FDA Panel Supports H5N1 Adjuvant Vaccine

Diana Mahoney

November 16, 2012

By unanimous vote, an advisory committee of the US Food and Drug Administration (FDA) recommended approval this week of GlaxoSmithKline's H5N1 adjuvanted influenza vaccine based on the strength of supporting data from 2 pivotal trials.

In an open session streamed live over the Internet on November 14, the FDA's 14-member Vaccines and Related Biological Products Advisory Committee agreed that the safety and immunogenicity data for the monovalent influenza A vaccine, which contains GlaxoSmithKline's proprietary adjuvant AS03, supports licensure of the active vaccine in individuals aged 18 years or older who are at risk for exposure to the H5N1 influenza virus subtype. The move brings the vaccine a step closer to becoming the first FDA-approved adjuvant influenza vaccine in the United States.

Development of the antigen-sparing vaccine was sanctioned by the US government through a contract with the manufacturer. As such, if licensed, the vaccine will be owned and distributed by the government in the event of a pandemic and will not be marketed by GlaxoSmithKline.

Compared with influenza vaccines without adjuvants, which contain 15 μg of antigen, the AS03-boosted vaccine contains 3.75 μg of antigen, according to a briefing document supplied by the FDA. If the vaccine's biologic license application successfully navigates the FDA's accelerated approval process, it will be included in the US pandemic emergency stockpile for distribution as per the US Department of Health and Human Services Pandemic Influenza Plan.

The accelerated approval protocol allows licensing decisions to be made on the basis of evidence of immunogenicity via antibody response rather than evidence of actual protection from clinical trials. The latter will be required if accelerated approval is granted, the briefing document explains.

The question of how such confirmation would be made was addressed by the panel, with at least 5 members advocating an efficacy study of the vaccine conducted during an H5N1 influenza pandemic. Other panel members suggested that data from an efficacy study of a seasonal influenza vaccine manufactured using the same process of the adjuvanted product would be more feasible.

Bruce Innis, vice president of vaccine discovery and development at GlaxoSmithKline, said the company plans to pursue the latter approach, suggesting that data from the efficacy study of FluLaval, the company's seasonal, unadjuvanted H1N1 vaccine, "uses the same manufacturing process and could be used to confirm the clinical benefit of Q-Pan H5N1," which is the informal name for the adjuvanted vaccine.

Need for 2 Doses Raises Flag

As part of the assessment of supporting evidence for the current recommendation, Andrea James, MD, from the FDA's Center for Biologics Evaluation and Research, discussed the findings of the 2 key North American multicenter trials, including a 680-participant study (in which the vaccine was compared with the same vaccine without the adjuvant) and a trial involving 4561 adults (in which the active vaccine was compared with placebo).

In the former study, "2 doses of the vaccine were required to achieve an adequate immune response based on the FDA criteria [defined as a titer greater than 1:40 measured by a hemagglutination inhibition assay]," Dr. James said.

The need for 2 doses raised a flag for at least 1 panel member, Pedro Piedra, MD, from Baylor College of Medicine in Houston, Texas, who acknowledged that although the Center for Biologics Evaluation and Research's definition for immunogenicity was met, "many individuals may only get 1 dose. One needs to think about how down the road we can do better than a 2-dose requirement."

The second study demonstrated achievement of a positive antibody response in 70% of adults aged 18 to 65 years and in 60% of those older than 65 years. "After 2 doses of the vaccine, the seroconversion rate among working-age adults was approximately 91%, and among older adults it was 74%," Dr. James reported. The respective seroconversion rates for the placebo recipients in both age groups were 1.3% and 2.5%, she said.

With respect to adverse events, "we saw more frequent local and systemic reactogenicity and more severe local reactogenicity associated with the vaccine in both trials," Dr. James said during the open session. Specifically, injection-site pain was 4 times more prevalent and myalgia twice as prevalent in the adjuvant group compared with in the no-adjuvant group in the first trial, and both events were twice as common in the vaccine group in the second trial.

Because mortality associated with influenza A H5N1 subtype viral infection is highest among children and young adults, GlaxoSmithKline is currently conducting studies of the vaccine in children older than 16 months and plans to expand the approval application accordingly, Innis stated.

The FDA expects to reach a final decision on the vaccine's approval in December 2012, according to the briefing document. "If approved, the vaccine is to be used only according to official guidance from the US Government."

Dr. James and Dr. Piedra have disclosed no relevant financial relationships.