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Promising preclinical results with live attenuated H5N1 vaccines

September 12, 2006

Several approaches are in progress to develop vaccines against the avian flu variety of the influenza virus. Kanta Subbarao (National Institutes of Health) and colleagues are working on live attenuated vaccines, which have the potential to elicit a strong, broad, and lasting immune response. As they now report in the international open-access medical journal PLoS Medicine, results from mice and ferrets (the rodent flu model of choice) are very encouraging and pave the way to testing these vaccines in human volunteers.

The researchers developed vaccines using 3 artificially constructed, weakened forms of the influenza virus. The 3 vaccine viruses were constructed using flu virus proteins other than H and N from artificially weakened (attenuated) strains of influenza. These were combined with H and N proteins from H5N1 viruses isolated from human cases during three different years: 2004, 2003, and 1997. They grew larger quantities of the resulting viruses in hen eggs, and tested the vaccines in chickens, ferrets, and mice.

In tests of safety, the study found that, unlike the natural viruses from which they were derived, the vaccine strains did not cause death when injected into the bloodstream of chickens, and did not even cause persistent infection when given through the birds' breathing passages. Similarly, while the natural viruses were lethal in mice at various doses, the vaccine strains did not cause death even at the highest dose. In ferrets, infection with the vaccine strains was limited to the upper respiratory tract, while the natural viruses spread eadily to the lungs.

In tests of protection, all mice that had received any of the 3 vaccines survived following injection with any of the natural viruses (so-called viral challenge), while unvaccinated mice died following viral challenge. This occurred even though standard blood tests could not detect a strong immune responses following a single dose of vaccine. Challenge virus was detected in the lungs of the immunized mice, but at lower levels than in the unvaccinated mice. Mice given two doses of a vaccine showed stronger immunity on blood tests, as well as almost complete protection from respiratory infection following challenge. In addition, mice and ferrets that had received two doses of vaccine were protected against challenge with H5N1 strains from more recent outbreaks in Asia that differed substantially from the strains that were used for the vaccine.

This study shows that live attenuated vaccine based on a single H5N1 virus strain can provide protection (in mice and ferrets, at least) against different H5N1 viruses that emerge years later. One of the vaccines is now being tested in human volunteers who participate in carefully conducted clinical trials.

Public Library of Science