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NIH Research Matters

November 9, 2009

Catching Flu’s Drift

Influenza viruses evade the immune system by constantly changing the shape of their hemagglutinin protein, the protein that lets them attach to cells in the respiratory tract. This shape shifting, called antigenic drift, is why flu vaccines need to be reformulated every year. New findings about the evolutionary forces that drive antigenic drift suggest that it might be slowed by increasing the number of vaccinated children.

Cluster of rounded blue virions.

Influenza virions seen by transmission electron microscopy. Image by F. A. Murphy, CDC.

Seasonal flu shots are designed to prompt the immune system to produce antibodies matched to each year's circulating virus strains. A better understanding of antigenic drift will help improve flu vaccine strategies. Drs. Scott Hensley, Jonathan W. Yewdell and Jack R. Bennink of NIH's National Institute of Allergy and Infectious Diseases (NIAID) led a research team exploring the mechanism of antigenic drift. Dr. Ram Sasisekharan headed a collaborating group at the Massachusetts Institute of Technology (MIT) supported by NIH's National Institute of General Medical Sciences (NIGMS) and the Singapore–MIT Technology Alliance for Research and Technology.

The researchers used a strain of seasonal influenza virus that had circulated in Puerto Rico in 1934. They vaccinated some mice against this virus strain, while leaving others unvaccinated. All the mice were then infected with the 1934 influenza strain. The scientists isolated virus from the lungs of both sets of mice and passed on these viruses to new mice. After repeating the process 9 times, the researchers sequenced the virus hemagglutinin genes. The results appeared in the October 30, 2009, issue of Science.

Sequencing revealed that the unvaccinated mice, which lacked vaccine-induced antibodies, had no mutated influenza viruses in their lungs. In contrast, vaccinated mice harbored hemagglutinin genes that had mutated to allow the viruses to bind more strongly to the receptors used to enter lung cells. Essentially, the viruses evolved to shield their hemagglutinin from antibody attack by binding more tightly to virus receptors.

The researchers next infected a new set of unvaccinated mice with the high-affinity mutant virus strains. In the absence of antibody pressure, the scientists found, the viruses reverted to a low-affinity form, enabling them to better propagate in lungs.

The researchers propose a model for antigenic drift in which high- and low-affinity influenza virus mutants alternate. In adults, who've been exposed to many influenza strains in their lifetime, the virus is pressured to increase its receptor affinity to escape antibodies. When these viruses are passed to people, such as children, who haven't been exposed to many influenza strains or haven't been vaccinated, receptor affinity decreases.

"The virus must strike the right balance," Yewdell says. "Excessively sticky viruses may end up binding to cells lining the nose or throat or to blood cells and may not make it into lung cells. Also, newly formed viruses must detach from infected cells before they can spread to the next uninfected cell. Viruses that have mutated to be highly adherent to the lung cell receptors may have difficulty completing this critical step in the infection cycle."

If this model is correct, Yewdell says, vaccinating more children against influenza could slow the rate of antigenic drift and extend how long seasonal flu vaccines remain effective.

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on December 4, 2012

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