A representative from Sanofi Pasteur today spelled out eagerly anticipated findings from a large clinical trial of the company's high-dose influenza vaccine for seniors, which performed significantly better against lab-confirmed flu than the traditional vaccine dose.
The phase 3 trial was conducted over the past two flu seasons at 126 centers across the United States and Canada, enrolling about 32,000 seniors. It found that the high-dose version of Fluzone was 24.2% more effective than a standard-dose vaccine at preventing flu in adults age 65 and older.
David Greenberg, MD, Sanofi's director of scientific and medical affairs, presented the findings to the Advisory Committee on Immunization Practices (ACIP), a panel that guides the US Centers for Disease Control and Prevention (CDC) in its vaccine recommendations.
Older people bear a disproportionate burden of serious flu infections and deaths every year, but the impact of flu vaccines is limited in this age group, because immune response wanes as people age. A detailed analysis of flu vaccines last year underscored the point when it reported that the standard-dose vaccine doesn't offer consistent, high-level protection in older people and those at risk for flu complications—groups that could benefit most from vaccination.
Approved in 2009, high-dose Fluzone contains four times as much antigen as standard-dose flu vaccines. ACIP hasn't expressed a preference for high-dose Fluzone for older people, but its members have expressed great interest in how well the new product performs in the field. Today's presentation by Sanofi was for the group's background purposes.
Greenberg said the clinical team is still poring over the findings and will eventually publish them in medical journals. He said researchers hope to submit the post-licensure data to the Food and Drug Administration (FDA) in the first part of 2014.
Researchers conducted the randomized controlled trial during the 2011-12 season, one of the mildest in the past several years, and the 2012-13 season, which was considered moderately severe. About half of the patients received the high-dose vaccine, and half were immunized with the standard dose. Researchers routinely called the participants to ask about flu-like symptoms, and the study subjects were also asked to report any symptoms.
Medical teams obtained nasopharyngeal swabs whenever patients reported any respiratory illness.
The 95% confidence interval for the 24.2% relative increase in efficacy against lab-confirmed flu ranged from 9.7% to 36.5%. Greenberg told ACIP members that the lower limit was above the 9.1% limit required by FDA to show superior clinical benefit.
He noted that the benefit extended across both study years, despite the differences in flu activity, and held for all flu strains, and age subgroups. The study also suggested that the high-dose vaccine provided better protection against pneumonia, hospitalization, and cardiorespiratory conditions. [
Safety findings were similar to earlier findings, which showed a slightly higher risk of local reactions but not of serious adverse events, Greenberg said.
ACIP members had several questions about the study methodology, such as how the research team assessed people with respiratory symptoms, what comorbidities the subjects had, and whether the scientists are looking at duration of protection. Greenberg said that so far the group has seen steady efficacy 90 days past vaccination, but added that further analyses are underway.
Jamie Loehr, MD, an ACIP liaison from the American Academy of Family Physicians (AAFP) and physician at Cayuga Family Medicine in Ithaca, N.Y., asked for a breakdown of how many infections the high-dose vaccine prevents per 1,000 people. Greenberg estimated that there would be four to five fewer cases for each 1,000 immunized with the high-dose vaccine.
Lisa Jackson, MD, MPH, who isn't an ACIP member but is a flu vaccine researcher and has seen some of the information presented at today's meeting, told CIDRAP News that the high-dose Fluzone findings are pretty big news, because it is the only flu vaccine available for use in seniors that is proven by a valid randomized controlled trial to prevent flu. Jackson is senior investigator at Group Health Research Institute in Seattle.
"In the absence of a placebo group we don't know whether the standard dose comparator had 50% efficacy or 0% efficacy, but we do know that people who received high dose were less likely to have lab documented flu than the comparator group," she said.
What was missing from the findings was an assessment of absolute risk reduction, Jackson said, adding that her calculation based on today's presentation slides is that it would take 217 high-dose vaccinations to prevent one additional case, which is consistent with Greenberg's estimate.
From a biologic standpoint, a one-size-fits all approach to dosage of flu vaccine and other vaccines doesn't make sense, she said.
"The immunogenicity data clearly indicate that the immune response to standard-dose flu is less in the elderly than in younger people. Both younger and older have higher responses with higher doses, to a point," Jackson said. "So this also raises the question of whether everyone could benefit from a higher dose."
For now, it's unclear if the new findings will sway future policy decisions, she said. "I don't know if ACIP will make a preferential recommendation for high-dose flu vaccine, but they should, in my opinion."
Oct 23 and 24 ACIP meeting agenda
Aug 26 Sanofi press release
Dec 28, 2009, CIDRAP News story "FDA licenses high-dose flu vaccine for elderly"
Mar 30, 2010, CIDRAP News story "ACIP silent on high-dose flu vaccine for elderly"
Oct 15, 2012, CIDRAP News story "Report: complacency, misperception stymie quest for better flu vaccines"