Large study supports FluMist use in toddlers

Feb 16, 2007 (CIDRAP News) – The live-virus, intranasal influenza vaccine FluMist strongly outperformed conventional killed-virus vaccines in a study involving close to 8,000 children younger than 5 years, a finding that may help pave the way for US approval of the vaccine for that age-group.

In the international trial conducted in the 2004-05 flu season, there were almost 55% fewer cases of flu in children who received FluMist than in those who received the conventional injectable vaccine, according to a report published in the Feb 15 New England Journal of Medicine (NEJM). The live vaccine worked better than the conventional ones regardless of how well the vaccines matched the circulating viruses.

"It's a pretty convincing result," commented vaccine expert John Treanor, MD, of the University of Rochester (New York), who was not involved in the research.

On the downside, 6- to 11-month-old children in the FluMist group had significantly more hospitalizations for any reason after vaccination and also had a few more episodes of wheezing than their counterparts in the other group.

FluMist is currently licensed for use in healthy people between the ages of 5 and 49. On the basis of their findings, the authors, led by Robert B. Belshe, MD, of St. Louis University, conclude that the vaccine is effective and safe for children from 12 to 59 months old with no history of asthma or wheezing.

The Centers for Disease Control and Prevention (CDC) currently recommends annual flu vaccination for children from 6 through 59 months old, among other groups considered to have an increased risk of serious complications from flu. Only inactivated, injectable vaccines are licensed for that age-group.

FluMist, made by MedImmune Inc., based in Gaithersburg, Md., has been on the market since 2003, but demand for it has been hampered by a higher cost than conventional vaccine and by the requirement to keep it frozen during storage. Last month the Food and Drug Administration (FDA) approved a new formulation that requires refrigeration but not freezing. The refrigerator-stable formulation was used in the new study.

MedImmune, which sponsored the study, submitted preliminary results to the FDA in July 2006 with a request to permit use of the vaccine in children aged 1 through 4 years with no history of wheezing, according to Jamie Lacey, a company spokeswoman in Gaithersburg. She called the study "the pivotal trial" supporting the request.

The company expects to hear an initial response from the FDA by May 28, Lacey told CIDRAP News. "We're prepared for approval of this expanded indication for next [flu] season. That's what we're gearing up for," she said.

Study included 16 countries
The study involved 249 physcians' offices and clinics in 16 countries, with about half of the sites in the United States. The researchers recruited more than 8,300 children, of whom 7,852 completed the study. Children with a history of severe asthma or a recent history of wheezing were excluded, but those with mild or moderate asthma were included.

Both FluMist and the injectable vaccines used in the trial, made by Aventis Pasteur, contained the three virus strains recommended by the FDA for the 2004-05 season. In equal numbers, children were randomly assigned to receive either FluMist or the injectable vaccine, and each participant also received a placebo version of the other vaccine (FluMist recipients received dummy injections, and injectable-vaccine recipients received a placebo dose of nasal spray). Participants and medical workers were blinded to the treatment assignments.

The researchers reported 153 cases of flu in the FluMist group, for an attack rate of 3.9%. This was 54.9% lower than the 338 cases in the conventional vaccine group, with an attack rate of 8.6% (P<.001). For culture-confirmed flu cases, the attack rates were 5.0% for the FluMist group and 10.0% for the inactivated vaccine group.

The live vaccine worked well against both well-matched and mismatched flu strains. Compared with the inactivated-vaccine group, the FluMist group had 89.2% fewer cases of influenza A/H1N1, a strain for which the vaccine was well-matched, and 79.2% fewer cases of A/H3N2, which the vaccine did not match well, the report says. Both differences were significant.

The 2004-05 season saw several strains of influenza B, of which some matched the vaccine and some did not. The FluMist group had 16.1% fewer cases of type B flu than the other group, a nonsignificant difference.

As for vaccine safety, 6.1% of FluMist recipients between 6 and 11 months old were hospitalized for any cause within 180 days after vaccination, versus 2.6% of children in that age range who received inactivated vaccine, a significant difference. There was no significant difference in hospitalization rates between the two groups overall.

The investigators also noted that among children who had a history of wheezing, there was a trend toward a higher rate of all-cause hospitalization among 6- to 47-month-olds in the FluMist group, though it was not significant.

The researchers found no significant difference between the two groups in the overall rate of wheezing episodes. But among previously unvaccinated children, 3.8% of FluMist recipients aged 6 to 11 months had a wheezing episode within 42 days after their first vaccine dose, as compared with 2.1% of the same age-group among inactivated vaccine recipients (P=.076). The episodes occurred in the second, third, and fourth weeks after vaccination, after the peak of viral replication, the report says.

Overall, the authors write, the findings suggest that FluMist can play an important role in controlling flu. "On the basis of our results, the risk-benefit ratio for live attenuated vaccine appears favorable among children 12 to 47 months of age who have no history of wheezing.

"Until additional data are available, the observations related to medically significant wheezing and rates of hospitalization will restrict the use of live attenuated vaccine in children younger than 1 year and in children 12 to 47 months of age who have a history of asthma or wheezing," the report states.

Though 'definitive,' study lacked placebo group
Treanor, a veteran vaccine researcher and professor of medicine, microbiology, and immunology, commented, "I think one of the things about the study that's remarkable is how carefully done it was and its size. It's quite definitive."

He said the study strengthens his general impression that the immune response to live attenuated flu vaccines varies with age. "It really does look like younger children support the replication of the cold-adapted [intranasal] virus more than do adults," leading to a stronger immune response, he commented.

Evidence about immune responses and the ability of the vaccine virus to replicate in the nose suggests that the live vaccine probably works better than inactivated vaccine in children, Treanor said. In young and middle-aged adults it appears that the two types are roughly equivalent, though the live vaccine may be slightly better, while inactivated vaccine seems to work better in elderly people, he added.

"This all reflects the impact of the host on the ability of the live vaccine to replicate and induce an immune response," Treanor said. He said the immunogencity of live vaccines "starts to tail off as you get older and have been exposed to the flu many times," though it's not clear where the age boundaries are.

Treanor also commented that in the FluMist study, the flu attack rate of 8.6% in the inactivated-vaccine group is "a reminder that flu vaccines are not perfect in young kids."

One limitation of the FluMist study is that the investigators "did not feel they should include a placebo group," Treanor said. That limits the ability to assess the relative benefits of FluMist and the conventional vaccine as compared with no vaccine—a point also made in a NEJM editorial by Nancy J. Cox, PhD, and Carolyn Buxton Bridges, MD, of the CDC.

"It's hard to have a placebo group in a population where a vaccine is already recommended as a routine step," Treanor said. "But this gap in the knowledge will make it harder for policy makers."

For example, he said, the CDC's Advisory Committee on Immunization Practices may eventually want to consider making a specific recommendation about the use of FluMist in small children. Given the likelihood of cost differences and safety issues to consider, "the lack of a placebo group will make that decision more difficult," he said.

In their editorial, Cox and Bridges say the live attenuated vaccine may offer "significant advantages" for children, because it doesn't involve needles and may provide better protection against flu than conventional vaccines do.

"However, enthusiasm for the vaccine must be tempered" by the signs of an increased risk of wheezing and of hospitalization in children less than 1 year old, they write. Although the results are "encouraging, further discussion and careful review of the safety data" will be necessary before policy decisions are made, they add.

Belshe RB, Edwards KM, Vesikari T, et al. Live attenduated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007 Feb 15;356(7):685-96 [Abstract]

Cox NJ, Bridges CB. Inactivated and live attenuated influenza vaccines in young children—how do they compare? (Editorial) N Engl J Med 2007 Feb 15;356(7):729-31

See also:

Jan 9, 2007, CIDRAP News story "FDA approves refrigerated form of FluMist"

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