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February 2, 2006

Pitt’s avian flu vaccine holds promise for humans

Pitt researchers have developed an avian flu vaccine that they say may show promise in protecting people from the disease, should it mutate in a way that enables it to be readily transmitted among humans.

The vaccine, which contains a live H5N1 avian flu virus, completely protected mice and chickens from infection in lab tests.

The H5N1 avian flu virus, along with culling of flocks to prevent its spread, has killed an estimated 150 million to 200 million birds in the past eight years, making it the largest-scale killer of birds in known history. Outbreaks in poultry have occurred in Asia and eastern Europe.

Although the deadly virus typically does not infect humans, the first documented case of transmission from a bird to a human occurred in 1997 in Hong Kong. The World Health Organization has confirmed 160 human cases and 85 deaths from the H5N1 virus since 2003.

Because of flu’s ability to mutate rapidly, health officials are concerned that the virus has the potential to cause pandemic illness for which the world is poorly prepared.

The Pitt study, published on line and in the Feb. 15 issue of the Journal of Virology, indicates several advantages to the new vaccine. Because it contains a live virus, it may be more immune-activating than other avian flu vaccines. And, because it is grown in cells rather than in fertilized chicken eggs as are traditional vaccines, it can be produced faster, making it useful in preventing the spread of the virus in domestic flocks and potentially in humans.

“The results of this animal trial are very promising, not only because our vaccine completely protected animals that otherwise would have died, but also because we found that one form of the vaccine stimulates several lines of immunity against H5N1,” Andrea Gambotto, assistant professor in the departments of surgery and molecular genetics and biochemistry in the School of Medicine and lead author of the study, stated in a prepared release.

“It takes a little over a month for us to develop a recombinant vector vaccine compared to a minimum of several months via traditional methods,” he said.

“This capacity will be particularly invaluable if the virus begins to mutate rapidly, a phenomenon that often limits the ability of traditional vaccines to contain outbreaks of mutant strains.” A clinical trial of the vaccine in humans is planned.

Gambotto and his colleagues constructed the vaccine by genetically engineering a common cold virus, called adenovirus, to express either all or parts of an avian influenza protein called hemagglutinin (HA) on its surface. HA allows the virus to attach to the cell that is being infected, making the protein critical to the virus’s ability to cause illness and death.

Members of the Pitt Vector Core Facility, led by Wentao Gao, research instructor in the School of Medicine’s Department of Surgery, constructed several adenovirus “vectors” — viruses that have been modified to serve as a delivery vehicle for foreign genes or DNA — containing either the full genetic sequence of the HA protein or sequences for only parts, or subunits, of HA from the Vietnam strain of the virus. They also constructed a vector containing sequences for a portion of the HA protein from the H5N1 Hong Kong strain.

Collaborating with investigators from the Centers for Disease Control and Prevention, Gambotto’s team tested the ability of their slightly different vaccines to protect mice from infection by wild-type H5N1 by comparing its performance to an “empty vector” — an adenovirus vector containing no H5N1 genes.

All of the mice immunized with the empty vector vaccine were dead within six to nine days of avian flu exposure. In sharp contrast, most of the mice immunized with the adenovirus containing either the whole or part of the HA protein survived H5N1 infection.

When the investigators looked for evidence of a specific immune response to H5N1, they found similar results. Although they were able to isolate high levels of infectious H5N1 from multiple organs in the mice vaccinated with the empty vector, and to various degrees in animals vaccinated with the vectors containing the HA subunits, they isolated only very small amounts of H5N1 from the mice immunized with the full-length HA vaccine three days after infection. Six days after infection, they could not detect any infectious H5N1 in the organs of mice immunized with the full-length HA vaccine.

Moreover, when they looked at the cellular immune response to vaccination, they found that all of the animals immunized with full-length HA or the subunit vaccines developed strong cellular immune responses. However, only the full-length HA-immunized mice developed strong T-cell responses to both of the HA subunits.

According to Simon Barratt-Boyes, associate professor of infectious diseases and microbiology in the Graduate School of Public Health (GSPH), and one of the co-authors of the study, the ability of this particular recombinant vaccine — a vaccine carrying only the important immune-stimulating proteins — to induce both antibody- and T cell-directed immunity is extremely encouraging.

“This means that this recombinant vaccine can stimulate several lines of defense against the H5N1 virus, giving it greater therapeutic value. More importantly, it suggests that even if H5N1 mutates, the vaccine is still likely to be effective against it. How effective, we are not sure,” Barratt-Boyes cautioned.

The vaccine’s effectiveness also was tested in chickens, which have almost a 100 percent mortality rate to H5N1 exposure. Researchers inoculated four groups of chickens either through the nose or by injection with the HA-containing vaccine or the empty vector vaccine.

All of the chickens that were immunized subcutaneously survived H5N1 exposure, developed strong HA-specific antibody responses and showed no clinical signs of disease. In contrast, half of the chickens immunized intranasally died and all those immunized with the empty vector died after H5N1 exposure.

The researchers suggested the superior effectiveness of subcutaneous vaccination compared to intranasal immunization may be because the adenovirus vector they used has limited infectivity via the nose and respiratory tract.

Because it appears to be so successful in immunizing chickens against H5N1, widespread inoculation of susceptible poultry populations could prevent the spread of the virus in areas (including the U.S.) that so far have been spared from avian flu.

The research was supported by internal University funds. Others involved in this study include Paul D. Robins and Angela Montecalvo of the School of Medicine and Adam C. Soloff of GSPH.


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