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Safety, efficacy data support FluMist use in younger children
Data to support indication for toddlers aged 12 to 59 months without a history of wheezing or asthma are undergoing regulatory review.
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ATLANTA — The cold-adapted influenza vaccine trivalent appears safe and effective against influenza in young children aged 12 to 59 months without a history of wheezing or asthma.
At the Meeting of the Advisory Committee on Immunization Practices, Robert Walker, MD, presented data from a study on the safety and efficacy of the cold-adapted influenza vaccine trivalent (CAIV-T; FluMist, MedImmune) in young children. The New England Journal of Medicine published the results from the study, in which CAIV-T was compared with trivalent inactivated vaccine (TIV) in children aged 6 to 59 months.
“The proportion of children with influenza was statistically significantly reduced in the FluMist group compared with the TIV group,” said Walker, who is vice president of clinical development at MedImmune.
However, Walker acknowledged that the risks and benefits of CAIV-T in children with a history of wheezing and asthma and children aged younger than 12 months require further study.
CP111 study
In 2004, Bergen et al and Belshe et al published reports of the AV019 Kaiser study, which was a placebo-controlled trial of CAIV-T. The study consisted of 9,689 children and adolescents aged 1 to 17. The researchers found an increase in asthma and other reactive airway diseases in children aged 18 to 35 months who received CAIV-T (2.2%), compared with children who received placebo (0.54%), according to Walker. A post hoc analysis could not rule out the increased risk in children aged up to 59 months.
The researchers found no increase among children aged older than 5 years, and in some analyses they found the risk for asthma and other reactive airway diseases decreased in older children, Walker said. However, the researchers did not design the study to prospectively assess the risk for asthma, and MedImmune did not seek approval for CAIV-T in children aged younger than 5 years at that time.
Walker and colleagues conducted the CP111 study during the 2004-2005 influenza season. They designed the randomized, double blind study to compare CAIV-T with TIV. CP111 took place at 249 sites in 16 countries. Researchers included 8,475 children aged 6 to 59 months. Exclusion criteria included a known hypersensitivity to any component of CAIV-T, a known immunosuppressive condition and severe or recent medically diagnosed or treated wheezing.
The researchers defined the primary endpoint as culture-confirmed modified CDC influenza-like illness, which included fever plus either sore throat, cough or runny nose/nasal congestion. They defined the safety endpoint as medically significant wheezing, Walker said.
All of the children received their first vaccine dose in October 2004, and the researchers found 153 cases of CDC influenza-like illness in children in the CAIV-T group and 338 cases in children in the TIV group overall for the season. This represented a 55% reduction in influenza in the CAIV-T group (P<.001).
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Adverse events and CAIV-T
The rates of serious adverse events were similar in the CAIV-T and TIV groups. Children in the CAIV-T group had more runny or stuffy noses, and children in the TIV group had more injection site reactions, according to Walker.
The researchers found no increase in medically significant wheezing among children aged at least 2 years in the CAIV-T group. However, they did find a statistically significant increase (P=.076) among children younger than 2 in the CAIV-T group (3.2%) compared with the TIV group (2%) after the first dose.
The increase occurred primarily among children aged 6 to 11 months; 3.8% of children aged 6 to 11 months in the CAIV-T group had medically significant wheezing, compared with 2.1% of children in the TIV group. Among children aged 12 to 23 months, 2.8% of children in the CAIV-T group had medically significant wheezing compared with 2% in the TIV group.
Among children younger than 24 months who had medically significant wheezing within 42 days of the first dose, Walker and colleagues found that the proportion who had tachypnea, dyspnea, retractions or hypoxemia were similar in the CAIV-T group (27%) and the TIV group (26%). Nine children in this age group in the CAIV-T group (0.5%) and three children in the TIV group (0.2%) were hospitalized for medically significant wheezing within 42 days after a dose, according to Walker. None of the children required ICU care or mechanical ventilation, and there were no deaths related to medically significant wheezing.
The researchers analyzed recurrent medically significant wheezing, and found that, among those younger than 24 months who had medically significant wheezing within 42 days, 32% of children in the CAIV-T group compared with 28% in the TIV group had at least one additional episode during the approximate seven month follow up period. In addition, 4.3% of children in the CAIV-T group had two or more additional episodes compared with 5.3% in the TIV group, Walker said.
A post hoc risk-benefit analysis analyzed events through 180 days following last vaccination, and included culture-confirmed modified CDC influenza-like illness, medically significant wheezing and all-cause hospitalization. The researchers also compared event rates in children with and without a history of wheezing or asthma.
Among the 6,580 children who had no history of asthma or wheezing, a statistically significant risk for all-cause hospitalization was observed in the subset of children aged 6 to 11 months, Walker said. However, these children did significantly benefit from CAIV-T against influenza. In children 12 to 59 months of age without a past history of wheezing or asthma there was a non-significant trend in the opposite direction in that there were fewer hospitalizations in children who received FluMist compared with TIV. In children 12 to 59 months of age without a past history of wheezing or asthma, the rates of medically significant wheezing were not statistically different in children who received FluMist (4.7%) compared with TIV (4.9%).
Among the 1,772 children with a history of wheezing or asthma, CAIV-T was associated with a higher risk for medically significant wheezing and all-cause hospitalization in all but the older children (aged 48 to 59 months); however, the elevated risks were not statistically significant, according to Walker. The highest risk occurred among the youngest children aged 6 to 11 months. Until further studies are available, MedImmune will not seek an indication for CAIV-T for children younger than 12 months, Walker said.
The researchers found that in placebo-controlled trials, rates of all serious adverse events (most of which were hospitalizations) and rates of specific serious adverse events of wheezing, pneumonia and gastroenteritis among children in both groups were comparable, Walker said. The researchers selected these serious adverse events to analyze because they were among the most common in the CP111 study. Of the children aged 12 to 59 months and those aged 6 to 11 months in the trials, rates of wheezing, pneumonia and gastroenteritis were similar in the CAIV-T and placebo groups. Children aged 6 to 11 months had higher rates of the severe adverse events than the older children, but the rates in the CAIV-T group were generally lower than the placebo groups, Walker said.
Future indications?
In 2006, Fleming et al reported on a study in which they compared the safety of CAIV-T with TIV in children and adolescents aged 6 to 17 who had asthma (n=2,229). Children with asthma are excluded from the current CAIV-T indication, but the data from Fleming’s study indicate that asthma exacerbations, associated with hospitalizations, unscheduled clinic visits or increased asthma medication use, were similar between children who received TIV and those who received CAIV-T, according to Walker.
“Thus there is no evidence from this study that receiving FluMist resulted in worsening asthma control compared with TIV during the six weeks following vaccination,” Walker said.
The CP111 trial supported the superior efficacy of CAIV-T against matched and mismatched influenza strains compared with TIV, according to Walker. However, the use of CAIV-T among children with a history of wheezing and asthma requires further study.
“The review of placebo-controlled trials supports the safety of FluMist in children 12 to 59 months,” Walker said.
The data to support the proposed indication of CAIV-T in children aged 12 to 59 months are currently under regulatory review.
Dr. Belshe is a consultant for MedImmune.
Dr. Walker is vice president of Clinical Research at MedImmune, and has a direct financial interest in FluMist. – by Lauren Riley
For more information:
- Walker R. FluMist (influenza virus vaccine live, intranasal) safety update. Presented at: Meeting of the Advisory Committee on Immunization Practices; Feb. 21-22, 2007; Atlanta.
- Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.