Background
Description and Action Mechanisms. LAIVs have been
in development since the 1960s in the United States,
where they have been evaluated as mono-, bi-, and
trivalent formulations. The LAIV licensed for use
in the United States beginning in 2003 is produced
by MedImmune, Inc. (Gaithersburg, Maryland; http://www.medimmune.com)
and marketed under the name FluMist™. It
is a live, trivalent, intranasally administered
vaccine that is
- attenuated, producing mild or no signs or symptoms
related to influenza virus infection;
- temperature-sensitive, a property that limits
the replication of the vaccine viruses at 38ºC–39ºC,
and thus restricts LAIV viruses from replicating
efficiently in human lower airways; and
- cold-adapted, replicating efficiently at 25ºC,
a temperature that is permissive for replication
of LAIV viruses, but restrictive for replication
of different wild-type viruses.
In animal studies, LAIV viruses replicate in the
mucosa of the nasopharynx, inducing protective
immunity against viruses included in the vaccine,
but replicate inefficiently in the lower airways
or lungs.
The first step in developing an LAIV was the derivation
of two stably attenuated master donor viruses (MDV),
one for type A and one for type B influenza viruses.
The two MDVs each acquired the cold-adapted, temperature-sensitive,
attenuated phenotypes through serial passage in
viral culture conducted at progressively lower
temperatures. The vaccine viruses in LAIV are reassortant
viruses containing genes from these MDVs that confer
attenuation, temperature sensitivity, and cold
adaptation and genes from the recommended contemporary
wild-type influenza viruses, encoding the surface
antigens hemagglutinin (HA) and neuraminidase (NA).
Thus, MDVs provide the stably attenuated vehicles
for presenting influenza HA and NA antigens, to
which the protective antibody response is directed,
to the immune system. The reassortant vaccine viruses
are grown in embryonated hens' eggs. After the
vaccine is formulated and inserted into individual
sprayers for nasal administration, the vaccine
must be stored at –15ºC or
colder.
The immunogenicity of the approved LAIV has been
assessed in multiple studies, which included approximately
100 children aged 5–17 years, and approximately
300 adults aged 18–49 years. LAIV virus strains
replicate primarily in nasopharyngeal epithelial
cells. The protective mechanisms induced by vaccination
with LAIV are not completely understood but appear
to involve both serum and nasal secretory antibodies.
No single laboratory measurement closely correlates
with protective immunity induced by LAIV.
Shedding and Transmission of Vaccine Viruses. Available
data indicate that both children and adults vaccinated
with LAIV can shed vaccine viruses for >2
days after vaccination, although in lower titers
than typically occur with shedding of wild-type
influenza viruses. Shedding should not be equated
with person-to-person transmission of vaccine viruses,
although, in rare instances, shed vaccine viruses
can be transmitted from vaccinees to nonvaccinated
persons.
One unpublished study in a child care center setting
assessed transmissibility of vaccine viruses from
98 vaccinated to 99 unvaccinated subjects, all
aged 8–36 months. Eighty percent of vaccine
recipients shed one or more virus strains, with
a mean of 7.6 days' duration. One vaccine type
influenza type B isolate was recovered from a placebo
recipient and was confirmed to be vaccine-type
virus. The type B isolate retained the cold-adapted,
temperature-sensitive, attenuated phenotype, and
it possessed the same genetic sequence as a virus
shed from a vaccine recipient in the same children's
play group. The placebo recipient from whom the
influenza type B vaccine virus was isolated did
not exhibit symptoms that were different from those
experienced by vaccine recipients. The estimated
probability of acquiring vaccine virus after close
contact with a single LAIV recipient in this child
care population was 0.58%–2.4%.
One study assessing shedding of vaccine viruses
in 20 healthy vaccinated adults aged 18–49
years demonstrated that the majority of shedding
occurred within the first 3 days after vaccination,
although one subject was noted to shed virus on
day 7 after vaccine receipt. No subject shed vaccine
viruses >10 days after vaccination. Duration
or type of symptoms associated with receipt of
LAIV did not correlate with duration of shedding
of vaccine viruses. Person-to-person transmission
of vaccine viruses was not assessed in this study.
Stability of Vaccine Viruses. In clinical trials,
viruses shed by vaccine recipients have been phenotypically
stable. In one study, nasal and throat swab specimens
were collected from 17 study participants for 2
weeks after vaccine receipt. Virus isolates were
analyzed by multiple genetic techniques. All isolates
retained the LAIV genotype after replication in
the human host, and all retained the cold-adapted
and temperature-sensitive phenotypes.
Using Live, Attenuated
Influenza Vaccine
LAIV is an option for vaccination of healthy persons
aged 5–49 years, including persons in close
contact with groups at high risk and those wanting
to avoid influenza. Possible advantages of LAIV
include its potential to induce a broad mucosal
and systemic immune response, its ease of administration,
and the acceptability of an intranasal rather than
intramuscular route of administration.
Persons Who Should Not Be Vaccinated with LAIV
The following populations should not be vaccinated
with LAIV:
- persons aged <5 years or those aged >50
years;*
- persons with asthma, reactive airways disease
or other chronic disorders of the pulmonary
or cardiovascular systems; persons with other
underlying medical conditions, including such
metabolic diseases as diabetes, renal dysfunction,
and hemoglobinopathies; or persons with known
or suspected immunodeficiency diseases or who
are receiving immunosuppressive therapies;*
- children or adolescents receiving aspirin or
other salicylates (because of the association
of Reye syndrome with wild-type influenza infection);*
- persons with a history of GBS;
- pregnant women;* or
- persons with a history of hypersensitivity,
including anaphylaxis, to any of the components
of LAIV or to eggs.
Close Contacts of Persons at High Risk for Complications
from Influenza
Close contacts of persons at high risk for complications
from influenza should receive influenza vaccine
to reduce transmission of wild-type influenza viruses
to persons at high risk. Use of inactivated influenza
vaccine is preferred for vaccinating household
members, health-care workers, and others who have
close contact with severely immunosuppressed persons
(e.g., patients with hematopoietic stem cell transplants)
during those periods in which the immunosuppressed
person requires care in a protective environment.
The rationale for not using LAIV among health-care
workers caring for such patients is the theoretical
risk that a live, attenuated vaccine virus could
be transmitted to the severely immunosuppressed
person and cause disease. No preference exists
for inactivated influenza vaccine use by health-care
workers or other persons who have close contact
with persons with lesser degrees of immunosuppression
(e.g., persons with diabetes, persons with asthma
taking corticosteroids, or persons infected with
human immunodeficiency virus), and no preference
exists for inactivated influenza vaccine use by
health-care workers or other healthy persons aged
5–49 years in close contact with all other
groups at high risk.
If a health-care worker receives LAIV, that worker
should refrain from contact with severely immunosuppressed
patients as described previously for 7 days after
vaccine receipt. Hospital visitors who have received
LAIV should refrain from contact with severely
immunosuppressed persons for 7 days after vaccination;
however, such persons need not be excluded from
visitation of patients who are not severely immunosuppressed.
Personnel Who May Administer LAIV
Low-level introduction of vaccine viruses into
the environment is likely unavoidable when administering
LAIV. The risk of acquiring vaccine viruses from
the environment is unknown but likely to be limited.
Severely immunosuppressed persons should not administer
LAIV. However, other persons at high risk for influenza
complications may administer LAIV. These include
persons with underlying medical conditions placing
them at high risk or who are likely to be at risk,
including pregnant women, persons with asthma,
and persons aged >50 years.
LAIV Dosage and Administration
LAIV is intended for intranasal administration
only and should not be administered by the intramuscular,
intradermal, or intravenous route. LAIV must be
stored at –15ºC or colder.
LAIV should not be stored in a frost-free freezer
(because the temperature might cycle above –15ºC),
unless a manufacturer-supplied freezer box is used.
LAIV must be thawed before administration. This
can be accomplished by holding an individual sprayer
in the palm of the hand until thawed, with subsequent
immediate administration. Alternatively, the vaccine
can be thawed in a refrigerator and stored at 2ºC–8ºC
for <24 hours before use. Vaccine should
not be refrozen after thawing. LAIV is supplied
in a prefilled single-use sprayer containing 0.5
mL of vaccine. Approximately 0.25 mL (i.e., half
of the total sprayer contents) is sprayed into
the first nostril while the recipient is in the
upright position. An attached dose-divider clip
is removed from the sprayer to administer the second
half of the dose into the other nostril. If the
vaccine recipient sneezes after administration,
the dose should not be repeated.
LAIV should be administered annually according
to the following schedule:
- Children aged 5–8 years previously unvaccinated
at any time with either LAIV or inactivated
influenza vaccine should receive 2 doses† of
LAIV separated by 6–10 weeks.
- Children aged 5–8 years previously vaccinated
at any time with either LAIV or inactivated
influenza vaccine should receive 1 dose of LAIV.
They do not require a second dose.
- Persons aged 9–49 years should receive
1 dose of LAIV.
- LAIV can be administered to persons with minor
acute illnesses (e.g., diarrhea or mild upper
respiratory tract infection with or without
fever). However, if clinical judgment indicates
nasal congestion is present that might impede
delivery of the vaccine to the nasopharyngeal
mucosa, deferral of administration should be
considered until resolution of the illness.
- Whether concurrent administration of LAIV with
other vaccines affects the safety or efficacy
of either LAIV or the simultaneously administered
vaccine is unknown. In the absence of specific
data indicating interference, following the
ACIP general recommendations for immunization
is prudent. Inactivated vaccines do not interfere
with the immune response to other inactivated
vaccines or to live vaccines. An inactivated
vaccine can be administered either simultaneously
or at any time before or after LAIV. Two live
vaccines not administered on the same day should
be administered >4 weeks apart when
possible.
LAIV and Use of Influenza Antiviral Medications
The effect on safety and efficacy of LAIV coadministration
with influenza antiviral medications has not been
studied. However, because influenza antivirals
reduce replication of influenza viruses, LAIV should
not be administered until 48 hours after cessation
of influenza antiviral therapy, and influenza antiviral
medications should not be administered for 2 weeks
after receipt of LAIV.
LAIV Storage
LAIV must be stored at –15ºC
or colder. LAIV should not be stored in a frost-free
freezer because the temperature might cycle above –15ºC,
unless a manufacturer-supplied freezer box or other
strategy is used. LAIV can be thawed in a refrigerator
and stored at 2ºC–8ºC
for <24 hours before use. It should not
be refrozen after thawing. Additional information
is available at 1-877-FLUMIST (1-877-358-6478)
or at www.FluMist.com.
Side Effects and Adverse
Reactions
Twenty prelicensure clinical trials assessed the
safety of the approved LAIV. In these combined
studies, approximately 28,000 doses of the vaccine
were administered to >20,000 subjects. A subset
of these trials were randomized, placebo-controlled
studies in which >4,000 healthy children aged
5–17 years and >2,000 healthy adults aged
18–49 years were vaccinated. The incidence
of adverse events possibly complicating influenza
(e.g., pneumonia, bronchitis, bronchiolitis, or
central nervous system events) was not statistically
different among LAIV and placebo recipients aged
5–49 years.
Children
Signs and symptoms reported more often among vaccine
recipients than placebo recipients included
runny nose or nasal congestion (20%–75%),
headache (2%–46%), fever (0%–26%),
and vomiting (3%–13%), abdominal pain
(2%), and myalgias (0%–21%). These symptoms
were associated more often with the first dose
and were self-limited. In a subset of healthy
children aged 60–71 months from one clinical
trial, certain signs and symptoms were reported
more often among LAIV recipients after the first
dose (n = 214) than placebo recipients (n =
95) (e.g., runny nose, 48.1% versus 44.2%; headache,
17.8% versus 11.6%; vomiting, 4.7% versus 3.2%;
myalgias, 6.1% versus 4.2%), but these differences
were not statistically significant. Unpublished
data from a study including subjects aged 1–17
years indicated an increase in asthma or reactive
airways disease in the subset aged 12–59
months. Because of this, LAIV is not approved
for use among children aged <60 months.
Adult
Among adults, runny nose or nasal congestion (28%–78%),
headache (16%–44%), and sore throat (15%–27%)
have been reported more often among vaccine recipients
than placebo recipients. In one clinical trial
(94), among a subset of healthy adults aged
18–49 years, signs and symptoms reported
more frequently among LAIV recipients (n = 2,548)
than placebo recipients (n = 1,290) within 7 days
after each dose included cough (13.9% versus 10.8%);
runny nose (44.5% versus 27.1%); sore throat (27.8%
versus 17.1%); chills (8.6% versus 6.0%); and tiredness/weakness
(25.7% versus 21.6%).
Safety Among Groups at High Risk from Influenza-Related
Morbidity
Until additional data are acquired, persons at
high risk for experiencing complications from influenza
infection (e.g., immunocompromised patients; patients
with asthma, cystic fibrosis, or chronic obstructive
pulmonary disease; or persons aged >65
years) should not be vaccinated with LAIV. Protection
from influenza among these groups should be accomplished
by using inactivated influenza vaccine.
Serious Adverse Events
Serious adverse events among healthy children aged
5–17 years or healthy adults aged 18–49
years occurred at a rate of <1%. Surveillance
should continue for adverse events that might
not have been detected in previous studies.
Health-care professionals should promptly report
all clinically significant adverse events after
LAIV administration to VAERS, as recommended
for inactivated influenza vaccine.
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