Widespread vaccination will probably be the cornerstone of public-health measures for controlling an H5N1 bird-flu pandemic. But vaccines must be broadly-protective and rapidly produced to be effective against this disease which is devastating in humans, with a mortality of over 60%. These are the conclusions of authors of a Seminar in this week’s edition of The Lancet. The Seminar appears in the same issue as a paper on probable human-human bird-flu transmission, which was published on www.thelancet.com two weeks ago.
Dr Andrea Gambotto, Department of Surgery and Medicine, Division of Infectious Diseases, University of Pittsburgh, USA and colleagues bring together all the latest developments on human infection with bird-flu virus in the Seminar, beginning with modes of transmission. The main route of transmission is direct handling of or close contact with live poultry. However, infection is possible through contact with the contaminated environment and through the gastrointestinal tract. The authors say: "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. 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 2-4 days after exposure to the sick poultry, and usually include fever, cough, shortness of breath, and radiological evidence of pneumonia. Many patients also complain of diarrhoea, vomiting, and abdominal pain. Mortality exceeds 60% and patients usually die of progressive respiratory failure. Diagnosis can be difficult since isolation of H5N1 is time-consuming and requires facilities with a high-level of biosafety. The authors say the preferred method for rapid diagnosis is reverse transcriptase-PCR* (RT-PCR) assays, several of which have been developed by the US Centres for Disease Control and approved by the US Food and Drug Administration for diagnostic use in human beings. The authors highlight their concerns over the various genetic sublineages of the H5N1 virus and the changing nature of the H5 gene, both of which are challenges to keeping the design of RT-PCR assays reliable. Genetic sequence information of the most recent human and bird H5N1 isolates are essential for this. The authors say: "Improving accessibility of databases within the 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."
WHO advises the use of the antiviral drug oseltamivir for treatment of human H5N1 infection, however clinical experience does not suggest this substantially decreases mortality overall (30% survival with oseltamivir versus 26% in untreated patients). However, the survival rates in the oseltamivir patients were 53% when treatment was started within five days of infection compared with 26% when treatment was started on day six or later. The authors also discuss the problems of inadequate drug concentrations and drug resistance.
A number of H5N1 vaccines that have been experimentally tested to date, both protein-based and gene-based, and the advantages and disadvantages of both are discussed.** The common feature of protein-based vaccines is the presentation of so-called preformed proteins to the immune system that preferentially stimulate humoral immune responses and neutralising antibodies. These include inactivated influenza virus vaccines, and the H5N1 type of this vaccine already has FDA approval, but the disadvantages are that an adjuvant molecule is needed with the vaccine and there is limited production capability. However it is already in clinics in preparation for the pandemic. Gene-based vaccines allow host cells to produce the viral proteins themselves, again inducing an immune response. Live attenuated influenza vaccine falls into this category, which is already licensed for human influenza virus vaccination.
The authors conclude: "If H5N1 influenza viruses acquire the capacity for effective human-to-human transmission while retaining their characteristically high pathogenicity, the ensuing pandemic will be devastating. 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."
Notes to editors: *RT-PCR is a means to take extraordinarily a tiny amount of a specified genetic material (eg, RNA) from biological samples, formulate it with a complicated mixture and amplify it into billions of copies in few hours. Once amplified there is enough of it for various purposes, such as sequence it or just see if is there at all. Because RT-PCR can be made to recognize very specific known sequences it can be used to identify RNA virus strains such as H5N1 avian influenza.
**see p1470 full Seminar for table of candidate vaccines plus advantages and disadvantages
For Dr Andrea Gambotto, Deparment of Surgery and Medicine, Division of Infectious Diseases, University of Pittsburgh, USA, please contact Michelle Baum, University of Pittsburgh Media Relations T) +1 412 647 3555 E) baummd@upmc.edu / gambottoa@upmc.edu
http://multimedia.thelancet.com/pdf/press/H5N1.pdf
Journal
The Lancet