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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 as follows].
Pharmacodynamics: Shedding Studies: 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 1. (See Table 1.)
Click on icon to see table/diagram/imageThe 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 Individuals: 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 recipients.
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 243 HIV-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.
Transmission Study: 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.
Clinical Studies: 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 and Adolescents: A multi-national, 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 2 for a description of the results by strain and antigenic similarity. (See Table 2.)
Click on icon to see table/diagram/imageA 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 3 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 3 for a description of the results. (See Table 3.)
Click on icon to see table/diagram/imageDuring the second year of Study AV006, children remained in the same treatment group as in Year 1 and 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 and Adolescents: A multi-center, 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 Adults: 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 4. Effectiveness was not demonstrated for the primary endpoint in adults 18 through 49 years of age. (See Table 4.)
Click on icon to see table/diagram/imageEffectiveness 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 Virus Vaccines: 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.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: FluMist Quadrivalent has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.
