Performance of inhaled flu vaccine confounds experts

Why the live-attenuated influenza vaccine (LAIV), FluMist, performed poorly in America during the 2015-16 flu season but well in Canada, Finland, and the United Kingdom continues to stump flu experts.

Late last month, Public Health England (PHE) published provisional findings on LAIV efficacy rates in British children during last winter's flu season, showing the inhaled mist was 65.8% effective in protecting children against lab-confirmed flu.

Based on these findings, Naomi Ramage, a communications officer with PHE, said the agency will be encouraging the use of LAIV vaccine during the upcoming flu season.

"It's early days, but already we are seeing encouraging results and indications that the LAIV will be successful in protecting children, their families and others in the community," Ramage said in an interview. "We are continuing to encourage LAIV for children in school years reception 1, 2, 3, and 4 [kindergarten through grade 3] this winter."

US officials, however, are recommending against the use of LAIV for the second year in a row, a decision announced by the Centers for Disease Control and Prevention (CDC) in June.

In 2015-16, when the UK saw a 57.6% effective rate for LAIV in children 2 to 17 years old, the United States found a dismal performance in the same age-group, of about 5% protection, a number that was not statistically significant. For the H1N1 flu strain, the coverage was even less, at -19%.

The US data were published last month in the New England Journal of Medicine (NEJM). The authors of the report concluded the vaccine needed more investigation.

LAIV numbers underperform globally

Edward Belongia, MD, director of the Center for Clinical Epidemiology & Population Health at the Marshfield Clinic in Wisconsin, has published several studies on LAIV's performance in children and was an author of the NEJM study.

"We have an intense interest in these numbers, we'd like to see this resolved, and we have a clear role to play because [a vaccine] has to do better than this," Belongia said. Unfortunately, he said, until there's another flu season dominated by H1N1, it will be impossible for researchers to fully evaluate LAIV's performance.

Though Belongia is troubled by LAIV, he said comparing the US numbers to Canada, Finland, and the United Kingdom does not offer all the answers.

"The confidence interval in studies conducted in each country is wide and overlaps, but even the countries that use the LAIV saw that it did not perform as well as the inactivated vaccine against H1N1," said Belongia.

A recent study looking at LAIV from 2009 to 2015 published by researchers from Medimmune (the company that produces FluMist) in Open Forum Infectious Diseases concluded, "Live-attenuated influenza vaccine was not shown to be effective against A(H1N1)pdm09 strains in 2010-2011, 2012-2013, and 2013-2014, whether LAIV was distributed as a trivalent [three-strain] or quadrivalent [four-strain] formulation." In 23 studies included in the meta-analysis, the LAIV was anywhere from 18% to 83% effective in protecting children against all flu strains.

The authors concluded that the reason may be that initial testing and development of LAIV, which showed 83% effectiveness for children ages 2 to 17 years, occurred before the 2009 flu pandemic. Whether the pandemic altered recipient's immunity, exposures, or vaccine performance is unknown.

Attempts to explain US differences

"All of us have picked up the signal that LAIV is not as effective as inactivated vaccine," said Danuta Skowronski, MD, an influenza expert at the University of British Columbia. Canada will continue using LAIV, she said, but Skowronski points out that her country still saw LAIV underperforming.

"For me I consider it a question of methodology," said Skowronski. "In Canada in 2015-2016, we found the LAIV offered 50% protection for children compared against unvaccinated, but the likelihood of failure is three- to four-fold higher than the inactivated vaccine, which is similar to what the US found."

Skowronski said what could be at play are research differences. Finland, for example, uses cohort studies to determine flu vaccine effectiveness. In Canada, febrile illness was required in vaccine efficacy studies, while the US CDC used medically attended cases with only cough as the qualifying symptom.

"So now we have a question of how well the vaccine performs against classic 'full blown' flu in Canada, versus respiratory illness in the United States," Skowronski said.

Michael Jackson, PhD, MPH, an associate investigator at the Kaiser Permanente Washington Health Research Institute in Seattle said that while nobody knows why the LAIV underperformed so ferociously in the United States, previous immunity and exposure are intriguing theories.

"One notable difference is US children are first recommended a flu vaccine after 1 year of age," said Jackson, "FluMist isn't recommended until age 2, so a child's previous exposure to an inactivated vaccine may be at play here. Specifically, immunity to H1N1 viruses may be primed differently."

But Skowronski said that theory doesn't hold water for her.

"We have similar patterns of infant and toddler influenza vaccine priming in Canada," Skowronski said. Instead, it may be that because Canada, the United Kingdom, and Finland used adjuvanted vaccine in 2009, there would have been a difference in the priming dose to the new virus.

"Maybe now in 2015-2016, we're just seeing lasting effects," Skowronski said.

See also:

Aug 31 PHE press release

Aug 10 N Engl J Med abstract

Aug 10 CIDRAP News story "Study: Change in inhaled flu vaccine did not help in 2015-16"

Jul 24 Open Forum Infect Dis study

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