Live H5N1 vaccines show potential in animal study

Sep 13, 2006 (CIDRAP News) – Live-virus vaccines made from a combination of H5N1 avian influenza virus and another flu strain protected laboratory mice and ferrets from deadly infection with several different H5N1 strains, according to a report published yesterday.

The researchers say the findings are promising because live, weakened virus vaccines can trigger a faster and broader immune response than inactivated vaccines. Such vaccines may offer protection with one dose and be effective against more than one H5N1 strain, which would be major advantages in a flu pandemic, they assert.

The new study was the result of collaboration between the National Institute of Allergy and Infectious Diseases (NIAID) and MedImmune, Inc., maker of the live, intranasal vaccine FluMist. It was published in Public Library of Science–Medicine, with Kanta Subbarao of the NIAID as senior author.

"The encouraging findings of this study suggest that vaccines based on live but weakened versions of the H5N1 avian influenza virus may quickly stimulate protective immunity," NIAID Director Anthony S. Fauci, MD, commented in a news release. "We are further exploring this live, attenuated vaccine strategy as one of several tools that we hope to have available in the event of an influenza pandemic."

Attempts to make H5N1 vaccines so far have focused on inactivated viruses or pieces of viruses. Killed-virus vaccines have generated "suboptimal" immune responses and have required at least two doses, say the authors of the new study.

Subbarao's team made three vaccines by combining six internal protein genes from an influenza A/H2N2 virus with hemagglutinin (H) and neuraminidase (N) genes from three H5N1 viruses, according to the report. The H2N2 virus was a "cold-adapted" strain—one grown in a lab in progressively cooler temperatures so it can't spread from the relatively cool upper respiratory tract to other parts of the body.

The H5N1 viruses used to make the vaccine were isolated from human cases in Hong Kong in 1997 and 2003 and in Vietnam in 2004. For safety, however, the hemagglutinin (H5) genes were modified by changing the amino-acid sequence at a key site to a form found in avian flu viruses that are not highly pathogenic in chickens. The vaccines were grown in chicken eggs.

In safety tests, the researchers determined that the vaccine viruses were not lethal in chickens or mice, whereas naturally occurring H5N1 viruses were.

The team tested the protective power of the vaccines by administering them to mice and ferrets in nose drops and then exposing them to high doses of natural (wild-type) H5N1 viruses. In mice, a single vaccine dose induced only a low antibody response and did not prevent growth of the wild-type virus in the lungs, but it did protect the mice from death, the report says.

When mice were given a second dose of vaccine 28 days after the first, they showed a stronger and faster immune response and had nearly complete protection from respiratory infection with the viruses. The findings were similar for ferrets given two doses. The vaccines protected the animals not only from the 1997 and 2004 H5N1 viruses used in the vaccines, but also from strains collected in 2005 in Indonesia and Vietnam, according to the NIAID.

In the news release, Subbarao said the world needs a vaccine that will protect people against a range of H5N1 viruses, since it's impossible to predict what strain of H5N1 (if any) will cause a pandemic. The next step, he said, is to test the safety and immunogenicity of the engineered vaccines in people, including whether they produce cross-reactive antibodies.

The NIAID and MedImmune launched such a study in June at the Johns Hopkins Bloomberg School of Public Health in Baltimore, using a 2004 H5N1 virus. The vaccine is being tested in about 20 healthy adults, the NIAID said.

The authors contend that live vaccines generate a stronger antibody response than killed-virus vaccines and that this is especially true in the mucus membranes of the upper respiratory tract. The combination of antibodies in the blood and the respiratory mucosa "results in broad protection against antigenically drifted [virus] strains," they write.

"This may be a particularly useful feature in the event of a pandemic, in which a vaccine generated from the emergent virus strain is not available," the report adds. "Whether these theoretical advantages will be seen with live, attenuated H5N1 vaccines remains to be seen."

In an accompanying commentary, two experts who weren't involved in the study, Stacey Schultz-Cherry and Jonathan A. McCullers, write that the research offers clinicians "a powerful tool in the fight against pandemic H5N1 influenza viruses: an 'off-the-shelf' seed virus that could be standardized, rapidly produced, and safely handled by vaccine manufacturers for vaccine production against a diverse population of H5N1 viruses." Schultz-Cherry is in the Department of Medical Microbiology and Immunology at the University of Wisconsin in Madison, and McCullers is at St. Jude Children's Research Hospital in Memphis.

Although a single dose of vaccine didn't completely protect animals from lung infection, "this partial protection may translate to protection from severe illness and death in humans," Schultz-Cherry and McCullers write. In addition, the hemagglutinin modification that prevented the vaccine from killing chickens means that it would pose only limited risk to the poultry industry if it got loose in the environment, they state.

The commentary raises two caveats, however. One is that the immunogenicity of live, attenuated vaccines against H5 viruses has yet not been demonstrated in humans. Other vaccines have protected mice from H5N1 viruses but turned out to generate little immune response in humans.

The second concern is the risk that the vaccine virus could combine (reassort) with a seasonal flu virus in a human, producing a transmissible hybrid strain of H5 virus, potentially triggering a pandemic, Schultz-Cherry and McCullers write. "This concern will limit clinical testing of the vaccine in humans and may restrict use of this vaccine approach to the period after a new pandemic strain has begun to circulate," they state.

Suguitan AL, McAuliffe J, Mills KL, et al. Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med 2006 Sep;3(9) [Full text]

Schultz-Cherry S, McCullers JA. A step closer to meeting the threat of avian influenza. (Editorial)  PLoS Med 2006 Sep;3(9) [Full text]

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