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Researchers Draw First Complete Picture of Human Antibody Response to Avian Influenza Virus

An international team of scientists including NIAID’s Kanta Subbarao, M.D., who collaborated with scientists from the Food and Drug Administration, have produced a detailed picture of the human antibody response following infection by avian influenza virus H5N1. The findings could aid researchers in developing diagnostic tests capable of distinguishing avian H5N1 infections from typical seasonal influenza infections. The information about what the immune system “sees” when it encounters H5N1 influenza virus could also speed efforts to develop vaccines designed to elicit a protective antibody response.

Human infections with avian H5N1 influenza are rare—about 400 people are known to have contracted the infection since 2003—but over 60 percent of infected people have died. The virus has not acquired the ability to spread easily from person to person, but experts fear that if it does, it could spark a worldwide pandemic. Researchers are working to devise effective vaccines against H5N1 viruses, but their efforts are hampered by a lack of detailed information about the human antibody defenses that arise when a person is infected with a virus that normally infects only birds. In particular, scientists want to know exactly which regions of the H5N1 virus prompt the immune system’s B cells to generate antibodies capable of binding to—and incapacitating—the virus.

Building a Library and Finding Human Antibodies

FDA’s Hana Golding, Ph.D., and her colleagues adapted an existing technique (called whole genome fragment phage display libraries) that uses genetically modified viruses (phages) to create a library of protein fragments that collectively represented all of the proteins in an H5N1 virus that circulated in Viet Nam in 2004.

Next, the scientists mixed the viral protein fragments with blood from fiveVietnamese people who had recovered from H5N1 infection in 2004. The blood samples were taken between 2 and 6 months after the patients became ill. The blood contained antibodies that recognized small regions (epitopes) of several H5N1 proteins. The researchers found human antibodies that recognized the virus’s hemagglutinin protein (the “H” in H5N1) and others that bound to another viral surface protein, neuraminidase (the “N” in H5N1). The recovered patients also made antibodies against M2, a viral protein that, unlike neuraminidase and hemagglutinin, varies relatively little. Other scientists have been exploring the possibility of targeting the M2 protein with a vaccine. In theory, a vaccine designed to elicit antibodies against a relatively unchanging viral protein would not need to be reformulated as often as the current seasonal influenza vaccines, which are aimed at the constantly changing H and N proteins.

The researchers also found antibodies that reacted strongly to a viral protein called PB1-F2. Although little is known about the recently discovered PB1-F2 protein, it is thought to contribute significantly to the virus’s ability to cause disease. This was the first report showing that humans produce antibodies against PB1-F2. This viral protein could be a target for future vaccine development, the scientists said.

In addition, the team found epitopes that did react with the antibodies from the convalescent H5N1 patients but that did not react to blood samples obtained from people who had recovered from seasonal influenza infections. These newly discovered epitopes could be the basis for a test that would allow doctors to distinguish H5N1 infections—in which patients produce H5N1-specific antibodies—from seasonal influenza infections (where H5N1-specific antibodies are absent.)

It is not possible to conclude from this study alone that the antibodies discovered in the blood samples from recovered patients would, in fact, protect a person from developing disease after being infected by H5N1 viruses. Still, the work does provide the first picture of the full scope of the human antibody repertoire aimed against this bird virus. The information will likely be extremely valuable as scientists worldwide continue to look for ways to prevent an influenza pandemic. 

Reference: S Khurana et al. Antigenic fingerprinting of an h5N1 avian influenza virus using convalescent sera and human monoclonal antibodies reveals potential vaccine and serodiagnostic targets. PLoS Medicine 6(4): e1000049. DOI:10.1371/journal.pmed.1000049 (April 20, 2009).

Last Updated June 10, 2009