Predicting the flu’s antigenic ducking and weaving from year to year may become easier in light of a recent discovery, enabling the timely development of seasonal vaccines that won’t be caught flatfooted by the flu’s feints. The discovery emerged after researchers created and evaluated viruses that had a variety of amino acid substitutions—and different combinations of substitutions. This work revealed that seasonal flu escapes immunity and develops into new strains typically by just a single amino acid substitution. What’s more, these single amino acid changes occur at only seven places on its surface.

That the flu depends on changes at so few sites to alter its outer coat, and thereby evade vaccines, comes as something of a surprise. Previously, it was thought that the flu could change amino acids at as many as 130 sites.

This discovery was described in a paper published November 21 in Science, in a paper entitled “Substitutions Near the Receptor Binding Site Determine Major Antigenic Change During Influenza Virus Evolution.” The paper’s authors, besides reporting that the flu typically relies on amino acid substitutions at just seven places, also noted that all these places are immediately adjacent to the receptor binding site—the area where the flu virus binds to and infects host cells.

“The virus needs to conserve this, its binding site, as it uses this site to recognize the cells that it infects in our throats,” said Björn Koel, Ph.D., lead author of the paper and a researchers at the Erasmus University Medical Center in the Netherlands.

In their paper, the authors speculate that the influenza virus would not change so close to the receptor binding site unless it had to. Moreover, they suggest that flaws arising from changes close to the receptor binding site could explain how the flu could have such a high mutation rate, and yet change its antigenic profile so slowly: “Given the high mutation rate of influenza virus and the observation that single amino acid substitutions are sufficient to cause antigenic cluster transitions, it is surprising that new antigenic clusters appear as slowly as they do—on average every 3.3 years. One hypothesis is that antigenic change has an intrinsic fitness cost that slows down the antigenic evolution of the virus.”

Reflecting on the study’s implications, Professor Derek Smith, Ph.D., study co-leader and researchers at the University of Cambridge, commented, “This work is a major step forward in our understanding of the evolution of flu viruses, and could possibly enable us to predict that evolution. If we can do that, then we can make flu vaccines that would be even more effective than the current vaccine.”

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