Vaccines, Blood & Biologics

Mutation is enabling some influenza viruses to evade neutralization by previously broadly-active antibodies.

Scientists at the U.S. Food and Drug Administration (FDA) have shown that past seasonal influenza vaccines as well as an influenza vaccine from as long ago as 1976 frequently induced antibodies that were able to neutralize the pandemic 2009 H1N1 influenza virus. However, these antibodies, which target a shared region on the surface of the viruses, are losing their effectiveness as some influenza viruses develop an unusual mutation that is helping them to avoid detection by those antibodies.

Specifically, the FDA scientists found t hat 77% of the antibody samples archived from people who were vaccinated in 1976 against the 1976 “swine influenza” H1N1 virus neutralized the recent pandemic 2009 H1N1 influenza A virus in laboratory tests. In addition, 45% of those antibody samples also neutralized a recent influenza virus called A/New Calendonia/20/99, which circulated from 2000 through 2007. Further, 83% of people who received seasonal influenza vaccines during the 2004/05 through 2008/09 influenza seasons and had a past history of having been vaccinated with the “swine influenza” vaccine in 1976, had antibodies that neutralized the pandemic 2009 H1N1 virus. And among those who had only received the 2004/05-2008/09 seasonal influenza vaccines, but not the 1976 vaccine, 68% had antibodies that neutralized the pandemic 2009 H1N1 virus.

These findings suggest that past vaccinations with the 1976 “swine influenza” vaccine and/or prior immunizations with seasonal influenza vaccines against A/New Calendonia/20/99 induced “cross-neutralizing antibodies” to the pandemic 2009 H1N1 virus that may have contributed to protection from the pandemic influenza.

The scientists also found that these cross-neutralizing antibodies recognized and attacked the same target on both the pandemic 2009 H1N1 and NCD/20/99 virus--a stalk-like protein called HA2. This protein is connected to a cap-like protein called HA1; together, they comprise a larger structure called HA. HA1 enables influenza viruses to attach to cells that they infect and is the major target of antibodies against influenza viruses, whether these antibodies are generated by infection or vaccination. Thus HA1 readily mutates, enabling the virus to avoid being recognized by neutralizing antibodies.

After HA1 attaches the virus to the cell, it uses HA2 to gain entry inside the cell by a process called membrane fusion. Antibodies to HA2 can neutralize the virus by preventing fusion. HA2 mutates less frequently than HA1 and is gaining attention as an attractive target for developing “universal” influenza vaccines that can protect against many different viruses.

Importantly, the FDA scientists found that a single, small, mutation in a specific location in HA2, naturally acquired in viruses that circulated in 2007 through 2009, prevented the cross-neutralizing antibodies from recognizing this protein. This finding was unexpected since mutations that enable influenza viruses to escape antibodies usually occur in HA1. This mutation could make them resistant to the cross-neutralizing antibodies against HA2, eliminating this additional protection against these viruses. Information about the effects of HA2 mutations on neutralization by antibodies will inform the design of future universal influenza vaccines.


“Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2”

PLoS Pathogens 2011, Volume 7, Issue 6 e1002081 Published online 2011 9 June


Wei Wang1, Christine M. Anderson2, Christopher J. de Feo1, Min Zhuang1, Hong Yang3, Russell Vassell1, Hang Xie1, Zhiping Ye4, Dorothy Scott2, Carol D. Weiss1*

1Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Bethesda, Maryland, 2Division of Hematology, CBER, FDA, Bethesda, Maryland, 3Office of Biostatistics and Epidemiology, CBER, FDA, Bethesda, Maryland, 4Laboratory of Pediatric and Respiratory Diseases, Division of Viral Products, CBER, FDA, Bethesda, Maryland

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