Mechanism of Action

Immunemechanisms 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. Therefore, influenza vaccines are standardized to contain the strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year [1].

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

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 overmultiple years, using different vaccine strains. Safety and efficacy have been studied where FluMist was compared to an inactivated influenza vaccine made by Sanofi Pasteur Inc. among children as young as 6 months of age. FluMist is not approved for use in children < 24 months of age [see ADVERSE REACTIONS].

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 vaccinemade 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-confirmedmodified CDC-ILI (CDC-defined influenza-like illness) was defined as a positive culture for a wild-type influenza virus associated within ±7 days ofmodified 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-ILI^a Caused by Wild-Type Strains in Children < 5 Years of Age

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 cultureconfirmed 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 antigenicallymatched 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 : Efficacy^a of FluMist vs. Placebo Against Culture-Confirmed Influenza Illness Due to Antigenically Matched Wild-Type Strains (D153-P501 & AV006, Year 1)

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 FluMist^a in Adults 18-49 Years of Age During the 7-Week Site-Specific Outbreak Period

Effectiveness was shown in a post-hoc analysis using CDC-ILI in the age group 18-49 years.

Studies in Immunocompromised Individuals

Safety and shedding of vaccine virus following FluMist administration (frozen formulation) were evaluated in 28 HIV-infected adults [median CD4 cell count of 541 cells/mm³] and 27 HIV-negative adults 18-58 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 recipients.

Safety and shedding of vaccine virus following FluMist administration (frozen formulation) were also evaluated in children in a randomized (1:1), cross-over, double-blind, placebo-controlled trial in 24 HIVinfected children [median CD4 cell count of 1013 cells/mm³] and 25 HIV-negative children 1-7 years of age, and in a randomized (1:1), open-label, inactivated influenza vaccine-controlled trial in 243 HIV-infected children and adolescents 5-17 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 5-17 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 in preventing influenza illness in HIV-infected individuals has not been evaluated.

Twenty mild to moderately immunocompromised children and adolescents 5-17 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 (frozen formulation) or 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 in preventing influenza illness in immunocompromised 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.

Shedding Studies

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 (shedding). Shedding of vaccine viruses within 28 days of vaccination was evaluated in 1) multi-center study MI-CP129 which enrolled healthy individuals 6-59 months of age (N = 200); and 2) multi-center study FM026 which enrolled healthy individuals 5-49 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 6.

Table 6 : Characterization of Shedding in Specified Age Groups by Frequency, Amount, and Duration

The highest proportion of subjects in each group shed one or more vaccine strains on Days 2-3 postvaccination. After Day 11 among individuals 2-49 years of age (n = 443), virus titers did not exceed 1.5 log₁₀ TCID50/mL.

Transmission Study

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 temperaturesensitive (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.

REFERENCES

1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010; 59(RR-8): 1-62.

Last reviewed on RxList: 1/10/2012
This monograph has been modified to include the generic and brand name in many instances.