Influenza B viruses. The

B/Victoria lineage viruses started out having their

neuraminidase genes down here, but genetic

reassortment occurred and so what happened was the

majority of the viruses that had B/Victoria

hemagglutinins actually had neuraminidase genes from

this group up here last year. So during our outbreak

we had viruses not this current year, but the previous

year where we had a significant amount of B activity,

the viruses had HAs down here and neurominidases up

here.

You can see that the neuraminidase genes

for some of the viruses that I have pointed out,

Jilin/20, for example, and Shangdong/22, Ulan Ude/6

and so on have their neuraminidase genes here. So

these are viruses that really have both the Yamagata

HAs and the Yamagata lineage NAs.

So in summary, viruses both the B/Yamagata

and B/Victoria lineages have continued to circulate.

However, although the numbers are fairly small,

B/Yamagata viruses have predominated over all.

Relatively little influenza activity has been

attributed to Influenza B viruses in recent months and

most recent Influenza B viruses from the U.S., Europe

and Asia are most closely related antigenically to

B/Shanghai/361/2002 and B/Jilin/20/2003. I apologize

for the typos.

Influenza B neuraminidase gene sequences,

they also form two separate lineages and the majority

of recent viruses have neuraminidase genes from the

Yamagata lineage as well as their HA from the Yamagata

lineage.

I think with that, I will close and if

there are any questions, I'll be happy to answer them.

CHAIRMAN OVERTURF: Are there any

questions for Dr. Cox?

Yes.

DR. MARKOVITZ: David Markovitz. Nancy,

I wanted to ask you about the microneutralization

assays. So those were done with human sera, right,

did I understand correctly?

DR. COX: We had microneutralization

assays done both with ferret antisera and with human

sera.

DR. MARKOVITZ: Both.

DR. COX: Both. So the bottom part of the

table was an assay done, actually a compilation of

five assays done with the ferret sera and the top part

of the table was with the human sera from the Montose

study.

DR. MARKOVITZ: And do you have an

estimate, if you wanted to put a percentage of

efficacy on ‑‑ in terms of ‑‑ if you look at the

microneutralization the Fujian being neutralized by

the current vaccine strain, what ‑‑ can you put a

percentage on how effective that was?

DR. COX: No, no. We wouldn't really want

to extrapolate from the laboratory tests to what

happens in humans. I mean the laboratory tests are

done with post‑infection ferret sera, the ferrets have

never seen influenza before, so we're really looking

at very clean results without much cross reactivity

because the ferrets are unprimed when they're given

the virus. And so I think extrapolating and also we

don't really know what level of cross reactivity in

this laboratory‑based test would correlate with

protection in humans, so even with the human post‑

infection or post‑vaccination sera, we don't know and

at this point wouldn't like to predict what efficacy

we would expect. It's an index of cross reactivity.

It tells us that there is antibody there that's

reacting, but we wouldn't really ‑‑ it would be very

dangerous to try to extrapolate to protection in human

beings.

DR. MARKOVITZ: So it's just an index of

cross reactivity, so you're just trying to show that

there are ‑‑

DR. COX: That the antibodies that are

there are neutralizing the virus.

DR. MARKOVITZ: Yes.

DR. COX: In a laboratory assay. So if

you take the virus and add the antibody that's

developed to that vaccine, you have neutralization of

the virus and that's what we're talking about.

DR. MARKOVITZ: What would you like the

take message of that slide to be then in terms of

picking vaccine antigens?

DR. COX: The take ‑‑

DR. MARKOVITZ: Or how the vaccine‑picking

in the past ‑‑

DR. COX: The take home message is that

clearly there is cross reactivity between antibodies

developed to the Panama vaccine strain and the

currently circulating strains. I can ‑‑ so there is

neutralizing antibody there.

How that level of neutralizing antibody

translates into protection in a human population, I

really can't extrapolate, but it clearly is there.

DR. MARKOVITZ: Okay, thanks.

DR. KARRON: Ruth Karron. Nancy, do you

think that the greater difference that you've seen

with microneutralization versus HAI has to do with the

divergence of the neuraminidase in these H3N2 viruses?

DR. COX: I don't think so, but I don't

have concrete evidence, but I really don't think so.

DR. KARRON: And also as a follow‑up

question, first I wanted to thank you for including

the sera from the pediatric population. I know it was

something that the Committee brought up last year and

it's good to see it. Do you think it's useful if sera

were available in this pediatric population to look at

microneutralization in this population also?

DR. COX: I suspect that we would see very

similar results. We've looked at microneutralization

tests in the past and really had expected to see a

much more dramatic difference between HI and microneut

data.

Nevertheless, when there is a situation

where there a lot of questions being raised, you know,

the data just aren't falling out the way we think they

should or there are questions about vaccine efficacy

or something, we like to do the more labor intensive

microneutralization tests as we've done for the H3

here, but generally speaking, we don't get any more

information from a microneut test than we do from an

HI test, but it does provide confirmation that there

is functional cross reactive antibodies so that's

basically what we're looking for.

DR. HJORTH: Richard Hjorth, Aventis

Pasteur. Nancy, you mentioned that there are a number

of egg isolates of the B types, B/Jilin related and I

wonder if you've kind of looked at yield at all and if

they're winding their way to the manufacturers?

DR. COX: Good question. We have not

looked at yield and our way of looking at yield is

much less sensitive than your way of looking at yield,

so I don't know really what to tell you about their

ability to grow. I know some of the manufacturers

have the B/Jilin/20 virus and others will be

forthcoming.

CHAIRMAN OVERTURF: Are there any other

questions from the Committee members or the audience?

It must all be perfectly clear, Nancy.

(Laughter.)

If there are no more questions, we'll

proceed then. Thank you.

The next report is from Linda Canas from

DOD.

MS. CANAS: Good afternoon. It's always

a pleasure to come to this meeting. The Department of

Defense has long recognized the threat of just

influenza illness and the possibility of a pandemic is

something we take very seriously.

In fact, as you've heard before,

vaccination is a mandatory procedure for all active

duty military personnel. We give this to them for

their own health, but we don't make the decision on

what's going to be in the vaccine. And since we are

out in the world, and carrying on public health

surveillance, we find it important that we share with

you what we find so that perhaps it can help make your

decision somewhat easier.

This has been an on‑going procedure for

the Air Force since the 1970s where we've collected

influenza surveillance data from our facilities around

the world and it was a very successful program. So

when the Global Emerging Infection System came into

being in the 1990s, we joined forces and it's now a

tri‑service program and funded by the Department of

Defense.

This actually takes place in two different

arenas. The one I'm reporting on today is the Global

Influenza Surveillance carried out in San Antonio,

Texas from military installations of all three

services and the Coast Guard around the world.

Another area is carried out in San Diego from the

Naval Health Research Center and they do baseline

surveillance, population‑based at the recruit centers.

I will, of course, be reporting on the

Global Program and how we work this, just as a quick

overview, we have our annual meeting which is overseen

by GEIS. The laboratory and the epidemiologists work

very closely. We get together and decide what our

surveillance site should be. You saw the map earlier

that we've had. We choose our sites on mission,

people that are going to be out in the world, that

could be traveling in areas that could be infected,

coming in and out of the country, training sites and

those that have historically participated.

We supply them with all of the materials

they need to do surveillance, the collection kits and

all the instructions and I would point out that this

takes place in the context of a full service reference

laboratory. This is not an operation all on its own.

We are receiving medical samples from these medical

treatment facilities around the world, so it's very

easy for them to add respiratory samples to the FedEx

box that's coming to us. So daily, we get samples in,

sometimes one or two samples, sometimes in the middle

of an outbreak, it could be 50. But it makes it much

more low cost than if we were trying to do this all on

our own.

Conventional laboratory methods. In our

laboratory, we only do isolation. We don't work with

any rapid tests because we want an isolate. We want

to be able to examine what that influenza sample is

like. These reports go back to the facility as a

patient report. This is a medical treatment that

we're carrying on. We're doing kind of a dual duty

with surveillance and with medical surveillance. We

have our sentinel sites, but we get samples from other

facilities also.

So in order to be able to track for

reports, we work with the epidemiologists and they

report back to the facility that you do have

influenza. This lets them know they have it and also

facilitates them to go back and do follow‑up work on

vaccination status and be able to do reports like

Colonel Neville reported earlier on vaccine efficacy.

Meanwhile, back in the laboratory, we're

taking selected samples, subtyping them, perhaps

sending them on for molecular sequencing and

characterization and then some on to CDC for further

characterization and then meetings like this today

where we can actually decide on the sites.

This is our map for this year. It's hard

to see the map on your handout. You have them listed,

but it's hard to read. We do have 27 sentinel sites

that cover all three different services and this year

we got the Coast Guard, up in Ketchikan, Alaska.

Cruise ships come in there. They had some very early

outbreaks, so we were able to get set up with them for

samples to come in.

We also work with the Army and Navy in

areas of the world where they have research protocols

going on, particularly in South America. There are

several sites. And they've been very proactive. In

fact, we've just last week received another box with

115 samples. These are all from Peru. We do get them

also from Ecuador, Bolivia, Colombia and more recently

we got some from Nicaragua.

Over in Thailand, the Army collects

samples from Thailand, Nepal and Cambodia and I have

a report that we're going to get some from Maldives in

a shipment that we should be receiving fairly soon.

So you have a list and I'd be glad to go over it with

you some time if you really want to know what they

are.

When we look at our results over all for

everything, everything we got for the year, this is

from the beginning of October until now. We've seen

quite an increase in our recovery from last year and

of course a lot of that has to do with the fact that

there was a lot more influenza. But we operate, as

everyone else has said, on a case definition: fever,

equal to or greater than 100.5 degrees and cough or

sore throat. Well, that's what we say we collect.

But there was some question last year, I mean the

sample comes into our laboratory. We don't know if

somebody just said oh, I'm low on my quota, let's

collect samples.

So we've been a little bit more proactive.

We have a questionnaire which we're encouraging them

to fill out at the time the sample is taken and we're

collecting that data. Also, in one of the facilities

that had sent us quite a few samples, a team of

epidemiologists actually visited and did a limited

records review and found that, in fact, the majority

of what we were getting did not meet our case

definition. If it did, if there was fever of greater

than 100.5, more than 40 percent of those samples were

positive for a respiratory virus. If it did not meet

the case definition, only about 20 percent was

positive.

AUDIENCE (OFF MIC): Eight percent.

MS. CANAS: Okay. Excuse me. Also,

another thing we found in our overall work this year

is the role of the rapid‑flu kits. We don't use them

in our facility, but we know that many of our bases

did. And one of our big concerns and it's been

brought up is if these become more common, are we

going to have fewer isolates to examine.

What we found this year, in years past, we

have battled the mindset of I know what flu looks

like, I don't need a result. But now we have rapid

tests out there and what we were getting in our lab in

very large numbers were those that were rapid test

negative and those tests are very good. They're very

specific, but they are not as sensitive, somewhere

around 65, 75 percent sensitive. So many of our

isolates, the majority of our isolates this year were

from rapid flu test negatives. So we are still

getting many results and probably more because now

people want a result. They're used to having

something and they want a result. And that presented

somewhat of a problem for us this year because we were

so overwhelmed, we were afraid we were going to run

out of materials and we were also getting urgent

requests of laboratories who were afraid they were

going to run out of rapid tests so they were going to

start sending everything to us. We had to do a lot of

negotiating on you know what's going on in your

facility, let's concentrate on the people who might

really benefit from the testing. We didn't want to

miss those that were particularly important.

And down below, you can see that we're

still getting quite a variety of other viruses along

with the influenza. I will say here, talk about

everything, 46 percent of our positives were subtyped.

One was an H1N1, everything else was H3 and 2 of the

As. We did isolate 5Bs. They were widely dispersed

throughout the season and throughout the world. We

had two from Hawaii, one from Korea, one from

California and one from Okinawa. One was very recent.

We haven't subtyped it. We had three that were

B/Sichuan in the B/Yamagata family and one that was a

B/Hong Kong.

The H1N1, we were curious about, because

even though it was early, we knew it was rare. I

asked our epidemiologist to do a travel history and

was, in fact, from a dependent wife whose Filipino

family had just been visiting and some of those family

members had been ill.

When we look at just those that came from

Asia and the Pacific and we do concentrate on that

area, again, we had pretty much the same kind of

percentages, 40 percent of everything we received was

positive; 71 percent of the positives were Influenza

A and again, these were all H3N2. And when we did

sequencing data they were all of the Fujian subtype.

This was also true in North America. Of

course, North America makes up the bulk of what we do

receive. Again, we were seeing the same kind of

percentages, 47 percent were positive, 71 percent of

the positives were Influenza A. This was consistent

throughout everything we did. Again, one of those was

an H1N1, probably having been imported everything else

H3N2.

We do get samples in from South America.

This, of course, being more their summer season. This

particular shipment represented pretty much

exclusively Peru. We did not have any from other

areas. We get more from them later on. We had a much

bigger variety of respiratory viruses in this sample,

too. They also were seeing the same H3N2.

In Europe, it started very early,

especially at our base in the United Kingdom at

Lakenheath Air Base there. It started early and

continued on, probably one of the longest lasting

outbreaks that we saw. Again, they were H3N2. They

came through very nicely. We also got samples there

from Germany, Italy and Turkey, all of them being the

same.

Very important for us, I'm not sure it's

as important for international surveillance was to be

able to establish surveillance sites in deployed areas

because again for the Department of Defense, sharing

this data is important today, but public health of the

troops is one of the main reasons that we carry out

this surveillance and being able to get surveillance

in deployed areas is very important. This was spurred

on, actually, last spring when SARS outbreak hit,

right about the same time when we were moving into

this area of the world.

We haven't gotten big numbers, but the

system is in place and being able to have a system

that we can rely on has made it very important. One

of the bases is in Afghanistan. It's fairly large.

There seems to be a good bit of interaction from

various groups of people, so this could represent some

isolation from that area. From the base in Kyrgystan,

this is much more remote. There is not as much

interaction and I don't know if this is what we have

isolated there, if it's just the people coming in and

bringing it or if there's some from the area. But

since everybody seems to have the same virus, it's

probably both.

If we look at a different graph of the

same information, again you can see very clearly that

Influenza A has been the most important isolate,

respiratory isolate this year. We target for it and

we get it. If we take that out of the picture, and

for the military, adenovirus is a very big player,

especially in the recruit centers. We've had a

vaccine for adenovirus before. We lost it. We're in

the process of getting it back. So it's very

important for us to track this and have an idea of

what's going on.

This is our dendogram. This actually was

supplied to us from the CDC from isolates that we had

sent to them. A little hard to see, but they're all

very closely related on this graph. You can see that

we have sequenced 90 of our isolates. We do tend to

target those that are overseas, but we try to get some

from each area, each base that we get samples from.

We target to get some of those samples so that we can

have an idea.

All of them were showing the amino acid

change 155/156 which is consistent with the A/Fujian

virus. And we also found a good number that had the

substitution of 140 amino acid.

So this is a good summary of what we have

done this year. It's an exceptional year because it

has been pretty much the same thing. The last few

years we've seen a variety of different viruses. This

was especially true last year. This year was very

consistently H3N2 with just a few of the Influenza Bs

and in our case only one H1N1.

We, of course, are poised, like everyone

else waiting for the H5H7 that we hope not to see.

But everything that we have analyzed has been

consistent with the variant, the A/Fujian.

Thank you. Would there be any questions?

CHAIRMAN OVERTURF: Are there questions?

Yes?

DR. McINNES: (off mic)

MS. CANAS: Would our Quatar specimens

have captured Iraq?

MAJ. GOULD: No, those would have been

patients in Qatar.

MS. CANAS: Just in that area in

Kyrgyzstan.

MAJ. GOULD: No, in Qatar. Qatar is in

the Gulf. There was a mislabeling. Afghanistan

should have read Kyrgystan.

DR. McINNES: So do we have Iraq troops

data?

MS. CANAS: No. We're still working.

Shipping is a problem, getting the lines open. We

don't have a lot of priority over there.

CHAIRMAN OVERTURF: Questions?

MAJ. GOULD: Just a comment. Major Gould

from AFIOH. On that study it was about 42 percent of

those patients who met the ILI case definition had a

virus present and only 8 percent in those that did not

meet the ILI case definition. So about a five fold

difference.

CHAIRMAN OVERTURF: Were there other

questions for the speaker?

Thank you.

(Pause.)

The next speaker is Dr. Maria Zambon from

HPA from the UK.

DR. ZAMBON: Good afternoon, ladies and

gentlemen. Thank you for inviting me to speak. I'm

here today to summarize the experience of United

Kingdom influenza surveillance from last winter season

and I do so on behalf of the Health Protection Agency

which is a newly formed agency and comprises what many

of you will be familiar with, the Public Health

Laboratory Service which has been amalgamated with a

number of other government agencies to give an overall

health protection agency.

In common with many developed countries

and the United States, we have a comprehensive

national influenza surveillance system which looks at

a number of different aspects and indices to try to

give the best overall picture of the impact of

influenza. And within our surveillance system, we

monitor various different aspects. We monitor what

goes on in primary care, particularly through a

sentinel general practitioner network which I'll talk

more about later.

We monitor through secondary and tertiary

care hospitalization. We monitor obviously deaths

through our Office of National Statistics. And we

combine elements of our primary and secondary care

surveillance system wherever possible linked

pharmacological sampling.

The entire surveillance outputs, if you

will, are integrated within the Health Protection

Agency in Colindale which comprises both laboratory,

centralized laboratory reference facilities and the

epidemiological work, so in other words, the Colindale

site is, if you will, the equivalent of the United

Kingdom and CDC.

So our GP surveillance comprises a

sentinel network of about 80 practitioners which cover

a population of about 1 million. Health care

provision in the United Kingdom at primary care level

is denominator based and we can therefore get very

good population estimates of morbidity. And GPs

record the incidents of new cases of influenza. In a

subset of those GPs, actually take samples for

virological analysis from the population under

surveillance.

As a consequence of our general

practitioner influenza‑like illness monitoring, we

have very good historical data and we have learned, we

think how to interpret it, to give a picture of

overall morbidity and impact of influenza. We set

somewhat arbitrary the level of baseline activity at

a consultation rate of 50 per 100,000. When

consultation rates rise about that, we describe that

as normal seasonal activity in the sense that we

recognize the circulation of influenza viruses every

year, year in, year out, although the timing and

duration and magnitude of the epidemics may actually

vary.

So to orient you somewhat, if we take Year

1989/90, we recognize that as being the last very

major epidemic year in the United Kingdom and if I

were to orientate you further and put 1968 which you

will recall is a pandemic year, that would be around

about a thousand consultations per 100,000.

If we look at 2004, you can see that it is

really overall quite a moderate year and certainly

fairly similar to the last few years of influenza

surveillance. I'd like to draw your attention to

1989/90 because I'll come back to that. As I will

also to 1995/96 which was the year in England that we

saw the emergency of the Wuhan/395/95(H3N2).

And also here, in 1999/2000 where we saw

the emergency of the A/Sydney virus. So all of those

years here were pure H3N2 virus years, 1989/90,

1995/96 and 1999/2000. And I'd like you to contrast

that with this current year.

Now there's been a lot of indication about

the impact of influenza in children and that's one of

the main concerns this year. I think as has been

pointed out by a number of previous speakers, the

influenza season began early in the United Kingdom and

we see from our consultation data which are broken

down by age that the peak of consultations was indeed

in the youngest age group with relatively little

impact in the elderly age group.

Influenza watchers who have been around

the block a few times will know that season to season

influenza is a very unpredictable disease. And if we

look over a number of years, one of the things that is

characteristic about influenza epidemics is that they

can impact differently and in different age groups in

the population.

If we take 1969 which was the pandemic

year, this was primarily an epidemic which affected

the working age population. If we look at 1989 which

I pointed out to you previously, this was in contrast

an epidemic which was particularly hard on the

children with peak consultations in the naught to four

age group.

If we look at 1999/2000, we saw that this

was an epidemic which was particularly affecting the

older age groups and that, of course, can translate

into the mortality figures, but my point here is that

it is important to recognize that each influenza year

is different in terms of its impact and it's therefore

not always possible to predict what's actually going

to happen.

If we look at the death statistics for

this year, these are total deaths from all causes

reported to our Office of National Statistics. We've

taken the last four years and plotted them in this

particular graph and there's one feature I would like

to point out. You will see that the baseline here for

1999/2000 is somewhat higher than the three subsequent

years and that actually reflects and overall change in

reporting practice so that there are some differences

in the way that deaths are actually registered as

being due to the respiratory system.

If we look at this year's death data, the

thing that we notice particularly is this early peak

in deaths. And one point I should make is that we did

have an earlier influenza season which peaked really

between about weeks 46 and 52, as you will see, but we

do have an excess, a very small excess of deaths here

which is noticeable against an otherwise flat

background.

Now to come back to the virological data,

our virological data is derived both from community

and hospital sources and community sampling takes

place from GP practices throughout the United Kingdom.

What you see here is the clinical index of morbidity,

here it is, rising above the threshold of 50 for a

number of weeks, so peaking between about weeks 45 and

50.

In the pink, we have the number of samples

coming in from GPs and in the green, we have the

percentage positive. Our surveillance system is

somewhat susceptible to external influences, for

example, here a postal strike meant that many samples

were sitting in the post for weeks, leading to

somewhat reduced recovery. But importantly, we look

also for RSV in this surveillance data and one of the

things that is interesting is that our flu peaked

before the RSV started to kick in and normally it's

quite difficult to disassociate them since ‑‑ and

that's particularly important in assessment of

morbidity and mortality in the younger age is to know

when flu is circulating relative to RSV.

One of the ways that we analyze our

strains, particularly from community sources, is we

analyze them genetically first, so we PCR samples and

then once we have a PCR positive we attempt to grow

virus which is slightly the wrong way around, but

gives us a very rapid turnaround and gives GPs a quick

answer as to whether or not flu is positive in the

samples that they've submitted.

Rather than try to characterize a lot of

our data antigenically, we developed and RFLP which

just allows us to distinguish between Panama and

Fujian‑like viruses, so here, for example, use of

different restriction enzymes allows you to pick out

Panama viruses versus Fujian viruses.

So my point here is that this is a typing

method which isn't dependent on antigenic analysis,

but is consistent with the antigenic data that we

have.

And by using this sort of genetic

approach, it's allowed us to look at the analysis of

our influenza strains over the course of 2003. Here

is the start of 2003, so the last winter season was

for us primarily Influenza B, but with some H3

influenza activity and a little bit of H1.

So during last winter season we saw some

H3 viruses of which over 90 percent Panama‑like. We

had a couple of low reactors which turned out to be

Fujian‑like.

SARS came towards the end of the last

influenza season. We had an enhanced surveillance

program in the United Kingdom for returning travelers

and this allowed us to characterize rather more

viruses over the summer than we would have got a hold

of. And we could see the proportion of Fujian‑like

viruses changing in here. The viruses that we

recovered from returning travels were almost entirely

H3N2.

And just over half of those viruses, up

until the 1st of September were Fujian‑like.

Following the 1st of September, all of the viruses

that we've received were H3N2, this current winter,

having been Fujian‑like with just one or two Panama‑

like viruses. So my point here is that this influenza

season has been almost entirely pure H3N2 and also

Fujian‑like, so evidence of a new drift variant in the

population.

If we look at the distribution of the

isolates, in general, from either the community or

from hospital cases, the vast majority of the isolates

that we've had have been from young people with

relatively few from the elderly population. I think

that's important because that certainly does contrast

with other years.

In terms of respiratory outbreaks, we

would say it was a fairly quiet season with 13 major

outbreaks reported. Eleven of these were in schools

or nurseries and 10 out of 11 were associated with

Fujian‑like viruses. Two outbreaks occurred in

elderly homes, one of which was associated with

Fujian.

Now, this winter one of the reasons

there's been a lot of interest, particularly in

influenza, has been I think heightened awareness of

the existence of a new drift variant, heightened

awareness I think because of SARS and the impact of

emerging viruses.

Across the United Kingdom, we had 17

laboratory confirmed associated deaths. They were

laboratory confirmed either by PCR detection and

sequencing or by virus isolation so that would usually

be detection in more than one laboratory so

confirmation by reference laboratory ourselves. So

those are, if you will, rock solid laboratory

confirmed influenza associated deaths in pediatric

cases. For us, we would call that under 18. And we

saw those deaths throughout really our influenza

season. We obviously did have some deaths in the

older populations too which were laboratory‑

associated.

What I can say about these 17 deaths that

we had is that none of them were vaccinated and only

two of them would have fallen into the risk categories

for vaccination anyway. So the majority of these were

children not perceived to be at risk of severe

influenza.

Now in common with United States, we have

attempted some modeling work based on excess mortality

calculations to allow us to get at the question of

whether the number of deaths which we saw this year in

children was consistent with what might be expected.

It's been pointed out previously that in the U.S.

there is no formal mechanism for getting at laboratory

confirmed pediatric deaths and we have exactly the

same problem in the United Kingdom. We don't have a

way of referring back, but what we do have is good

enough data which allow us to calculate excess

morbidity with reference to knowledge of when

influenza is circulating and therefore a way of

estimating mortality in different age groups.

I think many of you will be familiar with

the papers put out in New England Journal of Medicine,

I think it was or perhaps JAMA from Bill Thompson at

CDC who's used a modeling approach to derive excess

mortality. My point here is that if we look at

1989/90, 1995/96 and 1999/2000, all of which we know

to be H3N2, pure H3N2 years, virologically, if we look

at the estimates of excess mortality in the young age

groups that we have, the observations that we have

this year are consistent with those estimates. I

think that doesn't say exactly why those children have

died, but what it does say is that the numbers that

we've seen are consistent with previous years.

Let me move on now to virological

characterization of our data. Nancy has already

explained much of the hemagglutination inhibition

difficulties of this year. One of the things that we

noticed in our strains was quite a wide range of HI

reactivity to the Fujian antisera and this strain

here, Scotland/50 is a strain recovered from a fatal

case which does have reduced reactivity, although

we've seen this reduced reactivity of other strains

and we do not think there's anything particularly

unusual about that.

When we put our sequences into more

limited dendograms based only on England strains, we

also see two genetic groups which we've just for the

sake of rather arbitrary reasons called it Group 1 and

Group 2. These ones have the N126D substitution which

have already been mentioned and this Group 2 is

consistent with the other genetic groups that's been

previously discussed.

The cases here in blocked out, represent

some of our preliminary sequence data from the fatal

cases which suggest that the fatal cases fall into

both genetic groups, but importantly are closely

related to other similarly circulating strains, at

least on the hemagglutinin sequence that we've

developed so far.

Our N2 data, neuraminidase data from the

H3N2 also demonstrates the phenomenon which Nancy has

alluded to, the fact that the neuraminidase of the

recently circulating strains is closer to Panama virus

than to Fujian‑like viruses which is consistent with

a reassortment event and here is the neuraminidase

from a fatal case, closely related to two other

nonfatal cases, also from young children.

With respect to Influenza B, we've had

only two isolates of Influenza B this season, both of

which reacted well to Harbin and Sichuan serum,

placing them clearly in the Yamagata lineage and

distinct from Influenza B isolates that we had at the

end or during the season of 2002/2003. So this

evidence is certainly suggestive of a resurgence of

the Yamagata lineage in the United Kingdom, but based

on a sample of two, I'm not sure how much we can infer

from it. And that is consistent also with the genetic

data which places these closest to the Harbin lineage

here.

With respect to Influenza H1, we've had

one Influenza H1N1 detection which has a somewhat

reduced reactivity to New Caledonia, but again, with

a sample size of one it's hard to know how to

interpret that information. We do know that it was an

H1N1 and it sequenced, clustered very closely with

H1N1s and H1N2s which were circulating over the last

year in the United Kingdom.

So in conclusion then, the 2003/04

influenza season in the UK could be summarized as

being early, young and low. The majority of viruses

were H3N2 and of those H3N2, it was almost exclusively

A/Fujian‑like viruses with some evidence of both

genetic and antigenic heterogeneity.

The neuraminidase sequences of the viruses

which we sequenced were certainly more closely related

to Panama, suggesting reassortment events. And so far

our data suggests that the laboratory confirmed

deaths, the number of deaths are consistent with

previous estimates, but they do not act ‑‑ that

statement doesn't imply anything about the

susceptibility of those individuals. And the

Influenza B isolates which we've got suggest that they

belong to the B/Yamagata lineage which is consistent

with data elsewhere from Europe.

I think I'll stop there and ask for

questions.

CHAIRMAN OVERTURF: Are there questions?

DR. MYERS: I'd like to ask Dr. Royal's

question from this morning on the pediatric patients.

Were these all pneumonia‑related deaths or were some

of them neurologic?

DR. ZAMBON: The laboratory‑associated

deaths, all the subject of the public health inquiry

in English, we should have the full, if you will,

pathological data available on those towards the end

of March. The evidence so far is that there's a range

of syndromes involved. There is definitely one with

post‑mortem findings consistent with encephalopathy.

There are others which have occurred as sudden deaths

without antecedent illness and there are others which

have had antecedent respiratory illness recorded. So

I think there's a spectrum of illnesses in there and

our propriety at the moment is to college together in

one place the pathology findings with all of those

deaths so that we can try to make some sense of it,

but I don't think what will come out of it is a single

unified pathology description of those deaths.

DR. MYERS: And just to be sure I heard

you right, none of those children had been immunized?

DR. ZAMBON: That's correct. What I can

say about immunization in the United Kingdom is that

it is age‑related. The policy is age‑related, 65 and

above and we know from monitoring of immunization

uptake which occurs mandatorily that there is a 70

percent coverage in our over 65 population. The at‑

risk population below 65 is much less well covered

than that of the order of 30 to 40 percent and perhaps

lower and immunization of at‑risk children is probably

lower than that still. It's of the order of 10 to 15

percent.

CHAIRMAN OVERTURF: Are there other

questions for Dr. Zambon?

May I missed it. What was the actual

number of children that were analyzed for this year

were pediatric deaths?

DR. ZAMBON: Sorry, the number of

pediatric deaths was 17.

CHAIRMAN OVERTURF: Okay, thank you.

DR. ZAMBON: The number of children

analyzed and indeed the number of deaths which came to

light was somewhat higher, but what we focused on are

those which are definitely laboratory confirmed.

One of the questions that I see keeps

coming up in my mind and I haven't heard an answer to

it today is ‑ and actually what we're seeing in terms

of the higher morbidity and mortality seemingly in

children this year, brings up the question again about

what influence, particularly this year where there was

so much heterogeneity in the Fujian strain, what

influence repetitive immunization, yearly immunization

has in increasing or decreasing protection. Does

anybody have data on that, the effectiveness of the

vaccine?

Because one of the things that has

occurred over recent years is that we have certainly

increased our immunization rates, particularly in

elderly populations and many of those persons are

likely who have been ‑‑ obviously, they've lived a

long time, but they've also ‑‑ and been exposed, but

they've also been immunized many times. So is there

data on that?

Dr. Eickhoff?

DR. EICKHOFF: The data I'm aware of such

as it is, comes largely from Houston. I think Bob

Couch and his colleagues have collected data in

several settings showing or studying the efficacy of

influenza vaccine in a group of adults who have been

sequentially immunized on an annual basis over a

number of years. And as I recall the data, there was

really no difference in vaccine efficacy among those

who were repeatedly immunized as opposed to those who

were relatively new to influenza vaccination.

That's my recollection of the data. In

other words, while we think those were repeatedly

immunized are immunologically somehow different, the

data do not seem to support that.

CHAIRMAN OVERTURF: Dr. Monto?

DR. MONTO: The group in the Netherlands

have been much interested in the so‑called Hoskins

phenomenon which actually doesn't relate to older

individuals at all, but to children in a boarding

school who were repeatedly vaccinated. They've

reanalyzed those data. The third year, clearly, was

wrong in terms of the conclusions that were reached

and they've done a fair amount of modeling recently

which is a little difficult to describe succinctly

because it suggests that if you ‑‑ for some people if

you don't have an exact match, you do better in terms

of long‑term protection than if you do have an exact

match, but the bottom line is that there really is no

evidence that repeated immunization is bad for you

which is really what the Hoskins study was talking

about, that if you were going to make antibody to the

older strain, invoking the law of the original

antigenic sin which really doesn't apply in this

situation anyway, but saying that this was certainly

bad for you and the conclusion is that repeated

immunization really is good for you.

CHAIRMAN OVERTURF: Dr. Decker?

DR. DECKER: Yes, Aventis Pasteur conducts

annual studies of flu serum when it's first released

in the market. In a single small location where

there's a tendency for people to participate year

after year and we had caused recently to look at the

data from most recent year and analyze it by how many

times previously those participants have been in the

study in prior years and thus, were known to be

repeaters and found no clear predictive effect on

their antibody response.

On the other hand, that doesn't tell us

how many of them that weren't in the study in prior

years picked up their flu vaccine elsewhere, so I

can't rule out the possibility, but my impression is

the same as you just heard.

But the other thing is that my

understanding of the overall epidemiology,

particularly in pandemic years is that there tends to

be some evidence of protection from the severe

consequences of influenza and age cohorts old enough

to have been around when that strain last circulated,

so my own hunch in the absence of rigorous data

supported is that you do get some protection against

death, but you don't particularly get any higher

antibody titers as measured in a lab.

CHAIRMAN OVERTURF: Were there other

questions for any of the speakers in the afternoon

session?

We are about 15 or 20 minutes early so

what I would suggest we do is we adjourn at this time.

We are scheduled for a half hour break at 3 o'clock

and instead of that, we can be back at 10 minutes

after 3 and we'll begin at that time.

Thank you.

(Whereupon, the proceedings went off the

record from 2:40 p.m. to 3:14 p.m.)

CHAIRMAN OVERTURF: On the record. So

we'd like to begin the second half of the afternoon

with Dr. Levandowski who is going to give us a rundown

on vaccine responses.

DR. LEVANDOWSKI: Okay, thank you. I'll

try to be informative and clear and brief on influenza

vaccine responses. This is always a task. I'm afraid

people way in the back are not going to see what's on

the slides because it's going to be tables of results.

But I tried to do a better job this year. I hope it's

going to come across, at least color coded, that you

can tell where the hot zone is on the serology.

First of all, I should mention that the

material I'm going to present here comes from a number

of different laboratories. There are a number of

serum panels that are available to us from different

parts of the world. These are shared between

laboratories.

There are some sets of sera for adults and

elderly that are shared between five different

laboratories. All of them test these sera against

some of the same antigens and some different antigens

to try to get some estimate or some gage on how close

or different the currently circulating strains are

from the vaccine influenza viruses.

So on this first slide, there are three

serum panels shown here that come from Australia, from

England, and from Japan. These are for adults and

elderly. You can see ‑ you probably can't from the

back ‑ but the vaccines are pretty much the same.

They fit the recommendation from last year that

vaccines have an A/New Caledonia/20/99‑like strain for

the H1N1, an A/Moscow/10/99, or in our case an

A/Panama/2007/99 (H3N3)‑like strain, and then a B/Hong

Kong/330/2001 influenza B strain which is represented

in the first two serum panels here by B/Shangdong/7/97

and on the subsequent slide represented by B/Hong

Kong/1434/2002.

Serum panel number four, the first one on

this slide, is one that was made available to us that

included not only adult and elderly serum, but we had

a small number of sera from a second study in children

that I'll talk about a little more as we get to that

point. The amount of serum obviously for pediatric

studies is relatively limited so those sera are not

necessarily shared with all the other laboratories.

But those first four serum panels are shared amongst

all the laboratories that were involved in looking at

serologies.

There's another serum panel from children

which Nancy Cox talked about. She presented some of

that information. I may be redundant and go over that

again if that's okay with you. Then because the

B/Yamagata/16/88‑like viruses seem to be predominant

again, to try to get some information about previous

vaccine strains that were similar, whether those would

give us any coverage, we went back and tried to find

some sera.

Our lab and John Wood in the UK tried to

go back and find some sera from some old panels that

would have had a B/Yamagata‑like strain as the vaccine

strain. These would have been the most recent ones

from 2001‑2002. In our case, the B strain was

B/Victoria/504/2000. In the sera that John Wood was

able to examine, the strain was B/Johannesburg/5/99.

Those two are antigenically similar to the recommended

strain for that year which was B/Sichuan/379/99.

That's probably more than you want to know.

The antigens that were used for the H1N1

serologies are shown here. They are representative of

currently circulating strains and include H1N1

viruses, shown up at the top. The first three here

are H1N1 viruses. And the last four viruses on this

chart are H1N2 viruses. I don't know if it was

mentioned before but of course the H1N2 virus has the

hemagglutinin from the H1N1 strain as it was

originally existing and has all the internal genes and

the neuraminidase from the H3N2 strain.

The most important part for us however is

that the H1 here, actually as Nancy mentioned, they

are very similar between these representative strains.

So you can see we have them from a number of different

continents, from Africa, from Asia. Does Iceland

count as Europe? I think it does. And from the

Americas.

You won't be able to read this I'm sure

even at the back of the table. But what I have here

are an exemplary panel of anti‑sera. These are

adults. Actually it's three different panels of anti‑

sera; adults from the United States, from Europe, and

from Japan and tests that were done at CDC on these

sera and the antigens that they looked at. In blue on

every one of the slides, if you can see the blue, you

can tell what the vaccine strain is.

But A/New Caledonia/20/99 was the vaccine

strain that was used here. Then there were a number

of newer antigens; the Minnesota/18/2003,

Virginia/20/2003, and Belem/84066/2003. These last

two are H1N2s. That one is an H1N1. I mentioned that

I would show in red where there are significant

differences.

What I would like to try to do, although

I have all the information on these panels that you

normally see in serologic tables, I would like to

focus your attention more on the geometric mean titer.

This is probably the most non‑arbitrary measurement

that we can look at. We're interested in determining

whether in the post‑immunization sera there are

changes that would result in reductions in antibody

responses.

We have arbitrarily chosen a 50 percent

reduction which would be a two‑fold reduction in our

geometric mean titers. I think you can think of that,

if you will, similar to what Nancy Cox was talking

about as a four‑fold reduction with a ferret serum.

But it's another way to try to get to how different

are the strains that are circulating.

In this case, you can see from all of

these serum panels I don't have anything colored red

so there's nothing here that has a major reduction, as

much as a 50 percent reduction from the vaccine

strain. All of these strains, the H1N1s and the H1N2s

seem to be inhibited very well by the anti‑sera from

people who are immunized with current vaccines in

three different places.

This is a similar table for the H1 for an

elderly population. In this instance, the serologies

were performed at NIBSC. There are sera from Europe,

from the United States, and from Japan again here.

There are some different antigens shown here on these

tables; Dakar/85/2003, Virginia/20/2003 what we have

seen before, Iceland/123/2003, and Nagano/1328/2003.

Again, we have strains that are representing the H1N2

and also representing the H1N1.

Again, calling your attention the post‑

immunization geometric mean titers, I think you can

see that in all of these serum panels from these

different locations that all of these strains are

inhibited very well in this elderly population by the

anti‑serum in response to the New Caledonia vaccine

was pretty good. I should also point out that there

are going to be differences in the absolute numbers on

these tables.

What I would really again want you to

focus on is the relative differences between the

vaccine strain and the new test antigens and not worry

so much about the level of the antibody responses.

That's really not the point of this exercise. It's to

see if this can tell us anything about how similar the

current antigens are in terms of their recognition by

the anti‑sera from vaccines.

So now, there are pediatric sera as well.

These are studies that were done either at CDC or at

the Center for Biologics. The CDC, as Nancy Cox

mentioned, had the panel of anti‑sera from children

who were six to 23 months. I have already forgotten.

Someone told me what the mean age for the children

was, but they were very young, around a year old I

think on average.

Also there were some children who were six

to 38 months with a mean age of 21 months. Here

again, we're looking at the vaccine antigen in blue

and then some of these newer antigens. Again, what I

think you can see is even in these very young children

the antibody responses against these newer H1N1s was

very similar to what was seen with the vaccine. So it

suggests that children immunized with that vaccine

would have very good responses. I should mention the

sera were collected after two doses of vaccine so they

got the full immunization.

To try to pull this all together from all

of the data that we have, because not all of the

different groups tested all of the antigens and we had

a number of different antigens that were tested, I

have tried to summarize in the table here showing

where there was a 50 percent reduction in the

geometric mean titer of the test antigens as compared

to the vaccine antigen which here was A/New

Caledonia/20/99. By gestalt, I think you will see

that there are very few instances in which there was

as much as a 50 percent reduction in any of the

serologic tests that were done.

There was some reduction. We always see

that. There's always some amount of reduction in the

actual titers as compared to the vaccine strain. But

for the most part, these are very minimal and not very

indicative of much of a difference in terms of what we

might expect from this kind of serologic testing.

So moving on to the H3, again, the vaccine

strain was Panama/2007/99. There are a number of

representative strains here. The Chile/82660/2003

strain is in the New York/55 group or Chile group if

you want to use that terminology that Nancy Cox was

mentioning that's different from the Fujian group that

has been developing. All the rest of these strains,

and there are quite a few of them represented here,

are all Fujian/411/2002‑like strains.

Here again, this is for adults. These are

sera that were tested in Australia at the WHO center

there, European, U.S. and Australian sera. The

vaccine strain again is shown in blue in each of these

panels. Now what I think you can see, because there's

lots of red there, is that there are reductions in the

antibody titers in a number of these panels.

It's as much as 50 percent for the

Wyoming/3/2003 in all three of the panels. It's not

quite reaching 50 percent for some of these other

antigens. But you can see that somewhat consistent

with what we're seeing here that there is a reduction.

On a different day perhaps that absolute titer would

be a little bit less than it was there.

Again, from these sera, you can see that

all of these antigens, Victoria/584/2003,

Texas/584/2003 and the Chile/82660 which was in the

other lineage Fujian‑like strains, all of those are

relatively poorly inhibited by anti‑serum from the

current vaccine. And that's true with the Australian

sera here as well.

Again, looking at the elderly sera, CDC

did these tests, sera from the United States, from

Japan, from Australia. The vaccine strain is shown in

blue. Again, you can see that in the majority of

instances there's as much or more than a 50 percent

reduction in the antibody titers. That's not always

true. There are some of these panels where the

antibody titers seem to be a little bit higher. But

the general trend seems to be that there are

reductions.

This is looking at children. Again, the

serotested at the CDC and the serotested at the Center

for Biologics. These are two different separate

panels. Here, the Chile/82660 strain showed a 50

percent reduction. I think I have the numbers right.

It's not as much as a 50 percent reduction for these

other representative Fujian‑like strains. But there

is some reduction there.

Similarly, this group of children, the

Kumamoto/102/2002 strain which is a Fujian‑like strain

was not really reduced in this one test. I'm not sure

how many conclusions we can draw from that. But there

were reductions that were fairly substantial with the

other Fujian‑like strains.

To try to do the summary again for this

with the 50 percent reductions, here you can see

looking at the overall scope of testing that very

many, in fact the majority of the serological testing

indicated that there were some substantial reductions,

more than 50 percent reductions, in the geometric mean

titers of the test antigens versus the vaccine

antigen. Here, you also see that for the most part

the mean percent reduced is over 50 percent overall

with some of these in some instances having almost no

cross reactivity with the test antigen in the

particular test that was done.

There are some differences. You see that

not always do all the laboratories pick things up

quite the same way. This partly relates to the fact

that we're using this arbitrary cutoff of 50 percent.

It doesn't mean that there wasn't some reduction.

It's just that it wasn't that severe.

Now, finally, coming to the influence of

B serologies, this is a little more complex. The

current vaccine strains are Hong Kong/330/2001‑like

strains. Then these serologic panels are represented

by Shangdong/7/97 and Hong Kong/1434/2002. In that

same HA group, we have B/Sichuan/259/2003. That's the

only strain actually that's amongst these that was

included in the test. Partly this reflects that fact

that there have been so few recent influenza B

viruses.

But there were more that were in the

Yamagata/16/88 lineage. Some of the time we're

calling them Shanghai/361‑like. They are represented

by a number of different strains from different

locations including the United States, from North

America, from Asia several, and from Europe. As I

mentioned before, we have the older vaccine studies

which I'll get to at the very end with older

Yamagata/16/88‑like vaccine strain.

These are adults who the sera were tested

at NIBSC from Europe, Australia, Japan. I think they

give pretty much the same picture. The vaccine strain

is shown in blue. The Sichuan/259/2003 strain is

similar to the vaccine strain. You can see that in

all these serum panels there's very little, if any,

reduction as compared to the vaccine strain.

But in this case the B/Jilin/20/2003 is

one of the Yamagata‑like strains. It's related to

Shanghai/361 and there are some fairly substantial

reductions, 50 percent or more, in all cases here.

DR. FARLEY: Excuse me for interrupting.

Several people were asking for hard copies of your

slides. Apparently they were stapled by mistake to

the next speaker's presentation. So if you look at

the next speaker's presentation, page two, three, and

four are really for Dr. Levandowski. Sorry for the

interruption.

DR. LEVANDOWSKI: Okay, do you want me to

start over?

(Laughter.)

DR. LEVANDOWSKI: So moving on, elderly

tested at the CDC, serum from the United States, from

Europe, and from Japan. Here the vaccine strain or

what was representative of the vaccine strain in these

serologic panels was B/Hong Kong/1434/2002. We have

the vaccine‑like strain, the Sichuan/259/2003, and

then some other representatives of the Yamagata/1688

lineage.

In this case, it's somewhat variable, but

again I think it shows that there are reductions for

people who are immunized with the current vaccines.

There are reductions against these Yamagata‑like

strains, most marketably shown in this serum panel by

the Jiangsu/10/2003 strain. But that's true again you

see for B/Jilin/20/2003 and Washington/3/2003. You

see that there are some reductions in the titers here

as well for those strains.

Pediatric populations pretty much tell the

same tale. These are children who for the most part

have not been immunologically primed. Therefore, if

they haven't been exposed to both of the strains, we

would predict from all past experiences ‑‑ And we have

had a lot of them looking at this kind of data

although not in the past two or three years.

We had quite a lot of experience with it

in the early 1990s when the strains seemed to have

diverged. It's pretty clear that there's a big

difference between the Hong Kong‑like strains up here

and the Yamagata‑like strains. Maybe it should say

the Victoria/287‑like strains up here and the

Yamagata/1688 strains down here. There's essentially

no responsiveness of these children to the other HA

lineage. That's true in this panel down here. You

see a large difference between the vaccine and the

Yamagata‑like strain, the B/Jilin/20/2003.

So the last thing I'll cover here are some

studies that we did with an older vaccine, vaccines

from 2001‑2002. These studies were done at NIBSC for

some European sera or in the United States. We had

sera from adults in this instance. We had a small

number of sera from adults and elderly in the other

instance. Again, the vaccine strains are in blue here

in each case.

Although there was some reduction, it

wasn't as dramatic in this particular instance between

the vaccine strain and the test strains which are all

in the same HA lineage so it isn't too surprising.

But here in this particular panel ‑ and it's only one

and it's a small number of sera so it's hard to draw

too much conclusion from it ‑ there was more than a 50

percent reduction.

This is a little bit difficult to

interpret because the pre‑immunization titers in our

serologies here were different. So this was about

two‑fold higher to begin with. It's hard to know

whether that just represents something about the

technique in that particular instance. Here again, in

this particular panel, there's not much of a

difference between the older vaccine strain and

B/Jilin.

Going back to the main part of the

serology, here again, it's trying to sum it up with a

50 percent reduction for these newer strains. All of

these at the top are in the Yamagata/16/88 or

Shanghai/361 family. You can see that there are

reductions. If you add this up, that the majority of

instances there's some reduction in titer. Although

it's not quite 50 percent on mean, there is a tendency

for these to be higher. They are in between what we

saw with the H1N1 and the H3N2 but there is somewhat

of a difference there.

But if we looked at the viruses that are

in the same HA lineage as the vaccine strain, actually

the coverage would look pretty good. There's a

divergence here coverage good for the vaccine strain,

coverage not so good for the currently circulating

strains in the other HA lineage.

So to try to summarize then, studies with

the sera that were collected after immunization show

that representative influenza H1N1 and H1N2 viruses

are very well inhibited. Many of the

A/Fujian/411/2002 (H3N2)‑like viruses are less well

inhibited than the vaccine strain. The B/Hong

Kong/330/2001‑like viruses are well inhibited by

current anti‑sera.

But the Shanghai/361/2002 and similar

viruses are less well inhibited than the vaccine

strains. That's most marked in the instance of young

children who have not been immunologically primed for

both strains. I can just stop there and take

questions.

CHAIRMAN OVERTURF: Are there questions

for Dr. Levandowski?

DR. ROYAL: This sort of reflects my

ignorance about how you look at the data. But when

you look at a 50 percent reduction, that's not exactly

what you are doing in analyzing your other

neutralization data in that you are looking at at

least a four‑fold change in your neutralization or

your titer. Here, you are looking at a 50 percent

reduction instead of at a range of 25 to 75. Could

you explain that to me?

DR. LEVANDOWSKI: Yes, in terms of the

ferret sera, we're looking at individual ferrets.

There, you have a one time test basically. But here,

we're looking at pooled data. We were looking at more

than one serum at a time so the geometric mean titer

is from whatever the number is we happen to have in

the serum panel. You can see that that was variable

for this time.

It's an arbitrary measurement. The four‑

fold of course in the ferret serum is because when you

do two‑fold dilutions, you have the possibility of

having one two‑fold dilution error. To try to factor

that out, you take four‑fold to make sure it wasn't

just the crossing. With the geometric mean titers,

it's actually a little bit firmer.

Although, on any given day, I think we

could be two‑fold off on our geometric mean titer. I

wouldn't put it beyond the scope of imagination for

that to happen. I think that's less likely to be

true. When we were looking at a two‑fold difference,

when we're looking at the geometric mean titers, it's

not quite the same as looking at the four‑fold

difference. But I tried to sell that. If you don't

buy it, okay.

(Laughter.)

CHAIRMAN OVERTURF: Yes, Dr. Palese.

DR. PALESE: We heard that we have

basically no influenza B or in H1 this year in the

United States. What is your assessment in terms of

the B lineages worldwide, particularly in terms of the

B/Yamagata and B/Victoria, this season and the summer

season on the Southern hemisphere?

Basically we would like to get some

feeling which one of these lineages, Victoria ‑‑ And

I know there have been many names given to these

different lineages. But let's stick with Victoria and

Yamagata. So what is your feeling in terms of

worldwide distribution of these two lineages just in

terms of B?

DR. LEVANDOWSKI: I think I'm going to

have to defer that question to Nancy Cox probably.

But I guess I could take a stab at it and give you a

quick answer. The majority of the strains that are

appearing are in the B/Yamagata lineage. There are

very few that seem to be in the B/Victoria/287

lineage.

Thinking back to a similar experience,

although someone said that influenza is totally

unpredictable and what happened in the past is not

necessarily likely to happen in the future. But the

situation was somewhat similar in 1989. All the

strains that were circulating that anybody had seen

were really Victoria/287. B/Yamagata/16/88 itself was

identified just that first winter in Japan. It hadn't

been seen any place else.

Interestingly enough, in many countries in

the world the following year it was the predominant

strain. In some countries, it was still a 50‑50

spread of those two. But it was a fairly ramped

spread. I don't know if that was because of a

susceptible population. I tend to think that it was

because there was a big difference in the percent of

people who had antibodies that cross reacted with both

of these strains.

It depended on whether they were

immunologically primed or not. Again, we're really

referring to children. So I'm rambling off the

question that you asked. But I think we have a

similar situation where there is a susceptible

population that's been developing for a couple of

years. The current strains that have spread to a

number of different areas, because they have been

identified on several continents, have the opportunity

for spreading further.

DR. PALESE: Do we have in our handouts

precise numbers? Looking at 115 isolates, how many of

them are Victoria and how many are Yamagata? Do we

have that in our handouts?

DR. LEVANDOWSKI: Nancy, can you help me

here?

DR. COX: Okay, if you look on the

influenza C isolates characterized in the CDC package

which is the second page after the influenza B viruses

start, you'll see just the influenza viruses

characterized by the CDC. But these are really

reflected of the overall global data as well.

You can see it divided up by time

interval. So if we look back at the time interval

from April 2002 to September 2002, you see that

approximately 90 percent of the viruses were Hong Kong

or Victoria lineage viruses. Likewise, the following

time interval, October 2002 to March which was our

last winter season, we had a large number of influenza

B isolates. Over 90 percent of them were B/Victoria

lineage viruses.

Then if you look to the next time

interval, Southern hemisphere influenza season, you'll

see that it starts to change slightly and we have

smaller numbers. But we had a higher proportion of

viruses that were actually Yamagata lineage. It's

represented here by Sichuan/379‑like and Sichuan/379‑

like (low).

Then admittedly for the most recent

period, we have a small number of influenza B viruses

that we analyzed at CDC. But the proportions here are

reflective of similar numbers and similar proportion

of viruses that were analyzed by two other WHO

Collaborating Centers; one in the UK and one in Tokyo.

DR. PALESE: Do we have those numbers

because 11 is very little and very low?

DR. COX: I don't have those numbers at my

fingertips. But it is similar numbers.

DR. PALESE: But again, in order to make

some informed prediction, one would like to have some

statistical ‑‑

DR. COX: I'll get those for you at the

break.

CHAIRMAN OVERTURF: Are there any further

questions for Dr. Levandowski? Okay, we'll go on

then. The next issue is the availability of strains

and reagents by Dr. Ye.

DR. YE: This presentation is related to

the status of candidates vaccine strains and potency

reagents for production and the standardization of the

influenza vaccine. Current influenza vaccine contains

three antigenic components, two type A which are H1N1

and H3N2, and one B component.

New Caledonia/20/99 is a current vaccine

strain for H1N1. IVR‑119 is a reassortant between New

Caledonia/20/99 and A/Puerto Rico/8/34 or PR8 which is

a high growth virus. This reassortant gives moderate

to high yield in A. Additional research of this virus

from NIBSC in the UK is available for evaluation.

However, currently we do not have any candidate

strains for this virus for distribution.

A current H3N2 is A/Panama/2007/99 which

is A/Moscow/10/99‑like strain. IVR‑17 is a

reassortant between A/Panama/2007/99 and PR8. This

reassortant gives a high yield in A. The candidate

strains are Fujian/411/02‑like strains. There are two

strains right now. One is Wyoming/03/2003 and

Kumamoto/102/2002.

IVR‑134 X‑147 or X‑149 are the different

reassortants between Wyoming/03/2003 and PR8. They

all have moderate to high growth in A. IVR‑135 is a

reassortant between A/Kumamoto/102/2002 and the PR8.

This reassortant has moderate to high yield in A.

The current vaccine for B components are

B/Hong Kong/330/01‑like strain. It's been mentioned

that there are two HA antigenic lineages for influenza

B viruses. They are the Victoria lineage and the

Yamagata lineage. The current influenza vaccine is

B/Hong Kong/330‑like which is Victoria lineage. There

are three viruses; B/Hong Kong/330/2001, B/Hong

Kong/1434/2002, and the B/Shangdong/07/97 that all

have moderate yield in A.

The candidate strain on the other hand is

B/Shanghai/361/2002‑like strain which belong to the

Yamagata lineage. There are two strains. One is

B/Shanghai/361/2002 itself and another one is the

B/Jilin/20/2003. The growth characteristics of those

two viruses is still in early development. But in our

hand it seems likely Jilin/20/2003 gave us a

reasonable year in A.

Now I'll move on to the potency reagents.

The anti‑sera and antigens for A/New Caledonia/20/99

and for Panama/2007/99 are available in CBER for

distribution. Since Fujian/411 has been recommended

for the Southern hemisphere, the anti‑sera and antigen

for A/Wyoming/03/2003 are available from NIBSC in the

UK and TGA in Australia. CBER has anti‑sera for

Wyoming/03/2003.

Both anti‑sera and antigens for

A/Kumamoto/102/2002 are available in TGA in Australia.

However, they only have a limited amount of both

antigens and anti‑sera for distribution. However, if

other strains are chosen, specific reagents will be

available in May at the earliest.

The current reagents for B are B/Hong

Kong/330/01, B/Hong Kong/1434/2002, and the

B/Shangdong/07/97. Both anti‑sera and antigens are

available in CBER. If we decide to switch from

Victoria lineage to Yamagata lineage, the anti‑sera

and antigens for previously used vaccines are

available in CBER which could be used for initial

potency tests. However, if a new strains are chosen,

specific reagents will be available in May at the

earliest. Thank you.

CHAIRMAN OVERTURF: Are there questions

for Dr. Ye?

DR. DOWDLE: Walter Dowdle. Would you

remind us again about the recommendations from the

Southern hemisphere for B?

DR. YE: For B, I will refer to Roland.

DR. LEVANDOWSKI: The recommendation

currently is the same as it was for the Northern

hemisphere. It's B/Hong Kong/330/2001‑like strain.

It includes several different strains just as it does

here. So there was no change in the recommendation

for the Southern hemisphere this past season.

CHAIRMAN OVERTURF: Are there other

questions regarding reagents or potency? Thank you.

At this time, we'll have comments from the

manufacturers and Greg Slusaw.

DR. SLUSAW: Thank you for this

opportunity to address the committee today and chair

the manufacturer's perspective on flu vaccine

manufacturing. I would like to talk about a couple of

things today. First is a brief discussion of some of

the time lines we face and some of the constraints

when manufacturing flu vaccine and also to emphasize

some of the activities that have to come together to

ensure a successful flu vaccine manufacturing cycle.

I'd like to start with just a brief overview of a high

level view of the process. This is where we are right

now in February.

As mentioned several times earlier today,

manufacturers often will begin production of one of

the vaccine strains prior to this meeting, taking the

risk of doing that vaccine in advance but basing the

decision on some of the early available surveillance

data that's out there then of course soon after that

manufacturing the monovalent component of the second

strain and then the third strain preferably with a

period of the end where all three strains may be

manufactured intermittently to balance off equivalent

amounts of the three antigens to support formulation

of the final bulk vaccine which of course leads to the

production of the final vaccine doses which are

distributed at the end of July through October.

A couple of key things I would like to

emphasize here are first of all let me put some dates

in your mind for beginning manufacturing of the second

and third vaccine strains. For the second strain, for

us at least, that's right about now, in February,

where we have manufactured large amounts of the first

vaccine strain, the New Caledonia H1N1. We need to

begin production of the second vaccine strain. Also

a reasonable time frame would be April or so at the

latest to begin manufacturing the third vaccine

strain.

A few messages though that I would like to

leave with this slide to keep in mind is although

these may be the dates for beginning manufacturing of

the strain, as Dr. Levandowski mentioned this morning,

there's some pre‑work, some ground work that needs to

be laid before we can actually start manufacturing.

That's making the working vaccine seed to use in

production as well as making the high growth

reassortants which are really critical to supporting

the number of doses that we're manufacturing the last

few years since the production yields are two to four‑

fold higher than they would be for the corresponding

wild‑type virus.

So again, although we're looking at these

time frames to start, remember that we had to make a

decision back here a little bit earlier that a new

isolate was unique enough that it was something that

we wanted to look at for making a reassortant and

considering it as a potential vaccine candidate strain

for this year. Another point I would like to make is

in order to produce the number of doses we did last

year, we need to keep this manufacturing pipeline full

from the December/January timeframe up until all the

monovalent components are manufactured in August or so

without any gaps or delays in production.

One of the consequences if we do have a

brief delay in production, for example, if there's a

delay in selecting the third strain and the second

component is completed being manufactured, is that

will push everything out that period of time. But it

will still take the corresponding number of days to

complete manufacturing.

So delaying monovalent manufacturing due

to a delay in strain selection or availability of the

seed virus will ultimately push out the distribution

of final vaccine doses. I think as the manufacturers

have learned from previous years, vaccine doses which

are made available much after the end of October or so

are generally not saleable doses and they often end up

being destroyed.

Something in the manufacturing time line

that Dr. Levandowski mentioned this morning that I

would like to amplify a bit is we're often asked "Why

does it take you so long to make flu vaccine?" That

question usually comes internally from our marketing

departments. But I've laid out a hypothetical process

here from the first eggs going into the pipeline to

the first vaccine doses coming out.

We really don't have to pay attention to

all the details in the process throughout here. But

just distilling it down into the basic operations, I

wanted to emphasize that only about 15 percent, ten

days or so in this scenario, is actual manufacturing

time where there is processing of vaccine going on.The

rest is quality control testing, release document

review and so on and all the quality checks that need

to go into ensuring the quality characteristics of the

vaccine. So that's something to keep in mind. There

really aren't a lot of opportunities to expedite the

time line here at least by streamlining the

manufacturing process itself.

So an update on the current status, where

are we now? I just wanted to mention this has been a

subject of discussion in previous years, the critical

nature of egg supply and ensuring that enough

embryonated eggs are available for vaccine production.

I think we have undertaken major efforts over the

years to enhance the reliability of the supply to the

point where it's really become almost a non‑issue.

We currently have a reliable egg supply

that will fully saturate our available manufacturing

capacity. This supply is available virtually all year

long in part because the manufacturing cycle has

become so long but also because several manufacturers

manufacture vaccine for the Southern hemisphere as

well. So there's a second flu campaign going on each

year.

We have supplemental back‑up flocks

available to replace any birds that are lost

throughout the year. We have undertaken efforts to

make sure the flocks are geographically dispersed,

particularly getting some of the flocks away from

other commercial chicken production areas too. Then

of course, we put biosecurity precautions in place.

This includes limiting access to the flocks as well as

disinfection procedures for people, equipment,

vehicles, and so on.

I'll run through this really quickly.

This is basically the same information that Dr. Ye

just presented. As I mentioned, as a manufacturer, we

took a risk last year. Although, we normally begin

early production. We have manufactured virtually all

of the New Caledonia H1N1 that would be required for

this year's vaccine.

That was partially a response, trying to

be proactive to the unique situation we had with the

perceived vaccine shortage last year and looking at

the best available surveillance information that was

available in December. We undertook the risk to make

that monovalent component at that time.

Among the H3N2 candidates, of course we

have last year's vaccine strain and a number of

A/Wyoming/03 reassortants which we have evaluated.

The X‑147 seems to be the best one in your hands right

now. Another possible candidate would be the

A/Kumamoto.

The B strains, of course we mentioned the

Hong Kong strains from the current vaccine formula,

the 1434 and the 330. We have limited information

with the B/Jilin. The early data indicates that this

one is also a moderate grower. But that's very early

in the initial stages of seed preparation right now.

But it looks like a potential candidate strain if the

decision is made to switch B strains.

Okay, so for the ten minutes or so that I

have the soap box here, this is my wish list. Step

one, choose the right strains and also in a time frame

that's appropriate for vaccine manufacturing so we can

ensure that we can make the maximum number of doses in

the time frame that's required. But that's what

today's meeting is all about.

Also the timely availability of seed

viruses. That includes again those steps that have to

be undertaken in preparation of starting manufacturing

such as making high growth reassortants and giving the

manufacturers time to make the working seeds for

vaccine production.

Not directly related to this committee but

something we also have to keep in mind which is a

collaborative effort between the manufacturers and

regulatory agencies is timely availability of the

potency reagents. Finally, an opportunity for

manufacturers to participate in this process and

evaluate the growth and purification characteristics

of candidate strains before the final selection takes

place. Thank you. Any questions?

DR. MCINNES: Greg, I wonder if you could

describe how you characterize a reassortant as a

medium grower or a high grower? What are you

measuring when you say that?

DR. SLUSAW: That would be the actual

hemagglutinin yield based on when we have the official

homologous potency test reagents. So that translates

directly into two to four times more vaccine being

available.

DR. GELLIN: This is Bruce Gellin. Is the

maximum availability of vaccine related to what you do

on a given day or how long you extend the process?

DR. SLUSAW: Could you be more specific by

what we do in a given day?

DR. GELLIN: Are you running at 100

percent capacity on April 12?

DR. SLUSAW: Yes, virtually.

DR. GELLIN: So to make more vaccine, you

just have to make more monovalents and more over time.

You have to extend the period by which you campaign

each monovalent run.

DR. SLUSAW: Right, I think the important

thing is that we keep the manufacturing queue full by

manufacturing every given day without a break of time

in there waiting for strain selection, for example.

But now of course as in this case, we have

manufactured virtually all of the H1N1 that would be

required. So we need a second strain to move on or we

will have a gap in manufacturing.

DR. GELLIN: I don't know the situation.

But assuming that you had bulk from last year, would

you be able to use bulk H1N1, or do you have to make

fresh bulk?

DR. SLUSAW: Generally we haven't been

carrying over bulk material from previous years. It's

made fresh annually.

DR. GELLIN: Generally, okay.

DR. SLUSAW: Currently we don't carry

over.

CHAIRMAN OVERTURF: Dr. Eickhoff.

DR. EICKHOFF: If I recall correctly,

there was one year perhaps in the mid‑80s that avian

influenza decimated the manufacturer's flocks such

that they had to stretch very hard to find enough

chickens who were free of avian influenza where the

eggs from which could be used to make vaccine. To my

knowledge, and please correct me if I'm wrong, this

has not been a problem for the last 20 years. Is that

threat the reason for the biosecurity precautions that

you mentioned?

DR. SLUSAW: Yes, I think the reason for

the biosecurity is people's memory of the events of

the mid‑80s as well as the sporadic annual outbreaks

of avian influenza that we experience. Realizing

again how critical the egg supply is, we put these

measures in over the last five or ten years or so to

ensure the flocks are isolated and to protect them to

the extent we can. Of course, nothing is completely

iron clad. But the measures that are in place today

are much more sophisticated than they were ten years

ago or during the mid‑1980s, for example.

DR. GELLIN: This is Bruce Gellin again.

I'm going to push you on the eggs. You said it was a

non‑issue. I would like you to qualify which parts

are non‑issues. You just talked about biosecurity.

Given the situation this year where there was a high

demand and no one knows how that will translate into

next year and should there be an increased demand by

X percent next year, do you have enough eggs to meet

such a demand? I can give you numbers. But I was

wondering what not an issue means.

DR. SLUSAW: Okay, let me clarify that.

Eggs are an issue in that they are an absolutely

critical raw material for our process. However, they

are not really an issue for expanded manufacturing

capacity because we already have an adequate supply of

eggs to max out the available plant capacity. So

really to produce substantially more doses we would

need more physical manufacturing plant.

DR. GELLIN: So you have enough eggs to

maximize your existing capacity year round.

DR. SLUSAW: Potentially year round if

there were a demand for doses produced outside that

July to October window.

CHAIRMAN OVERTURF: Dr. Farley.

DR. FARLEY: What would be the impact of

pandemic strain emerging or having to shift gears? Or

is that just opening a can of worms in terms of having

to manufacture two kinds of vaccines I guess is what

I'm asking?

DR. SLUSAW: Well, clearly if we were

going into full scale manufacturing of a pandemic

strain it would be an either/or situation, either the

conventional trivalent vaccine or the pandemic strain.

So they couldn't produce the full normal doses of a

trivalent strain in addition to pandemic vaccine.

CHAIRMAN OVERTURF: Dr. Myers.

DR. MYERS: There's obviously a lag

whenever there's a change in strain. But it sounded

from what you described as if there would be less of

a delay in the changing to A/Fujian than for the

Yamagata strain of B. But are they directly additive

if you change two strains? I know we do this every

year. Would the impact of that be directly additive

or not?

DR. SLUSAW: Not directly additive in that

a lot of the activities involved can be done in

parallel and done concurrently. But you are also

correct in noting that we're in a closer position to

begin the A/Wyoming H3N2 production before we are the

B/Jilin production because we still have seed

development to do and things to prepare for there.

DR. MYERS: The other manufacturers, are

they similarly positioned?

DR. SLUSAW: Would any of my colleagues

like to comment?

DR. HJORTH: I'm from Aventis Pasteur as

well, Richard Hjorth. I just wanted to add to

something Greg was saying. It might have less to do

with the number of strains that are changed as it

would with the amount of time we have had to work with

them.

We've had the X‑147 for quite a while.

We've been able to get that ready to go. The other

reassortants we just received recently. So it would

be a lot harder to use them. Now, if we had the X‑47

and the B/Jilin back in September, I think we could

pretty easily make that change. But since we're just

getting the B/Jilin and similar kinds of strains,

there would be a lag because we need to do at least a

month's worth of work and probably more.

CHAIRMAN OVERTURF: Dr. LaRussa.

DR. LARUSSA: Relative to last year, are

you planning on making more or less or the same number

of doses of vaccine?

DR. SLUSAW: I think the manufacturing

forecast ‑ and Dr. Decker, you can correct me if I'm

wrong ‑ is similar to last year.

DR. DECKER: You keep looking at me so

I'll comment. Ultimately we make what you order. If

you want vaccine, put in an order. The expectation is

that demand for vaccine in the upcoming year will

probably be higher than the average for prior years

because of the stimulus everybody got from the events

of this past fall. But in truth, it's the orders that

come in that determine the amount that everybody

makes. I would predict that we'll end up making at

least as much as we did last year. But that's just my

prediction.

CHAIRMAN OVERTURF: Dr. Myers.

DR. MYERS: Can I ask a question that goes

back to Roland and Nancy probably?

CHAIRMAN OVERTURF: Yes, they're fair

game.

DR. MYERS: Roland quite correctly noted

there was a difference in the age groups in the two

pediatric populations so there were differences, both

magnitude of serologic response as well as the

demographics of the populations, particularly with the

B strains. And they were tested in the same

laboratories. I understand all those copy ads.

But the sera that we supplied to CDC were

much younger children. Their mean age was 11 months.

All but two of the children were less than 15 months.

I think the other panel of sera were from children

that were on the average of two years of age. The

geometric mean titers are very different between those

two groups of children for the B strain.

Like Dr. Royal, when I think about

geometric mean titers, I understand that what we're

doing with these sera pools is looking for the 50

percent reduction because that's how we look for a

drift. But if you look at the 50 percent reduction in

those young infants, they have no response to the

other strain, to the Jilin strain.

So 50 percent reduction to them is no

response at all in the young infants. I think we need

to keep that in mind that the young infants are not

being primed. Whereas if you look at the older

infants and the adults, a 50 percent reduction doesn't

take them down to zero.

CHAIRMAN OVERTURF: Did you have a

question for Dr. Levandowski?

DR. MYERS: Well, we're supposed to be

looking at this as a reduction in geometric mean

titer. But I wonder about the effectiveness of the

vaccine if there's no immune response in the young

infants and how that should weigh in on our

consideration of strain selection.

CHAIRMAN OVERTURF: Yes, Roland.

DR. LEVANDOWSKI: Okay, I can add some

information from older data again from a study that we

collaborated with CDC on. We had some young children,

some of whom had been immunologically primed and some

who were quite clearly not. They were young children.

They were immunized with the Victoria vaccine

strain. We looked at both HI and

neutralizing antibodies in those children. There was

a perfect correlation between the hemagglutination

inhibition and the neutralizing antibodies. It

indicated that there were good vaccine responses but

it was really zero, as Marty is pointing out, against

the other HA lineage. This is something we've seen

going on for a long time so that's no surprise.

There, we really don't need to talk about

50 percent reductions because there's really no

antibody response to the antigen for which there's no

priming. I think I probably ought to point out that

there is a bigger difference between the two influenza

B lineages, as Nancy showed on her slides with the

ferret sera, than there is between the H3N2 strains

we're talking about.

CHAIRMAN OVERTURF: For those very young

children we're talking about, these children receive

two doses.

DR. MYERS: Yes.

CHAIRMAN OVERTURF: Yes, Dr. Decker.

DR. DECKER: I want to go back and finish

addressing a couple of things that got left dangling.

One was the question about the impact of changing two

strains versus one. Greg gave you most of the answer

to that. The other thing that I would comment though

is that there's always a hard to quantify risk

involved in a strain change.

There's the unpredictable risk of having

unexpectedly low growth. In fact, in 2000 when we had

such a debacle, much of that was traceable to the fact

that we had not only low growth but because we had no

reagents available until late in the spring. We

didn't know we had low growth. By "we," I mean the

industry, not just Aventis Pasteur.

So it looks this year there is a decent

chance I would guess we might change two strains and

that's not to say that would not be the right thing to

do. But every time we think about that, we have to

recognize we're doubling the risk that something

unexpected like this will happen and interfere with

supply. So it's important to keep that in mind.

The second thing is there was a question

raised whether Greg's comments were applicable to all

of the manufacturers' situations or just to Aventis

Pasteur. In the break just now, I had the chance to

put my head together with my colleague from Chiron and

confirm that their situation is, as far as I can tell,

identical to ours in that we must leave this meeting

with the ability to begin production of strain two if

you want optimal timing and supply of vaccine. And it

would be very good to know what strain three is so

that the work can get hard going in an aggressive

fashion on being ready to manufacture that.

CHAIRMAN OVERTURF: Yes.

DR. MARKOVITZ: I wanted to follow up with

something else you said, Mike. The question was posed

as to the ability essentially of industry to continue

to ramp up. I understand industry has ramped up

considerably over the last years. Your response was

well, it depends on what you order. But my question

is it depends what who orders and when do they order

it and when does that come relative to your decision

about how much to make and how reversible is that

decision if subsequently it becomes clear that more is

needed?

DR. DECKER: The answers are a little

complex so recognize anything I say is a

simplification. Pretty much production facilities

like this are in use year round. So in response to

Bruce's question, I would simply say eggs are not the

right limiting step.

Now, if you want us to now make flu

vaccine for the Southern hemisphere because you want

for some reason for us to continue making it for the

Northern hemisphere when we should be making it for

the Southern hemisphere, they both take eggs. It's

just a matter of what we use the eggs for.

If there's a crisis that would force us to

stop using that facility to make some other vaccine

that's otherwise considered important in order to use

those eggs in that facility for flu, then that can be

done. But the facility is pretty much in use year

round. The eggs are going into it everyday. So eggs

aren't the issue.

Can we build new facilities? Sure, we can

and we do. Do you build factories to make stuff

nobody wants? No, you don't do that. U.S. Public

Health Service has set a goal for Healthy People 2010

of 150 million Americans immunized. Last year we had

the greatest uptake ever and we got 85 million or

something. That's a pretty big gap.

If tomorrow 150 million people wanted a

flu vaccine, the industry would certainly be panting.

But if you ramp that up, as everyone hopes you do,

smoothly over the course of a decade, I'm confident

we'll all be right there with you.

DR. MARKOVITZ: I know you are speaking a

little bit figuratively. But when do you actually

know how much people are likely to want from you?

When is that relative to other decisions like today's

decision and other decisions in the future?

DR. DECKER: Well, we open the ordering

lines in December for the vaccine that will be

distributed late summer or early fall this year. I'm

not sure. Maybe one of the other guys here knows when

the ordering lines will close down. But typically

they close down around April or May or something like

that. As you have seen from the charts, if you don't

finish your monovalent production by May or June, you

are not going to have stuff ready on time.You have to

pretty much finish by then. It's not to say you can't

push all of it forward. If we have the orders in the

spring to know that there's going to be more demand

for flu, we can extend the production cycle at that

point in time pretty easily. If you come back in

November and say we want more flu, we're already

working on some other product in that factory. It's

just not feasible.

DR. MARKOVITZ: So you do at least have a

pretty good early indication of what people anticipate

they want when you make those decisions.

DR. DECKER: Yes, and then we always over

manufacture. I will use mythical numbers for the

point of example. If we had orders for 40 million

doses, we might make 50 million doses. In fact, in

the year that just ended, we over produced by a larger

margin than we ever had before because we thought the

orders looked a little light and we were worried

people would want more. Well, they sure did.

CHAIRMAN OVERTURF: I guess what I'm

trying to clarify is what you told Dr. Gellin

regarding the egg supply. If you make a decision that

you're going to make 50 million doses, then you start

by making that first monovalent quantity in 50 million

doses. If you have to ramp up, it wouldn't be eggs

that would be the problem. It would be whether you

could grow enough of each of the monovalent bulk.

DR. DECKER: Ramp up isn't an applicable

consideration. Once we know how to make it, your turn

around time, if the facility is not busy doing

something else ‑‑ For example, let's suppose we finish

a campaign for one strain. We can be back in full

scale in the campaign for another strain very quickly.

The eggs are available. Once we know how to do it,

it's just a matter of walking in and doing it.

Greg, if I say something wrong, you

correct me here because it's your factory. But

basically it's not a ramp up. Ramp up is applicable

right now where you are talking about introducing a

new strain and we don't know how to make it.

We have to figure out how to make it. FDA

and others have to go through and create the high

growth reassortants. We have to adapt them to the

industrial process and so on. Once we have all that

done, once the cookbook is written, it's just you want

a pie in the morning and a cake in the afternoon, no

problem.

CHAIRMAN OVERTURF: Dr. Cox.

DR. COX: Yes, I thought before we go onto

other topics or have a break I would go ahead and

provide the committee and particularly Peter with the

data from the other WHO Collaborating Centers for the

influenza B viruses. I'm sorry I don't have a slide

but I can give you the numbers fairly slowly and

clearly I'm sure.

For the WHO Collaborating Center in Tokyo,

they had a total of 26 influenza B isolates that they

analyzed. Twenty‑six of those 26 were Yamagata

lineage viruses. It's from October to the present

time. So what I have here I think is comparable data

for all three centers.

For the WHO Collaborating Center in the

UK, six influenza B isolates were analyzed, five of

which were Yamagata lineage and one of which was

Victoria. Our WHO Collaborating Center in Atlanta had

17 influenza B viruses of which 15 were Yamagata

lineage and two were Victoria lineage.

So we have a total of 49 influenza B

viruses of which 46 are Yamagata lineage and three are

Victoria lineage. There just hasn't been that much

influenza B activity globally. So these are all the

data that we have.

DR. MONTO: Nancy, were the specimens, the

viruses from Tokyo mainly from China?

DR. COX: They were mainly from Japan but

there were a few viruses from China as well. We had

some from China as well.

CHAIRMAN OVERTURF: Are there any further

questions for industry? Yes.

DR. ROYAL: Maybe I could just make

another comment about supply. As Mike was saying, we

produce full bore and then we have to decide when to

stop at the end of the season. That's based on our

early orders, how many orders we have in hand. We

asked everyone to order early. But we're the

manufacturers, and I'm not sure that carries a lot of

weight.

But I think if other groups and bodies

were to encourage early ordering of vaccine, I think

that would do something to reduce the ups and downs of

vaccine supplies and the shortages. We realize that

some people don't know they want it until late. But

there are other people who might just procrastinate or

might not think it's that important. If there were

some neutral bodies advocating early ordering, I think

that would help as you can see.

CHAIRMAN OVERTURF: Dr. Gellin.

DR. GELLIN: I have a question for

somebody over there about this ordering. Are these

binding orders? Do you know for sure that the people

who order are actually going to pick it up at the end

of the line? Particularly after the seasons when

there were some mismatch between supply and demand,

whether or not the health professionals or

organizations might want to hedge their bets and order

multiply. Is there a system in place that keeps a

check on that?

DR. DECKER: Yes, honestly I can't tell

you and I can't tell you for sure if the answer is the

same for all the manufacturers. I know from

historical experience at least through some of the

manufacturers it's possible to cancel your order.

Whether that currently remains true for any of the

manufacturers, I'm just not sure because I don't

personally handle that stuff. I think everybody has

a policy right now of once you receive your product

it's nonreturnable. That's to reduce gaming of the

system and so on. I shouldn't speculate. I just

don't know.

CHAIRMAN OVERTURF: Are there further

questions or clarification needed? We are scheduled

for the H5 update at 5:00 p.m. Are the people who are

ready to do that here now? I think I would suggest we

go ahead and proceed with that rather than take a

break. There's no break scheduled. I'm getting a

request for a five minute break. Why don't we take a

15 minute break and come back at 20 minutes till 5:00

p.m. which is 15 minutes? Off the record.

(Whereupon, the foregoing matter went off

the record at 4:27 p.m. and went back on

the record at 4:44 p.m.)

CHAIRMAN OVERTURF: On the record. We're

going to put aside the issue for just a moment of

selecting the strains for this year's vaccine. The

votes and the discussion on that will be continued

tomorrow morning. Right now, we're going to discuss

and get an update regarding the H5 strains. Dr. Cox

will begin that discussion.

DR. COX: Thank you. So you've probably

discerned from the previous presentations that

although this year influenza activity started very

early, it really wasn't that unusual overall. But we

were scrambling to figure this out. A lot of people

thought there was something really unusual going

on. There was really an unprecedented amount

of attention devoted to influenza during the normal

influenza season. But just as things were winding

out, influenza threw us another curve ball. Influenza

A (H5N1) activity was detected in Asia. So I'm going

to try to give you a brief summary of what we know

about the viruses and the activity that's going on in

Asia.

There's also been quite a bit of media

attention devoted to what's going on in Asia. This is

one of my favorite headlines, "Killer Bird Flu

Rampant." I think it depicts how people are reacting

to the information coming out of Asia which indeed is

really quite frightening.

This is a slide that had been made about

a year ago. Some of these photographs here were

actually taken by one of our CDC investigators who

went to Hanoi and set up some surveillance studies to

look at whether or not viruses that were present in

the birds in Vietnam in the live bird markets were

transmitted to poultry workers who were selling the

birds, caring for the birds, and so on. So these are

actually very timely slides.

In addition, I have a clipping showing

that this is a problem that affects the United States

as well. You will remember about a year and a half

ago there was an outbreak of influenza A (H7N2) in

Virginia poultry farms. So it's a problem that is

universal. But there are different viruses

circulating in different parts of the world.

I just wanted to remind you of the

virologic and epidemiologic criteria for a pandemic.

First of all, we're looking for a novel subtype of HA.

It can be accompanied by a novel neuraminidase or NA

subtype but it's not necessary. In 1968, we had a

novel HA, the H3, but we still had N2 neuraminidase

which had been circulating in the hema population

previously.

Along with that, we have populations that

are immunologically naive. The viruses that emerge

must cause morbidity and mortality in humans. In

order to really have a pandemic, the viruses must be

easily transmissible from person to person.

Fortunately we have not had viruses that are readily

transmissable from person to person during the direct

interspecies transmissions of influenza A, AB, and

influenza A viruses to humans that were exposed to

infected poultry over the last seven years or so.

I would just like to refresh your memory

about what happened back in 1997. There were 18

documented cases of human respiratory illness caused

by highly pathogenic avian H5N1 viruses that are

related to the current strains. Among those 18 cases,

there were six deaths in Hong Kong.

In 1998 and 1999, there were at least

eight documented cases of human respiratory illness

much milder caused by H9N2 avian influenza viruses

with no accompanying deaths. Those illnesses were

documented in Hong Kong and South China. H9N2 viruses

circulate widely in the bird populations in Asia and

the Middle East.

In 2003, at just about this time last

year, there were two additional cases of H5N1. Again

high path viruses were isolated from two humans with

one death. These individuals had traveled to mainland

China from Hong Kong. Their illnesses were diagnosed

after they returned to Hong Kong. There was an

additional death in a member of that same family that

occurred while they were in China. That death was

never diagnosed.

Then in 2003 in the spring, there were

more than 80 cases of infection by high path H7N7

viruses in humans with one death in the Netherlands.

So we see that there have been cases where influenza

A viruses of the H7, H9, and H5 subtypes have jumped

from birds to humans and caused disease and even very

serious disease and death.

Now in 2004 ‑ actually I need to update my

slide ‑ there have been 29 cases of human respiratory

illness caused by high path H5N1 avian viruses in

Vietnam and Thailand. Of those 28 cases, there have

been 20 deaths. There might even be an update on the

Internet as of today. I haven't had an opportunity to

check that.

I just wanted to give you an idea of

extent of circulation of the H5N1 viruses in birds.

This slide just shows in this yellow amber color the

countries that have reported outbreaks of H5N1 virus.

Then in red, I have shown the countries Vietnam and

Thailand which have both avian cases and human cases.

So you can see that a tremendous area has been

affected.

Not all provinces in China, not all

provinces in some of these other countries have

reported outbreaks in birds. But we know that

provinces from the very south to the northern parts of

China and all the way into the west and even Tibet

have reported outbreaks in birds.

So we were very keen to get our hands on

some of these viruses and to find out how similar they

might be to the strains that had caused illness

previously. In particular, we were very interested to

find out if the vaccine candidates, the vaccine

reference strains that had been made using the viruses

isolated from humans in 2003, those most recent H5N1

cases, would be similar to the currently circulating

strains.

Last year at about this time of course the

SARS virus was emerging. In the background, we had

H5N1 cases in people who lived in Hong Kong but had

traveled to China. So there was concern about there

actually potentially being some H5N1 activities

smoldering in the background. So it was decided that

we would go ahead and see if we could produce a

candidate vaccine strain.

This particular candidate strain, A/Hong

Kong/213/2003 by A/PR8 was produced at St. Jude in Dr.

Rob Webster's laboratory. So we had this virus. We

developed ferret anti‑serum to it. We wanted to see

if the anti‑serum to the wild‑type virus into the

vaccine reference strain would cover the currently

circulating strains.

So you can see we have nice high

homologous titers here for both ferret anti‑sera and

their corresponding antigens. Here, we have test

antigens 8 through 19 which are viruses that were

isolated from a variety of birds in Vietnam. Then

down at the bottom, we have antigens 20, 21, and 22

which are isolates from human cases. Unfortunately,

these anti‑sera did not inhibit these viruses

particularly well. So it was a great disappointment.

There is some cross reactivity here. But it's not at

the level that we would have wished.

The only other thing that I would like to

point out in this slide is that there is some

indication of antigenic heterogeneity (PH). If we

look at, for example, this column here with ferret

serum to the Hong Kong/156 virus, which was the

prototype 1997 strain, it was isolated from the very

first case of H5N1 in 1997. Anti‑serum to that virus

does inhibit some of these viruses pretty well. But

other viruses are extremely poorly inhibited by anti‑

serum to that virus.

So there was indication that there was

some heterogeneity (PH) among these strains. That

proved to be true when we ‑‑ And I apologize. I don't

think that shows up nearly as well as it does here on

the screen. I think I'll go on to this one. When we

looked at the evolutionary relationships among the

neuraminidase genes of those viruses that I showed you

on the previous slide, you can see that they fall into

two groups.

These viruses down here are the viruses

that had higher titers to the Hong Kong/156 anti‑

serum. These viruses up here in blue are also

isolated from birds. All these are bird viruses.

These are really in a separate genetic group. All of

these bird viruses are grouped together with the

viruses shown in red which are the human influenza

isolates.

Now there are a number of markers for

these two groups. This particular group does not have

an amino acid deletion in the stark region of the HA

while all of these viruses have a 20 amino acid

deletion. Then there are a few additional viruses

that have a 3 amino acid deletion in addition to the

20 amino acid deletion. You can see the signature

amino acid changes that are characteristic of this

particular group.

We have analyzed not only the

hemagglutinin and neuraminidase genes but also most of

the other genes of most of these viruses.

Interestingly, the viruses that fall into this group

have an amino acid change in the M gene which confers

resistance to the adamantanes, amantadine and

rimantadine. When viruses in this group are then

tested in a phenotypic acate (PH) to look to see

whether they are susceptible or resistant to

adamantanes, they behave as one would expect from the

genetic characteristics in a resistant manner.

We have also recently received some

viruses that were isolated from birds in Laos. Those

sequences fall right up here with this group of

viruses. (Indicating.) I should also point out that

there is one virus right here which was isolated from

one of the cases in Thailand.

So we'll just go back to the HA slide.

One of the things I would like to point out is we have

a number of sequences that are marked St. Jude here.

We've had really excellent sharing of information

among all of the WHO Collaborating Centers, both the

human WHO Collaborating Centers and the avian or

animal influenza Collaborating Centers. We have been

able to really put these current viruses in the

perspective of what was going on in Hong Kong during

their outbreaks in 2002 and 2003.

I would just like to mention a couple more

things. All of these viruses are really descendants

of the Goose/Guangdong/96 strain which was isolated

during an outbreak in geese in Guangdong in 1996 of

course. These are the human isolates from Hong Kong

in `97. So you can see that there has been a lot of

evolution up to the point where these viruses are now

the viruses currently circulating it looks like in

Vietnam, in Thailand, and probably in Laos.

I would just like to go over a few of the

things that we've been involved in doing over the past

few weeks as the situation has developed in Asia.

First of all, we have needed to develop an updated WHO

kit for identification of H5N1 viruses. In order to

do that, we have to have an anti‑serum with high

antibody titer against the currently circulating H5N1

strains in Asia as well as an inactivated antigen that

can be put together in a kit and sent out to the

National Influenza Centers and others who need to

identify or potentially need to identify H5N1 viruses.

In addition, we have been developing rapid

detection methods for H5 viruses using real‑time PCR.

A lot of different laboratories have been asking us

for positive RNA controls and for primer sequences so

that they can get the method up and running.

Others will talk about this as well. In

addition, we have been involved in H5N1 vaccine

development. That is to say we've been trying to

develop a reference strain that could be used for a

safe manufacture of influenza H5 vaccine should that

be needed. We're using reverse genetics, a Modified

Fodor Vector system which probably doesn't mean too

much to some of you. Basically it's an eight plasmid

approach.

We have cloned and characterized the HAs

and we have removed HA and NA. We have removed the

polybasic peptide that makes these H5 viruses highly

pathogenic in birds. We want to remove that cleavage

site so that the viruses, the vaccine strains don't

pose a threat to the poultry industry and the birds in

this country. Of course, we're hoping to produce a

strain that would meet regulatory requirements.

This is just a schematic of the plasmid‑

based reverse genetic system. So we take the HA and

remove the polybasic amino acid cleavage site and then

rescue it into a PR8 backbone. Hopefully the PR8

backbone will give the vaccines a reference virus, the

ability to grow to high titers in eggs. Then we're

hoping to rescue this reassortant with the modified HA

and the neuraminidase of the H5N1.

Once the virus has recovered, well

actually, it has to be recovered and certified cells.

In this case, we're using certified Vero cells and

certified cell culture medium. Then the rescue virus

is amplified in eggs. Of course, the virus has to be

characterized and we have to make sure the HA and NA

of what comes out is actually what we want.

Once the virus is rescued, we have to test

it for safety and immunogenicity in animal models

before it can be given to the vaccine manufacturers.

Of course, we expect that after the modification the

virus would no longer be lethal to chick embryos and

that it would no longer be lethal to chickens. We

would look to see if the virus is attenuated in mice

and ferrets.

These H5N1 viruses have been really highly

pathogenic in mouse models as well as in ferrets.

Then we'll be looking at the immunogenicity just in

terms of looking at the HI cross tests using post‑

infection ferret serum to see how closely related the

vaccine candidate virus is to the previous strains.

Then additional protective efficacy studies can be

done in mice if necessary.

So I'll try to briefly summarize what we

know about the avian influenza outbreak in Asia. We

know that poultry outbreaks caused by these highly

pathogenic avian influenza H5N1 viruses have now been

reported and confirmed in Cambodia, China, Hong Kong,

Laos, Indonesia, Japan, South Korea, Thailand and

Vietnam. There are low path viruses circulating in

other countries.

But here, we're really concentrating on

the outbreaks caused by high path H5N1 viruses as

these are the viruses that appear to really pose the

threat to human health. I had mentioned that there

were cases in Vietnam. Now this count is up to 21.

I think the count in Thailand is still eight with six

deaths. No human cases have been reported in other

countries. But it's expected that where there is a

lot of exposure of humans to the sick and dying birds

there might be cases.

Most of the cases have documented exposure

to sick or dead birds. But there have been some

family clusters. Whenever there are family clusters,

questions are raised about the potential for person to

person transmission. But that has not been documented

thus far.

I showed you in the dendrogram that the

H5N1 viruses from birds and humans in Vietnam are

genetically and antigenically closely related. The

human isolates from Vietnam and Thailand and one group

of the Vietnam avian isolates are resistant to the

adamantanes. I neglected to mention that we've done

the phenotypic testing to see if all of the viruses

are sensitive to oseltamivir, one of the neuraminidase

inhibitors. Indeed they are sensitive.

So obviously there are treatment

implications for the findings that a number of these

viruses are resistant to the adamantanes. I also

demonstrated that a candidate vaccine reference strain

produced with the 2003 H5N1 virus is not an optimal

antigenic match to the 2004 H5N1 viruses. But I also

want to mention that based on some preliminary

neutralization data, there might be some cross

protection provided.

The construction by reverse genetics of a

new vaccine reference strain is being undertaken in

two U.S. labs and one in the UK. I think that the

subsequent speakers will be talking about their

results. We actually need genetic and antigenic

comparisons of H5N1 viruses for more countries so that

we have a better understanding of the spread and a

better understanding of whether one vaccine strain

would really cover all of the viruses that are

circulating.

It's been very difficult to get viruses

from birds in some of the countries that have been

affected. What we have found and we have known for a

long time is that there's often a silo approach to

animal health and human health. There's really not a

lot of cross talk. It's getting much better now, but

it still is sometimes difficult to get influenza

viruses that might have an implication for human

health from the agricultural side in some countries.

Culling infected birds and their proper

disposal is really necessary to reduce the risk of

human infection. But culling efforts have been

somewhat limited in certain countries. Human exposure

does continue in developing countries where backyard

flocks really constitute a majority of the poultry.

This is a recent statistic that I have heard. China

has about 13 billion birds and three‑quarters of the

farms have 100 birds or less. So we're talking about

a lot of human exposure to chickens and ducks.

I also need to mention that there's poor

or nonexistent human influenza surveillance in a

number of these countries that are affected by the

poultry outbreak. So if something is happening in

humans, we may not hear about it. So we do have

unprecedented human exposure to highly pathogenic H5N1

viruses.

There is a threat to global health. There

is close circulation of avian H5N1 and human H3N2

viruses in the region. So reassortment is possible.

Of course, I'm sure all of you have heard about and

have read in the newspapers that one of the things the

influenza experts are concerned about is that

reassortment might occur. So then the H5N1 virus

would acquire the ability to spread from person to

person by gaining some of the internal genes, the

replication machinery from the human influenza virus.

Therefore, the virus would be more easily spread from

person to person.

Another thing that influenza experts are

concerned about is that if these viruses have the

opportunity to jump to humans, to replicate in humans,

and possibly even to be transmitted at very low levels

from person to person, they have an opportunity to

adapt to replication in humans through mutation. It

seems unlikely that H5N1 viruses can be eradicated

from that region very soon.

A number of the countries are approaching

control of the virus in that they are talking about

culling and also use of vaccine. But I think

eradication is not very likely. Of course,

eradication of backyard flux is very difficult.

The farmers aren't being compensated so

they don't want to cull their birds. Furthermore,

infections have been documented in wild birds. Some

of these are migratory birds which potentially are

spreading the virus from country to country and region

to region.

Now, there are large international efforts

coordinated by the World Health Organization and the

Food and Agricultural Organization. They have been

assisting in culling, in surveillance, and in disease

control efforts. But there's really a lot more that

needs to be done. So as the outbreak continues, I

think there will be a need to consider H5N1 vaccine

production, to consider what the trigger points might

be, what the target populations might be, and what the

quantities of vaccine that might be needed would be.

I'd like to acknowledge both for this talk

and for my previous talk all of the members of the

Influenza Branch who have worked extremely hard this

past year and whose work I have presented today, along

with the WHO National Influenza Centers, the WHO

Collaborating Centers in London, Tokyo and Melbourne,

as well as the WHO Center in St. Jude, Memphis, the

WHO Regional Offices, and of course the WHO

Headquarters in Geneva. Thank you.

(Applause.)

CHAIRMAN OVERTURF: While we're setting up

the next presentation we can take some questions.

DR. DOWDLE: Walter Dowdle. I think we

sometimes forget in the H5 era that in the pre‑1977

era there were a considerable number of cases of

transmission of transmission of swine influenza from

swine to humans. This occurred not only with

illnesses but also with a few deaths. There were a

number of these sporadic reports. Of course, there

was also Fort Dix at the time.

But pigs have also figured rather

prominently in the potential transmission of new

influenza viruses from animals to man. I just wonder

in this area, are there now surveillance studies going

on looking at the pig populations and seeing what's

going on? We know for example there are continuous

introductions from man to pigs. But what's happening

at this point from chicken to pigs that we know of?

DR. COX: It's a very interesting

question. I'm sure many people have heard reports of

pie die‑offs in the Mekong Delta and all kinds of

things in the press. So it was a great interest to

try to find out what was going on.

Rob Webster has done a fairly extensive

study. Although it was short in duration, it was a

window looking at what was going on in a particular

two or three day interval. Linda may want to say more

about that. But as I understand it, he wasn't able to

find evidence or at least not very much evidence of

replication in pigs. I think that what we have heard

from people who have gone to the field to look for

sick pigs is that they have seen healthy pigs.

So we don't really know about the reports

in the Mekong Delta. Those are of great interest. I

think the studies are ongoing. There's a lot of

interest in Vietnam and some other countries in the

region to find out if pigs are affected. I think Rob

and Malik Peiris will have some interesting

information over the next few weeks.

DR. KARRON: Ruth Karron. Nancy, are

there any invitro data regarding the compatibility

between the H5N1 avian genes and the human internal

genes.

DR. COX: There aren't at this moment, at

least none that I know of. We had looked at the 1997

viruses in this respect but have not looked at the

current viruses.

CHAIRMAN OVERTURF: Any further questions?

Okay.

DR. MINOR: Well, Nancy mentioned two U.S.

labs and one UK lab but I am a UK lab. I'm head of

the division of NIBSC. We send out reference reagents

and strains to manufacturers to play with so we have

a considerable interest in terms of vaccine reagents

in general if you like. That's from the point of view

of looking at the quality of vaccines and

standardizing vaccines for the UK government and so on

and so forth.

One of the things that we do is

occasionally we will actually make the strains that we

send out to manufacturers. The conventional way of

doing this is by inoculating an egg with a wild‑type

strain you are interested in plus a high growth lab‑

adapted strain like PR8 for example. You then sift

through the harvest to find a virus which will grow

well which will normally have the core genes from the

PR8 high growth lab strain, if you like, plus the

surface antigens from the wild‑type strain that you

put in.

This works insofar as you get a high

growth strain out of it. Sometimes it doesn't work

because you don't get any strain out of it that grows

well. Sometimes you get the hemagglutinin and the

neuraminidase reassorting separately so you wind up

with the wrong strain coming out of it altogether.

So if you are good you can do this. The

people I have in the lab are very good and they can do

this. But it would be quite good in addition to have

a actually rather more direct way of doing this so

that you know exactly what you are doing and you can

predict what's going to happen. The advantages of

reverse genetics are of course that you start from

nucleic acid and work on from there.

So you can start off with your six core

genes from the lab‑adapted strain and you can put on

your wild‑type genes on top of that. It's a very

precise process. At least in principle, you can do it

very clearly and precisely. It's very directed. You

will get out what you want in terms of the actual

genetic structure. That's the first point here. It's

a directed approach to reassortment.

The second thing is you can get an

increased scope for reassortment. You could do this

now with B strains which you can't do at the moment

for reasons I won't go into. We can talk about it

later if you want. There were issues to do with the

origin of isolates in the field which is something

I'll be talking about tomorrow.

We'll be talking about cell grown viruses.

You can get rid of any other virus that happens to be

there that you don't know about which you may be

concerned about simply because you're going through

the nucleic acid. Finally, you can engineer the

hemagglutinin. As Nancy said, you can make a pussycat

out of a tiger.

So these are the reasons why reverse

genetics is attractive anyway. Now the reason why we

particularly at NIBSC would want to get involved in

this is because of the fact that we supply

manufacturers with strains. No matter where these

strains eventually come from we really want to know

how robust the system is. Is it really possible to

take any two hemagglutinin and neuraminidase genes and

graph them onto this high growth core if you like?

Secondly, how quick is it? You have heard

from the manufacturers already that when a strain

decision is made, they really want the strains

yesterday. We really want to make sure you can do it

rapidly and robustly as much as possible.

Finally, because we are involved in the

regulatory process to some extent, we are aware that

there are certain regulatory beefs that come up from

time to time. So we can maybe try and cope with those

maybe rather better than perhaps some academic labs

might be able to do. We have that kind of background

to it.

So for the last three years, I have been

very keen on my lab getting this going. I have to say

they now have it going. The work I'm going to

describe is by Carolyn Nicholson who works with Jim

Robertson. She does the work and he gets the credit.

Well, not here though, she's getting the credit here.

Nancy has already gone though this a

little bit. I'll go through it again. The current

events in Vietnam are H5N1. There was another event

last year in 2003 in Hong Kong. Before that, in 1997,

there was another one in Hong Kong. There was also a

strain called Duck/Singapore which is another H5 virus

from ducks as the name implies which looked very much

like the 1997 Hong Kong strain.

When the Vietnam 2004 isolates are

compared with these three preceding H5N1s, they are

clearly very antigenically different. Nancy showed

some data. We have data in house from post‑infection

ferret sera which there's really very little reaction

at all between the 2004 isolates and the 2003 isolate.

There is a major problem there. It does seem to me

that if you are presented with this, you wouldn't say

that was a vaccine strain.

We also have some evidence of the three

isolates we have, which are 1194, 1203, and 1204, 1203

is slightly different from 1194 and 1204. Again, this

is not unprecedented. It also happened in 1997. So

what we have gone with is 1194. That's the one you

are going to see data on for all it's worth.

The final thing is again Nancy mentioned

the need for post‑infection ferret serum. To my

knowledge, currently there are no post‑infection

ferret sera for the Vietnamese isolates as of yet.

The reason for that is this is an extremely nasty

virus.

As far as I'm informed at least ‑ maybe

people can correct me if I'm wrong ‑ the only living

ferrets who have actually been infected with the stuff

are currently at NIBSC in high containment. All the

other ferrets have died at around day six or seven.

So there are no post‑infection ferret sera which are

suitable for characterizing a strain. I'll come back

to that later.

This again is the technique that's used to

get rid of the polybasic sequence which makes the

virus lethal. Again, I won't go through the details

of this except there are some very clever features of

this. The polybasic sequence has been taken out. The

point mutations have been put into the sequence to

prevent the polyadenolation (PH) signals acting to

reintroduce those polybasic sequences.

The thing has been cloned and sequenced.

There are about three or four clones of this which are

now available which Carolyn has prepared and sequenced

through the actual region to show that she's taken out

what she meant to take out. This is the overall

strategy which has been followed. To cut a long story

short, we actually have a strain here which is

currently being tested for safety at the moment.

The idea is to recover Vero cells which

are a cell line which is pretty much approved for

vaccine production. The original recoveries were done

on 293 T‑cells which are slightly suspect if you like.

The idea then is that the harvest is put into an egg.

Then it's put into another egg. Then that's the seed

which would be characterized further.

We got to the second egg passage for this

particular material. It's called NIBRG 14. The titer

of this in the second egg is 1,280 HA units which is

actually quite good. That's actually quite a high

titer. That is quite promising. That's British for

very promising actually.

(Laughter.)

DR. MINOR: The basic structure under

which this has been done is some attention was paid to

the quality of how this was done. The first thing is

the cell is a Vero cell which was donated by Aventis

for pandemic use. I think the issues to do with IP

are perhaps something that maybe one could have a

little discussion about. But nonetheless, very

generously donated by Aventis for pandemic use.

They have been grown in a facility at

NIBSC which is involved in the UK stem cell bank and

which is more or less under GMP. I'm not totally

convinced that it's been inspected by the competent

authority yet. But it's more or less GMP. It's

certainly aimed at that particular level.

The media is prepared in a GMP compliant

consistent facility. The DNA is basically done away

in a nice clean safety cabinet. We have always been

fairly obsessed with TSEs at NIBSC as everybody else

has. The components, as far as we can tell, are

consistent with BSE guidelines. The intention at

least is to get the dossiers (PH) off to people that

we know who look at these things and say what do they

think about it or we think they are pretty good.

Finally, it's all been rescued in high

containment. There's a Category 4 unit that we have.

It's basically been rescued in there. There's no

other viruses in there at the same time. So we

believe the documentation we have on this is very

good. So if you consider the bits in green, those are

the bits that are definitely done.

The quality assurance, we have very good

lab records here about how this is done and documented

procedures by which the whole thing is actually

produced. The quality control now begins. The

pathogenicity testing is something that has to be done

before it comes out of high containment. What we have

to do is inject our recovered material into ferrets

and compare that compare that to what happens with the

wild‑type ferrets.

Now the wild‑type ferrets went in a week

ago last Monday. We had a phone call from John Wood

who is in Geneva on Friday saying that everybody

else's ferrets were dying and could we do something

about this please? They were dosed with Tamiflu which

is one of these chemotherapeutic jobs on Friday. On

day six which was Saturday, one of the ferrets was

looking extremely sick. But by day seven with

repeated doses of this stuff, he became better.

As far as I know, they are still alive.

They are due to get another boost with the same virus

today. So they should actually get a bit of a crank

up there. With a bit of luck, what's going to happen

is that we'll get post‑infection ferret sera which are

specific for the Vietnam isolates probably by next

Monday or maybe a bit after that.

What then has to be done is we have to do

the proper pathogenicity study which involves putting

wild‑types into ferrets, putting the recovered strain

into ferrets. We have to do the same thing with

chickens. This is a requirement of the UK Department

of Agriculture equivalent if you like. So then we

have to do a pathogenicity test there.

We also have to do an egg embryo test to

show that this is no longer lethal for egg embryos.

The original was you could slaughter them right away

which is why you get no virus out of an egg that's

infected with the original Vietnam strain. The

recovered strain so far at least has not killed the

embryos. So that's actually also quite an encouraging

observation that we've done something proper to this.

But you have to do that formally.

There are, as I said, no sera yet. But

there will be probably by next Monday or next Friday,

who knows? In which case, the antigenicity can be

looked at. The sequence is being done at the moment.

And away we go. So all of this will be carefully

documented.

What we've managed to set up at NIBSC over

the last two or three years is really routinely

rescuing things in Vero cells which are approved for

that kind of use. We have used the Aventis materials

for the potential pandemic strains. We also have our

own Vero cells which we play with. So we can recover

H5s, H1s, and H3s. There doesn't seem to be much of

an obstruction to it.

Now, when Carolyn was doing this for

A/Fujian, which some of you may be familiar with as a

strain that possibly raised a little problem last

year, it was 17 days from the time when the virus came

into the building to when she actually had the

reassortment strain in her hand. That's actually

quite slick I think.

For what it's worth, with respect to the

H5 construct, it was 19 days between when the virus

actually arrived and when we actually had the stuff

recovered as the first egg passage. So again, I think

that's really quite slick. I think she has done quite

a smart job on this. And it does seem to be quite a

robust system that she has going on over there.

This finally is the acknowledgment phase

here. We got the plasmids, which is a 12 plasmid

expression system, from Ervin Fodor and George

Brownlee who were at the University of Oxford at the

time. The Vero cells came from Aventis Pasteur.

Thank you very much. Hema Patel does the cell stuff.

There are people who do the animal work in NIBSC and

take their life into their hands which is when you are

handling an angry ferret.

Some people do chick pathogenicity tests.

We do that with the veterinary lab at Weybridge; Diane

Major, Jim Robertson, and John Wood. Jim Robertson

and John Wood, some of you may know, are the PhDs who

stand up and talk about this stuff. Diane does the

antigenic characterization. The big letters in yellow

at the bottom is Carolyn Nicolson who actually does

the work and God preserve her.

What she has been doing is dealing with

the technical aspects of this. Can you actually do

this in a robust manner? Can you get it out quickly?

What do you do? What's the time scale over which

we're actually going to have something we can send

out. The time scale is going to be probably around

the end of March when the pathogenicity studies are

actually finished and it can go out.

I think what happens to it then is really

a matter for some concern and debate perhaps. I think

there are IP issues which are still outstanding about

these issues. In Europe, at least, there are

genetically modified organism regulations which are

also an issue. There are all sorts of issues to do

with the Department of Health and the Ministry of

Agriculture and the Health and Safety Executive and

the European Commission and the regulatory framework

within Europe.

We have had discussions about the

regulatory framework in Europe. Just as a final

little lighthearted comment, the main concern seems to

be what language the package insert should be written

in. This seems to be the main obstacle to getting

this stuff actually on the market. Thank you.

(Applause.)

CHAIRMAN OVERTURF: Questions? Dr. Myers.

DR. MYERS: Just given what we're going to

talk about tomorrow morning, I was curious as to the

strategy to go back into eggs from the Vero cells. I

wondered if you could comment.

DR. MINOR: Right, egg cell vaccines are

licensed. I think there are huge obstacles to doing

anything but a pandemic strain. I think if you can

make sure that you are still using eggs to grow it in,

that may be one obstacle that you don't have.

Having said that, I think there are also

major logistic attractions at least from the outside

to go into a cell grown culture system because then

you don't worry about chicken flu taking out your

chicken flocks and things like that. We went back

into eggs because it will be eggs that the

manufacturers will be using to grow it in. But it's

a very fair comment.

DR. BUCHER: Yes, hi, Doris Bucher from

New York Medical College. I would just like to make

a few comments about the dirty way of making high

yield reassortants. Last Thursday we were very

excited and we felt that we had satisfied all of the

characterization of our high yield B reassortant, the

B/Hong Kong/1434 high yield reassortant.

I think we just shipped it off the CDC,

and someone told me it was now B/Jilin. However, the

reason we were able to do this is because we have gone

to enhanced techniques of selection using anti‑sera to

the purified surface antigens and kicking up selection

to the neuraminidase. We can very nicely pull out the

high yield B reassortants. We hope we can do B/Jilin

as soon as we get the stuff.

The other reason why we shouldn't throw

out the approach to high yield by selection is that if

you think about it, when you do reverse genetics, you

do one pattern. Kathy Coelingh will be relieved to

hear that I have gone over to her system of six PR8

genes and two of the target.

When you do it by the old fashioned but I

would say now with enhanced selection, you can allow

the other six genes to vary. Of course you have to

have the right hemagglutinin neuraminidase. So that

would be two to the six possible outcomes. You have

64 different variants that you are testing.

Now, going even further, if you look in

the past, I reviewed the gene composition of what was

available in the literature. Maybe only about half

have six PR8 genes and the two current genes. If you

also consider maybe dirty isn't necessarily bad, one

person's dirty is another person's quasi‑species.

If you consider variants of each gene that

may exist, maybe you have five variants for each of

those six genes both from PR8 and from your target.

I'm being generous perhaps. Then you are talking

about ten to the six so you are testing a million

possible high yield reassortants which sounds

incredible. I didn't believe it until I looked at the

numbers.

Ed Kilbourne reminded me that with the X‑

53, X‑53A ‑‑ I know maybe we don't want to be reminded

about X‑53, X‑53A, the high yield swine. But it was

just a single amino acid difference between X‑53 and

X‑53A that made a difference of maybe eight‑fold

increase in yield. That's what the manufacturers use.

Perhaps unfortunately we had a swine flu vaccine

because of that. And they could not be distinguished

anogenically. So anyway, let's not forget about

selection.

DR. MINOR: I don't think anybody's

forgetting about selection. We've been trying to brew

these things up for years. The fact is that mostly it

works. When it doesn't work, you are really stuck.

What happens with reverse genetics appears to be that

you tend not to get stuck. I find that a very

attractive option as somebody who has manufacturers on

the phone screaming in my ear saying when can we have

it, you see.

Nobody I don't think is going to go over

to reverse genetics full time. Apart from everything

else, there's the patent IP issues and all the other

issues that I was mentioning at the very end. So

nobody is going to abandon it at all to begin with.

But I'm not sure it has the advantages you say it has.

DR. BUCHER: Just one more quick comment,

when Barbara Pokorny, who has been Dr. Kilbourne's

chief assistant all those years, went back to her

record books, she made X‑53 in nine days. She made a

high yield reassortant in nine days so it can be done.

DR. MINOR: It can be done. She was

lucky, wasn't she?

(Laughter.)

CHAIRMAN OVERTURF: Additional questions

or comments?

DR. GELLIN: Yes, Phil, can you comment a

little bit about how you are going to navigate through

the genetically modified quagmire?

DR. MINOR: Right, well, what a very good

question. This is being discussed in the regulatory

circles in Europe. Until you have been in a

regulatory circle in Europe, you don't know what a

circle is.

(Laughter.)

DR. MINOR: They will come out as

contained use GMOs. So if manufacturers wish to use

them, they will have to have approval for contained

use. I don't think that's terribly difficult to get

but I'm not sure. But it does require manufacturers

to do it if they so wish.

So there's an element of do the

manufacturers want to go down this road anyway? It's

not a question of free release which would be

extremely difficult to deal with. Maybe one could

actually persuade the European ‑‑ No. I was going to

say maybe you could persuade them to change it a

little bit. I don't know if you could do that.

But I think to do contained use is

probably not quite such a challenge as to make an

organism ‑‑ But it does require effort. I'm not sure

the manufacturers necessarily have the incentive to

make that kind of effort. But those are the kinds of

discussions we're having. What would it actually

take? And that's not the least of the quagmires I

don't think.

CHAIRMAN OVERTURF: Other questions?

Thank you very much, Dr. Minor. The last presentation

is by Dr. Linda Lambert.

DR. LAMBERT: All right, I would first

like to thank the organizers of this meeting for

giving me the opportunity to update you with the

current activities that NIAID is supporting as we

address the H5N1 outbreak in Asia. My talk this

afternoon will be really broken into two parts.

The first part will be the research

resources or really the response capacity put in place

by NIAID to ideally prevent or as a fall back prepare

for the reemergence of H5N1. Then as Nancy already

alluded to, I will provide you with a little bit of

data about why we may be where we are in this current

situation. The second part will then specifically

update you on NIAID activities that are ongoing.

So as you heard now twice that there was

the first direct human transmission from an avian H5N1

to humans in `97. That happened late in `97 when we

first had the tally about what was going on with the

total number of deaths. In early `99, the NIAID

awarded a contract for pandemic preparedness in Asia.

That was to St. Jude Children's Research Hospital in

Memphis.

The PI on that contract is Robert Webster.

He participates with the WHO animal influenza

surveillance centers. Much of what I present today to

you will be work that is done in his laboratory in

Memphis with Richard Webby, Elena Gorbakova (PH),

Scott Kraus and then his collaborators at Hong Kong

University which include Malik Peiris and Yi Guan.

So the scope of this contract when it was

put in place in `99 was to establish an animal

influenza center, a center of excellence in Hong Kong

at Hong Kong University. The dynamic of what's going

on in Hong Kong is that there are on average about 26

million birds that are imported into Hong Kong each

year. So to try to get a sense of what was really

coming in from mainland China as well as what was

being propagated on farms in Hong Kong, one of the

high priority programs was to establish this animal

influenza center.

On average again anywhere from about

15,000 to 20,000 samples each year get assessed

through this contract and to try to keep a pulse on

what's happening in the live bird markets, what's

happening in swine slaughter houses, what's happening

with wild birds, pet birds, and essentially all types

of avian species. Another objective was to try to

determine the molecular basis of transmission; how

these viruses were spreading from one species of

poultry to another and what would really potentially

lay the groundwork for how they could get into humans.

Another key provision of this contract was

to identify and provide characterized viruses that

could be suitable for vaccine development, support

training of new laboratory personnel, and it seems

very timely to tell you that through this contract the

NIAID is supporting a WHO animal influenza training

class that will be the first week of March.

It was originally scheduled for last year

but was derailed for SARS. So that will be held for

the Pacific Rim students, if you will, in Hong Kong

the first week of March. And finally, to produce

selected reagents as needed for the research

community.

So you have also heard about some of these

results from the previous two speakers. But these are

really key findings that this contract has delivered

over the last few years and really lead us to

understand why we are faced with what we are right now

in Asia. So following the cull of all of the poultry

in Hong Kong in 1997, these investigators in Hong Kong

detected the first reemergence of H5N1 in the live

bird markets.

The Hong Kong public health authorities,

looking at that data, made a very proactive decision.

In the absence of any confirmed clinical cases in

humans, they decided to prospectively kill 1.2 million

birds. They have also instituted a rest day in the

market. I think it's gone from one day to two days to

try to clean out everything.

Unfortunately what we know though is while

the markets get cleaned within a couple of days,

surveillance tells us that these avian influenza

viruses are back in within a few days. In 2001, there

was another significant finding. These researchers

really identified a particular species of land‑based

poultry, and that was the quail, as the likely mixing

vessel for the spread of avian influenza viruses from

aquatic birds to land‑based birds such as chickens and

pheasants.

Again, looking at the data, the public

health authority in Hong Kong, which have worked very

closely with the group at Hong Kong University, made

a very bold and proactive decision to ban the sale of

live quail from bird markets in 2002. Again,

beginning two years ago, the second reemergence of

H5N1 was detected through ongoing surveillance in this

contract.

This time it wasn't limited to just a few

farms. There were more than 20 farms that were

infected. As Nancy alluded to, there's something

going on with these viruses. There were at that time

more than seven different H5N1 genotypes that were

identified. So the message is very clear. We're

continuing to hear that message which is the H5N1

viruses are not in evolutionary stasis and they are

continuing to reassort.

At the end of the 2002, the Hong Kong

Agricultural Fisheries Department was alerted to dead

ducks, geese, and swans in Kowloon's Penfold Park.

This park is just a few blocks in Kowloon from

Victoria Harbor so it's not far from a very densely

populated area. The Hong Kong U team went in and

identified highly pathogenic H5 as the cause.

Again, there was also a dead migratory

waterbird, a heron, that was found on the border of

Hong Kong and mainland China. This really sounded an

alarm for influenza researchers because it was really

the first time since 1960 that a highly pathogenic

avian influenza virus was identified to kill aquatic

birds.

So at the end of 2002, we were left with

the question of knowing this and wondering if aquatic

birds will then turn around and start spreading these

H5N1 viruses throughout Asia. The second question was

what is the potential for the spread of this virus to

other animals including humans?

So Nancy and I think Phil have also

basically told you that in early 2003 in February

there was a family that traveled from Hong Kong to

mainland China to Fujian Province. At the end of the

day, there were two confirmed cases of fatality. As

both have also described, the laboratories that had

the capacity to do so around the world essentially

raced to develop a suitable vaccine reference strain

using reverse genetics.

At least two candidates were created.

There may be more. Reference reagents were produced.

Essentially if what we're dealing with now had turned

out to be very close to 2003, we would be much further

ahead. Then just within a month or two after that, we

were dealing with SARS. Now looking at 2004, H5N1, as

you have also heard, there are studies that have shown

that the 2003 candidate may not be optimal.

There is one ferret study with preliminary

results have come out of St. Jude where ferrets were

vaccinated with a laboratory produced and activated

vaccine against the 2003 H5 virus and challenged with

the 2004 H5. Those animals appear to be protected.

But certainly those results would need to be

confirmed.

So in response to a question someone asked

about animal surveillance and specifically pigs, I am

just going to tell you briefly about some of the data

we have. Again, it's very preliminary. It was a

report that just came in a few days ago. At least in

Hong Kong what we know is that since the middle of

2003 in the avian species, poultry, there's been no

H5N1 viruses that have been isolated. Again, they are

very rigorously looking for this.

These are studies that are ongoing

collaborations with Dr. Robert Webster and Malik

Peiris and the Department of Agriculture in Vietnam.

In Vietnam, they have looked at approximately 200 pigs

from epidemic areas of Hanoi and have not cultured any

influenza viruses from them. They have also done

serological tests on approximately 450 pigs again near

an epidemic area in Hanoi and have shown that one of

the sera is positive for H5N1 by both HI and

neutralization studies.

The take home messages at least at this

point is it's one animal. This H5N1 virus appears to

be able to infect pigs but is not at this point

spreading in the area that is tested. In addition, it

appears that the avian H5N1 viruses that have now been

identified in Vietnam are genotypically like the human

isolates ‑ and I think Nancy alluded to this as well ‑appear to be derived from a genotype that was

detected in Hong Kong at the end of 2002.

Reagent production, a very important

component for researchers and those thinking about

developing vaccines, a reagent grade reverse genetics

H5N1/Vietnam/1203 PR8 reassortant was produced by St.

Jude. As Phil indicated, it was rescued in 293 T‑

cells which is not suitable for vaccine production.

But it is available as material that can be used to

generate an antigen for those who have the appropriate

biocontainment facilities.

Production of purified recombinant HA from

wild‑type Vietnam/1203/04 is underway by Protein

Sciences. The CDC provided the starting material.

The NIH is supporting the production. As soon as that

material is ready to go, the FDA will receive some of

that material and start producing sheep anti‑serum.

Production of monoclonal antibodies against 2004 H5N1

is underway.

I briefly want to tell you about some

animal studies at St. Jude. I suspect that what Phil

said is true for St. Jude, that there's no living

ferrets that's been challenged with 2004 H5N1. What

St. Jude has seen is lethal infection, neurological

symptoms, hind leg paralysis.

The virus is recovered in nasal washes out

to day seven and detected in all organs; brain,

olfactory bulb, lungs, heart, spleen, intestines. So

it's very bad for ferrets. My understanding in

talking to Richard Webby this morning, maybe it was a

BlackBerry email, was that it appears to be a

similarly nasty virus in mice as well.

So where we are and frankly where St. Jude

is that St. Jude is one of the laboratories around the

world that is participating with generating a vaccine

reference strain. They have prepared a reverse

genetically engineered H5N1 Vietnam/1203 that was

generated using the PR8 as the backbone. It was

rescued in St. Jude qualified Vero cells. Additional

plaque purification of that candidate is planned.

Pathogenicity studies of the first

material that was rescued is ongoing in chickens and

mice. As Nancy and Phil both alluded to, there are an

additional battery of tests that will need to be done.

Additional vaccine reference strains that are planned

and supported by the NIAID is the generation of a live

tenuated vaccine reference strain. This is also

planned via collaboration with NIAID's Intramural

Laboratory of Infectious Diseases and MedImmune. The

PI is Dr. Kanta Subbarao.

My last slide is to tell you where we are

with vaccine development. We are currently having

technical discussions with manufacturers who are

interested and who have questions about production of

small pilot lots of investigational vaccine that can

be produced and used in clinical trials.

The NIAID, as most of you know, supports

a clinical trial network called the Vaccine and

Treatment Evaluation Units. We also support a Viral

Respiratory Pathogens Research Unit. Both of these

can support phase one and phase two clinical trials.

The NIAID has also initiated discussions with the

clinical investigators of these units to identify

points to consider and are involved in the design of

clinical protocols which is ongoing. With that, I

will end and be very happy to answer any questions.

CHAIRMAN OVERTURF: Are there questions

for Dr. Lambert?

DR. MARKOVITZ: Yes, I was curious if you

or anyone else could comment. What's the extent of

the number of laboratories do you think that are

actually working on this type of vaccine?

DR. LAMBERT: Generating the reference

strain?

DR. MARKOVITZ: Yes, in other words, labs

that are either academic, government, or industrial

that are working on H5 vaccines, do you have any

ballpark idea?

DR. LAMBERT: Let me try to list them.

Nancy can jump in if I miss anybody that she knows of.

In the U.S., it is St. Jude in Memphis, CDC in

Atlanta. It soon will be Kanta Subbarao in Bethesda

at NIAID. You have heard from Phil so the NIBSC

group. There's also a group in Japan. That's the

extent that I know of. Nancy, do you know of any

others?

DR. COX: No, I think that the group at

NIID, the National Institute of Infectious Diseases,

in Japan has also begun some work.

CHAIRMAN OVERTURF: Any further questions?

DR. WHITAKER: Linda, can you comment on

some of the challenge grants that may also be working

on this type of H5 or related H5?

DR. LAMBERT: Thank you, Charlie, for

bringing that up. In 2000, the NIAID awarded three

challenge grants. It was the first time the NIAID had

ever been given challenge grant resources. It's

matching dollars so we were able to make awards to

companies for a certain amount of money provided they

put at least the same amount of money into the

project.

So there were nine awards that were made

in 2000. Three of them were made for influenza. One

went to Aviron. One went to Aventis which is the one

I'm going to expand on. One went actually to Novavax

in Rockville.

So I think, Charlie, that all of the goals

of those grants were to develop first of all vaccine

candidates, reference strains, master seeds. At the

end, the end result of those grants was to and is to

get clinical trial material that can be tested either

by the company if they have the resources or the NIAID

through the Clinical Trials Network. Specifically,

they basically said up front which viral reference

strains they wanted to work with or they got feedback

from a collaborating interagency group that we had put

together.

At the end of the day, those grants are

still ongoing so they just turned three I think at the

end of last year. Some of them have had difficulties.

I'll be very clear. But that's science through

grants. Some of them have done very well. We suspect

that one or two of them will be able to produce

clinical trial material sometime in 2005.

Now, whether that's material that

addresses the 2004 H5 or another H5, the bottom line

is none of them had planned for what is going on now

because we weren't faced with this scenario when the

decisions were made. They have all invested a lot of

time and energy on picking their particular virus and

really making progress. So I think it's fair that for

those particular projects that they can continue to

make the clinical trial material that they set out to

do a couple of years ago. Does that address your

question?

CHAIRMAN OVERTURF: A question from the

floor.

DR. RUBEN: Fred Ruben, Aventis. Linda,

I have a question about animal models of the avian

strain. Are there any studies that have looked at

priming animals with an H5 and then challenging them

with some of these antigenically drifted or changed

strains? I think if you are getting a primary

infection, we see that influenza is very lethal in

some instances in children who are not primed at all.

I'm wondering if the same situation might not apply to

animals.

DR. LAMBERT: Yes, the only one that I can

tell you right now, Fred, and it's very relevant

today, is the preliminary study that was just reported

by St. Jude. They made an activated laboratory

developed vaccine. They immunized ferrets. They came

back and now have challenged those ferrets with the

2004 H5.

So even though what we're seeing

antigenically shows that those two viruses may be

significantly different, this one study is what we

have right now with these viruses. I'll tell you the

punch line. Those ferrets were protected. So I think

there's much more work that has to be done.

CHAIRMAN OVERTURF: Walter.

DR. DOWDLE: Walter Dowdle. Linda, is

there any additional work going on with H7 and H9?

DR. LAMBERT: Anything else we're

supporting?

DR. DOWDLE: Yes, anything else you are

supporting in H7 and H9 or is that all lumped under

the St. Jude's?

DR. LAMBERT: Yes, there's a lot. But I

guess most of what we have in place to rapidly respond

to scenarios that are unfolding like the one that's

happening now is a lot of our response capacity is

with St. Jude and the team that they have established.

Following the outbreak of H7N7 in the Netherlands ‑ I

think Nancy touched on it ‑ that killed one and I

guess infected more than 80 other individuals, St.

Jude also generated an H7N7 reference virus with

reverse genetics and rescuing it in the St. Jude‑

qualified Vero cells.

The H9N9, we are currently conducting a

study of an activated H9N2 vaccine. It was a staged

phase one, phase two study. So what we can tell you

is that it's being conducted in healthy adults. There

was a phase one study that was completed through the

end of last year.

We're about to start in early March the

phase two. It's focusing on safety and immunogenicity

of increasing dosage levels of an H9N2. But that's on

the vaccine front. There's lots going on with animal

surveillance of H9s and H7s and swine surveillance.

But those are key things with the vaccines at this

time.

DR. FARLEY: Monica Farley. Can you or

perhaps someone else clarify what level of clinical

trials would be necessary for approval if a pandemic

strain vaccine were made using the traditional

methodologies? I'm just wondering about the emergency

response capacity. Will it have to go through a full

traditional review process in an emergency setting?

DR. LAMBERT: I am going to turn this to

Roland after I comment. I think at the end of the day

we sit here waiting and we have to identify trigger

points to make decisions. So at NIAID, we have framed

the parameters of a clinical protocol.

It's aggressive. It's in multiple

populations, multiple different age groups. It steps

down from older to younger. The numbers of those

subjects are best guess at this time. We anticipate

fully developing it and submitting it as part of an

IND package when vaccine candidates are available and

vaccine material is available.

But I think your question as to what the

numbers would have to be to satisfy regulatory

agencies or other public health officials that you

would want to start producing a vaccine at a

particular formulation, it's going to be a balance of

a number of things that are unfolding at that moment.

So what we plan to do is to have a progressive

program, gear up as though we're focusing on getting

clinical trials underway as fast as possible knowing

that things could change drastically in a matter of a

few weeks, and then know that other people would get

involved in making much bigger decisions about vaccine

production. So Roland, anything to add?

DR. LEVANDOWSKI: No, if the question is

about the licensing process, I think that we're

envisioning that for a manufacturer that already has

a license, a current license manufacturer, that we

would approach this, at least from the paperwork side

of things, as more or less a strain change amendment

which we do every year for current vaccines. That's

what was done I guess pretty much for the return of H1

in 1978.

But the question about what the dose and

what the schedule would need to be I think would have

to be addressed as it was during those clinical trials

that were done during 1976 and 1977 with swine flu and

then the Russian flu strains to try to understand

whether people currently have antibodies that would

permit one dose or if they don't have antibodies, if

they are immunologically unprimed and it's very clear

that they are going to need two doses.

Those kinds of clinical trials would have

to be worked out and would be needed to support use of

the vaccine. But I think we see the licensing aspect,

at least for current manufacturers, as being more of

a straightforward road with just the current strategy

of changing the strain once we understand all the

other aspects of the process that goes into making the

vaccine.

CHAIRMAN OVERTURF: Dr. Monto.

DR. MONTO: Including the reverse genetics

and production in Vero cells?

DR. LEVANDOWSKI: I think we're prepared

to address those things, yes.

DR. EGAN: Yes, Bill Egan from the Office

of Vaccines, if I could just add one thing to what

Roland said. After the pandemic or while the pandemic

is coming, we're hopefully not going to be doing these

trials about what the dose should be and how many

times, seven and a half or 15 micrograms, whether it

should be with an adjuvant or not with an adjuvant, do

you need two doses? Those can be done up front.

For example, there's the trials that the

NIH are sponsoring now or considering now so that we

can get that information about how many doses and what

that dose should be, getting that information up

front, and then if the pandemic does come, to use that

information for the vaccine and then, as Roland said,

with a licensed manufacturer just treat whatever that

pandemic strain is as one of these strain changes.

CHAIRMAN OVERTURF: Marty.

DR. MYERS: It's a little unfair given

where I've been historically. But there's the obvious

question and that is that manufacturers are not likely

to go at risk for the production of a vaccine that

might never be used. What are the trigger points that

will cause the department to initiate the production

of vaccine in bulk and in what time frame is that

likely to occur?

DR. EICKHOFF: I guess that's not an FDA

question but perhaps somebody from the National

Vaccine Program could answer that.

(Laughter.)

CHAIRMAN OVERTURF: Bruce.

DR. GELLIN: Well, Marty used to be in the

National Vaccine Program and he didn't have an answer

to that. So why should I have an answer now?

(Laughter.)

DR. GELLIN: You waited until now to ask

the question. This is all in the transcript, right?

I think it's safe to say, as Linda had talked about,

that there are discussions now going on about

evaluating clinical grade material to begin that

process. The trigger points aren't clear. But the

discussions are in place recognizing that you can't

buy a newspaper without seeing something about the

bird flu in Asia.

CHAIRMAN OVERTURF: I think that was an

answer.

(Laughter.)

DR. GELLIN: If the trigger points were

clear, I could tell you. But as you know, they are

not entirely clear. I think that we're sensitive to

the situation and trying to advance the ball as

quickly as we can. But as Linda has highlighted, the

first step is the one of getting these evaluations.

The other thing that's going to be

important is trying to understand how a vaccine like

this might be used. With the situation in Asia, you

can envision ‑ and I heard Klaus Stohr from WHO

talking about this on NPR last week ‑ that there might

be endemic uses of this vaccine in Asia. In which

case, it becomes a question larger than just an HHS

question.

CHAIRMAN OVERTURF: Any other questions or

comments?

DR. HJORTH: Richard Hjorth with Aventis.

I was just wondering and I think it would be great if

we could have a model vaccine as NIID is doing to

reduce some of the time after pandemic is announced.

But I guess I was just concerned that the pandemic

strain would behave the same as the model strain. I

presume if it was H5 it would probably be the same.

But if an H13 or something came along or whatever, I

don't know. What's the thinking? Would that be a

good enough model?

DR. LAMBERT: You know, Richard, if you

had asked me in `98, when I was relatively new in this

position, if we were going to be set, if we had one

H5, one H6, one H7, made one prototype vaccine

reference strain for each of the HA subtypes, I would

have said yes. So we had H5 in `97. The two

subsequent H5s have been different from `97 and

different from each other.

So what this tells us is that we can't

wait to start making these things and testing them.

We have to get the information about novel HAs in

vaccines and clinical trials and immune response

safety profiles. I think at the end of the day if you

haven't made the right one ‑ you hope you have but now

I presume we won't because what's happening now could

be drifted and very different six months from now ‑

but you have to keep doing it.

If we dodge this bullet, a year from now

we will still probably be in the same scenario if an

emerging H5 happens. If it's different, we go back

into the drill; production of investigation lots of

vaccines, clinical trials, and hope that there's

enough time, as Bruce said, to get it done before it

comes. That's what I've learned in the last six years.

CHAIRMAN OVERTURF: Any further comments?

I'm sure this is clarified in everybody's mind.

(Applause.)

CHAIRMAN OVERTURF: Tomorrow morning we

will begin at 8:30 a.m. The meeting is adjourned this

afternoon. Thank you for all of your attention.

(Whereupon, the above‑entitled matter

concluded at 6:07 p.m.)