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Heading off a Bird-Flu Pandemic: We Need Broadly Protective Vaccines That Can Be Rapidly Produced and Administered

University of Pittsburgh School of Medicine-led team report dissects bird flu in The Lancet

PITTSBURGH, April 24, 2008 — Widespread vaccination likely will be the cornerstone of public-health measures for controlling an H5N1 bird-flu pandemic, say Andrea Gambotto, M.D., assistant professor of surgery at the University of Pittsburgh School of Medicine, and his colleagues, in this week’s edition of The Lancet. However, any vaccines must be broadly protective and rapidly producible to be effective against H5N1, which is devastating in humans, the authors write in a journal Seminar. In this comprehensive “state of the science” report on bird flu vaccine research, the scientists note that the primary route of transmission for the H5N1 virus appears to be direct handling of or close contact with live poultry. Infection also is possible through contact with the contaminated environment and through the gastrointestinal tract.

“A few possible human-to-human transmissions of H5N1 influenza virus have been reported, which all involved lengthy, close and unprotected contact with infected patients,” the authors note. “Reports of clustering of human H5N1 virus infections within families, usually without crossing blood lines, might suggest the presence of genetic factors which predispose to H5N1 virus or severe disease.”

In most cases, symptoms develop within four days of exposure, and usually include fever, cough, shortness of breath and X-ray evidence of pneumonia. Many patients also complain of diarrhea, vomiting and abdominal pain. Mortality exceeds 60 percent, and patients usually die of progressive respiratory failure. Diagnosis can be difficult since isolation of H5N1 is time-consuming and requires high-level biocontainment laboratory facilities. The preferred method for rapid diagnosis is reverse transcriptase-polymerase chain reaction (RT-PCR) assays, several of which have been developed by the U.S. Centers for Disease Control and Prevention and approved by the U.S. Food and Drug Administration for diagnostic use in human beings, Dr. Gambotto and his colleagues note.

RT-PCR allows researchers to generate billions of copies of a tiny amount of a specified RNA sequence from biological samples within a few hours for further sequencing and testing. Because RT-PCR can be made to recognize specific known sequences, it can be used to identify RNA virus strains such as H5N1 avian influenza.

In addition, the authors highlight their concerns over genetic variants of the H5N1 virus, which they say provide constant challenges to the reliability of RT-PCR assay design. Because of these challenges, genetic sequence information of the most recent human and bird H5N1 isolates are essential.

“Improving accessibility of databases within the World Health Organization’s (WHO) influenza networks that are restricted, and in which such information is mostly stored, would help with and improve the establishment and maintenance of reliable diagnostics in many laboratories in countries affected by H5N1 influenza virus,” the authors write.

While WHO advises the use of the antiviral drug oseltamivir for treatment of human H5N1 infection, clinical experience suggests the drug is not particularly effective for decreasing mortality overall (30 percent survival with oseltamivir versus 26 percent in untreated patients). Importantly, however, survival rates in the oseltamivir patients were 53 percent when treatment was started within five days of infection, compared with 26 percent when treatment was started on day six or later. The authors also consider problems associated with inadequate drug concentrations and resistance.

For the Seminar, the authors discuss a number of protein- and gene-based H5N1 vaccines that have been tested in clinical trials so far, enumerating the advantages and disadvantages of each.

The common feature of protein-based vaccines appears to be the presentation of pre-formed proteins to the immune system that preferentially stimulate humoral immune responses and neutralizing antibodies. These include inactivated influenza virus vaccines. An H5N1 type of this vaccine already has FDA approval, but the disadvantage is that an adjuvant molecule is needed with the vaccine and there is limited production capability. This inactivated influenza virus for H5N1 is already in clinics in preparation for a possible pandemic.

Gene-based vaccines allow host cells to produce the viral proteins themselves, again inducing an immune response. Live but weakened influenza vaccine falls into this category, which already is licensed for human influenza virus vaccination.

“If H5N1 influenza viruses acquire the capacity for effective human-to-human transmission while retaining their characteristically high pathogenicity, the ensuing pandemic would be devastating,” Dr. Gambotto and his colleagues conclude. “Therapeutic approaches for control of the disease can be restricted, leaving widespread vaccination as the probable cornerstone of public-health measures for pandemic control. Continued research into influenza pathogenesis and development of broadly-protective vaccines that can be rapidly produced is needed in anticipation of an H5N1 influenza virus pandemic.”

In addition to Dr. Gambotto, other authors are Simon M. Barratt-Boyes, Ph.D., University of Pittsburgh Graduate School of Public Health; Menno D. de Jong, M.D., Ph.D., Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Gabriele Neumann, Ph.D., and Yoshiro Kawaoka, Ph.D., University of Wisconsin-Madison.

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