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Antibodies Neutralize Multiple Flu Strains

Influenza virus hemagglutinin protein bound by neutralizing antibodies (red and orange).William C. Hwang, Burnham Institute for Medical Research.

Two separate scientific teams have discovered antibodies that attach to a vulnerable region in a broad range of influenza A viruses, including the H5N1 avian virus, the 1918 pandemic influenza virus and seasonal H1N1 flu viruses. The finding could potentially help scientists develop tools to prevent or treat the flu during an outbreak or pandemic.

Seasonal influenza (flu) kills more than 250,000 people worldwide each year, despite the availability of influenza drugs and vaccines. The H5N1 avian flu virus primarily infects birds now, but has caused a high rate of mortality in people who’ve become infected. Influenza viruses constantly change, or mutate, raising the possibility that lethal H5N1 viruses could become easily transmissible among humans and cause a worldwide flu pandemic.

A team led by Dr. Wayne Marasco of the Dana-Farber Cancer Institute and Harvard Medical School screened human monoclonal antibodies for their ability to neutralize influenza viruses. These well-characterized infection-fighting proteins are derived from cells that can relatively quickly produce large quantities of identical antibodies. In the past, it’s been difficult to design monoclonal antibodies that are effective against multiple flu strains because flu viruses mutate so rapidly.

The researchers, supported by NIH’s ×îÐÂÂ鶹ÊÓƵ Institute of Allergy and Infectious Diseases (NIAID) and the U.S. Centers for Disease Control and Prevention, began their study with avian flu viruses. As reported online in Nature Structural & Molecular Biology on February 22, 2009, they scanned tens of billions of monoclonal antibodies produced in bacterial viruses, or bacteriophages. Ten of the antibodies proved active against the 4 major strains of H5N1 avian influenza viruses. Three of these monoclonal antibodies also neutralized representative strains of other known influenza A viruses in cell cultures. When tested in mice, the antibodies protected against illness.

The researchers next determined the atomic structure of the region on the flu virus where the monoclonal antibodies bind. This genetically stable, hidden part of the virus is located on the narrow stem of the hemagglutinin (HA) protein, 1 of the 2 main surface proteins on the influenza virus.

The researchers also determined the atomic structure of one of the monoclonal antibodies bound to the H5N1 HA. Their detailed picture shows one arm of the antibody inserted into a genetically stable pocket on the stem of the HA protein (see illustration). Once the antibody binds, the virus can't change its shape and fuse with the cell to gain entry.

There are 16 known subtypes of HA proteins, classified into 2 groups. The new antibodies neutralized all testable viruses with the Group 1 HAs, including the seasonal H1 viruses, the virus that caused the 1918 pandemic and the highly pathogenic avian flu viruses. However, the antibodies had no significant effect on Group 2 HAs.

In a related finding, just days later, NIH-supported investigators at The Scripps Research Institute and their colleagues reported on February 26 in the online edition of Science that they’d discovered antibodies in human blood samples capable of neutralizing a broad range of influenza viruses. A structural analysis revealed that the antibodies attach to the same region of HA as the monoclonal antibodies found by the Dana-Farber group.

Taken together, these 2 studies uncover a new mechanism of antibody action against influenza. Dr. Marasco and his colleagues next aim to test the safety and effectiveness of their monoclonal antibodies in ferrets, the gold standard influenza animal model.