Nov 15, 2012 (CIDRAP News) – A government advisory committee yesterday endorsed the safety and immunogenicity of an adjuvant-containing H5N1 influenza vaccine proposed for inclusion in the US pandemic emergency stockpile, signaling that it could become the first adjuvanted flu vaccine to win approval in the United States.
On two unanimous votes, the Food and Drug Administration's (FDA's) Vaccines and Related Biological Products Advisory Committee (VRBPAC) said the immunogenicity and safety data on GlaxoSmithKline's (GSK's) H5N1 vaccine are adequate to support its licensure for use in adults. The aim is to strengthen the US stockpile for the threat of an H5N1 pandemic.
The vaccine contains GSK's proprietary adjuvant AS03, which is used in several other GSK vaccines licensed in other countries. One of these, Pandemrix, used in Europe during the 2009 H1N1 flu pandemic, was linked with an increased risk of narcolepsy in children in Finland, Sweden, and Ireland.
The purpose of the adjuvant is to induce a stronger immune response with less antigen or active ingredient, which AS03 achieves, according to GSK. The vaccine contains 3.75 micrograms (mcg) of antigen, compared with 15 mcg in standard flu vaccines without adjuvants.
No seasonal flu vaccines used in the United States contain adjuvants, nor does the existing H5N1 vaccine in the US emergency stockpile. The government has acquired a supply of adjuvants for possible emergency use, but they are not part of a specific vaccine.
The US Department of Health and Human Services (HHS) contracted with GSK to develop an H5N1 vaccine with antigen-sparing potential for use in the US Strategic National Stockpile, according to an FDA briefing document.
GSK has submitted a Biologics License Application to the FDA for the vaccine, which has no trade name but is known informally as Q-Pan H5N1, because it's made in Quebec and is intended for pandemic use.
The FDA is using its "accelerated approval process" to review the vaccine, which means that the licensing decision will be based on immunogenicity as evidenced by antibody response rather than actual protection against flu as demonstrated in clinical trials or observational studies.
GSK submitted data from an observational case-control study of the company's AS03-containing pandemic H1N1 vaccine in support of Q-Pan's effectiveness, the FDA document says. The agency concluded that the data did not provide a reliable estimate of Q-Pan's effectiveness to support traditional approval, but it said Q-Pan has met the immunogenicity criteria for licensing under accelerated approval.
The 14-member advisory committee heard lengthy presentations from GSK and FDA officials before voting on the vaccine. The meeting was streamed over the Web.
Two key trials
Andrea James, MD, a medical officer with the FDA's Center for Biologics Evaluation and Research (CBER), discussed two "pivotal" Q-Pan trials conducted at multiple sites in the United States and Canada.
One trial, which involved 680 adult volunteers, compared Q-Pan with the same vaccine without an adjuvant. The results supported the 3.75-mcg dose of antigen but showed that two doses were required to generate an adequate immune response to meet the FDA criteria, James said.
A second trial involved 4,561 adults, including working-age and older volunteers, and compared Q-Pan with a saline placebo vaccine. At least 70% of the younger adults met the FDA's criterion (an antibody titer of 1:40 as measured by hemagglutination-inhibition [HI]), and at least 60% of the older volunteers met the standard.
The briefing document shows that the seroconversion rate after two doses of vaccine was 90.8% in working-age adults, compared with 1.3% for the placebo group. In the older (65 and up) group, the seroconversion rate was 74% in vaccine recipients, versus 2.5% in controls.
More adverse events
Q-Pan was associated with more adverse events in both trials, James said. In the first trial, injection-site pain was four times as common in the adjuvant group as in the no-adjuvant group, and myalgia was twice as common. In the second trial, myalgia and arthralgia were twice as common in the Q-Pan group as in the placebo group.
Slightly more Q-Pan recipients than controls had unsolicited adverse events, but medically attended adverse events were about the same in both groups, James said.
Summing up, she said, "We saw more frequent local and systemic reactogenicity and more severe local reactogenicity" in Q-Pan recipients in the two trials. "There were imbalances in reported adverse events, both expected injection-site reactions and unexpected events."
But she cautioned that the higher number of unexpected adverse events may have reflected the 3-to-1 size ratio between the Q-Pan and control groups.
The second trial led to 16 "events of special interest," James said. For most of those, the FDA agreed with GSK that there were plausible causes other than the vaccine. But there were three cases on which GSK and CBER officials disagreed, she said.
In one case, a 77-year-old man with hypertension experienced cranial nerve palsy 22 days after his second dose of the vaccine. GSK considered that hypertension was the likely cause, but there was no evidence that the man had uncontrolled hypertension at the time of the diagnosis, James said.
"I believe that the temporal association with the vaccine makes a hyperinflammatory event plausible," she said.
The FDA briefing document says that in the second trial, 0.4% of Q-Pan recipients and 0.2% of placebo recipients reported at least one serious adverse event within 42 days after their first dose.
James also reviewed the post-marketing safety record for GSK's other flu vaccines containing AS03. She said an estimated 31 million people received Pandemrix and 59 million received Arepanrix during the 2009 pandemic.
Studies in Finland, Sweden, and Ireland showed a 6- to 13-fold increase in narcolepsy in children who received Pandemrix, which amounted to 3 to 7 excess cases per 100,000 vaccinees, she said. As a result, use of the vaccine in those under 20 was stopped, and narcolepsy was added to the label as a possible side effect.
For Arepanrix, James said, three studies found that febrile convulsions were the most common adverse events in children under age 10, with a rate of 1 event per million vaccinees aged 0 to 2 years and 0.75 event per million for ages 3 through 9. Also, the observed number of Guillain-Barre syndrome cases was higher than expected. Those findings prompted labeling changes.
In response to questions, a GSK official said Q-Pan is more immunogenic than the H5N1 vaccine already in the US stockpile, though the two vaccines have not been compared directly. The stockpiled vaccine is made by Sanofi Pasteur.
Bruce Innis, MD, vice president for vaccine discovery and development, said the reported seroconversion rate induced by the stockpiled vaccine was 43%, whereas the rate for the GSK vaccine was over 90% in the same age-group.
Several committee members said they found the immunogenicity data convincing.
Roland Levandowski, MD, commented, "I agree that the sponsor has done a very nice job of demonstrating the immunogenicity of their product in the context of what they are showing us with the adjuvanted as compared to the unadjuvanted vaccine. I don't think it needs to be in the context of any other product; I think the data they have stand on their own."
Another member, Gillian Air, PhD, said, "We don't know what these HI titers mean in terms of protection, but they've demonstrated this is immunogenic."
Pedro Piedra, MD, added a note of concern that it took two doses to achieve the FDA immunogenicity criteria.
"I think they've met the CBER definition for immunogenicity for two doses," he said. "But many individuals in a pandemic may only get one dose. One needs to think about how down the road one can do better than a two-dose requirement." He added that in the 2009 pandemic the vaccine arrived late.
The FDA document says the proposed indication for the GSK vaccine is "the prevention of influenza disease in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine." One member asked if the FDA envisioned that the vaccine could be used in laboratory workers who handle H5N1 viruses.
An FDA official indicated that the agency was not thinking of laboratory workers as among the target groups for the vaccine.
Robin Robinson, PhD, director of HHS's Biomedical Advanced Research and Development Agency, suggested that, apart from an actual pandemic, the vaccine might be used in individuals who go into areas of H5N1 exposure risk in foreign countries.
A GSK official said company employees who work with H5N1 have not received the vaccine.
When the question of vaccine indications surfaced again later, an FDA official said, "We'd like for you to vote on this in the context of this product being used in a pandemic."
Q-Pan is made with the conventional egg-based process. It is based on a 2005 strain of H5N1 from Indonesia, but a GSK official said that once the vaccine is licensed, the strain used in the vaccine can be changed.
On a 14-0 vote, the committee agreed that the immunogenicity data support licensure for the vaccine.
A fairly short discussion preceded the committee's vote on whether the safety data supported licensure of the vaccine. The panel voted 14-0 in favor.
Before the vote, one member said, "The question is whether we've seen the full experience GSK has had with this adjuvant. How or when might there be more data on these rare but concerning adverse events?"
GSK officials replied that they had presented all their safety data. One of them said the company tested through phase 3 a different version of the adjuvant, called AS03B, but it didn't meet the objective of conferring superior protection in an efficacy trial. The trials, which involved 43,000 adults, revealed no signal of an increase in potential immune-mediated diseases, the official said.
Nov 14 VRBPAC meeting announcement
Nov 14 VRBPAC meeting agenda
FDA briefing document for VRBPAC meeting: