Study: Antibody binds to all influenza A subtypes

Jul 29, 2011 (CIDRAP News) – A team of European researchers reported yesterday the discovery of a human monoclonal antibody that binds to all types of influenza A viruses, raising the prospect of a new flu treatment and improving the chances of developing a broadly protective or "universal" flu vaccine.

Writing in Science, the team said the antibody, called FI6, recognizes all 16 types of hemagglutinin found in influenza A viruses and that it protected mice and ferrets from lethal doses of two different flu subtypes.

A number of researchers in recent years have reported finding human antibodies that target multiple influenza A subtypes, but the new findings are the first report of an antibody that recognizes all of them.

"FI6 is the only antibody that has been discovered to date that binds and neutralizes both Group 1 and Group 2 human and animal influenza A viruses," says a press release issued on behalf of Humabs Biomed, a Swiss company that participated in the research. Humabs, of Bellinzona, Switzerland, collaborated with the Institute for Research in Biomedicine, also of Bellinzona, and the United Kingdom Medical Research Council.

Group 1 viruses include H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16 subtypes, while group 2 includes H3, H4, H7, H10, H14, and H15. The type A subtypes that now most commonly infect humans are H1N1 and H3N2, but human are also susceptible to avian flu viruses such as H5N1, H7N7, and H9N2, and to H2, which caused the pandemic of 1957-58.

The new findings relate only to influenza A viruses, not influenza B strains, which circulate at varying levels every year.

Thousands of cells screened
In their hunt for exceptional human antibodies, the researchers used a special single-cell culture method to screen or "interrogate" 104,000 plasma cells from eight donors, their report says. Four plasma cells from one donor yielded an antibody that reacted with H1, H5, and H7 viruses.

The researchers reproduced this antibody and, using various tests, found that it showed binding and neutralizing activity against all 16 influenza A hemagglutinins. Further, they designed an optimized variant of FI6, called FI6v3, that lacks certain unnecessary mutations, the report says.

The team tested the prophylactic effects of the antibody by administering it to mice and then exposing them to normally lethal doses of a lab strain of H1N1 virus. The mice were fully protected when they received an FI6 dose of 4 micrograms per kilogram of body weight.

The authors also tested the effects of the antibody when used to treat mice previously exposed to lethal doses of flu virus. When given 1 or 2 days after infection, a dose of 15 mcg per kg protected mice from death. And in other experiments, the antibody

  • reduced weight loss and prevented death in mice infected with an H3 virus
  • protected ferrets from a lethal challenge with a 2004 strain of H5N1 virus

In other work, the team used x-ray crystallography to determine that the antibody bound to a particular region in the "F subdomain" of the hemagglutinin. They describe the site as conserved, meaning it is the same in different hemagglutinin types. Their report goes into great detail about how the antibody meshes with the surface contours of the hemagglutinin.

Previous reports have noted that the globular head of the hemagglutinin protein, which studs the surface of flu viruses, mutates often to keep the immune system from recognizing it, whereas the stalk or stem of the protein is much more stable.

"The results of prophylaxis and therapy that we report identify FI6 as the first example of a neutralizing monoclonal antibody for potential use against all influenza A viruses," the authors conclude.

Study wins praise
Gary Nabel, MD, PhD, director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases, praised the report while cautioning that it will take time to translate the findings into something clinically useful.

"It's a very elegant paper," he said. "It clearly gives a new window on antibody recognition of flu and neutralization of flu, and it offers potentially a better reagent in terms of inhibiting flu. So it's all good."

He commented that very recent studies have demonstrated sets of antibodies that bound to multiple influenza A viruses in group 1 or group 2, but not both. "So we were going under the assumption that there was some difference between group 1 and group 2 that antibodies couldn't distinguish, and clearly this report says otherwise," he said.

Nabel said the study offers some insights about the ways the immune system can approach conserved sites on the hemagglutinin. "The more we understand about how antibodies bind to highly conserved sites, the better off we'll be. . . . Not to mention that if this proves efficacious in treating infection, that would be another nice implication."

He said it would not be too difficult to produce the antibody in quantity for use as a flu treatment, but added, "I think the real question is whether the pharmaceutical industry sees that there's enough of a market to do that and whether there is a way to do the kind of clinical trial that could show the efficacy of a flu antibody."

To use the discovery to make a broadly protective vaccine, researchers will need to isolate and exploit the hemagglutinin region targeted by the antibody, Nabel said.

"Ideally what you do is refine it further to just the stem region that the antibody is seeing," he said. "You remove that stem region from the rest of the hemagglutinin, which is, in a way, a distraction to the immune system, and then present that in its mot obvious way to elicit the antibody response."

Nabel said this challenge is "not trivial" and will take years: "I think anything less than 5 years would be aggressive, and everything would have to just roll out without complications, which kind of never happens," he said. "But there are a lot of people working on the problem, there are a lot of different approaches, and universal flu [vaccine] is high on the radar screen, so I think we'll be seeing a lot of activity there."

Corti D, Voss J, Gamblin SF, et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 2011 Jul 28 (early online publication) [Abstract]

See also:

Jul 28 EurekAlert press release

Jul 28 UK Medical Research Council press release

Jan 14 CIDRAP News story "Antibodies from H1N1 patients raise hope for more versatile flu vaccines"

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