Current Topics Experts Formulate Seasonal and Prototype Avian Flu Vaccines on the Fly

Early each calendar year, experts assemble to reformulate the trivalent vaccine that protects people against influenza viruses anticipated to circulate in the northern hemisphere during the next season, designating appropriate antigens based on what seems to be circulating locally and in the opposite hemisphere. This past February, members of the Food and Drug Administration (FDA) advisory committee who undertake this task opted for a vaccine containing three new antigenic ingredients to ward off the seasonal influenza expected late this year—something of a departure from customary practices, but sensible in the face of flu viruses now circulating. The advisory committee also grappled with a more abstract and perplexing set of issues of how to formulate and use vaccines against what could become the next pandemic flu. In terms of seasonal flu, although influenza A (H1N1) viruses predominated through mid-January of 2008, (H3N2) viruses were on the rise through late February, making them “the most common identified subtype for the season overall,” according to officials of the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga. Based on those findings as well as reports from elsewhere in the Northern Hemisphere, advisory group members concurred with the World Health Organization (WHO) and recommended formulating the 2008– 2009 seasonal flu vaccine to contain three new antigens: A/Brisbane/10/ 2007-like H3N2, A/Brisbane/59/2007like H1N1, and B/Florida/4/2006. (In a related development involving a CDC advisory panel whose members met late in February, experts recommended that children from 6 months through 18 years of age be vaccinated yearly against influenza. This advice marks a shift from the previous recommendation to vaccinate only those children aged from 6 to 59 months against flu. The revised recommendation is to take effect no later than the 2009–2010 influenza season.) Once finished with their annual duty of reformulating the seasonal flu vaccine, members of the FDA vaccine advisory panel wrestled with a related but grander challenge: How to formulate and then deploy vaccines to protect humans against avian flu—not only the H5N1 strain that continues to be more than 60% deadly for those it infects, but also its anticipated mutated successors that could prove much more efficient at moving from one human to the next. Avian flu is continuing to circulate among humans, albeit causing small numbers of cases. In 2007, for example, it caused 86 human cases with 59 fatalities, mainly in Indonesia and the Nile Valley in Egypt, with additional cases in Vietnam, China, and other countries, according to WHO. In the majority of those cases, infected individuals had been exposed to sick or dead poultry. As of 11 March this year, WHO officials recorded another 23 human cases of H5N1 flu, 18 of them fatal. Thus, avian flu is “off to a rapid start” in 2008, says Nancy Cox of CDC, who advises the FDA committee. Still relatively rare but extraordinarily deadly in humans, H5N1 influenza is circulating abundantly in domestic poultry and wild bird populations in many regions, particularly Asia and the Middle East, providing plenty of opportunities for genetic variants to emerge. By now, those variants fall into 9 clades (10 if those from the 1997 Hong Kong outbreak are counted), making the nomenclature to describe and track them increasingly “arcane,” Cox says. Although viruses from any of those clades could lead to what instigates a pandemic, “only some” are being used to develop experimental vaccines, leaving “gaps where antisera don’t inhibit well.” All those H5N1 variants and plenty of other uncertainties raise practical and philosophical questions about vaccine readiness plans. Experts now talk of developing both “pre-pandemic” and pandemic vaccines to protect against such infections—aiming first to prevent deaths and, next, to block severe infections. For example, officials of the FDAlike European Medicines Agency in February endorsed Prepandrix, a vaccine developed by GlaxoSmithKline Biologicals to trigger protective immune responses against H5N1 influenza, as acceptable for use in humans. It is one of several such vaccines intended to help European member states “prepare for pandemic influenza.” Other “mock-up vaccines” in this group include Daronrix, Focetria, and Pandemrix. None of these vaccines is considered ideal, and exactly what populations are to receive them is uncertain. For instance, the antigens in several of these vaccines prove poorly immunogenic on their own but are enhanced when adjuvants are added. The big questions are when and how to use them. “Look how long we’ve lived—5 years—with the risk of a pandemic