Evolution of Pandemic Viruses Sweetly Deceptive, Yet Age May Add Protection

Evolutionary changes in viruses reveal why seasonal flu vaccines don’t protect against the 2009 H1N1 flu and provide insight into why older people have immunity to the pandemic virus, two new studies in Science Translational Medicine and Science report.

In Science Translational Medicine, Chih-Jen Wei and colleagues from the National Institutes of Health and Centers for Disease Control and Prevention show how the H1N1virus is different from seasonal flu viruses but similar to the pandemic “Spanish” flu that swept the globe in 1918. The findings are important for predicting how H1N1 will evolve in the future, and provide a model for developing a preemptive vaccine that could turn potentially pandemic viruses into more manageable ones.

The researchers injected groups of mice with seasonal and pandemic flu viruses from both 1918 and 2009. By analyzing the immune response to these viruses in mice, they found that the antibodies triggered by exposure to pandemic viruses protected mice from both the 2009 and 1918 flu.

 

Structure of the influenza virus hemagglutinin from pandemic and seasonal strains, highlighting sites of antibody neutralization and sugar modifications that confer resistance to antibodies. Shown here are surface renderings (side and top views) of the pandemic (left) and seasonal (right) influenza hemagglutinin viral spike (gray). In red, we show the site of antibody neutralization that is shared between the 1918 and 2009 pandemic viruses, called the RBD-A region. In blue, we depict glycosylation sites that interfere with the access of antibodies to the sensitive RBD-A site. The RBD-A region of HA is completely exposed in the pandemic strains, but in the seasonal strains, the added glycosylation effectively shields the RBD-A region from neutralizing antibodies. View the full-size image. [Image courtesy of Jeffrey C. Boyington and Gary J. Nabel]

Structure of the influenza virus hemagglutinin from pandemic and seasonal strains, highlighting sites of antibody neutralization and sugar modifications that confer resistance to antibodies. Shown here are surface renderings (side and top views) of the pandemic (left) and seasonal (right) influenza hemagglutinin viral spike (gray). In red, we show the site of antibody neutralization that is shared between the 1918 and 2009 pandemic viruses, called the RBD-A region. In blue, we depict glycosylation sites that interfere with the access of antibodies to the sensitive RBD-A site. The RBD-A region of HA is completely exposed in the pandemic strains, but in the seasonal strains, the added glycosylation effectively shields the RBD-A region from neutralizing antibodies.
[Image courtesy of Jeffrey C. Boyington and Gary J. Nabel]

A different outcome occurred with seasonal flu antibodies: they had no protective effect on pandemic viruses, although they protected against seasonal flu perfectly. These results indicate that the 2009 and 1918 viruses share some common elements that make it easy for antibodies to offer equal protection against these two otherwise distant viruses.

 

Wei and colleagues observed that antibodies that successfully guarded against the pandemic flu attached themselves atop the spike protein—a lethal molecule that sits on the surface of the virus and helps it to infect host cells.

Intriguingly, the spike proteins on the 1918 and the 2009 viruses are remarkably similar. Moreover, the spike protein on seasonal flu viruses has two sugar groups attached to the spike protein that the pandemic flu is missing; these sugar groups are particularly deceptive because they can mask the seasonal virus from recognition by the host immune system. This is one evolutionary trick the seasonal flu uses to evade vaccines that work on the pandemic flu.

The results may also explain the resistance of older people to the present H1N1 virus. Exposure to a close relative of the 1918 virus during youth means immune systems of older people may recognize the spike protein of the 2009 H1N1 flu virus, and so are able to halt its ability to infect host cells.

In a related Science paper, Rui Xu of the Scripps Research Institute and colleagues use crystal structures to show how human antibodies bind to the top of the spike protein from the 1918 and 2009 pandemic viruses. They found that human antibodies generated by either virus can protect equally against both viruses. Taking a closer look, the researchers found that the viruses share a nearly identical epitope—a portion of a molecule that acts like a tag to which an antibody binds.

The findings may explain why older people, especially those over 65, have a pre-existing immunity to the 2009 H1N1 virus. A Perspective in this issue of Science Translational Medicine discusses the implications of these findings on the future of flu vaccine design.

Science Translational Medicine, the newest journal from Science, focuses on outstanding science with promise to improve human health and quality-of-life. Under the direction of Chief Scientific Adviser Elias Zerhouni, former director of the National Institutes of Health, and Editor Katrina Kelner, the journal aims to publish groundbreaking research from basic biology that will help make significant advances in medical care, along with commentary on the latest issues in translational medicine.

Links

Listen to Robert Frederick’s Science Podcast interview with author Ian A. Wilson.