Electron microscopy shows hemagglutinin on the surface of a flu virus particleImage credit: Stephen HarrisonWhy do you need a new flu shot every year, when most other vaccines give long-lived or even lifelong immunity?

The reason is that the influenza virus can mutate as it spreads from person to person, so the variety of virus that shows up next year will be different from the one you might have suffered from this year.

These differences allow the virus to “escape” the protective immunity that people acquire by recovering from an infection or getting last year’s vaccine.

Researchers have been trying to develop a flu vaccine that confers longer-lasting immunity, not least because predicting the next year’s strain is often inaccurate. Recent work led by the laboratory of Stephen Harrison, the Giovanni Armenise–Harvard Professor of Basic Biomedical Science at Harvard Medical School, takes us one step closer toward this goal.

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However, two sites on hemagglutinin do not change, because mutations in those places would prevent the virus from infecting a cell. One of these two sites is where the virus attaches to a receptor on the cell surface.

Researchers suspect that altering or blocking the hemagglutinin receptor site might prevent the virus from latching on to the cell despite mutations it evolves elsewhere. This would conceivably prevent flu infection for years.

“Suppose we could develop a vaccine that stimulates a person’s immune system to make antibodies targeting the receptor site. That person would gain a level of immunity that could resist influenza-virus escape,” said Harrison.

“To figure out how to make a vaccine with such properties, however, we need to understand better than we do at present about how our immune system responds to a flu vaccine,” he said.

It’s now possible to obtain that information, thanks to contemporary technologies for studying the cells that make antibodies and for sequencing their DNA. Harrison’s laboratory, in collaboration with investigators at the Duke Human Vaccine Institute at Duke University, discovered that some people indeed make antibodies that recognize the hemagglutinin receptor site.

Reporting in Cell, the team found that a person who participated in a vaccination study at Duke in 2008 made several different antibodies of this kind.

The researchers used X-ray crystallography to work out exactly how the antibodies bind to hemagglutinin. Comparing the various structures, they realized that a person whose immune system is generating several such antibodies would be very unlikely to get infected, even by a new strain, because a mutated hemagglutinin that escapes protection by one antibody would not escape protection by another.

The only points at which all the antibodies contact hemagglutinin are also points at which mutations would compromise the virus’ ability to infect a cell.

Harrison suggests that a useful goal for an improved flu vaccine would be one that stimulates a person’s immune system to make receptor-site-directed antibodies, such as those he and his colleagues have characterized.

He says that he finds the new results particularly gratifying because “experiments designed to probe fundamental properties of the human immune system are also suggesting potential new strategies for developing improved influenza vaccines.”

The lessons learned might also apply to the development of vaccines against other rapidly changing viruses, such as HIV.

This work was supported by National Institutes of Health grant P01AI089618.

Protection against the flu comes from antibodies that bind to the virus and block it from infecting a cell. Most protective antibodies recognize a protein on the surface of the influenza virus particle called hemagglutinin. The mutations that allow the virus to escape occur on the surface of hemagglutinin where the antibodies try to bind.