Researchers move a step closer toward universal flu vaccine and therapies

they mark functionally important sites, or “epitopes,” on the virus that are relatively unchanging (conserved) from one flu strain to the next.

Wilson’s team at Scripps Research characterized the newly discovered antibodies’ binding sites on influenza viruses using electron microscopy and X-ray crystallography techniques. They found that CR8033 binds to a highly conserved epitope — a functionally important site — on the “head” of the hemagglutinin protein, a structure that studs the outer coat of flu viruses and allows the viruses to stick to vulnerable cells. CR8071 binds to the base of the hemagglutinin head. Most antibodies that bind to the hemagglutinin head and neutralize influenza do so by blocking the virus’s attachment to host cells.

“The unique thing about these two antibodies is that they neutralize flu viruses chiefly by preventing virus particles from exiting infected cells,” said Nick Laursen, a research associate in Wilson’s laboratory who was a lead author of the study.

Antibody CR9114 turned out to bind to a site on the hemagglutinin stem. “It prevents the hemagglutinin protein from undergoing the shape-change needed for the virus to fuse to the outer membrane of a host cell,” said Cyrille Dreyfus, a Wilson lab research associate who also was a lead author of the study. “This appears to be a real weak point of the virus, because this epitope is highly conserved among influenza A subtypes as well as influenza B.”

Wilson notes that in a study published in 2009 his laboratory determined the structure of another Crucell antibody that broadly neutralizes influenza A viruses by binding to essentially the same site on the hemagglutinin stem — but in a subtly different way, so that it fails to get a grip on influenza B viruses, too. “With some tweaking of that antibody’s binding domains, we might have been able to get a broader effect like CR9114’s,” Wilson said.

The viral epitope to which CR9114 binds will now be studied extensively by researchers as a target for vaccines and therapies, because it is the only one found so far that is broadly vulnerable to neutralization on both influenza A and B viruses.

The release also notes that, remarkably, CR9114 performed poorly against influenza B viruses in initial lab-dish tests known as microneutralization assays, which test the ability of an antibody to protect cells from viral infection. Yet CR9114 was clearly effective under more realistic conditions in mice, even at low doses. Because it attacks the stem rather than the head of flu virus hemagglutinins, CR9114 also failed to show effects in a widely used test known as the hemagglutinin-inhibition assay.

“As we move towards design of a universal flu vaccine, we need to find more inclusive assays to screen for antibodies such as CR9114, which may be highly effective but have novel mechanisms for neutralization that cannot be detected by the current methods used in influenza vaccine development,” Goudsmit said.

— Read more in Cyrille Dreyfus et al., “Highly Conserved Protective Epitopes on Influenza B Viruses,” Science (9 August 2012) (DOI: 10.1126/science.1222908)