MRC National Institute for Medical Research, London
Science for Health
An antibody that binds to group 1 and group 2 influenza A haemagglutinin
29 July 2011
The isolation of broadly neutralising antibodies against influenza A viruses has been a major goal for therapeutic approaches and vaccine design. The main target of influenza A virus–neutralising antibodies is the haemagglutinin protein (HA). It undergoes continuous evolution driven by the selective pressure of the antibody response, which is primarily directed against the membrane-distal receptor-binding subdomain of the molecule. Genetically, there are 16 influenza A subtypes of HA, which form two groups. Antibodies neutralize primarily homologous strains within a given subtype, and new vaccines are produced every year to match these strains. Antibodies capable of neutralising multiple subtypes within group 1 or group 2 have been isolated from immunised mice, phage libraries, and memory B cells and plasma cells of immune donors. However, influenza A–neutralising antibodies targeting epitopes conserved on all 16 subtypes of group 1 and group 2 viruses have not been found before.
Steve Gamblin (pictured) and John Skehel, from NIMR's Division of Molecular Structure, investigated the molecular basis of virus recognition by the antibody. They collaborated with scientists from the Institute for Research in Biomedicine (IRB) and at Humabs BioMed, both in Switzerland, led by Antonio Lanzavecchia. The Lanzavecchia lab developed a high-throughput culture method to interrogate large numbers of human plasma cells. The method involves culture of single plasma cells in a medium that supports plasma cell survival, followed by screening of the culture supernatants and rescue of the selected antibodies by single-cell reverse transcription polymerase chain reaction.
They isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. The NIMR team determined the structures of antibody complexes with HAs from the group 1 H1 and the group 2 H3 subtypes by x-ray crystallography. These showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
This single–plasma cell culture method allowed the interrogation of thousands of plasma cells and led to the isolation of a rare pan–influenza A–neutralising antibody. The rarity of this antibody is underscored by the fact that, from interrogation of plasma cells isolated from seven other donors, the researchers isolated several antibodies that, although they bound to group 1 and group 2 HAs, were unable to neutralise virus infectivity.
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The figure shows a trimer of haemagglutinin binding to three molecules of antibody. One of the HA monomers is coloured, the others are in grey.
The work in this paper represents an exciting development in influenza research because it addresses the problem that arises when a new virus, to which there is limited immunity in the population, transfers and spreads in humans. Because of the threat and the cost of severe influenza, emphasised in the UK during the 2009 pandemic, there has been strong interest in developing therapeutics that would block all influenza virus infections and could, therefore, be stockpiled for use in emergencies. Antibodies that neutralise virus infections could be ideal candidates for such stockpiles. A number have been reported to be effective against one or the other group of influenza A viruses and this paper describes a human antibody that reacts with all influenza A viruses by binding to one of their membrane glycoproteins, the haemagglutinin. Characterisation of the antibody including X-ray crystallography of antibody-haemagglutinin complexes, shows how, unlike previously reported antibodies, the new antibody is able to bind to both groups of viruses despite their characteristic structural features.
Steve Gamblin
Original article
A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins (2011)
Davide Corti, Jarrod Voss, Steven J. Gamblin, Giosiana Codoni, Annalisa Macagno, David Jarrossay, Sebastien G. Vachieri, Debora Pinna, Andrea Minola, Fabrizia Vanzetta, Chiara Silacci, Blanca M. Fernandez-Rodriguez, Gloria Agatic, Siro Bianchi, Isabella Giacchetto-Sasselli, Lesley Calder, Federica Sallusto, Patrick Collins, Lesley F. Haire, Nigel Temperton, Johannes P. M. Langedijk, John J. Skehel, Antonio Lanzavecchia.
Science epub ahead of print. Publisher abstract
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