Human Antibodies Prevent Avian Flu in Mice

HO CHI MINH CITY, Vietnam, May 29 -- Antibodies from human survivors of an infection with the highly pathogenic avian influenza H5N1strain appear to offer mice protection against the virus.

When mice were immunized before being exposed to the virus, some of the antibodies offered complete protection from dying of the disease, according to Cameron Simmons, Ph.D., of the Oxford University Clinical Research Unit here, and colleagues in Switzerland and the U.S.

And therapeutic doses of the antibodies -- delivered up to 72 hours after infection -- gave the animals significant protection from death, the reported online in PLoS Medicine.

"We have shown that this technique can work to prevent and neutralize infection by the H5N1 'bird flu' virus in mice," Dr. Simmons said.

"We are optimistic that these antibodies, if delivered at the right time and at the right amount, could also provide a clinical benefit to humans with H5N1 infections," he said.

The antibodies were derived from the blood of four patients who survived infection with the A/Vietnam/1203/04 strain of the avian flu virus -- a so-called Clade I virus.

Human infection with the H5N1 avian flu is rare but highly dangerous. According to the World Health Organization, there had been 307 confirmed cases as of May 24 and 186 deaths.

Memory B-cells from the four donors were used to create monoclonal antibodies (using a technique first reported in 2004) in the lab of Antonio Lanzavecchia, M.D., of the Institute for Research in Biomedicine in Bellinzona, Switzerland. He was a co-author of the current research.

Then they were tested in vitro to find those with activity against the Vietnam strain of the virus, Dr. Simmons and colleagues reported, and four active antibodies were isolated to be tested in animals.

Mice susceptible to the avian flu virus were passively immunized with one of the four antibodies or a control antibody to either diphtheria or anthrax.

The researchers found that one of the antibodies -- dubbed FLA5.10 -- completely protected the mice from death at all doses. The protection was significantly greater (P=0.001) than that provided by the control antibody.

Another antibody (FLA3.14) prevented death in a dose-dependent manner, with the highest dose offering almost complete protection (greater at P=0.001 than the control antibody) while the lowest dose was no better than the control.

Mice immunized with the control antibody had high levels of virus in their lungs, with evidence that the virus had spread beyond the lungs and into the brain and spleen.

In contrast, mice immunized with either FLA3.14 or FLA5.10 had a 10^th to a 100^th the levels of virus in the lungs -- differences that were significant at P=0.01 for FLA3.14 and at P=0.001 for FLA5.10.

They also had undetectable levels of virus in the brain and low levels in the spleen.

The finding is important because humans who die of H5N1 infection usually have high levels of the virus in their lungs and evidence of extra-pulmonary dissemination, while those who survive do not, the researchers noted.

The researchers also tested the antibodies as therapy, giving them to mice 24, 48, or 72 hours after infection, and found that all four provided "robust protection" against death at all time points when compared to a control antibody. The differences were all significant at P=0.003.

"This is particularly important as people who have become infected with the virus do not tend to report to their local health-care facilities until several days after the onset of illness," Dr. Simmons said.

Interestingly, the researchers found that some of the antibodies were also effective against a related virus, the Clade II strain A/Indonesia/5/2005.

The findings require further research, Dr. Lanzavecchia said, if only because it is not certain that a future pandemic strain of flu would arise from the H5N1 strain that is currently causing a nearly world-wide epidemic among birds.

"Nevertheless, we are encouraged by the broad neutralizing activity of these antibodies in the lab and the moderate doses required," he said in a statement.