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A closer look at vaccines for pandemic influenza and for the 2007-2008 influenza season
The FDA Vaccines Advisory Committee recently recommended Sanofi Pasteur’s pandemic H5N1 vaccine for licensure.
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On page 6 of the print issue of Infectious Disease News, there is a brief report of the VRBPAC meeting held at the end of February. (VRBPAC is officially the Vaccines and Related Biological Products Advisory Committee; previously in this space I have referred to this committee simply as the FDA Vaccines Advisory Committee, to avoid having to deal with the somewhat unwieldy acronym.) The article reports the fact that Sanofi Pasteur’s pandemic H5N1 vaccine was recommended for licensure and that the committee basically agreed with WHO recommendations for next year’s seasonal vaccine, updating only the H1N1 component for the first time in seven years.
The article sounds “matter-of-fact,” suggesting that there was nothing controversial to report. Since I was privileged to be at the meeting as a temporary voting member and since it took place as an open public meeting, I will relate to you some of the points discussed that were not at all “matter-of-fact.”
First, the Sanofi Pasteur vaccine: This is the same vaccine that was described in the report by John Treanor and his colleagues, which was published in The New England Journal of Medicine a year previously. In fact, almost all of the data available for consideration by the committee were contained in that published report. The virus strain used was A/Vietnam/1203/2004 (clade 1), and about 450 adults age 18 to 64 participated in the trial. Those who read that report will recall that two 90 mcg doses, given 28 days apart, produced a protective immune response in 45% of participants. That level is actually somewhat lower than the 54% level reported in the report by Treanor and colleagues, a difference introduced by a slightly different way of calculating the antibody dilution series. Doses lower than 90 mcg produced correspondingly lower levels of seroimmunity.
Safety data
Safety data were encouraging; there were virtually no serious adverse reactions, even at the 90 mcg dose. It should be noted, however, that only 101 participants received that (highest) dose. Representatives from Sanofi Pasteur outlined their plans for additional studies of both safety and efficacy in the event that this vaccine would ever need to be used.
Recall that both Sanofi Pasteur and Chiron were awarded contracts from Department of Health and Human Services for preparing this pandemic subvirion H5N1 vaccine. Sanofi Pasteur has sufficient 90-mcg doses on hand to immunize 6 million people; the government goal is to have a stockpile of sufficient vaccine to immunize 20 million people. This is a “prepandemic” vaccine, to be used only if/when WHO declares that a pandemic is imminent or already underway; the target population for this vaccine would be the critical work force, ie, health care workers, vaccine manufacturers, essential government personnel, et cetera. If/when a pandemic is declared, work would immediately begin to prepare an “epidemic” vaccine, using the pandemic strain, likely in tissue culture, and using contemporary adjuvant technology. Based on estimates derived from other manufacturers, especially GlaxoSmithKline, the government estimates that 600 million doses of a pandemic vaccine could be produced beginning within six months.
Even when licensed, the entire amount of the Sanofi Pasteur vaccine is to be stockpiled; none will be available for purchase in the open market. To its credit, the FDA requested Sanofi Pasteur to prepare and submit a licensure application for this vaccine, feeling that the use of this vaccine as an investigational drug in an early pandemic would present untenable problems. In the voting, it became apparent that committee members were accepting a new standard of safety and efficacy for emergent conditions, and virtually all expressed the hope that this vaccine would never need to be used. However, in the event of an imminent pandemic, as Bob Couch put it, “something is better than nothing!”
Seasonal influenza vaccine
The 2007-2008 seasonal influenza vaccine: For the last several years, the strain selection meeting for the United States has been held in late February, shortly after the WHO strain selection meeting. This has presented several structural problems, since manufacturers are already growing virus for the fall season. They started growing, at their own risk, at least one strain they thought was least likely to change. This has been necessary to ensure timely delivery of finished product in the fall. H1N1 influenza has been a cause of significant morbidity, but little if any mortality. The virus seems to mutate only slowly, and no “updating” of the vaccine strain has been necessary for the last seven years. An increasing proportion of recently isolated strains have more closely resembled an A/Solomon Islands/3/2006 strain than the old A/New Caledonia/20/99 strain, and it was therefore an easy decision to update this component of the vaccine, even though there is no imminent threat.
The A/H3N2 component was actually updated last year, but still caused some concerns this year. An increasing proportion of recent isolates have shown relatively low titers against A/Wisconsin/67/2005 antisera; however, no single strain had emerged clearly, and lacking a suitable alternative, the committee agreed to retain the current vaccine strain.
Influenza B strain selection is complicated by the fact that there are two co-circulating distinct lineages of influenza B viruses, the “Victoria” lineage and the “Yamagata” lineage. One or the other of these two “families” seems to predominate for several years, followed by several years when the alternate family, or lineage, seems to predominate. In the past year the Victoria lineage has predominated in North America and Asia, and lacking a clear direction or alternative, the committee voted to retain the same Victoria vaccine strain, a B/Malaysia/2506/2004-like virus.
Meanwhile, the current 2006-2007 influenza season is clearly winding down. All three virus types have been co-circulating, with A/H1N1 predominating, followed by influenza B, followed by a modest number of A/H3N2 isolates. All in all, the season has been mild to moderate at best, and there has been no excess pneumonia-influenza mortality. Perhaps it won’t be necessary to touch this subject again until this fall; influenza never ceases to surprise us, however, so it would be unwise to make any promises.
For more information:
- Treanor JJ, Campbell JD, Zangwill KM, et al. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med. 2006;354:1343-1351.