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Influenza A H1N1 Intranasal Vaccine

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Influenza A H1N1 Intranasal Vaccine

CLINICAL PHARMACOLOGY

Mechanism of Action

Immune mechanisms conferring protection against influenza following receipt of FluMist vaccine are not fully understood. Likewise, naturally acquired immunity to wild-type influenza has not been completely elucidated. Serum antibodies, mucosal antibodies and influenza-specific T cells may play a role in prevention and recovery from infection.

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine.

Pharmacokinetics

Biodistribution

A biodistribution study of intranasally administered radiolabeled placebo was conducted in 7 healthy adult volunteers. The mean percentage of the delivered doses detected were as follows: nasal cavity 89.7%, stomach 2.6%, brain 2.4%, and lung 0.4%. The clinical significance of these findings is unknown.

Clinical Studies

MedImmune's Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal and the seasonal trivalent Influenza Vaccine Live, Intranasal (FluMist) are manufactured by the same process.

Data in this section were obtained in clinical studies conducted with FluMist.

FluMist, in refrigerated and frozen formulations, was administered to approximately 35,000 subjects in controlled clinical studies. FluMist has been studied in placebo-controlled trials over multiple years, using different vaccine strains. Comparative efficacy has been studied where FluMist was compared to an inactivated influenza vaccine made by Sanofi Pasteur Inc.

Studies in Children and Adolescents

Study MI-CP111: Pediatric Comparative Study

A multinational, randomized, double-blind, active-controlled trial (MI-CP111) was performed to assess the efficacy and safety of FluMist compared to an injectable influenza vaccine made by Sanofi Pasteur Inc. (active control) in children < 5 years of age, using the refrigerated formulation. During the 2004-2005 influenza season, a total number of 3916 children < 5 years of age and 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. 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) plus 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 3 for a description of the results by strain and antigenic similarity.

Table 3: Comparative Efficacy against Culture-Confirmed Modified CDC-ILIa Caused by Wild-Type Strains in Children < 5 Years of Age

    Active Controlb % Reduction in Rate for FluMistc 95% CI
  # of Cases Rate
(cases/N)
N # of Cases Rate
(cases/N)
Matched Strains
  All strains 3916 53 1.4% 3936 93 2.4% 44.5% 22.4, 60.6
  A/H1N1 3916 3 0.1% 3936 27 0.7% 89.2% 67.7, 97.4
  A/H3N2 3916 0 0.0% 3936 0 0.0% -- --
  B 3916 50 1.3% 3936 67 1.7% 27.3% -4.8, 49.9
Mismatched Strains
  All strains 3916 102 2.6% 3936 245 6.2% 58.2% 47.4, 67.0
  A/H1N1 N 3916 0 0.0% 3936 0 0.0% -- --
  A/H3N2 3916 37 0.9% 3936 178 4.5% 79.2% 70.6, 85.7
  B 3916 66 1.7% 3936 71 1.8% 6.3% -31.6, 33.3
Regardless of Match
  All strains 3916 153 3.9% 3936 338 8.6% 54.9% 45.4, 62.9
  A/H1N1 3916 3 0.1% 3936 27 0.7% 89.2% 67.7, 97.4
  A/H3N2 3916 37 0.9% 3936 178 4.5% 79.2% 70.6, 85.7
  B 3916 115 2.9% 3936 136 3.5% 16.1% -7.7, 34.7
ATP Population.
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.
b Injectable influenza vaccine made by Sanofi Pasteur Inc.
c Reduction in rate was adjusted for country, age, prior influenza vaccination status, and wheezing history status.

Study D153-P501: Pediatric Study

A randomized, double-blind, placebo-controlled trial (D153-P501) was performed to evaluate the efficacy of FluMist in children 12 to 35 months of age without high-risk medical conditions against culture-confirmed influenza illness, using the refrigerated formulation. 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 4 for a description of the results.

Study AV006: Pediatric Study

AV006 was a multi-center, randomized, double-blind, 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 using the frozen formulation. 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. During the first year of the study 1602 children 15-71 months of age were randomized 2:1 (vaccine:placebo). Approximately 85% of the participants in the first year returned for the second year of the study. In Year 2, children remained in the same treatment group as in year one and received a single dose of FluMist or placebo. See Table 4 for a description of the results.

Table 4: D153-P501 & AV006, Years 1a: Efficacy of FluMist vs. Placebo against Culture-Confirmed Influenza Illness due to Wild-Type Strains

  D153-P501 AV006
FluMist
nb (%)
Placebo nb (%) % Efficacy
(95% CI)
FluMist
nb (%)
Placebo
nb (%)
% Efficacy
(95% CI)
Nc=1653 Nc=1111 Nc=849 Nc=410
Any strain 56
(3.4%)
139
(12.5%)
72.9%d
(62.8, 80.5)
10
(1%)
73
(18%)
93.4%
(87.5, 96.5)
A/H1N1 23
(1.4%)
81
(7.3%)
80.9%
(69.4, 88.5)e
0 0 --
A/H3N2 4
(0.2%)
27
(2.4%)
90.0%
(71.4, 97.5)
4
(0.5%)
48
(12%)
96.0%
(89.4, 98.5)
B 29
(1.8%)
35
(3.2%)
44.3%
(6.2, 67.2)
6
(0.7%)
31
(7%)
90.5%
(78.0, 95.9)
a D153-P501 and AV006 data are for subjects who received two doses of study vaccine.
b Number and percent of subjects in per-protocol efficacy analysis population with culture-confirmed influenza illness.
c Number of subjects in per-protocol efficacy analysis population of each treatment group of each study for the “any strain” analysis.
d For D153-P501, influenza circulated through 12 months following vaccination.
e Estimate includes A/H1N1 and A/H1N2 strains. Both were considered antigenically similar to the vaccine.

During the second year of Study AV006, 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.

Study in Adults

AV009 was a multi-center, randomized, double-blind, placebo-controlled trial to evaluate effectiveness in adults 18-64 years of age without high-risk medical conditions. Participants were randomized 2:1, vaccine:placebo. Cultures for influenza virus were not obtained from subjects in the trial, so that the 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 50-64 years of age. Primary and secondary effectiveness endpoints from the age group 18-49 years of age are presented in Table 5. Effectiveness was not demonstrated for the primary endpoint in adults 18-49 years of age.

Table 5: Effectiveness of FluMista in Adults 18-49 Years of Age During the 7-week Site-Specific Outbreak Period

Endpoint FluMist
N=2411b
n (%)
Placebo
N=1226b
n (%)
Percent Reduction (95% CI)
Participants with one or more events of: Primary Endpoint:c
  Any febrile illness 331 (13.73) 189 (15.42) 10.9 (-5.1, 24.4)
  Secondary Endpoints:        
  Severe febrile illness 250 (10.37) 158 (12.89) 19.5 (3.0, 33.2)
  Febrile upper respiratory illness 213 (8.83) 142 (11.58) 23.7 (6.7, 37.5)
a Frozen formulation used.
b Number of evaluable subjects (92.7% and 93.0% of FluMist and placebo recipients, respectively).
c 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 CDC-ILI in the age group 18-49 years.

Study in Adults with Human Immunodeficiency Virus (HIV) Infection

Safety and shedding of vaccine virus following FluMist administration were evaluated in 57 HIV-infected [median CD4 cell count of 541 cells/mm3] and 54 HIV-negative adults 18-58 years of age in a randomized, double-blind, placebo controlled trial using the frozen formulation. 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 none of the HIV-negative FluMist recipients. No adverse effects on HIV viral load or CD4 counts were identified following FluMist. The effectiveness of FluMist in preventing influenza illness in HIV-infected individuals has not been evaluated.

Refrigerated Formulation Study

A double-blind, randomized multi-center trial was conducted to evaluate the comparative immunogenicity and safety of refrigerated and frozen formulations of FluMist in individuals 5 to 49 years of age without high risk medical conditions. Nine hundred and eighty-one subjects were randomized at a 1:1 ratio to receive either vaccine formulation. Subjects 5-8 years of age received two doses of study vaccine 46-60 days apart; subjects 9-49 years of age received one dose of study vaccine. The study met its primary endpoint. The GMT ratios of refrigerated and frozen formulations (adjusted for baseline serostatus) for H1N1, H3N2 and B strains, respectively, were 1.24, 1.02 and 1.00 in the two dose group and 1.14, 1.12 and 0.96 in the one dose group.

Transmission Study

FluMist contains 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. The relationship of viral replication in a vaccine recipient and transmission of vaccine viruses to other individuals has not been established.

Using the frozen formulation, a prospective, randomized, double-blind, placebo-controlled trial was performed in a daycare setting in children < 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 8-36 months of age were randomized to receive one dose of FluMist (n=98) or placebo (n=99). Virus shedding was evaluated for 21 days by culture of nasal swab specimens. Wild-type A (H3N2) influenza virus was documented to have circulated in the community and in the study population during the trial, whereas Type 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 (influenza a h1n1 monovalent intranasal vaccine live) , 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 duration of FluMist vaccine virus replication and shedding have not been established.

REFERENCES

1. Centers for Disease Control and Prevention. Serum Cross-Reactive Antibody Response to a Novel Influenza A (H1N1) Virus After Vaccination with Seasonal Influenza Vaccine. MMWR 2009; 58(19): 521-524.

Last reviewed on RxList: 11/5/2009
This monograph has been modified to include the generic and brand name in many instances.

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