Natural antibody brings universal flu vaccine closer
that bound to one such vulnerable structure. In mice, an injection of the antibody, CR6261, could prevent or cure an otherwise-lethal infection by about half of flu viruses, including H1 viruses such as H1N1, strains of which caused deadly global pandemics in 1918 and 2009.
The Crucell researchers approached Wilson, whose structural biology lab has world-class expertise at characterizing antibodies and their viral targets. Ekiert, Wilson, and their colleagues soon determined the three-dimensional molecular structure of CR6261 and its binding site on HA, as they reported in Science in 2009. That binding site, or “epitope,” turned out to be on HA’s lower, less-accessible stalk portion. The binding of CR6261 to that region apparently interferes with flu viruses’ ability to deliver their genetic material into host cells and start a new infection. That antibody is about to begin tests in human volunteers.
The release notes that Crucell researchers subsequently searched for an antibody that could neutralize some or all of the remaining flu viruses unaffected by CR6261, and recently found one, CR8020, that fits this description. As the team now reports in the Science Express paper, CR8020 powerfully neutralizes a range of human-affecting flu viruses in lab-dish tests and in mice. The affected viruses include H3 and H7, two subtypes of great concern for human health that have already caused a pandemic (H3) or sporadic human infections (H7).
As with the CR6261 project, Ekiert and colleagues were able to grow crystals of the new antibody bound to an HA protein from a deadly strain of H3N2, and to use X-ray crystallography techniques to determine the antibody’s structure and its precise epitope on the viral HA protein.
“It’s even lower on the HA stalk than the CR6261 epitope; in fact it’s closer to the viral envelope than any other influenza antibody epitope we’ve ever seen,” said Ekiert.
Crucell is about to begin initial clinical trials of CR6261 in human volunteers, and the company expects eventually to begin similar trials of CR8020. If those trials succeed, aside from a vaccine the two antibodies could be combined and used in a “passive immunotherapy” approach. “This would mainly be useful as a fast-acting therapy against epidemic or pandemic influenza viruses,” said Wilson. “The ultimate goal is an active vaccine that elicits a robust, long-term antibody response against those vulnerable epitopes; but developing that is going to be a challenging task.”
— Read more in Damian C. Ekiert et al., “A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses,” Science (7 July 2011) (DOI: 10.1126/science.1204839)
