The immune response is like parenting in at least one way: The loudest response to both infections and infractions is not always the most effective one.
During an infection, the immune system makes most of its antibodies to a few highly antigenic bits of the invader. Those sites, though, are not necessarily the ones that are most critical to a virus. As a result, escape mutations can allow viruses - especially those that mutate rapidly - to get around vaccines.
But the body also can make antibodies that recognize those parts of the virus that are critical for its entry into host cells. "What we're trying to do is to target the immune response against a region of the virus that is constrained," Gary Nabel told BioWorld Today. Such constrained sites, which are critical to viral survival, exist on every virus. "It's there, it's just not something the body pays attention to naturally," he said.
Antibodies to constrained sites have the usual effect of neutralizing the virus, but they have an additional effect: They "minimize the chances that [the virus] can escape easily," he said. In other words, a virus could acquire mutations in its receptor binding domain that render the vaccine ineffective - but if it did, those same mutations likely would render the virus ineffective at entering cells in the first place, making the issue moot.
In the Aug. 10, 2007 issue of Science, Nabel, director of the vaccine research center at the National Institutes of Health, and his colleagues at NIH and Emory University School of Medicine, described the results of making such constrained antibodies to the H5N1 strain of avian influenza virus.
Public health officials are concerned that H5N1, the highly lethal avian influenza strain that to date has killed roughly two-thirds of people with confirmed infections, ultimately will cause a pandemic. But if it will, the strain that will do the damage does not exist yet.
H5N1 is "highly lethal in birds, and highly lethal in humans," Nabel said, making it Undesirable No 1 on the list of possible pandemic-causing agents. But it hasn't adapted to spread easily from human to human.
The structure-based vaccine design approach that Nabel and his team used tries to "anticipate what would happen if these viruses . . . actually made the jump" to become easily transmissible from person to person.
Influenza viruses enter cells by using the viral surface protein hemagglutinin to bind to complementary molecules on the host cell surface. Currently, H5N1 hemagglutinin binds to a form of sialic acid with what's known as 2,3 linkage sugars on host cells. The human upper respiratory tract, where the virus would have to take up residence to become easily transmissible from human to human, has mainly 2,6 linked sialic acids. For that reason, an optimal vaccine would be one that is effective not primarily against current strains, but against any future strains that prefer to dock to 2,6 linked sialic acids.
Nabel's team mutated specifically those parts of the hemagglutinin that make contact with the host cell, and identified several forms that were either more partial to 2,6 linkages, or less interested in 2,3 linkages, than current wild-type strains.
They next raised monoclonal antibodies against different mutants, and found that some were effective at neutralizing 2,6 linkage preferring viral models.
The authors concluded in their paper that structure-based hemagglutinin modifications "can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains." Nabel was cautiously optimistic about the benefits the approach ultimately could bring. "There's no guarantee" that a vaccine directed against a receptor-binding domain that prefers 2,6 linked sialic acids would be more effective, he said. "But it would put us in a much better position."