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Scientists report in the current issue of the journal Nature Structural and Molecular Biology the isolation of a group of high-affinity antibodies that are potent inhibitors of a wide range of influenza viruses, including the H5N1 avian flu, the 1918 Spanish flu and some seasonal strains . The antibodies may someday be used to create a vaccine that provides lifetime immunity from the flu.
Seasonal flu hospitalizes an average of 226,000 people in the U.S. annually, killing 36,000 every year . Influenza A viruses have been associated with an increasing number of deaths; from 1990 — 1999, the greatest mean number of flu deaths were associated with influenza A (H3N2) viruses . Each season, between one quarter- and a half-million people die of influenza worldwide .
Influenza A is an RNA virus that causes influenza in birds and some mammals. It uses two cell surface proteins to mediate entry and exit from host cells; the virus is subclassified according to the viral protein subtypes used. The protein hemagglutinin (pronounced hem-a-gloot-nin) allows the virus to bind to the cell that is being infected: there are 16 different hemagglutinin subtypes (H1 — H16). The protein neuraminidase (pronounced neur-a-min-i-dase), an enzyme that cleaves sialic acid from host and viral proteins, facilitates viral exit from the host cell: there are 9 neuraminidase subtypes (N1 — N9). All known strains of influenza A are made up of combinations of hemagglutinin and neuraminidase subtypes. For example, the recent spread of avian influenza A (bird flu) is caused by the H5N1 strain, while the 1918 Spanish flu pandemic was caused by the H1N1 strain.
In the current study, researchers screened a panel of human immunoglobulins against the lineage of H5 hemagglutinin and identified 10 antibodies that recognized the protein. Surprisingly, they found that three of the antibodies they tested further also recognized eight of the 15 other hemagglutinin subtypes, including the versions used by the avian flu, the 1918 Spanish flu pandemic strain and the most common human influenza subtypes.
The antibodies were then tested in mice treated with lethal doses of avian flu (H5N1). Mice that were given the antibodies 1 hour before or up to 3 days after infection survived, remaining healthy and showing minimal body weight loss over a 2-week observation period. The ability of the antibodies to protect the mice demonstrated therapeutic value.
Hemagglutinin consists of a globular head region connected to a fibrous stem domain, the base of which is associated with the virus (imagine a small mushroom on the surface of a sphere; see the illustration above). Vaccines principally generate antibodies that target the globular head region of hemagglutinin . However, the head region changes rapidly, giving rise to new flu strains that are no longer recognized by the generated antibodies. This is the reason why annual vaccination is so important — to provide continued immune protection.
Antibodies typically block the binding of hemagglutinin to its cellular receptor. However, high-resolution structure analysis revealed that the antibody interferred with the subsequent step of hemagglutinin-mediated virus-host membrane fusion, inserting into a ‘pocket’ in the stem of hemagglutinin.
Three hydrophobic pockets (meaning having little or no affinity for water) are located below the globular head region of hemagglutinin. In the complex analyzed by scientists, one antibody binds in each pocket. Many influenza subtypes have the same stem structure, providing an explanation not only for the ability of the antibodies to block virus-host membrane fusion but to inhibit other influenza subtypes.
According to the World Health Organization, as of February 2009 there has been a total of 408 confirmed human cases of avian influenza A and 256 deaths. The researchers are starting animal safety tests and hope to begin clinical trials of antibody treatments by the 2011 — 2012 flu season .
This study has profound implications for the generation of a universal influenza vaccine. However, development of a vaccine that can produce those antibodies will take longer, since the stem domain of hemagglutinin typically typically escapes immune surveillance.
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