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A Flu Vaccine That’s Always in Season

A single shot to thwart all flu viruses may be within reach
vaccine illustration



Thomas Fuchs

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In the spring of 2013 a strain of influenza virus that had never infected humans before began to make people in China extremely ill. Although the virus, known as H7N9, had evolved among birds, it had mutated in a way that allowed it to spread to men, women and children. Within several months H7N9 sickened 135 individuals, of whom 44 died, before subsiding with the advance of summer weather.

We got lucky with H7N9. Had it triggered a pandemic—an explosion of infectious disease across a large geographical area—we would have been woefully unprepared, and millions might have died. The trouble is that every new virus requires a new vaccine, and making new vaccines takes time. Even a typical flu season is brimming with slightly mutated versions of familiar viruses. In most cases, manufacturers anticipate these changes and tweak existing formulas so that they will still work against the new strains. When a virus like H7N9 makes a surprise appearance in people, however, manufacturers must scramble to concoct an entirely new vaccine from scratch, which takes too long to prevent a large number of people from becoming sick and dying.

Public health officials have longed for years to turn the tables, envisioning a “universal” flu vaccine that would be ready and waiting on the shelves to defeat either a marginally mutated strain or a completely unexpected virus. After numerous disappointments, a handful of recent studies indicate that a universal vaccine may at last be close at hand. In an interview last summer National Institutes of Health director Francis Collins suggested that one might be achieved in the laboratory in just five years. Before such a vaccine can reach the general public, however, researchers will have to convince either manufacturers or the government to pay for more studies and demonstrate to the U.S. Food and Drug Administration that the new vaccines are just as safe as those we already use.

Stalking a Killer
Flu vaccines have worked on the same principles since investigators first made them in the 1940s. Each vaccine contains flu antigens—bits of viral molecules that can trigger an immune response. The antigens used in routine flu vaccines are fragments of a mushroom-shaped protein, called a hemagglutinin, that protrudes from a flu virus's surface and helps the pathogen cling to cells inside an infected individual. Once exposed to those bits of protein, a person's immune system produces sentinel molecules called antibodies that will recognize any flu virus possessing the same hemagglutinin and direct an attack against it.

Flu is a rapidly evolving virus, however, and the structure of hemagglutinin in a given strain changes in small ways every season. Even a minor alteration can make it much more difficult for the immune system to identify and eliminate a flu virus that is nearly identical to its earlier version. This is why we have to get new flu shots every year.

Scientists have searched for decades for a way to outsmart the flu virus rather than always hurrying to outpace it. The first glimpse of more efficient vaccines appeared in 1993, when Japanese researchers discovered that mice sometimes generate a single antibody that blocks infection by two flu strains with different hemagglutinins. Fifteen years later several different teams demonstrated that humans occasionally make these cross-protective, or broadly neutralizing, antibodies as well. Most of these antibodies bind not to a hemagglutinin's mushroom cap but rather to its slender stem—a region of the molecule where, as it turns out, less structural mutation takes place. Because the stem's makeup is similar across many strains of flu, the researchers reasoned, an antibody that recognizes it could potentially protect against a range of viral strains with distinct caps.

Building on this discovery, several groups have altered the structure of hemagglutinins, creating a cap to which the immune system does not react. Animals exposed to these tweaked proteins produce cross-protective antibodies that bind to the stalk rather than strain-specific antibodies that home in on the cap. Other scientists are trying to get animals and people to make antibodies against a different viral protein, M2, which is embedded in the flu virus's membrane and helps it enter cells. Like the hemagglutinin stalk, M2 changes little.

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