Safety of the intranasal, trivalent, live attenuated influenza vaccine (LAIV) in children with intermittent wheezing in an open-label field trial.

BACKGROUND: Safety of the intranasal, trivalent, live attenuated influenza vaccine (LAIV) in children with asthma is unknown. A previous report showed an "asthma signal" in children aged 18-35 months. METHODS: Healthy children aged 1.5-18 years with history of intermittent wheezing received single annual LAIV doses during a 4-year trial. Rates of medically-attended acute respiratory illnesses, including acute asthma exacerbation, during 0-14 and 0-42 days post-LAIV were compared with respective reference periods (before day 0 and after 14 or 42 days). To assess the risk of new-onset asthma, LAIV recipients without history of wheezing were analyzed. RESULTS: During each of the 4 years, 454, 656, 656, and 430 children, respectively, with intermittent wheezing who received LAIV had no increased risk for medically-attended acute respiratory illnesses, including asthma exacerbation. First-dose LAIV recipients, including those aged 1.5-4 years, and those receiving 2-4 consecutive annual doses had no increased risk. Children with parents' report of intermittent wheezing and those with administrative database codes for asthma during 2 prior years had no increased risk. During the 4 years, 2952, 3092, 2953, and 2478 children without history of wheezing had no increased risk of new-onset asthma. CONCLUSIONS: LAIV administration in children aged 1.5-18 years with history of intermittent wheezing was safe, and was not associated with increased risk for medically-attended acute respiratory illnesses, including acute asthma exacerbation. This was true for the first and 2-4 consecutive annual doses. Parents' report of intermittent wheezing was reliable. First-dose LAIV was not associated with new-onset asthma in children without history of wheezing.

Trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children.

OBJECTIVE: Live attenuated influenza vaccine may protect against wild-type influenza illness shortly after vaccine administration by innate immunity. The 2003-2004 influenza A (H3N2) outbreak arrived early, and the circulating strain was antigenically distinct from the vaccine strain. The objective of this study was to determine the effectiveness of influenza vaccines for healthy school-aged children when administered during the influenza outbreak. DESIGN/METHODS: An open-labeled, nonrandomized, community-based influenza vaccine trial was conducted in children 5 to 18 years old. Age-eligible healthy children received trivalent live attenuated influenza vaccine. Trivalent inactivated influenza vaccine was given to children with underlying health conditions. Influenza-positive illness was compared between vaccinated and nonvaccinated children. Medically attended acute respiratory illness and pneumonia and influenza rates for Scott and White Health Plan vaccinees were compared with age-eligible Scott and White Health Plan nonparticipants in the intervention communities. Herd protection was assessed by comparing age-specific medically attended acute respiratory illness rates in Scott and White Health Plan members in the intervention and comparison communities. RESULTS: We administered 1 dose of trivalent live attenuated influenza vaccine or trivalent inactivated influenza vaccine to 6569 and 1040 children, respectively (31.5% vaccination coverage), from October 10 to December 30, 2003. The influenza outbreak occurred from October 12 to December 20, 2003. Significant protection against influenza-positive illness (37.3%) and pneumonia and influenza events (50%) was detected in children who received trivalent live attenuated influenza vaccine but not trivalent inactivated influenza vaccine. Trivalent live attenuated influenza vaccine recipients had similar protection against influenza-positive illness within 14 days compared with >14 days (10 of 25 vs 9 of 30) after vaccination. Indirect effectiveness against medically attended acute respiratory illness was detected in children 5 to 11 and adults 35 to 44 years of age. CONCLUSION: One dose of trivalent live attenuated influenza vaccine was efficacious in children even when administered during an influenza outbreak and when the dominant circulating influenza virus was antigenically distinct from the vaccine strain. We hypothesize that trivalent live attenuated influenza vaccine provides protection against influenza by both innate and adaptive immune mechanisms.

Efficacy of trivalent, cold-adapted, influenza virus vaccine against influenza A (Fujian), a drift variant, during 2003-2004.

In the 2003-2004 influenza season, the predominant circulating influenza A (H3N2) virus in the United States was similar antigenically to A/Fujian/411/2002 (H3N2), a drift variant of A/Panama/2007/99 (H3N2), the vaccine strain. That year, a field study of trivalent live-attenuated influenza vaccine (LAIV-T) was conducted in Temple-Belton, Texas, as part of a larger community-based, non-randomized, open-label study in three communities that began in August 1998 [Gaglani MJ, Piedra PA, Herschler GB, Griffith ME, Kozinetz CA, Riggs MW, et al. Direct effectiveness of the trivalent, cold-adapted, influenza virus vaccine (CAIV-T) against the 2000-2001 influenza A (H1N1) and B epidemic in healthy children. Arch Pediatr Adolesc Med 2004;158:65-73; Piedra PA, Gaglani MJ, Kozinetz CA, Herschler G, Riggs M, Griffith M, et al. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 2005;23:1540-8; Piedra PA, Gaglani MJ, Riggs M, Herschler G, Fewlass C, Watts M, et al. Live attenuated influenza vaccine, trivalent, is safe in healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-based, nonrandomized, open-label trial. Pediatrics 2005;116:397-407]. Participants were healthy children aged 5-18 years. The analysis here concerns 6403 children in the Scott & White Health Plan (SWHP) database living within zip codes of the Temple-Belton area, of whom 1706 received LAIV-T and 548 received trivalent inactivated vaccine (TIV) in 2003, 983 had been previously vaccinated in 1998-2001, but not in 2002-2003 or 2003, and 3166 had never been vaccinated. The main outcome measure was medically-attended acute respiratory illness (MAARI). Surveillance culture results were incorporated into the analysis to estimate efficacy against culture-confirmed influenza illness. Vaccine effectiveness of LAIV-T against MAARI was 26% (95% confidence interval (CI) 11, 39). Vaccine efficacy of LAIV-T against culture-confirmed influenza illness including surveillance cultures of children in the SWHP database in the validation calculation was 56% (95% CI 24, 84). LAIV-T was cross-protective with a drift variant strain in 2003-2004, evidence that such vaccines could be important for preparing for a pandemic and for annual influenza.

Live attenuated influenza vaccine, trivalent, is safe in healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-based, nonrandomized, open-label trial.

OBJECTIVE: Influenza-associated deaths in healthy children that were reported during the 2003-2004 influenza season heightened the public awareness of the seriousness of influenza in children. In 1996-1998, a pivotal phase III trial was conducted in children who were 15 to 71 months of age. Live attenuated influenza vaccine, trivalent (LAIV-T), was shown to be safe and efficacious. In a subsequent randomized, double-blind, placebo-controlled LAIV-T trial in children who were 1 to 17 years of age, a statistically significant increase in asthma encounters was observed for children who were younger than 59 months. LAIV-T was not licensed to children who were younger than 5 years because of the concern for asthma. We report on the largest safety study to date of the recently licensed LAIV-T in children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a 4-year (1998-2002) community-based trial that was conducted at Scott & White Memorial Hospital and Clinic (Temple, TX). METHODS: An open-label, nonrandomized, community-based trial of LAIV-T was conducted before its licensure. Medical records of all children were surveyed for serious adverse events (SAEs) 6 weeks after vaccination. Health care utilization was evaluated by determining the relative risk (RR) of medically attended acute respiratory illness (MAARI) and asthma rates at 0 to 14 and 15 to 42 days after vaccination compared with the rates before vaccination. Medical charts of all visits coded as asthma were reviewed for appropriate classification of events: acute asthma or other. We evaluated the risk for MAARI (health care utilization for acute respiratory illness) 0 to 14 and 15 to 42 days after LAIV-T by a method similar to the postlicensure safety analysis conducted on measles, mumps, and rubella and on diphtheria, tetanus, and whole-cell pertussis vaccines. RESULTS: All children regardless of age were administered a single intranasal dose of LAIV-T in each vaccine year. In the 4 years of the study, we administered 18780 doses of LAIV-T to 11096 children. A total of 4529, 7036, and 7215 doses of LAIV-T were administered to children who were 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age, respectively. In vaccination years 1, 2, 3, and 4, we identified 10, 15, 11, and 6 SAEs, respectively. None of the SAEs was attributed to LAIV-T. In vaccination years 1, 2, 3, and 4, we identified 3, 2, 1, and 0 pregnancies, respectively, among adolescents. All delivered healthy infants. The RR for MAARI from 0 to 14 and 15 to 42 days after LAIV-T was assessed in vaccinees during the 4 vaccine years. Compared with the prevaccination period, there was no significant increase in risk in health care utilization attributed to MAARI from 0 to 14 and 15 to 42 days after vaccination in children who were 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in the 4 vaccine years. In children who were 18 months to 4 years of age, there was no significant increase in the risk in health care utilization for MAARI, MAARI subcategories (otitis media/sinusitis, upper respiratory tract illness, and lower respiratory tract illness), and asthma during the 0 to 14 days after vaccination compared with the prevaccination period. No significant increase in the risk in health care utilization for MAARI, MAARI subcategories, and asthma was detected when the risk period was extended to 15 to 42 days after vaccination, except for asthma events in vaccine year 1. A RR of 2.85 (95% confidence interval [CI]: 1.01-8.03) for asthma events was detected in children who were 18 months to 4 years of age but was not significantly increased for the other 3 vaccine years (vaccine year 2, RR: 1.42 [95% CI: 0.59-3.42]; vaccine year 3, RR: 0.47 [95% CI: 0.12-1.83]; vaccine year 4, RR: 0.20 [95% CI: 0.03-1.54]). No significant increase in the risk in health care utilization for MAARI or asthma was observed in children who were 18 months to 18 years of age and received 1, 2, 3, or 4 annual sequential doses of LAIV-T. Children who were 18 months to 4 years of age and received 1, 2, 3, or 4 annual doses of LAIV-T did not experience a significant increase in the RR for MAARI 0 to 14 days after vaccination; this was also true for children who were 5 to 9 and 10 to 18 years of age. CONCLUSIONS: We observed no increased risk for asthma events 0 to 14 days after vaccination in children who were 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age, In vaccine year 1, children who were 18 months to 4 years of age did have a significantly higher RR (2.85; 95% CI: 1.01-8.03) for asthma events 15 to 42 days after vaccination. In vaccine year 2, the formulation of LAIV-T was identical to the vaccine formulation used in vaccine year 1; however, in children who were 18 months to 4 years of age, no statistically significant increased risk was detected for asthma events 15 to 42 days after vaccination. Similarly, in vaccine years 3 and 4, children who were 18 months to 4 years of age did not have a statistically significant increased risk for asthma events 15 to 42 days after vaccination. Also, LAIV-T did not increase the risk for asthma in children who received 1, 2, 3, or 4 annual doses of LAIV-T. Although the possibility for a true increased risk for asthma was observed in 1 of 4 years in children who were 18 months to 4 years at 15 to 42 days after vaccination, it is more likely that the association is a chance effect because of the 190 comparisons made without adjustment for multiple comparisons. We conclude that LAIV-T is safe in children who are 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age. The hypothesis that LAIV-T is associated with an increase in asthma events in children who are younger than 5 years is not supported by our data. Reassessment of the lower age limit for use of LAIV-T in children is indicated.

Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children.

Highest attack rates for influenza occur in children. Immunization of schoolchildren with inactivated influenza vaccine in Michigan and Japan was associated with decreased morbidity and mortality, respectively, in older community contacts. An open-labeled, non-randomized, community-based trial in children with the cold adapted influenza vaccine, trivalent (CAIV-T) was initiated to determine the coverage necessary to reduce spread of influenza in the community. Age-specific baseline rates of medically attended acute respiratory illness (MAARI) for Scott and White Health Plan (SWHP) members at intervention (Temple and Belton) and comparison communities (Waco, Bryan, and College Station) were obtained in 1997-1998. During three subsequent vaccination years, 4298, 5251 and 5150 children received one dose per season of CAIV-T. Vaccinees represented 20-25% of the age-eligible children. Age-specific MAARI rates were compared for SWHP members in the intervention and comparison sites during the influenza outbreaks. Baseline age-specific MAARI rates per 100 persons for the influenza season were comparable between the intervention and comparison communities. In the subsequent three influenza seasons, the age groups 35-44, 45-54, 55-65 and >64 years experienced reductions in MAARI rates in the intervention communities. In adults > or =35 years of age, significant reductions in MAARI of 0.08 (95% CI: 0.04, 0.13), 0.18 (95% CI: 0.14, 0.22) and 0.15 (95% CI: 0.12, 0.19), were observed in the influenza seasons for vaccination years 1, 2 and 3, respectively. No consistent reduction in MAARI rates was detected in the younger age groups. Vaccination of approximately 20-25% of children, 1.5-18 years of age in the intervention communities resulted in an indirect protection of 8-18% against MAARI in adults > or =35 years of age.

Direct and total effectiveness of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine against the 2000-2001 influenza A(H1N1) and B epidemic in healthy children.

BACKGROUND: The efficacy of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine (CAIV-T) against influenza A(H3N2) and B infections in healthy persons is established, but its effectiveness against natural influenza A(H1N1) infection is unknown. OBJECTIVE: To assess the effectiveness of CAIV-T in healthy children during the 2000-2001 influenza A(H1N1) and B epidemic. DESIGN: Community-based, nonrandomized, open-label trial from August 1998 through April 2001. SETTING: Intervention and comparison communities in central Texas. PARTICIPANTS: Healthy children, aged 1.5 to 18 years, from the intervention communities received a single dose of CAIV-T at least 1 time or more in 1998, 1999, and/or 2000. MAIN OUTCOME MEASURES: The incidence of medically attended acute respiratory illnesses during the 2000-2001 influenza epidemic was compared in 3794 health plan CAIV-T recipients with age-eligible, health plan nonrecipients in the intervention communities for direct effectiveness (n = 9325), and with those in the 2 comparison communities for total effectiveness (n = 16,264). RESULTS: The 2281 CAIV-T recipients in 2000 had significant direct protection against medically attended acute respiratory illness of 18% to 20% during the biphasic influenza A(H1N1) and B epidemic, and 17% to 26% during influenza A(H1N1) predominance. The 931 recipients of CAIV-T in 1999 containing influenza A/Beijing/262/95(H1N1) and B/Beijing/184/93-like viruses had persistent heterovariant protection against the 2000-2001 influenza A/New Caledonia/20/99(H1N1) and B/Sichuan/379/99 variants. The 616 recipients of a single CAIV-T dose in 1999 only, including those younger than 5 years with no prior natural exposure to influenza A(H1N1) viruses, showed persistent protection. CONCLUSION: Healthy children who received CAIV-T in 2000 or 1999 were protected against new variants of influenza A(H1N1) and B in the 2000-2001 influenza epidemic.