A passive defence against the flu?

Influenza is a disease that kills hundreds of thousands of people every year, and periodically causes global pandemics that kill many millions.  There are three major types, A, B and C that can infect humans, although the A is responsible for the most cases and deaths. Within influenza A virus there are two major groups, 1 and 2, each of which includes several subtypes, and finally within each subtype there are many strains. Currently available vaccines can only protect against a narrow range of strains, sometimes only one, and as a consequence every year the World Health Organization (WHO) has to try to predict which strains will cause problems over the following year and make vaccines to protect vulnerable people from them, and naturally they can’t always get the prediction right. More worryingly it takes several months to develop each vaccine so in the event that a new pandemic strain arises a vaccine to protect against it may not become available before it has spread widely. For this reason scientists are working to develop vaccines that will protect against a broad range of influenza strains and subtypes, while at the same time others are developing improved treatments for those who do become infected.

In an exciting paper published online in Nature Structural & Molecular Biology (1) a team led by Wayne Marasco of the Dana-Farber Cancer Institute, Robert Liddington of the Burnham Institute for Medical Research, and Ruben Donis of the Centers for Disease Control and Prevention (CDC) have used an in vitro screening method to identify human antibodies that bind to a protein called hemagglutinin (the “H” in H5N1) that is found on the surface of the virus and is required for the virus to enter a cell once it has bound to it.  As described in in Nature news the antibodies they identified using an in vitro phage display screening method bind to a portion of hemagglutinin known as the stem that varies little between different subtypes of group 1  influenza A virus and stop the virus entering the cell. Having proved that the antibodies could block virus entry into cells in vitro the scientists then tested if clinically realistic doses of antibody could protect animals from an otherwise lethal influenza A infection. They found that when these antibodies were given to mice that had previously been infected with highly pathogenic strains of the H5N1 and H1N1 virus subtypes the mice remained healthy and the spread of the virus through their organs greatly reduced, while mice that were not given the antibodies died. While H5N1 and H1N1 are both group 1 subtypes of  influenza A currently available vaccines against one do not protect against the other, so this result taken with the in vitro data demonstrated that the antibodies provide broad protection against group 1 influenza A viruses.  This protection was even observed when the antibodies were given 3 days after infection, indicating that these antibodies are suitable for a passive immunization approach to the treatment of influenza following infection, which would be a very valuable addition to the limited range of treatments currently available. Their research also indicated that their screening technique can be used to identify antibodies that can be used to protect against other groups of influenza virus.

But what of “classic” vaccines that stop people acquiring the flu in the first place? Well, the authors of this study suggests that by designing vaccines that direct the immune system to target the conserved stem region of hemagglutinin, rather than the more variable portions of hemagglutinin as is now the case, it may be possible to have vaccines that confer protection against a broad range of influenza subtypes. A combination of only a few such vaccines could yield a “universal” flu vaccine, which is certainly an exciting prospect, though since flu is also found in many wild and domesticated animal populations which can transmit it to us we will probably never be possible to control it as thoroughly we have controlled polio.

Regards

Paul Browne
1) Sui J. et al “Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses” Nat. Struct. Mol. Biol. Advanced Online Publication , 22 February 2009, doi:10.1038/nsmb.1566

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