Feb 27, 2009 (CIDRAP News) – For the second time this week, scientists have reported the discovery of a human antibody that, at least in theory, could lead to development of a vaccine or drug effective against most types of influenza A, including the deadly H5N1 avian flu virus.
A team from the Scripps Research Institute in La Jolla, Calif., and the Dutch company Crucell Holland BV describe the new antibody, called CR6261, in a report in Science. They write that the antibody recognizes a stable, or nonmutating, region of the hemagglutinin (HA) protein in the 1918 pandemic flu virus and a 2004 strain of the H5N1 virus.
As it is described, the antibody targets the same general region of the HA protein as do the monoclonal antibodies described in the report published Feb 22: the stem or neck of the molecule, which sits on the surface of the virus and helps it bind to host cells. And like the earlier report, the new one says the antibody neutralizes the virus by blocking it from fusing with cells.
"The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion," the Science report states. "Identification of the CR6261 epitope [the HA site the antibody targets] provides a lead for the design of antivirals and takes a significant step towards the development of a durable and cross-protective 'universal' vaccine against influenza A," it concludes.
The National Institute of Allergy and Infectious Diseases, which provided funding for both studies released this week, said in a statement yesterday, "Taken together, these studies provide a blueprint for efforts to develop new antiviral drugs as well as a potential universal flu vaccine."
The scientists, with Damian C. Ekiert of Scripps as first author, write that they isolated CR6261 from a healthy, vaccinated person by mixing a serum sample with HA from an H5 virus. In a previously reported study, they found that CR6261 neutralized several influenza A subtypes, including H1, H2, H5, H6, H8, and H9. They also found that it protected mice from H1N1 and H5N1 viruses when administered up to 5 days after infection.
To determine which part of the HA molecule the antibody targets and how it neutralizes the virus, the team studied the crystal structures of the antibody in combination with HAs from the 1918 H1N1 virus and a 2004 Vietnam strain of the H5N1 virus. They found that the antibody attaches to the base of the proteins rather than to the mushroom-shaped head—the portion targeted by existing flu vaccines.
In further experiments, the scientists concluded that the antibody prevents HA from initiating the process of fusing the viral membrane with the host cell membrane. "CR6261 appears to neutralize the virus by stabilizing the pre-fusion state and preventing the pH-dependent fusion of viral and cellular membranes," the report says.
The researchers also analyzed more than 5,000 HA genetic sequences in a flu database in an effort to learn why certain flu subtypes, such as H3 and H7, are not neutralized by CR6261. They concluded that the masking of a certain site on the HA molecule by glycoproteins (glycosylation) is the probable reason. From this analysis, they concluded that the antibody probably can neutralize HAs from 12 of the 16 influenza A subtypes: H1, H2, H4-H6, H8, H9, H11-H14, and H16.
The presence of the CR6261 epitope in a wide range of influenza viruses "suggests a critical role in membrane fusion," indicating the possibility of using it to develop new antiviral drugs and a broadly protective vaccine, the researchers write.
Experts who were not involved in the study said the latest findings are very similar to those reported earlier this week in Nature Structural and Molecular Biology.
John Treanor, MD, a vaccine researcher and professor of microbiology and immunology at the University of Rochester in New York, called the idea of using the "fusion region" of HA to develop a vaccine interesting, though not entirely new. "It's a long way to go between knowing you have an antibody that can recognize that region and making a vaccine," he said.
If the CR6261 target region were used to make a vaccine designed to induce the immune system to generate similar antibodies, immunogenicity could be a challenge, Treanor said. "Bear in mind that you don't really make this antibody when you're exposed [to flu viruses], or you don't make much of it. So presumably you'd have to cook up some way of presenting the epitope in such a way as to make it immunogenic."
He said the findings certainly raise the possibility making CR6261 antibodies for use as a flu treatment. "I don't have any doubt that we could do that. I will say that if the experience with palivizumab is any guide, you'd expect this type of passive antibody approach to be much more effective for prevention than for treatment."
Palivizumab is a human monoclonal antibody used to protect certain vulnerable children from serious infections with respiratory syncytial virus, he said.
Dr. Richard Webby, a virologist, flu researcher, and associate member of the Department of Infectious Diseases at St. Jude Children's Research Hospital in Memphis, called the latest findings "great stuff."
Given that monoclonal antibodies are already used to treat certain diseases, the findings certainly point to a possibility of antibody-based therapies for flu, he said.
"There are some limitations on the wider use of this approach, cost being the major one," he said. "As production techniques improve and costs come down, it becomes a little bit more viable."
Webby added that antibody-based flu therapies have been "very, very effective" in animal models, surpassing other drugs. "So I absolutely think it's an avenue that needs to be pursued aggressively."
As for the vaccine possibilities, he noted that a number of researchers are trying to make vaccines that induce immunity to more stable parts of influenza viruses, including sites on the HA, and have had mixed success. "There's no doubt that if we want to produce a more cross-reactive vaccine against influenza, we have to understand more about these cross-reactive epitopes," he said.
Ekiert DC, Bhabba G, Elsliger, MA, et al. Antibody recognition of a highly conserved influenza virus epitope. Science 2009 Feb 26 (early online publication) [Abstract]
Feb 26 NIAID statement
Feb 23 CIDRAP News story "Researchers find antibody that fights H5N1, seasonal flu strains"