Promising preclinical results with live attenuated H5N1 vaccines

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.

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Citation: Suguitan AL Jr., McAuliffe J, Mills KL, Jin H, Duke G, et al. (2006) Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med 3(9): e360.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030360

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-09-subbarao.pdf

CONTACT:
Kanta Subbarao
National Institutes of Health
Respiratory Viruses Section, Lab of Infectious Diseases
Bldg. 50, Room 6132, 50 South Drive, MSC 8007
Bethesda, MD 20892
United States of America
301-451-3839
301-496-8312 (fax)
ksubbarao@niaid.nih.gov

Related PLoS Medicine Perspectives article:

Citation: Schultz-Cherry S, McCullers JA (2006) A step closer to meeting the threat of avian influenza. PLoS Med 3(9): e375.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030375

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-09-schultz-cherry.pdf

CONTACT:
Stacey Schultz-Cherry
University of Wisconsin-Madison
Department of Medical Microbiology and Immunology
Madison, WA 53706 United States of America
608-265-6462
slschul2@wisc.edu

About PLoS Medicine

PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of human health and disease, together with commentary and analysis of important global health issues. For more information, visit http://www.plosmedicine.org

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The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. For more information, visit http://www.plos.org

All works published in PLoS Medicine are open access. Everything is immediately available without cost to anyone, anywhere--to read, download, redistribute, include in databases, and otherwise use--subject only to the condition that the original authorship is properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.


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