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 18 780 doses of LAIV- T to 11 096 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.

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.

BACKGROUND:Three important studies have supported licensure of live, attenuated, cold-adapted influenza vaccine (CAIV-T [FluMist; MedImmune Vaccines]): (1) a pediatric efficacy trial involving children 15-71 months of age, (2) a large safety study of medically attended events occurring among children 1-17 years of age, and (3) an effectiveness trial involving healthy working adults 18-64 years of age.METHODS:During the United States Food and Drug Administration (FDA) review for the approval of CAIV-T for use in healthy persons, additional subgroup analyses were conducted to evaluate the safety, efficacy, and effectiveness of the vaccine, by use of various age subsets not prespecified by the original protocols. CAIV-T is currently approved by the FDA for use in healthy persons 5-49 years of age. In this article, we present data from some of the aforementioned subanalyses.RESULTS:The efficacy of CAIV-T in children >or=5 years of age (age range of the children in year 1 of the study, 60-71 months; age range of the children in year 2 of the study, 60-83 months) was similar to that reported for the entire cohort in year 1 (90.6%; 95% confidence interval [CI], 70.3%-97.1%). In year 2 of the study, efficacy was 86.9% (95% CI, 70.8%-94.1%), despite the presence of antigenically drifted influenza type A/Sydney/5/97 (H3N2), which caused most illnesses that occurred in year 2. Safety outcomes for children 5-17 years of age revealed no significant difference between vaccine recipients and placebo recipients, with regard to acute respiratory events, acute gastrointestinal events, systemic bacterial infection, or rare events possibly related to influenza. Effectiveness among adults 18-49 years of age was similar to that reported for the entire cohort--for example, for occurrence of severe febrile illness, there was a 19.5% reduction (P=.02) in adults.CONCLUSIONS:The present reanalysis summarizes data on the indicated uses for CAIV-T in the indicated population aged 5-49 years.

Objective. To determine the safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV) in children and adolescents. Study design. A randomized, double blind, placebo-controlled safety trial in healthy children age 12 months to 17 years given CAIV (FluMist; MedImmune Vaccines, Inc.) or placebo (randomization, 2:1). Children <9 years of age received a second dose of CAIV or placebo 28 to 42 days after the first dose. Enrolled children were then followed for 42 days after each vaccination for all medically attended events. Prespecified outcomes included 4 prespecified diagnostic groups and 170 observed individual diagnostic categories. The relative risk and the 2-sided 90% confidence interval were calculated for each diagnostic group and individual category by clinical setting, dose and age. More than 1500 relative risk analyses were performed. Results. A total of 9689 evaluable children were enrolled in the study. Of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events and rare events potentially associated with wild-type influenza), none was associated with vaccine. Of the biologically plausible individual diagnostic categories, 3, acute gastrointestinal events, acute respiratory events and abdominal pain, had different analyses that demonstrated increased and decreased relative risks, making their association with the vaccine unlikely. For reactive airway disease a significant increased relative risk was observed in children 18 to 35 months of age with a relative risk of 4.06 (90% confidence interval, 1.29 to 17.86) in this age group. The individual diagnostic categories of upper respiratory infection, musculoskeletal pain, otitis media with effusion and adenitis/adenopathy had at least one analysis that achieved a significant increased risk ratio. All of these events were infrequent. Conclusion. CAIV was generally safe in children and adolescents. The observation of an increased risk of asthma/reactive airway disease in children <36 months of age is of potential concern. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine.

Background. Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children. Purpose. To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma. Methods. In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination. Results. The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2%vs. 0.4% for the treatment and placebo groups, respectively;P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 ≥15% from baseline, reductions in peak flows ≥15%, ≥30% or ≥2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively;P = 1.0). No serious adverse event occurred. Conclusion. CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.