Vaccine
Safety > Research
The Complicated Task of Monitoring Vaccine Safety
As published in the Journal of the U.S. Public Health Service, Public
Health Reports, January/February, 1997; Vol 112, No. 1; pp. 10-20.
Authors: |
Susan S.
Ellenberg, PhD
Robert T. Chen, MD, MA |
SYNOPSIS
Vaccination is an essential component of modern public health programs
and is among our most cost-effective medical interventions. Yet despite vaccines' clear
effectiveness in reducing risks of diseases that previously attacked large proportions of
the population, caused many deaths, and left many people with permanent disabilities,
current vaccination policies are not without controversy. Vaccines, like all other
pharmaceutical products, are not entirely risk-free; while most known side effects are
minor and self-limited, some vaccines have been associated with very rare but serious
adverse effects. Because such rare effects are often not evident until vaccines come into
widespread use, the Federal government maintains ongoing surveillance programs to monitor
vaccine safety. The interpretation of data from such programs is complex and is associated
with substantial uncertainty. A continual effort to monitor these data effectively and to
develop more precise ways of assessing risks of vaccines is necessary to ensure public
confidence in immunization programs.
INTRODUCTION
At the beginning of the 20th century, the most serious threat to human
life and well-being was infectious disease. Outbreaks of diseases such as diphtheria and
pertussis were common, and mortality was significant; 160 of every 1000 children born at
the turn of the century died of an infectious disease before the age of 5.1 Today, parents
in most developed countries no longer fear these diseases; a small group of parents,
however, question whether the very vaccines that have prevented so much morbidity and
mortality now cause more harm than is justified by the benefits they provide.
Vaccination is surely among the most significant public health
interventions of all time. Nevertheless, the concept of vaccination--essentially, the
introduction of foreign material into healthy individuals--has, at times, provoked
controversy. Pasteur's first administration of rabies vaccines to humans was strongly
protested by physicians and the public, and efforts to immunize British troops against
typhoid at the turn of the century were bitterly opposed despite the encouraging results
of earlier immunization efforts and the serious risk of typhoid faced by troops serving in
the Boer War.2
As the effectiveness of vaccines against diphtheria, pertussis, tetanus,
typhoid, rabies, and other diseases became incontrovertible and vaccines came into more
widespread use, the incidences of these diseases rapidly declined. In addition, advances
in vaccine technology brought substantial reductions in the incidence and severity of side
effects associated with rabies and typhoid vaccines. With the clear evidence of both
protection from disease and high levels of safety came increased acceptance of vaccination
as a valuable safeguard of individual and public health. Support for routine vaccination
was no longer controversial in the medical community by the mid-20th century.
Public concerns waned as well. By the mid-1950s, especially after the Salk
polio vaccine became available, the benefit to any individual child of being vaccinated
was clear: eliminating the possibility of contracting disease far outweighed the tiny risk
of a serious adverse side effect from the vaccine itself. Today, in developed countries,
diseases such as pertussis, diphtheria, measles and rubella are rare; polio has
essentially been eradicated from the Western Hemisphere.
The success of vaccination in reducing the risk of disease has led in
recent years to renewed public interest in and concern about vaccine safety; in the
context of minimal risks of contracting vaccine-preventable diseases, the risks of side
effects, especially the very small chance of serious adverse effects, take on greater
weight and need to be continually reevaluated.
A dramatic example of the need to balance adverse outcomes of vaccination
against protection from disease is the case of polio. In 1996 it is almost a certainty
that no child born in America will contract wild-virus polio, yet eight to ten people each
year will develop paralytic polio as a result of vaccination with (or contact with someone
vaccinated with) oral polio vaccine.3 This situation has led to recommendations for replacing some of
the oral polio immunizations with inactivated vaccine, which will reduce the risk of
vaccine-induced paralytic polio.4
In the late 1970s and early 1980s substantial public attention in the
United States as well as in other developed countries was given to the safety of
whole-cell pertussis vaccines. A few parents who believed their children had been
seriously injured as a result of vaccination brought their concerns to the public through
the media.5 Negative publicity about adverse events in Japan and the United
Kingdom led to precipitous declines in vaccine coverage, with the consequent return of
epidemic pertussis disease. 6,7 A similar disease upsurge was observed in Sweden
following discontinuation of pertussis vaccination in that country because of concerns
about the efficacy of the vaccine in use there as well as safety concerns.8 In the
United States, while public acceptance of pertussis vaccine generally remained high,
numerous lawsuits were filed against vaccine manufacturers.9 This resulted
in major increases in prices and decisions by several companies to discontinue manufacture
of pertussis vaccines, resulting in temporary shortages.10,11 These
events contributed to the passage of the National Childhood Vaccine Injury Act (NCVIA) in
1986.12 The NCVIA mandated important new initiatives relating to vaccine
safety: it established the National Vaccine Injury Compensation Program13, provided for
an independent review of the available scientific evidence on adverse events attributable
to vaccination14,15 and mandated physician reporting of certain vaccine-associated
adverse events to the Secretary of the Department of Health and Human Services.16
The Act also created a unified national system to help identify rare
vaccine reactions. This system, initiated in 1990 and jointly managed by the Food and Drug
Administration (FDA) and the Centers for Disease Control and Prevention (CDC), is called
the Vaccine Adverse Event Reporting System (VAERS). VAERS receives reports of adverse
events following vaccination from vaccine manufacturers, private practitioners, state and
local public health clinics, and vaccinees themselves (or their parents or guardians).17 It is similar
in intent and operation to surveillance systems for other types of pharmaceutical
products, such as the MedWatch system maintained by the FDA18, and to
safety surveillance programs in other countries.19 Such systems are essential to the
discovery of potential rare adverse consequences of pharmaceutical products that may not
become evident until millions of people have been exposed to these products. But these
surveillance systems have important limitations that complicate the interpretation of the
data they accumulate.
The remainder of this paper will address the ways in which vaccine risks
are assessed, some specific issues that have been raised by concerned members of the
public, and the potential of VAERS and other vaccine safety surveillance efforts to
address these and other important issues relating to vaccine safety.
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Safety Assessment during New Vaccine Development
Like other pharmaceuticals, vaccines must go through extensive clinical
testing before they are marketed. Yet unlike other pharmaceutical products, vaccines are
primarily targeted to healthy people, especially children; virtually every child will
receive some vaccinations. Because healthy people are less willing to accept risk than
people who need treatment for illness and because society is unwilling to impose
unnecessary risks on healthy infants and children, vaccine developers must be particularly
sensitive to the risks of adverse effects.
New vaccines are initially tested in small groups of adult volunteers
following a series of laboratory and animal tests that establish, to the extent possible,
the safety of delivery to humans.20 These adult studies are followed by larger but still preliminary
studies in children. In all studies at the early stage of vaccine development, subjects
are monitored intensively for any potential adverse effects. Rates of common expected
reactions, such as swelling and fever, can begin to be estimated at this stage.
Manufacturing processes are also reviewed carefully by regulators to
ensure appropriate conformance with good manufacturing practices designed to assure
consistency, prevent errors, and avoid contamination with unwanted substances.21
When preliminary studies indicate that the vaccine is both safe and
producing the desired immune responses associated with disease protection, larger-scale
clinical trials, usually randomized and placebo-controlled, are undertaken to provide
definitive estimates of protective efficacy and more precise estimates of rates of the
more common adverse effects.22 The control groups in these studies who do not receive the
investigational vaccine are critical in distinguishing between vaccine-induced effects and
those unrelated to the vaccine but occurring spontaneously in the population studied.
How Safe Is
"Safe"?
The total number of people who have been exposed to a new vaccine by the
time it is put on the market ranges from several hundred to tens of thousands, depending
on the intended use of the vaccine. Even the largest of these pre-marketing studies,
however, are inadequate to assess the vaccine's potential to induce infrequent but serious
reactions. With approximately four million births a year in the United States, an adverse
outcome occurring at a rate of one in 10,000 vaccinations--a rate far too low to be
detected in conventionally sized clinical studies performed prior to marketing--would
affect 400 babies each year.
Despite the difficulty of assessing these infrequent reactions, the
virtually universal exposure of the population to vaccines makes it vitally important to
understand even the very rare complications of vaccination. For this reason, it is
essential to continue to collect information on vaccine-related adverse events even after
the vaccine is approved for general use by the FDA.
Advent of a Unified Surveillance System
Prior to 1990, FDA and CDC each had their own reporting systems for
vaccine-associated adverse events. The FDA system received reports primarily from vaccine
manufacturers as they became aware of specific instances of adverse outcomes following
vaccination with their products23; the CDC system, known as MSAEFI (Monitoring System for Adverse
Events Following Immunization)24, collected reports from state public health coordinators based on
events observed at public clinics for which CDC provided vaccines.
As noted earlier, these systems were unified following passage of the
NCVIA in 1986. The goal of a unified surveillance system was to increase the efficiency of
the Public Health Service in collecting and assessing reports of adverse outcomes and in
monitoring the overall safety of vaccines.17
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How VAERS works.
VAERS is a passive surveillance system, a repository for voluntarily
submitted reports. (An active surveillance system, in contrast, would follow all
individuals in a defined population to determine their responses to vaccination.) To
encourage reporting of any possibly vaccine-induced adverse event, the criteria for
reporting to VAERS are unrestrictive; the system accepts and includes any report
submitted, no matter how tenuous the possible connection with vaccination might seem. The
NCVIA requires physicians to report--directly to VAERS or to the manufacturer--certain
categories of serious outcomes occurring within a short period of time following specified
childhood vaccinations; thus one might expect a fairly complete reporting of such events.
However, the lack of enforcement provisions or even any monitoring of reporting practices
precludes any assumptions about the extent to which such events are in fact reported.
Thus, VAERS potentially suffers both from underreporting--not all vaccine-induced events
are reported--and overreporting--coincidental events, not caused by vaccines, can be
reported.
Approximately 10,000 reports per year are submitted to VAERS.25 About 15% of
these describe a serious event, defined for regulatory purposes as an event resulting in
death, life-threatening illness, hospitalization, prolongation of existing
hospitalization, or permanent disability. These reports are entered into the system by a
Federal contractor and are reviewed by medical staff of the FDA's Center for Biologics
Evaluation and Research and CDC. Most of the approximately 85% of reports not classified
as serious describe events such as local reactions and fever occurring within a day or two
of vaccination. Many of these events are clearly caused by the vaccine. The serious
events, unfortunately, are much more difficult to evaluate with regard to their causal
association with vaccines. Most of these tend to be of a type known to occur in the
absence of vaccines as well, so in an individual case it is almost never possible to
definitively assess the role of the vaccine.
Temporal versus causal associations.
Because of the large number of vaccine exposures, it is clear that
temporal associations with adverse outcomes will occur even when there is no true causal
association. With hepatitis B vaccine now recommended for all newborns and other childhood
vaccines (DTP, OPV, Hib) being administered to nearly all infants starting at two months
of age, most health problems in infancy (of which there are many), whatever their cause,
will occur in children who have been vaccinated. Some of these problems will by chance
occur in recently vaccinated children.
An adverse event can be causally attributed to a vaccine more readily if: (a)
the event conforms to a specific clinical syndrome whose association with vaccination has
strong biological plausibility (such as anaphylaxis immediately following vaccination); (b)
a laboratory result confirms the association (for example, isolation of vaccine strain
mumps vaccine virus from a patient with aseptic meningitis); (c) the event recurs
on re-administration of the vaccine ("positive rechallenge"); or (d) a controlled clinical trial or carefully designed
epidemiologic study shows greater risk of adverse events among vaccinated than control
groups. Because few of the adverse events reported to VAERS meet any of the first three
criteria and because clinical trials are almost always too small to provide useful
information on serious rare events, epidemiologic evidence is the basis for assessing
causality for most serious adverse events that are investigated.
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Strengths and weaknesses of VAERS.
As a database for epidemiologic studies, VAERS has many weaknesses. One
major problem is that since unvaccinated people experiencing adverse events are not
reported to VAERS, there is no control group to study. Thus, there is no way to assess
whether the number of reported events is different from the number that would have been
observed in the absence of vaccination.
The quality of the data is also less than optimal. Because reports are
sent in by a wide variety of individuals, few of whom are experienced in completing data
forms for medical studies, many reports omit important data and contain obvious errors.
Given that VAERS receives over 10,000 reports annually, it is difficult to assure the
accuracy and completeness of the database with current resources, although checks and
follow-up are performed for a few key data items such as the type of vaccine administered
and the severity of the event.
Finally, the administration of multiple vaccines at the same time,
following currently recommended vaccine schedules26, further complicates the assessment
of adverse outcomes because there is usually no way to determine which of the vaccines (if
any) was most likely to cause the outcome.
This is not to diminish the value of such a system. While VAERS data can
rarely provide definitive evidence of causal associations between vaccines and particular
reported outcomes, this type of national reporting system can rapidly document possible
effects, generating early warning signals that can then be more rigorously investigated in
focused studies. In a sense, VAERS is the "front line" of vaccine safety surveillance, so sensitivity takes precedence
over specificity; reporting of all serious events following vaccination is encouraged,
inevitably resulting in large numbers of reports that do not represent vaccine-induced
problems.
VAERS data are especially valuable in assessing the safety of newly
marketed vaccines. Careful review of reports coming in during the initial months of
availability can provide additional reassurance about the safety of the vaccine or rapidly
identify potential problems not observed during the investigational phase. For example, a
recent review by Niu et al. provided reassuring confirmation of the safety of hepatitis B
vaccines in infants.27 FDA and CDC medical staff maintain ongoing intensive surveillance
of the recently approved varicella and hepatitis A vaccines.
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The case of sudden infant death syndrome (SIDS).
The case of SIDS exemplifies the problem with interpreting VAERS data.
About 200 deaths a year are reported to VAERS. Most of these are of infants under one year
of age; of these, most are diagnosed as SIDS. The reported time from vaccination until
death varies from a few hours to many weeks or even months. In most cases multiple
vaccines are involved, consistent with recommended immunization schedules. Because SIDS is
a well documented (if not well understood) phenomenon that occurs both in the absence and
presence of vaccination, one cannot presume a causal connection if SIDS follows shortly
after vaccination; in fact, one can predict that such events would occur even in the
absence of a causal connection because virtually all infants receive vaccines and because
SIDS occurs at the relatively high rate of somewhat over one per thousand live births in
the United States.
In response to public concerns arising in the early 1980s about the safety
of DTP vaccines, the National Institute of Child Health and Development conducted a large
case-control study directed specifically at the question of the association between SIDS
and DTP vaccination. This study did not support the hypothesis that DTP vaccine caused
SIDS; in fact, it demonstrated a lowered risk for SIDS in children receiving DTP vaccine.
(The authors of the report suggested that this lowered risk estimate was more likely the
result of differences in baseline health status between children who did and did not
receive scheduled vaccinations than to any protective effect of the vaccine against SIDS.)
While this and other studies with similar results resolved the issue to
the satisfaction of the scientific community, some members of the public have remained
concerned about a possible connection between DTP vaccine and SIDS, citing the SIDS cases
regularly reported to VAERS. In response to such concerns, FDA and CDC staff calculated
the number of SIDS cases expected to occur by chance within a fixed number of days
following immunization, accounting for the age-adjusted SIDS rate and the proportion of
infants vaccinated at specific intervals, and determined that the number of cases reported
for each time interval is far lower than would be expected to occur by chance alone. (Of
course, these estimates may have been artificially lowered by underreporting of SIDS
occurring shortly after vaccination.)
Advocacy groups raising concerns about vaccine safety regularly point out
that the reasoning described above for SIDS is flawed; since nearly all children are
vaccinated, how do we know that the "background" SIDS rate is not partially or even largely caused by vaccination?
It is true that there is no satisfactory unvaccinated control group to turn to, since the
small group of children in the United States who go unvaccinated through the first year of
life would almost certainly differ in important ways from those who do receive
vaccinations on schedule. Well-designed studies to date, including the study described
above, have used an alternative approach based on the assumption that if immunization
caused sudden infant deaths, it would do so within a few days of immunization. This
approach allowed researchers to compare children who died of SIDS with age-matched
controls with respect to time since vaccination.
Other risk factors for SIDS have been identified recently: these include
prone sleep position; the thermal environment, including use of heavy and confining
bedclothes; and maternal smoking.30,31,32 SIDS rates have decreased
dramatically in several countries33,34,35,36 in connection with "back to sleep" initiatives.37 These
findings, while providing no additional direct evidence on the role of vaccines, do
suggest a mechanism for SIDS that may be more related to the physical environment than to
systemic factors in the child that might be affected by vaccination. Overall, the evidence
continues to strongly negate any causal association between SIDS and vaccination.
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The safety of vaccine lots.
Vaccine advocacy groups, organized and led primarily by parents who
believe their children have died or suffered serious injury as a result of vaccination,
have questioned whether particular vaccine lots may be more likely to induce such
injuries. These groups have reviewed the publicly available VAERS database, which includes
the vaccine lot number for most reports, and have raised questions about the safety of
particular lots that appear to be associated with a higher number of reports.38
Vaccines are manufactured in large lots from which vials for individual
administration are derived. Procedures for the manufacture and release of vaccine lots are
strictly regulated; prior to public release, each vaccine lot must undergo stringent
testing to assure both the potency of the vaccine and the lack of contamination.39 Because of
these procedures, the likelihood that there could be something "wrong" with any
bulk lot is extremely low--but not zero.
VAERS can address the question of the safety of individual vaccine lots
much more effectively than the question of causality in individual cases of adverse
events. Since 1993, FDA medical officers have performed weekly reviews of lot-specific
reporting. These reviews require much more information than simply the number of reports
submitted for each vaccine lot; the numbers alone are inadequate to support any
conclusions about safety, for several reasons.
First, as noted earlier, there are errors in the database. Given that the
vaccine lot number is a string of letters and numbers, it may easily be miscopied by the
reporter onto the VAERS form. This results in numerous "lots" in the database
with a single report or a very few reports, providing a misleading contrast with the
numbers of reports for valid lots.
Second, lot sizes can vary greatly. Clearly, the number of reports
generated from a vaccine lot containing half a million doses cannot be sensibly compared
with the number of reports generated from a lot only one-tenth as large. Data on lot size,
although available to the FDA for monitoring purposes, do not appear in the VAERS database
because these data are legally considered proprietary to the manufacturer and their
release by FDA is prohibited.
Third, there is a time factor. A vaccine lot on the market for only a few
months will be associated with fewer reports than a lot released several years earlier.
Finally, there will always be chance variability in reporting rates. Even
when the numbers of reports are standardized for lot size and length of time on the market
(as they are for internal FDA review of the database), there will always be one lot
associated with the highest rate of reports and one lot with the lowest. The more lots,
the greater the difference between the highest and lowest rates will be; this difference
may be quite large for "old" and widely used vaccines such as DTP even assuming
all lots are equally safe.
When numbers of reports are compared between vaccines, there are further
considerations. The database will contain more reports for a vaccine administered five
times to each individual, such as DTP, than for a vaccine such as MMR that is administered
only twice. There will be more reports for a vaccine that has been on the market for many
years (such as DTP) than for a vaccine that has been available for only a few years (such
as Haemophilus influenzae Type B vaccine). More death reports will be seen for
vaccines given in infancy, when the background death rate is higher and SIDS is a factor,
than for vaccines given later in childhood.
The FDA staff must take all of these factors into consideration when
monitoring the database for unusual patterns of reporting from specific lots. Computerized
methods are in place to identify lots with high reporting rates, accounting for lot size
and time on the market. The threshold for identifying these lots is set deliberately low
to ensure the earliest possible signal of a real problem.
Lots identified at this first screening stage are subject to additional
scrutiny. The experience of related or "sister" lots (those made from the same large batch of product) is
considered, since most problems should affect all lots from the same batch. The types of
reports submitted are carefully reviewed; a series of similar events would be more
suggestive than a scattering of events of different types with no unique syndrome evident.
The results of the lot's initial safety testing is also reviewed. Additional information
may be requested from the manufacturer, and in some cases the safety testing might be
repeated.
Over the three years during which these monitoring procedures have been in
place, no lot has been found to be unsafe. This result is not surprising given the
stringency of the manufacturing and testing requirements to which vaccines are subject.
Nevertheless, because of the possibility of such a problem arising, regular attention to
lot-specific reporting will remain an important aspect of FDA's program of vaccine
safety monitoring.
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Using VAERS data to identify possible new reactions.
Several investigations of VAERS data have uncovered previously
unrecognized problems that may occur rarely in vaccine recipients. Beeler, Varricchio and
Wise40 noted occasional instances of life-threatening thrombocytopenias
following the administration of MMR vaccine, a previously unappreciated level of severity
of a known side effect. Wise and Kiminyo41 documented a series of cases in which hair loss followed
immunizations (primarily hepatitis B vaccine), a rare effect not previously reported.
Braun and colleagues42 have identified a series of cases of severe injuries resulting
from vaccination-induced fainting, or syncope.
Sometimes VAERS data may provide the useful and reassuring information
that new problems have not been identified after additional experience with a
vaccine, as in the previously noted report of Niu et al. with regard to hepatitis B
vaccine in infants.26
Using VAERS to study trends in reporting of adverse events.
VAERS data have also been used to compare reporting patterns over time and
investigate changes in reporting rates that might be due to changes in vaccine practices.
For example, CDC epidemiologists reviewed reports of fever, seizures, and hospitalizations
following administration of a newly licensed combination of diphtheria, tetanus and
acellular pertussis vaccine (DTaP). The rate of such reports was about one-third lower
than the reporting rate following the standard DTP vaccine43, consistent
with--and confirming in the context of general practice--the safety findings of the
prelicensure clinical trials.44,45
Ecologic studies--comparisons of outcomes during different time
periods--using data from MSAEFI, the CDC surveillance program that preceded VAERS, showed
that a change from separate to simultaneous immunization with DTP and MMR vaccines at 15
months of age did not change the types of adverse events reported.45 A
combined analysis of MSAEFI and VAERS data indicated that the rates of reported
hospitalizations and deaths following DTP vaccine remained constant from 1985 to 1992,
despite the addition of Haemophilus influenzae Type B vaccine to the routine
infant immunization schedule.46 These studies provided some reassurance that by adding vaccines to
the recommended immunization schedule gains in protection from disease were not offset by
an increased burden of adverse events caused by the vaccines.
Reporting patterns have also been studied to estimate the extent of
underreporting of adverse events. Researchers used the known rates of a variety of vaccine
reactions, as reported in controlled studies, to estimate the "reporting
efficiency"--the proportion of events actually occurring that are reported--of
VAERS and its predecessor passive surveillance systems. Reporting efficiencies were
similar and, perhaps not surprisingly, were the highest for serious events such as
vaccine-associated paralytic polio (about 70%) and lowest for minor events such as rashes
following measles vaccination (less than 1%). This study provides suggestive evidence that
for the events of greatest concern, VAERS reports represent substantially more than the
"tip of the iceberg."
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Newer Approaches to Vaccine Safety Monitoring
While VAERS is the initial safety screen, potentially providing the
earliest signal of any new vaccine reaction, a reporting system of this kind has major
limitations, including underreporting, lack of specificity, and lack of a natural control
group. To compensate for these limitations, other approaches to vaccine safety
surveillance have been developed.
The increasing availability in recent years of computerized medical
administrative databases for defined populations such as health maintenance organization
(HMO) enrollees has radically improved the ability to conduct pharmacoepidemiologic
studies.48 In these databases, vaccination records can be linked to records
of hospitalizations and diagnoses of serious conditions, minimizing the problem of
underreporting of serious events encountered in VAERS. The enrollment in individual HMOs
can number in the millions, permitting study of rare events. This capability can be
further enhanced by collecting data prospectively from several HMOs under a well-defined
research protocol and aggregating the data. In principle, all of the information necessary
for rigorous epidemiologic analysis is available in such settings, including numbers of
doses administered, comparison groups, and potential confounders.
Since 1990, the CDC has worked with four HMOs to organize a Large Linked
Data Base (LLDB) for vaccine safety studies as part of the Vaccine Safety Datalink (VSD)
Project. In this project, automated vaccination records on half a million children under
six years of age (representing about 2% of the U.S. population in this age group) are
linked to their medical records; the project will soon be expanded to include older age
groups. This resource is being used to examine the particular associations identified as
requiring further investigation by the Institute of Medicine in their study mentioned
earlier (for example, seizures following immunization).14,15 and is also
regularly utilized to further evaluate potential associations identified through VAERS.
One recent VSD investigation confirmed an association between seizures and DTP and MMR
vaccinations by comparing vaccine exposures within specified time periods (one day for
DTP, one week for MMR).49
The Vaccine Safety Datalink Project has its limitations, however. Because
few nonimmunized controls are available within the HMOs, the project relies predominantly
on comparison of incidence rates of adverse events between specified time periods
following vaccination. These studies are therefore limited in their ability to investigate
the association between vaccination and events with delayed or insidious onset such as
autism and learning disability. Adverse events that do not result in a health care visit
(or, more generally, data not automated in the HMO) are also not easily studied. The
geographic concentration of the project=s HMOs on the West Coast of the United States may also limit the
generalizability of results. Finally, even the large sample sizes available in this HMO
consortium currently do not provide enough power to study extremely rare events such as
Guillain-Barre syndrome (GBS) and encephalopathy in a timely manner; specialized studies
are still required to address such issues. For example, to evaluate the occurrence of GBS
following the 1993-1994 influenza vaccination season, a special study is being conducted
by the CDC in which all cases of the syndrome in four states are being sought through the
centralized statewide hospital discharge tapes.50
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Challenges for the Future
The continued development of new vaccines to prevent diseases such as
chicken pox, rotavirus, pneumococcal pneumonia, and respiratory syncytial virus will
intensify the challenges of vaccine safety monitoring. Concerns have been raised about
reactions being exacerbated when vaccines are combined; while current experience does not
suggest that there would be insurmountable safety problems with adding new vaccines to
currently available combinations, the possibility of increased reactogenicity is well
recognized.51
The public concerns about the safety of vaccines that are frequently
mandated prior to entry into public school, day care centers, universities, and workplaces
are legitimate and important. We would all like such products to pose zero risk of adverse
effects. Unfortunately, this goal is not achievable for any pharmacologically active
product--if there is a beneficial effect, there will be some risk, however tiny, of an
adverse effect.
It must be recognized that protection of individuals from serious diseases
depends not only on their own immunization but on the immunization of others in their
community; since vaccines are not 100% effective, people's chance of disease is
lower if those around them remain healthy than if those around them carry the disease.
This is why most communities require children to be vaccinated against certain diseases,
assuming no contraindication, rather than leaving the choice to individual parents on the
basis of their own risk-benefit assessments.
The overwhelming view of the medical/public health community is that the
risks of vaccine reactions, both the common mild reactions and the rare, more serious
reactions, are very much outweighed by the public health benefit conferred by current
vaccination practices and policies. Epidemiologists, pediatricians, statisticians, and
others involved in vaccine safety surveillance projects will continue to investigate new
and improved methods to monitor vaccine safety. The goal of understanding what events
might be caused or promoted by certain vaccines and which individuals might be at high
risk to experience such events will remain a challenging but extremely important one for
the public health community.
Dr. Ellenberg is Director, Division of Biostatistics and Epidemiology,
Office of Establishment Licensing and Product Surveillance, FDA. Dr. Chen is Chief,
Vaccine Safety and Development Activity, Epidemiology and Surveillance Division, CDC.
We would like to acknowledge contributions in the preparation of this
manuscript from Carol Krueger RN,BSN, David Davis, Peter Patriarca, Karen Goldenthal MD,
and Jerome Donlon MD, PhD of the FDA; Gina Terracciano DO, Penina Haber MPH, and Tara
Strine of the CDC; and Geoffry Evans MD of the Health Resources and Services
Administration.
Address correspondence to Susan Ellenberg PhD, 1401 Rockville Pike,
HFM-210, Rockville MD 20852-1448.
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