New Cold-Adapted FluMist More Effective Than Shots

SAN FRANCISCO — An experimental, refrigerator-stable formulation of the intranasal influenza vaccine marketed as FluMist was significantly more effective than flu shots in a study of children aged 6–59 months.

In the randomized, double-blind, phase III trial that enrolled more than 8,000 children, the influenza attack rate was 3.9% in children who inhaled the new cold-adapted influenza vaccine trivalent (CAIV-T) vs. 8.6% in those injected with the trivalent inactivated vaccine (TIV), Dr. Robert B. Belshe reported at the annual meeting of the Pediatric Academic Societies.

MedImmune Inc. of Gaithersburg, Md., manufacturer of FluMist, announced on the same day that it will ask the Food and Drug Administration to expand the FluMist indication to children as young as 6 months. MedImmune said it anticipates submitting supporting data by June 30.

The company also will seek approval of the new formulation for use in healthy children and adults aged 5–49 years for whom FluMist is already authorized, according to Dr. Belshe, director of the Center for Vaccine Development at St. Louis University.

As the current formulation must be stored in a freezer large enough to hold a special FluMist box, he predicted physicians will find the refrigerated version more convenient. The only other difference, he said, is that CAIV-T is administered in lower volume (0.2 mL) than the currently licensed FluMist vaccine (0.5 mL).

Dr. Julia McMillan of the American Academy of Pediatrics (AAP) Committee on Infectious Diseases described the possibility of a second vaccine becoming available for use in young children as “potentially a wonderful development” in an interview subsequent to the meeting.

Dr. McMillan, a professor of pediatrics at Johns Hopkins University, Baltimore, declined to comment on the limited data so far available, however, and expressed doubt that all review processes could be completed before next winter.

“It is hard to imagine that there would be both licensure and a recommendation in time for next year's flu season,” she said, distinguishing FDA approval of a vaccine from the AAP and Centers for Disease Control and Prevention recommendations on whom to vaccinate.

Current recommendations call for immunization of all children 6–23 months of age because they are at high risk of hospitalization for influenza. Injectable TIV is the only vaccine approved for this age group, and Dr. McMillan noted that adequate supply has been a problem.

Universal vaccination is not recommended for children older than 23 months. The AAP and CDC call for vaccination of older children only if they have health conditions that put them in a high-risk group.

Dr. McMillan said FluMist is not indicated for these children because it uses a live attenuated virus. Consequently, FluMist is used far less in children than in adults, she said, but this could change if it gains an indication in healthy infants and toddlers for whom universal vaccination is recommended.

Dr. Belshe said that only one adverse event was significantly more common with CAIV-T in the trial, and it occurred in this population. Children younger than 24 months who had not been previously vaccinated were more likely to wheeze at 42 days: 3.2% did so after CAIV-T vs. 2.0% of the TIV group. The increase did not persist beyond 42 days, and was not seen in older children.

The investigators have started a detailed analysis that will balance the risk of 21 additional wheezing cases against the benefit of 75 influenza cases that don't occur, according to Dr. Belshe.

“It's a knotty question,” he said in an interview after his presentation. “You cause a little more wheezing, but you prevent a lot more flu. Is that going to be acceptable to parents and docs? We are trying to understand that risk-benefit right now.”

Otherwise, adverse events were infrequent and similar between the two arms of the trial. In patients not previously vaccinated, 57% of children had runny noses and nasal congestion within 10 days of their first CAIV-T dose vs. 46% of children given their first dose of TIV. The adjusted difference of 1.2% was not statistically significant.

CAIV-T was most effective in preventing type A influenza strains regardless of whether they were well matched or mismatched to the vaccine. Compared with flu shots, it reduced the attack rate for the H1N1A strain by 89% and for the H3 strain by 79%. While the difference in influenza from B-strain viruses was 16.2%, the CAIV-T advantage was not significant.

Investigators at 249 sites enrolled 8,475 children from 16 countries during the 2004–2005 flu season. Of these, 7,836 completed the trial: 3,893 in the CAIV-T arm and 3,943 given TIV. Dr. Belshe said most of the exclusions were due to dosing errors.

The study excluded children with chronic aspirin use, severe asthma, immunosuppression, or wheezing within 42 days. Children with mild to moderate asthma or recurrent wheezing were enrolled. The mean age was 26 months, with 47.5% of the population less than 24 months old.

Just 22% of the children had previously been vaccinated. They received two doses of vaccine a month apart.

To blind the study from investigators, all children received an injection and a nasal formulation. The children given intranasal CAIV-T were injected with a saline solution, while those injected with TIV received saline intranasally.

Dr. Belshe spoke on behalf of the Influenza Vaccine Comparison Trial Group at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

He disclosed that he is a paid consultant for MedImmune and Chiron; gives medical education lectures for Sanofi, Merck, and MedImmune; and has received research grants from Merck and MedImmune, which sponsored the trial.