In 1980 Fiers first sequenced the gene for hemagglutinin derived from the human influenza strain H3N2 that circulated in 1965. He then compared the hemagglutinin gene of this strain with a similar hemagglutinin gene derived from the strain that had started the 1968 Hong Kong pandemic. His analysis proved that point mutations account for genetic drift.
Equally important, his studies led him to see how the virus can jump species through genetic shifts. At that time scientists knew that antibodies from people infected by the 1968 pandemic virus also reacted with an influenza strain isolated in 1963 from flu-ridden ducks. Fiers investigated the nucleotide sequence of the hemagglutinin gene of this duck virus and found that it was indeed very closely related to the strain that started the 1968 Hong Kong outbreak. Today infectious disease experts recognize that an avian flu virus could genetically change enough to trigger a human pandemic.
If such a jump occurred, the virus “would not be hindered by any preexisting immunity in the human population,” Fiers explains. “It would spread fast over the world because when it arrived here it would look like an entirely different virus. Therefore, you need a vaccine that is not invalidated by drift or shift.”
More specifically, he needed a vaccine based on a part of the influenza virus that does not change. Fiers found it in the viral coat protein M2, which creates a pore in the coat. Specifically, he noticed that a section of that protein, called M2e, remains stable even as the other viral surface proteins mutate. The M2 protein, however, occurs only in small numbers on the virus, which is too low to set off a good immune response.
The obvious solution was to amplify the number of M2e segments. But how? Fiers turned to the liver-attacking hepatitis B virus. This pathogen has an inner protein core called HBc, and something intriguing happens when the gene for HBc is inserted into the bacterium Escherichia coli. The bacterium starts producing HBc proteins and assembles them to produce viruslike particles. Fiers found that by linking M2e genes to HBc genes, the bacteria would produce viruslike particles studded with M2e.
In tests with mice and, later, ferrets, the M2e-HBc particles caused the formation of antibodies directed against M2e, thereby protecting the animals from a lethal dose of influenza. The vaccine works differently from conventional vaccines in that it does not prevent infection directly. “The target is not the virus, but the target is the virus-infected cell,” Fiers says. “If at an early stage, you can kill off these cells, then you will counteract the infection.”
In 1997 Fiers received a patent for the technology, and in 1999 he published a paper in Nature Medicine expounding his approach. The British-American company Acambis, based in Cambridge, Mass., and Cambridge, England, has obtained the license to start production of the vaccine. In a phase I trial completed last year, Acambis found that among the 79 volunteers who received the vaccine, 90 percent developed antibodies to the M2e segment.
Whether the antibodies protect against influenza now needs to be determined—no guarantee if the past is any guide. A decade ago a drug based on an internal protein of the flu virus, called NP (for nucleoprotein), set the immune system’s killer T cells into action, but it only partially protected mice from the flu.
Because intentionally infecting a volunteer to see if a vaccine works is unethical, the compound will have to face large field trials. “We have to find an area where there is a higher probability that an influenza epidemic will take place,” Fiers says. The likeliest places are where dense human populations live near farm animals. Thousands of people will have to be vaccinated to obtain statistically acceptable results. (The current version of the M2 vaccine would protect only against influenza A, the type that has launched pandemics.)