During year 1, the LAIV–LAIV and LAIV–placebo regimens showed efficacy of LAIV against influenza strains antigenically similar to those in the vaccine of 73.5% (95% CI: 63.6–81.0) and 57.7% (95% CI: 44.7–67.9), respectively (Table 2). Relative efficacy for subjects randomized to LAIV–LAIV was significantly higher than that of the LAIV–placebo group (37.3%; 95% CI: 9.5–56.9; Table 2).
In year 1, the majority of influenza cases were caused by strains antigenically similar to the vaccine strains, and consequently, the efficacies against any community acquired subtypes were similar: 72.0% (95% CI: 61.9–79.8) and 56.3% (95% CI: 43.1–66.7) for the LAIV–LAIV and LAIV–placebo groups, respectively (Table 2).
In the year 2 per-protocol population, the LAIV–LAIV/LAIV and LAIV–placebo/LAIV regimens showed significant efficacy against any strain of influenza virus antigenically similar to those in the vaccine: 73.6% (95% CI: 33.3–91.2) and 65.2% (95% CI: 31.2–82.8) for the LAIV–LAIV and LAIV–placebo groups, respectively (Table 2). There was no statistically significant difference in efficacy between the LAIV–LAIV/LAIV group and the LAIV–placebo/LAIV group. Many cases observed in year 2 were caused by an antigenically dissimilar influenza B strain and efficacy of LAIV–LAIV/LAIV or LAIV–placebo/LAIV against any community-acquired subtype was lower (ie, 46.6% and 46.4%, respectively).
Two doses of LAIV in year 1 (LAIV–LAIV/placebo) provided 57.0% efficacy (95% CI: 6.1–81.7) against antigenically similar strains through a second influenza season without revaccination compared with placebo (placebo–placebo/placebo). Efficacy was 35.3% (95% CI: −0.3, 58.7) and 20.4% (95% CI: −33.6, 52.9) against any community-acquired strain and antigenically dissimilar influenza B strains, respectively. In addition, comparison of placebo–placebo/LAIV and placebo–placebo/placebo in year 2 demonstrated 60.3% (95% CI: 10.9–83.8) efficacy of a single dose of LAIV against matched strains in children previously unvaccinated against influenza. Against any community-acquired strain and antigenically dissimilar influenza B strains, efficacy was 59.4% (95% CI: 32.3–76.4) and 54.9% (95% CI: 16.6–76.6), respectively.
The LAIV–LAIV regimen in year 1 was significantly effective against the first episode of AOM, the first and all episodes of febrile AOM, and the first and all episodes of influenza-associated AOM caused by strains antigenically similar to those in the vaccine (Table 3). The LAIV–placebo regimen was also significantly effective against the first episode of AOM and the first and all episodes of AOM associated with influenza strains antigenically similar to those in the vaccine (Table 3). The small number of subjects in the LAIV–LAIV/LAIV group during year 2 (n = 338) may have precluded any demonstration of efficacy against AOM; however, in year 2, LAIV–placebo/LAIV (n = 684) was effective against all episodes of AOM and febrile AOM and against the first and all episodes of AOM associated with culture-confirmed influenza (Table 3). The rates of any LRI in year 1 were similar among the 3 randomized treatment groups (LAIV–LAIV, LAIV–placebo, and placebo–placebo), that is, 20.4% (n = 193), 18.8% (n = 176), and 19.0% (n = 179), respectively (see Table 4, Supplemental Digital Content 2, http://links.lww.com/A873). The year 1 immunogenicity cohort consisted of 406 subjects of whom 334 (82%) were evaluable (LAIV–LAIV/LAIV, n = 113; LAIV–placebo/LAIV, n = 112; placebo–placebo/placebo, n = 109). In the evaluable immunogenicity population, seroconversion rates (P ≤ 0.003), GMTs, geometric mean fold rises (GMFRs), and ratios of GMFRs in year 1 were higher among LAIV–LAIV and LAIV–placebo recipients than placebo recipients (see Tables 5 and 6, Supplemental Digital Content 3 and 4, http://links.lww.com/A874 and http://links.lww.com/A875). Seroconversion rates and GMFRs after 2 doses of LAIV were significantly higher than after 1 dose (LAIV–LAIV vs. LAIV–placebo, P ≤ 0.037 for seroconversion rates; P < 0.001 for GMFRs).
The year 2 immunogenicity cohort consisted of 861 subjects of whom 524 (61%) were evaluable (LAIV–LAIV/LAIV, n = 133; LPS/L, n = 265; PP/P, n = 126). In year 2, increases in seroconversion rates and GMTs were noted among the immunogenicity-evaluable population for each LAIV group postvaccination (see Tables 5 and 7, Supplemental Digital Content 3 and 5, http://links.lww.com/A874 and http://links.lww.com/A876). Baseline seronegative patients had higher seroconversion rates than all subjects in both years (see Table 5, Supplemental Digital Content 3, http://links.lww.com/A874).
The most frequent reactogenicity events for all treatment groups after each dose were cough and runny nose/nasal congestion. No significant differences in the incidence of reactogenicity events were noted between excipient placebo and saline placebo recipients (all P ≥ 0.073; see Table 8, Supplemental Digital Content 6, http://links.lww.com/A877). However, comparing across all 3 groups, after dose 1 more saline placebo recipients had cough (58.2%) than excipient placebo recipients (53.9%) and LAIV recipients (50.3%) (P < 0.004).
The proportions of subjects experiencing one or more adverse events within 11 days after vaccination were similar among the treatment groups. The incidence for any event among LAIV, excipient placebo, and saline placebo recipients was 27.2% and 29.1%, 28.2% and 27.5%, and 29.0% and 26.7%, after dose 1 and dose 2, respectively. In season 2, the incidence of any event for LAIV or saline placebo recipients was 23.8% for each group.
The most frequently reported adverse events within 11 days after each of the 3 doses were administered were fever, upper respiratory tract infection, rhinitis, and coughing (see Table 9, Supplemental Digital Content 7, http://links.lww.com/A878). No statistically significant differences were noted among treatment groups for these events after any dose. The incidence of respiratory adverse events was similar among LAIV, excipient placebo, and saline placebo recipients in year 1 and LAIV and saline placebo recipients in year 2 (17.2%, 17.6%, and 18.6%; and 13.6% and 14.0% in years 1 and 2, respectively). The incidences of bronchitis (1.2%, 1.6%, and 1.7%; 1.2% and 0.5%, respectively) and bronchospasm (1.0%, 1.3%, and 0.8%; 0.7% and 1.2%, respectively) were also similar across treatment groups.
In year 2, the most frequently reported adverse events within 28 days after treatment were upper respiratory tract infection, rhinitis, fever, and coughing. No statistically significant differences were noted between treatment groups for these events. The incidence of respiratory adverse events was similar between LAIV and saline placebo recipients (28.3% and 28.5%, respectively). The incidences of bronchospasm (1.8% and 1.5%, respectively) were also similar between groups, but there was a significant difference in the rate of bronchitis between LAIV and saline placebo recipients (3.1% and 1.6%, respectively; P = 0.046).
In year 1, ≥1 serious adverse event was reported by 5.0% of LAIV–LAIV recipients, 3.8% of LAIV–placebo recipients, 3.4% of excipient placebo recipients, and 4.1% of saline placebo recipients. In year 2, 1.6% and 2.4% of LAIV and placebo recipients, respectively, reported ≥1 serious adverse event. The majority were respiratory events. Serious adverse events considered to be related to study product were reported in 29 subjects; the most frequent were pneumonia, bronchopneumonia, bronchiolitis, and bronchitis. Three deaths were reported; 2 deaths were accidental and 1 death was the result of Escherichia coli septicemia diagnosed 18 days after receipt of the second dose of LAIV in year 1. No death was judged to be related to the study product.
In children 6 to <36 months of age who were previously unvaccinated against influenza at enrollment, 1 and 2 doses of LAIV provided clinically significant protection against influenza illness. Efficacy of 2 doses was statistically and clinically significantly greater than the efficacy observed after 1 dose. These data confirm observations from 2 previous studies in influenza vaccine–naive young children that demonstrated 60%, 67%, and 89% efficacy versus placebo after a single dose of LAIV.12–14 After revaccination with a single dose in year 2, no significant differences in efficacy were found between children who were vaccinated with 1 dose versus 2 doses in the previous year. Given the implementation hurdles of compliance with the recommended 2-dose regimen, clinically significant efficacy against influenza illness after a single dose of LAIV is reassuring.12,14 The efficacy of 1 dose of LAIV, ranging from 57.7% (95% CI: 44.7–67.9) to 89% (95% CI: 65–96) in various studies,12 is comparable with that reported for 2 doses of TIV in children <9 years of age in a recent meta-analysis: 63% (95% CI: 45–70),15 but 2 doses of LAIV provide increased protection, and efforts to increase 2-dose compliance should continue.
The unintended year 2 treatment error permitted additional analyses. Vaccine protection against viruses antigenically similar to those in the vaccine, predominantly A/H1N1 strains, persisted through a second season without revaccination, with an efficacy of 57.0% (95% CI: 6.1–81.7). This observation is similar to a previous estimate of the persistent efficacy of 2 doses of LAIV through a second season without revaccination, which was 56.2% (95% CI: 30.5–72.7) against predominantly A/H3N2 strains.14 However, the treatment allocation error also reduced the sample size of 2 protocol-specified cohorts, namely placebo–placebo/placebo and LAIV–LAIV/LAIV. This limited the statistical power to observe differences in the LAIV–LAIV/LAIV cohort, as seen in the season 2 AOM endpoints.
As expected, immunogenicity was demonstrated in subjects receiving LAIV in year 1; subjects receiving LAIV continued to show increases in seroconversion in year 2, regardless of baseline serostatus. These findings support previous results from efficacy field trials of LAIV in children.14,16
Influenza in children is frequently complicated by AOM.2,17–19 Effectiveness of TIV in reducing the incidence of AOM associated with influenza has varied depending on the age of subjects studied, the circulating influenza strains, and the influenza attack rates in a given season.17,20–22 Similar variability has been reported in previous studies with LAIV.12,16,23,24 In particular, LAIV was shown in 1 study to reduce the incidence of febrile AOM by 30%.12 This study provides the first evidence that LAIV can significantly reduce the overall incidence of AOM, regardless of whether the AOM was associated with a positive influenza culture. Although efficacy against AOM has been shown in this study, a similar effect against all-cause LRI was not observed. Influenza-associated LRI was not analyzed in this study; therefore it is possible that the lack of effect against LRI may be because pathogens other than influenza were more common causes of LRI in this population during the season studied. In a subsequent comparative study of LAIV and inactivated influenza vaccine in children 6 to 59 months of age, LAIV demonstrated a 50.6% (P = 0.004) and 45.9% (P = 0.046) reduction in influenza-associated AOM and LRI, respectively, compared with the inactivated vaccine.25
LAIV was well tolerated; no significant differences in solicited reactogenicity events were seen between treatment groups. LAIV was not associated with an increased rate of adverse events through day 11 postvaccination. When adverse events were assessed through day 28 postvaccination in year 2, the rate of bronchitis was significantly increased in LAIV recipients, although rates of bronchospasm and any respiratory adverse events were similar between groups. Additionally, no differences in solicited reactogenicity events or other adverse events were seen after either saline or excipient placebo. This suggests that the excipients in LAIV, which include egg protein and acid-hydrolyzed gelatin, do not contribute to reactogenicity in vaccine recipients.
In this study, a single dose of LAIV provided clinically significant protection against influenza in young children previously unvaccinated against influenza and 2 doses provided persistent protection through a second season without revaccination. These benefits, together with the vaccine's safety profile in children 2 years of age and older,25 provide support for increased use of LAIV in children ≥2 years of age.
The authors thank the participating children and their parents, the study nurses and coordinators, the clinical testing laboratory staff, the clinical research associates and the scientists at Wyeth and MedImmune; Anita Moradoghli-Haftvani, who served as clinical project manager for this study; Drs. Maria Zambon and Richard Ward for performing the hemagglutination inhibition laboratory testing; Dr. Ruth Rappaport for nasal wash IgA ELISA testing, virus strain identification by PCR sequencing, and virus genotyping; Dr. Sheau-Mei Cheng for virus genotyping; Drs. Guadalupe Carballal, Celso Granato, and Nigel Blackburn for virus detection and isolation testing; Drs. Vilma Savy, Alan Hampson, Barry D. Schoub, and Nigel Blackburn for virus strain identification by serotyping; Dr. Jonathan B. Skinner for performing statistical analyses; and Christopher S. Ambrose, MD, and Robert E. Walker, MD, for their critical review of the manuscript and insightful comments, and John E. Fincke, PhD, and Gerard P. Johnson, PhD, who provided medical writing and editorial assistance.
The D153-P504 LAIV Study Group—-Argentina: Silvia Elena Gonzalez Ayala, Hospital Interzonal de Agudos Especializado en Pediatría, La Plata-Buenos Aires; Rosa María Bologna, Hospital Garrahan, Buenos Aires; Liliana María Calanni, CEIN Unidad Infectologica, Neuquén; Enrique Vicente Casanueva, Avenida Cabildo, Buenos Aires; Jose María Ceriani Cernadas, Hospital Italiano Vacunatorio, Buenos Aires; Eduardo Antonio Chiocconi, CEIN Unidad Infectologica, Neuquén; Aida Mercedes Torres de Navajas, FUNCEI, Buenos Aires; Luisa Mariana de Wouters, Hospital Privado de La Comunidad, Mar del Plata; Fernando Claudio Ferrero, Hospital Pedro Elizalde, Buenos Aires; Eduardo Luis Lopez, Hospital de Niños R. Gutierrez, Buenos Aires; Guillermo Fernandez Mac Loughlin, PAIDEIA, Buenos Aires; Raul Oscar Ruvinsky, Departamento Materno-Infantil del Hospital C.G. Durand, Buenos Aires; Jorge Bernardo Taborda, Buenos Aires; Ricardo Augusto Teijeiro, Hospital Ignacio Pirovano, Buenos Aires; Miguel Wenceslao Tregnaghi, Centro de Desarrollo de Proyectos Avanzados Hospital Infantil de Córdoba, Córdoba. Brazil: Emílio Carlos Elias Baracat, Hospital de Clínicas da UNICAMP, Campinas; Eitan Naaman Berezin, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo; Lúcia Ferro Bricks, Centro de Saúde Escola Prof Samuel B Pessoa–São Paulo, São Paulo; Antônio José Ledo Alves da Cunha, Instituto de Puericultura e Pediatria Martagão Gesteira da Universidade Federal do Rio de Janeiro, Rio de Janeiro; Clóvis Arns da Cunha, Hospital Nossa Senhora das Graças, Curitaba; Themis Reverbel da Silveira, Hospital de Clínicas de Porto Alegre, Porto Alegre; Calil Kairalla Farhat, Federal University of São Paulo, São Paulo; Victor Hugo Campos Lagos, Universidade Federal de Pelotas, Pelotas; Humberto Bracco Neto, Federal University of São Paulo, São Paulo; Priscila Maria de Oliveira Papaiordanou, Hospital de Clínicas da UNICAMP, Campinas; Renato Tetelbom Stein, Hospital São Lucas da Pontifícia Universidade Católica, Porto Alegre; Lily Yin Weckx, Centro de Referência de Imunobiológicos Especiais Universidade Federal de São Paulo, São Paulo. South Africa: Susan Annandale, 1 Military Hospital, Pretoria; Shabir A. Madhi, Chris Hani-Baragwanath Hospital, Johannesburg; H. Siebert, Sr Karien Camphor Nursing Clinic, Pretoria; E. J. Smit, Sr Karien Camphor Nursing Clinic, Pretoria; A. D. Steele, MEDUNSA, Pretoria; C. M. Taylor, Clintrial Consultants, Potchefstroom; A.E. van der Vyver, University of the Free State, Bloemfontein; Jacobus C. van Dyk, Femina Clinic, Pretoria; Jan. H. Vermeulen, Panorama Mediclinic, Cape Town; Azeem H. Walele, Wynberg, 2 Military Hospital, Cape Town; H. C. Weber, Jan S. Marais Hospital, Bellville Cape Town.
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Supplemental Digital Content
© 2009 Lippincott Williams & Wilkins, Inc.