Mechanism Of Action
Immune mechanisms conferring
protection against influenza following receipt of FluMist Quadrivalent vaccine
are not fully understood; serum antibodies, mucosal antibodies, and
influenza-specific T cells may play a role.
FluMist and FluMist
Quadrivalent contain live attenuated influenza viruses that must infect and
replicate in cells lining the nasopharynx of the recipient to induce immunity.
Vaccine viruses capable of infection and replication can be cultured from nasal
secretions obtained from vaccine recipients (shedding) [see Pharmacodynamics].
Shedding of vaccine viruses
within 28 days of vaccination with FluMist was evaluated in (1) multi-center
study MI-CP129 which enrolled healthy individuals 6 through 59 months of age (N
= 200); and (2) multi-center study FM026 which enrolled healthy individuals 5
through 49 years of age (N = 344). In each study, nasal secretions were
obtained daily for the first 7 days and every other day through either Day 25
and on Day 28 or through Day 28. In study MI-CP129, individuals with a positive
shedding sample at Day 25 or Day 28 were to have additional shedding samples
collected every 7 days until culture negative on 2 consecutive samples. Results
of these studies are presented in Table 5.
Table 5: Characterization of
Shedding with FluMist in Specified Age Groups by Frequency, Amount, and
Duration (Study MI-CP129a and Study FM026b)
||Number of Subjects
||Peak Titer (TCID50/mL)d
||% Shedding After Day 11
||Day of Last Positive Culture
||< 5 log10
||< 5 log10
||< 5 log10
||< 4 log10
||< 3 log10
|a NCT00344305; see www.clinicaltrials.gov
b NCT00192140; see www.clinicaltrials.gov
c Proportion of subjects with detectable virus at any time point
during the 28 days.
d Peak titer at any time point during the 28 days among samples
positive for a single vaccine virus.
e FluMist and FluMist Quadrivalent are not approved for use in
children younger than 24 months of age [see ADVERSE REACTIONS].
f A single subject who shed previously on Days 1-3; TCID50/mL was
less than 1.5 log10 on Day 23.
g A single subject who did not shed previously; TCID50/mL was less
than 1.5 log10.
h A single subject who did not shed previously; TCID50/mL was less
than 1.0 log10.
The highest proportion of
subjects in each group shed one or more vaccine strains on Days 2-3 post
vaccination. After Day 11 among individuals 2 through 49 years of age (n =
443), virus titers did not exceed 1.5 log10 TCID50/mL.
Studies In Immunocompromised
Safety and shedding of vaccine
virus following FluMist administration were evaluated in 28 HIV-infected adults
[median CD4 cell count of 541 cells/mm³] and 27 HIV-negative adults 18 through
58 years of age. No serious adverse events were reported during the one-month
follow-up period. Vaccine strain (type B)virus was detected in 1 of 28
HIV-infected subjects on Day 5 only, and in none of the HIV-negative FluMist
Safety and shedding of vaccine
virus following FluMist administration were also evaluated in children in a
randomized (1:1), cross-over, double-blind, AF-SPG placebo-controlled trial in
24 HIV-infected children [median CD4 cell count of 1013 cells/mm³] and 25
HIV-negative children 1 through 7 years of age, and in a randomized (1:1),
open-label, inactivated influenza vaccine-controlled trial in 243HIV-infected
children and adolescents 5 through 17 years of age receiving stable
anti-retroviral therapy. Frequency and duration of vaccine virus shedding in
HIV-infected individuals were comparable to that seen in healthy individuals.
No adverse effects on HIV viral load or CD4 counts were identified following
FluMist administration. In the 5 through 17 year old age group, one inactivated
influenza vaccine recipient and one FluMist recipient experienced pneumonia
within 28 days of vaccination (days 17 and 13, respectively). The effectiveness
of FluMist and FluMist Quadrivalent in preventing influenza illness in
HIV-infected individuals has not been evaluated.
Twenty mild to moderately
immunocompromised children and adolescents 5 through 17 years of age (receiving
chemotherapy and/or radiation therapy or who had received chemotherapy in the
12 weeks prior to enrollment) were randomized 1:1 to receive FluMist or AF-SPG
placebo. Frequency and duration of vaccine virus shedding in these
immunocompromised children and adolescents were comparable to that seen in
healthy children and adolescents. The effectiveness of FluMist and FluMist
Quadrivalent in preventing influenza illness in immunocompromised individuals
has not been evaluated.
A prospective, randomized, double-blind,
placebo-controlled trial was performed in a daycare setting in children younger
than 3 years of age to assess the transmission of vaccine viruses from a
vaccinated individual to a non-vaccinated individual. A total of 197 children 8
through 36 months of age were randomized to receive one dose of FluMist (N =
98) or AF-SPG placebo (N = 99). Virus shedding was evaluated for 21 days by
culture of nasal swab specimens. Wild-type A (A/H3N2) influenza virus was
documented to have circulated in the community and in the study population
during the trial, whereas Type A (A/H1N1) and Type B strains did not.
At least one vaccine strain was
isolated from 80% of FluMist recipients; strains were recovered from 1-21 days
post vaccination (mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca)
and temperature-sensitive (ts) phenotypes were preserved in 135 tested of 250
strains isolated at the local laboratory. Ten influenza isolates (9 influenza
A, 1 influenza B) were cultured from a total of seven placebo subjects. One
placebo subject had mild symptomatic Type B virus infection confirmed as a
transmitted vaccine virus by a FluMist recipient in the same playgroup. This
Type B isolate retained the ca, ts, and att phenotypes of the vaccine strain
and had the same genetic sequence when compared to a Type B virus cultured from
a vaccine recipient within the same playgroup. Four of the influenza Type A
isolates were confirmed as wild-type A/Panama (H3N2). The remaining isolates
could not be further characterized.
Assuming a single transmission
event (isolation of the Type B vaccine strain), the probability of a young
child acquiring vaccine virus following close contact with a single FluMist
vaccinee in this daycare setting was 0.58% (95% CI: 0, 1.7) based on the
Reed-Frost model. With documented transmission of one Type B in one placebo
subject and possible transmission of Type A viruses in four placebo subjects,
the probability of acquiring a transmitted vaccine virus was estimated to be
2.4% (95% CI: 0.13, 4.6) using the Reed-Frost model.
The effectiveness of FluMist
Quadrivalent is based on data demonstrating the clinical efficacy of FluMist in
children and the effectiveness of FluMist in adults, and a comparison of post
vaccination geometric mean titers (GMTs) of hemagglutination inhibition (HI)
antibodies between individuals receiving FluMist and FluMist Quadrivalent. The
clinical experience with FluMist is relevant to FluMist Quadrivalent because
both vaccines are manufactured using the same process and have overlapping
compositions [see DESCRIPTION].
Efficacy Studies Of FluMist In Children
A multinational, randomized,
double-blind, active-controlled trial (MI-CP111) was performed to assess the
efficacy of FluMist compared to an intramuscularly administered, inactivated
Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. (active control) in
children 6 months to less than 5 years of age during the 2004-2005 influenza
season. A total number of 3916 children without severe asthma, without use of
bronchodilator or steroids, and without wheezing within the prior 6 weeks were
randomized to FluMist and 3936 were randomized to active control. Children who
previously received any influenza vaccine received a single dose of study
vaccine, while those who never previously received an influenza vaccination (or
had an unknown history of influenza vaccination) received two doses.
Participants were then followed through the influenza season to identify
illness caused by influenza virus. As the primary endpoint, culture-confirmed
modified CDC-ILI (CDC-defined influenza-like illness) was defined as a positive
culture for a wild-type influenza virus associated within ±7 days of modified
CDC-ILI. Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or equivalent) with cough, sore throat,
or runny nose/nasal congestion on the same or consecutive days.
In the primary efficacy
analysis, FluMist demonstrated a 44.5% (95% CI: 22.4, 60.6) reduction in
influenza rate compared to active control as measured by culture-confirmed
modified CDC-ILI caused by wild-type strains antigenically similar to those
contained in the vaccine. See Table 6 for a description of the results by
strain and antigenic similarity.
Table 6: Comparative
Efficacy Against Culture-Confirmed Modified CDC-ILIa Caused by
Wild-Type Strains (Study MI-CP111)b,c
||% Reduction in Rate for FluMiste
||# of Cases
||# of Cases
|Matched Strains All strains
|Mismatched Strains All strains
|Regardless of Match All strains
a Modified CDC-ILI
was defined as fever (temperature ≥100°F oral or equivalent) plus cough,
sore throat, or runny nose/nasal congestion on the same or consecutive days.
bIn children 6 months through 5 years of age
c NCT00128167; see www.clinicaltrials.gov
Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered
e Reduction in rate
was adjusted for country, age, prior influenza vaccination status, and wheezing
A randomized, double-blind, saline placebo-controlled
trial (D153-P501) was performed to evaluate the efficacy of FluMist in children
12 through 35 months of age without high-risk medical conditions against
culture-confirmed influenza illness. This study was performed in Asia over two
successive seasons (2000-2001 and 2001-2002). The primary endpoint of the trial
was the prevention of culture-confirmed influenza illness due to antigenically
matched wild-type influenza. Respiratory illness that prompted an influenza
culture was defined as at least one of the following: fever (≥ 100.4°F
rectal or ≥ 99.5°F axillary), wheezing, shortness of breath, pulmonary
congestion, pneumonia, or otitis media; or two of the following: runny
nose/nasal congestion, sore throat, cough, muscle aches, chills, headache,
irritability, decreased activity, or vomiting. A total of 3174 children were
randomized 3:2 (vaccine:placebo) to receive 2 doses of study vaccine or placebo
at least 28 days apart in Year 1. See Table 7 for a description of the results.
During the second year of Study D153-P501, for children who
received two doses in Year 1 and one dose in Year 2, FluMist demonstrated 84.3%
(95% CI: 70.1, 92.4) efficacy against culture-confirmed influenza illness due
to antigenically matched wild-type influenza.
Study AV006 was a second multi-center, randomized,
double-blind, AF-SPG placebo-controlled trial performed in U.S. children without
high-risk medical conditions to evaluate the efficacy of FluMist against
culture-confirmed influenza over two successive seasons (1996-1997 and
1997-1998). The primary endpoint of the trial was the prevention of
culture-confirmed influenza illness due to antigenically matched wild-type
influenza in children who received two doses of vaccine in the first year and a
single revaccination dose in the second year. Respiratory illness that prompted
an influenza culture was defined as at least one of the following: fever (≥
101°F rectal or oral; or ≥ 100.4°F axillary), wheezing, shortness of
breath, pulmonary congestion, pneumonia, or otitis media; or two of the
following: runny nose/nasal congestion, sore throat, cough, muscle aches,
chills, headache, irritability, decreased activity, or vomiting. During the
first year of the study, 1602 children 15 through 71 months of age were
randomized 2:1 (vaccine:placebo). See Table 7 for a description of the results.
Table 7: Efficacya of FluMist vs. Placebo
Against Culture-Confirmed Influenza Illness Due to Antigenically Matched
Wild-Type Strains (Studies D153-P501b & AV006c, Year 1)
|FluMist nf (%)
Ng = 1653
|Placebo nf (%)
Ng = 1111
|% Efficacy (95% CI)
||FluMist nf (%)
Ng = 849
|Placebo nf (%)
Ng = 410
|% Efficacy (95% CI)
||72.9%h (62.8, 80.5)
||93.4% (87.5, 96.5)
||80.9% (69.4, 88.5)i
||90.0% (71.4, 97.5)
||96.0% (89.4, 98.5)
||44.3% (6.2, 67.2)
||90.5% (78.0, 95.9)
|a D153-P501 and AV006 data are for subjects
who received two doses of study vaccine.
b In children 12 through 35 months of age
c In children 15 through 71 months of age
d NCT00192244; see www.clinicaltrials.gov
e NCT00192179; see www.clinicaltrials.gov
f Number and percent of subjects in per-protocol efficacy analysis
population with culture-confirmed influenza illness.
g Number of subjects in per-protocol efficacy analysis population of
each treatment group of each study for the “any strain” analysis.
h For D153-P501, influenza circulated through 12 months following
i Estimate includes A/H1N1 and A/H1N2 strains. Both were considered
antigenically similar to the vaccine.
During the second year of Study AV006, children remained
in the same treatment group as in Year 1and received a single dose of FluMist
or placebo. During the second year, the primary circulating strain was the
A/Sydney/05/97 H3N2 strain, which was antigenically dissimilar from the H3N2
strain represented in the vaccine, A/Wuhan/359/95; FluMist demonstrated 87.0%
(95% CI: 77.0, 92.6) efficacy against culture-confirmed influenza illness.
Immune Response Study Of FluMist Quadrivalent In Children
A multicenter, randomized, double-blind,
active-controlled, non-inferiority study (MI-CP208) was performed to assess the
immunogenicity of FluMist Quadrivalent compared to FluMist (active control) in
children and adolescents 2 through 17 years of age. A total of 2312 subjects
were randomized by site at a 3:1:1 ratio to receive either FluMist Quadrivalent
or one of two formulations of comparator vaccine FluMist, each containing a B
strain that corresponded to one of the two B strains in FluMist Quadrivalent (a
B strain of the Yamagata lineage or a B strain of the Victoria lineage).
Children 2 through 8 years of age received 2 doses of
vaccine approximately 30 days apart; children 9 years of age and older received
1 dose. For children 2 through 8 years of age with a history of influenza
vaccination, immunogenicity assessments were performed prior to vaccination and
at 28 days after the first dose. For children 2 through 8 years of age without
a history of influenza vaccination, immunogenicity assessments were performed
prior to vaccination and 28 days after the second dose. For children 9 years of
age and older, immunogenicity assessments were performed prior to vaccination
and at 28 days post vaccination.
Immunogenicity was evaluated by
comparing the 4 strain-specific serum hemagglutination inhibition (HAI)
antibody geometric mean titers (GMTs) post dosing and provided evidence that
the addition of the second B strain did not result in immune interference to
other strains included in the vaccine.
Effectiveness Study Of FluMist In
AV009 was a U.S. multi-center,
randomized, double-blind, AF-SPG placebo-controlled trial to evaluate
effectiveness of FluMist in adults 18 through 64 years of age without high-risk
medical conditions over the 1997-1998 influenza season. Participants were
randomized 2:1 (vaccine:placebo). Cultures for influenza virus were not
obtained from subjects in the trial, thus efficacy against culture-confirmed
influenza was not assessed. The A/Wuhan/359/95 (H3N2) strain, which was contained
in FluMist, was antigenically distinct from the predominant circulating strain
of influenza virus during the trial period, A/Sydney/05/97 (H3N2). Type A/Wuhan
(H3N2) and Type B strains also circulated in the U.S. during the study period.
The primary endpoint of the trial was the reduction in the proportion of
participants with one or more episodes of any febrile illness, and prospective
secondary endpoints were severe febrile illness and febrile upper respiratory
illness. Effectiveness for any of the three endpoints was not demonstrated in a
subgroup of adults 50 through 64 years of age. Primary and secondary
effectiveness endpoints from the age group 18 through 49 years are presented in
Table 8. Effectiveness was not demonstrated for the primary endpoint in adults
18 through 49 years of age.
Table 8: Effectiveness of
FluMist to Prevent Febrile Illness in Adults 18 through 49 Years of Age During
the 7-Week Site-Specific Outbreak Period (Study AV009)
N = 2411a
N = 1226a
|Participants with one or more events of:b
|Any febrile illness
|Severe febrile illness
|Febrile upper respiratory illness
||142 (1 1.58)
|a Number of evaluable subjects (92.7% and 93.0% of FluMist
and placebo recipients, respectively).
b The predominantly circulating virus during the trial period was
A/Sydney/05/97 (H3N2), an antigenic variant not included in the vaccine.
Effectiveness was shown in a
post-hoc analysis using an endpoint of CDC-ILI in the age group 18 through 49
years of age.
Immune Response Study Of FluMist
Quadrivalent In Adults
A multicenter, randomized,
double-blind, active-controlled, and non-inferiority study (MI-CP185) was
performed to assess the safety and immunogenicity of FluMist Quadrivalent
compared to those of FluMist (active control) in adults 18 through 49 years of
age. A total of 1800 subjects were randomized by site at a 4:1:1 ratio to
receive either 1 dose of FluMist Quadrivalent or 1 dose of one of two
formulations of comparator vaccine, FluMist, each containing a B strain that
corresponded to one of the two B strains in FluMist Quadrivalent (a B strain of
the Yamagata lineage and a B strain of the Victoria lineage).
Immunogenicity in study
MI-CP185 was evaluated by comparing the 4 strain-specific serum
hemagglutination inhibition (HAI) antibody geometric mean titers (GMTs) post
dosing and provided evidence that the addition of the second B strain did not
result in immune interference to other strains included in the vaccine.
Concomitantly Administered Live
In Study AV018, concomitant
administration of FluMist, MMR (manufactured by Merck & Co., Inc.) and
Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) was
studied in 1245 subjects 12 through 15 months of age. Subjects were randomized
in a 1:1:1 ratio to MMR, Varicella vaccine and AF-SPG placebo (group 1); MMR,
Varicella vaccine and FluMist (group 2); or FluMist alone (group 3). Immune
responses to MMR and Varicella vaccines were evaluated 6 weeks post-vaccination
while the immune responses to FluMist were evaluated 4 weeks after the second
dose. No evidence of interference with immune response to measles, mumps,
rubella, varicella and FluMist vaccines was observed.