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H5N1 Influenza ? Continuing Evolution and Spread
<CENTER>Robert G. Webster, Ph.D., and Elena A. Govorkova, M.D., Ph.D. </CENTER><TABLE cellSpacing=0 cellPadding=0 width=200 align=right border=0><TBODY><TR><TD width=20> </TD><TD bgColor=#336699><TABLE cellSpacing=1 cellPadding=0 border=0><TBODY><TR vAlign=top><TD align=middle width=200 bgColor=#e8e8d1>
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</TD><TD vAlign=center><TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TD></TD><TD vAlign=center>by Oner, A. F.</TD></TR></TBODY></TABLE></B></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Related Article</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center><TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TD></TD><TD vAlign=center>by Kandun, I. N.</TD></TR></TBODY></TABLE></B></TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>Find Similar Articles</TD></TR><TR vAlign=top><TD vAlign=top align=middle width=15></TD><TD vAlign=center>PubMed Citation</TD></TR><TR vAlign=top><TD colSpan=2></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE><!-- end of outer content box1 --></TABLE><!-- end of outer content box2 --><!-- <CENTER>H5N1 Influenza — Continuing Evolution and Spread</CENTER> --><!-- <CENTER></NOBR><NOBR>Robert G. Webster, Ph.D.</NOBR> and <NOBR>Elena A. Govorkova, M.D., Ph.D.</NOBR></CENTER>
-->There is no question that there will be another influenza pandemic<SUP> </SUP>someday. We simply don't know when it will occur or whether<SUP> </SUP>it will be caused by the H5N1 avian influenza virus. But given<SUP> </SUP>the number of cases of H5N1 influenza that have occurred in<SUP> </SUP>humans to date (251 as of late September 2006) and the rate<SUP> </SUP>of death of more than 50%, it would be prudent to develop robust<SUP> </SUP>plans for dealing with such a pandemic.<SUP> </SUP>
The epicenters of both the Asian influenza pandemic of 1957<SUP> </SUP>and the Hong Kong influenza pandemic of 1968 were in Southeast<SUP> </SUP>Asia, and it is in this region that multiple clades of H5N1<SUP> </SUP>influenza virus have already emerged. The Asian H5N1 virus was<SUP> </SUP>first detected in Guangdong Province, China, in 1996, when it<SUP> </SUP>killed some geese, but it received little attention until it<SUP> </SUP>spread through live-poultry markets in Hong Kong to humans in<SUP> </SUP>May 1997, killing 6 of 18 infected persons (see map and time line).<SUP> </SUP>The culling of all poultry in Hong Kong ended the first wave<SUP> </SUP>of H5N1, but the virus continued to circulate among apparently<SUP> </SUP>healthy ducks in the coastal provinces of China.<SUP> </SUP>
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</NOBR> </TD><TD vAlign=top align=left>The Spread of H5N1 Influenza Virus and Time Line Showing Its Emergence.
The shaded area across southern China is the hypothetical epicenter for the emergence of H5N1 clades and subclades. The H5N1 viruses are being perpetuated in the domestic birds of the region, despite the use of universal vaccination of all domestic poultry. The red dot in the time line denotes the occurrence of the first human case, followed by the number of confirmed human cases in that country. The green and blue solid bars represent documented H5N1 infection in domestic poultry and wild birds, and dashed bars indicate that H5N1 in the avian population is suspected. These limited surveillance data are adapted from the World Health Organization and the U.N. Food and Agriculture Organization (www.fao.org). HA denotes hemagglutinin.
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From 1997 to May 2005, H5N1 viruses were largely confined to<SUP> </SUP>Southeast Asia, but after they had infected wild birds in Qinghai<SUP> </SUP>Lake, China, they rapidly spread westward. The deaths of swans<SUP> </SUP>and geese marked H5N1's spread into Europe, India, and Africa.<SUP> </SUP>Infections with highly pathogenic H5N1 viruses were confirmed<SUP> </SUP>in poultry in Turkey in mid-October 2005, and the first confirmed<SUP> </SUP>human cases in Turkey occurred in early January 2006. Thus,<SUP> </SUP>H5N1 influenza viruses continue to emerge from the epicenter.<SUP> </SUP>
The H5N1 viruses can be divided into clade 1 and clade 2; the<SUP> </SUP>latter can be further subdivided into three subclades. The bad<SUP> </SUP>news is that these clades and subclades probably differ sufficiently<SUP> </SUP>in their antigenic structure to warrant the preparation of different<SUP> </SUP>vaccines. Studies in ferrets suggest that vaccine against one<SUP> </SUP>clade will not protect against infection with another clade,<SUP> </SUP>though it will protect against influenza-associated death.<SUP>1</SUP><SUP> </SUP>Thus, the available information supports the notion that a vaccine<SUP> </SUP>against H5N1 is worth stockpiling as a "prepandemic" vaccine,<SUP> </SUP>since very few persons have been immunologically exposed to<SUP> </SUP>H5 antigens and priming with one clade may be beneficial.<SUP> </SUP>
Another key question is whether these clades and subclades vary<SUP> </SUP>in sensitivity to available anti-influenza drugs. The majority<SUP> </SUP>of H5N1 clade 1 viruses (e.g., A/Vietnam/1203/2004) are resistant<SUP> </SUP>to the adamantanes (amantadine and rimantadine), but the majority<SUP> </SUP>of clade 2 viruses (e.g., A/Indonesia/5/2005) are sensitive.<SUP> </SUP>All H5N1 viruses that have been tested are sensitive to the<SUP> </SUP>neuraminidase inhibitors; these drugs may be effective when<SUP> </SUP>used prophylactically, but the window for effective treatment<SUP> </SUP>will probably be limited to 1 to 2 days after initial infection.<SUP> </SUP>Kandun et al. make clear in their report in this issue of the<SUP> </SUP>Journal (pages 2186?2194) on three clusters of patients<SUP> </SUP>with H5N1 infection in Indonesia that the difficulty with the<SUP> </SUP>use of a neuraminidase inhibitor (oseltamivir) in those cases<SUP> </SUP>was that treatment began 5 to 7 days after initial infection.<SUP> </SUP>Such delayed administration of the drug limits its value in<SUP> </SUP>decreasing the viral load and might lead to the selection of<SUP> </SUP>resistant strains.<SUP> </SUP>
The use of rapid diagnostics for H5N1 virus infection can permit<SUP> </SUP>specific antiviral treatments to be initiated early. Oner et<SUP> </SUP>al. report in this issue of the Journal (pages 2179?2185)<SUP> </SUP>that in a human outbreak of H5N1 in Turkey, it was difficult<SUP> </SUP>to detect H5N1 virus infection with standard techniques; the<SUP> </SUP>authors found that a real-time polymerase-chain-reaction assay<SUP> </SUP>performed on nasopharyngeal specimens had the best diagnostic<SUP> </SUP>value.<SUP> </SUP>
The continuing evolution of H5N1 viruses and the clusters of<SUP> </SUP>human infections in Indonesia and Turkey raise important questions.<SUP> </SUP>First, can the source of H5N1 be eliminated? And second, is<SUP> </SUP>the increasing number of clusters of human infection an indicator<SUP> </SUP>of evolution toward consistent human-to-human transmission?<SUP> </SUP>
Controlling H5N1 influenza by eradicating it at the source in<SUP> </SUP>domestic poultry has worked for some wealthy countries: in 2003,<SUP> </SUP>Japan and South Korea eradicated H5N1 through a strategy of<SUP> </SUP>quarantine and culling of poultry and implementation of improved<SUP> </SUP>biosecurity measures for poultry facilities. In Thailand, however,<SUP> </SUP>the same strategy resulted in only a temporary respite; after<SUP> </SUP>nearly a year with no H5N1 activity, new cases in humans in<SUP> </SUP>July 2006 heralded the resurgence of H5N1 in domestic poultry.<SUP> </SUP>
An alternative strategy adopted by China, Indonesia, and Vietnam<SUP> </SUP>has been to vaccinate uninfected poultry in conjunction with<SUP> </SUP>the quarantine and culling of infected birds. This approach<SUP> </SUP>has failed, however, and its critics explain that poultry vaccines<SUP> </SUP>are largely of poor quality, do not provide sterilizing immunity,<SUP> </SUP>and promote antigenic drift. Yet vaccines against H5N1 influenza<SUP> </SUP>virus have been used successfully since 2004 on all poultry<SUP> </SUP>sold in Hong Kong, where no H5N1 virus has been isolated from<SUP> </SUP>fowl in live-bird markets despite extensive prospective surveillance.<SUP> </SUP>
Perhaps the most important experiment in controlling H5N1 is<SUP> </SUP>one that is ongoing in Vietnam. Since the country adopted a<SUP> </SUP>strategy of vaccinating all poultry with inactivated, oil-emulsion<SUP> </SUP>H5N1 vaccine, there have been no additional cases in humans<SUP> </SUP>and no reported H5N1 infections in chickens. But in September<SUP> </SUP>2006, H5N1 was reported to have reemerged in ducks and geese<SUP> </SUP>in Vietnam. Thus, H5N1 influenza vaccine seems to protect chickens<SUP> </SUP>and, indirectly, humans, but probably not waterfowl.<SUP> </SUP>
Given that the vaccine predominantly used in Vietnam is prepared<SUP> </SUP>in China, where the policy is to vaccinate all poultry, some<SUP> </SUP>have questioned why H5N1 is not under control in China. The<SUP> </SUP>problem may be the lack of protection in waterfowl. Ducks may<SUP> </SUP>be the stealth carriers (the Trojan horses of H5N1 influenza),<SUP> </SUP>for wild mallard ducks do not always show signs of disease when<SUP> </SUP>infected with any of a range of highly pathogenic H5N1 viruses.<SUP>2</SUP><SUP> </SUP>Our knowledge about the efficacy of H5N1 influenza vaccines<SUP> </SUP>in domestic waterfowl is limited, and highly pathogenic H5N1<SUP> </SUP>viruses continue to be isolated from waterfowl in the epicenter<SUP> </SUP>of the epidemic. If the reservoir of highly pathogenic H5N1<SUP> </SUP>virus is domestic waterfowl, the virus should theoretically<SUP> </SUP>be eradicable, but eliminating it would require improved vaccines<SUP> </SUP>for waterfowl and draconian prospective surveillance and culling.<SUP> </SUP>
Meanwhile, the number of infections in humans continues to increase.<SUP> </SUP>By mid-August, 97 humans had been infected in 2006 ? the<SUP> </SUP>same number as in all of 2005. Perhaps the most surprising thing<SUP> </SUP>about highly pathogenic H5N1 is that although more than 230<SUP> </SUP>million domestic birds have died or been killed, only 251 humans<SUP> </SUP>have become ill from H5N1 infection, and there has been little<SUP> </SUP>or no evidence of subclinical infection in humans. The current<SUP> </SUP>H5N1 virus is apparently not well "fitted" to replication in<SUP> </SUP>humans, although the genetic makeup of a small proportion of<SUP> </SUP>humans supports attachment and replication of the virus, if<SUP> </SUP>not its transmission. The specific receptor for the current<SUP> </SUP>avian influenza virus (
2-3 sialic acid) is found deep in the<SUP> </SUP>respiratory tract of humans,<SUP>3</SUP> but it seems likely that only<SUP> </SUP>a minority of people have receptors for avian influenza viruses<SUP> </SUP>in their upper respiratory tracts. Moreover, receptor specificity<SUP> </SUP>is only one of the requirements for human infection; the virus<SUP> </SUP>must also find compatible enzyme systems in the infected human<SUP> </SUP>cells if the viral polymerase complex is to function. Currently,<SUP> </SUP>these conditions are apparently met in only a few persons. But<SUP> </SUP>the virus is always changing, and mutations that make it more<SUP> </SUP>compatible with human transmission may occur at any time.<SUP> </SUP>The seasonality of H5N1 influenza seems similar to that of human<SUP> </SUP>influenza: the virus has apparently been more transmissible<SUP> </SUP>among chickens, and consequently to humans, during the cooler<SUP> </SUP>months. The cases in humans in Turkey, Iraq, and Egypt occurred<SUP> </SUP>during the cooler months and coincided with explosive outbreaks<SUP> </SUP>of the disease in wild and domestic poultry. In the tropical<SUP> </SUP>areas of Asia, there have been two resurgences of H5N1 during<SUP> </SUP>the warmer months of the year ? a pattern that resembles<SUP> </SUP>that followed by human influenza in the tropics, with its multiple<SUP> </SUP>peaks of activity. With winter approaching in the northern hemisphere,<SUP> </SUP>H5N1 may spread further. Will it cross from Eurasia to the Americas?<SUP> </SUP>Will wild migratory birds carry it from their breeding sites<SUP> </SUP>in northern Europe and Siberia to commercial poultry in Europe,<SUP> </SUP>Africa, and America? If it is endemic in wild migratory birds<SUP> </SUP>that are not rapidly killed by it, then spread to domestic backyard<SUP> </SUP>poultry is inevitable. The intermittent spread to humans will<SUP> </SUP>continue, and the virus will continue to evolve.<SUP> </SUP>
Clearly, we must prepare for the possibility of an influenza<SUP> </SUP>pandemic. If H5N1 influenza achieves pandemic status in humans<SUP> </SUP>? and we have no way to know whether it will ? the<SUP> </SUP>results could be catastrophic.<SUP> </SUP>
<SUP></SUP>
Drs. Webster and Govorkova report receiving research funding<SUP> </SUP>from Hoffmann?La Roche and BioCryst Pharmaceuticals. Dr.<SUP> </SUP>Webster reports receiving consulting fees from GlaxoSmithKline;<SUP> </SUP>and Dr. Govorkova, consulting fees from BioCryst Pharmaceuticals.<SUP> </SUP>No other potential conflict of interest relevant to this article<SUP> </SUP>was reported.<SUP> </SUP>
Source Information
Dr. Webster is a professor and Dr. Govorkova a senior scientist in the Department of Infectious Diseases, Division of Virology, St. Jude Children's Research Hospital, Memphis, TN.
References
- <!-- null --><LI value=1>Govorkova EA, Webby RJ, Humberd J, Seiler JP, Webster RG. Immunization with reverse-genetics-produced H5N1 influenza vaccine protects ferrets against homologous and heterologous challenge. J Infect Dis 2006;194:159-167.<!-- HIGHWIRE ID="355:21:2174:1" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE --><!-- null --> <LI value=2>Hulse-Post DJ, Sturm-Ramirez KM, Humberd J, et al. Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc Natl Acad Sci U S A 2005;102:10682-10687.<!-- HIGHWIRE ID="355:21:2174:2" --> <NOBR>[Abstract/Full Text]</NOBR><!-- /HIGHWIRE --><!-- null -->
- Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006;440:435-436.<!-- HIGHWIRE ID="355:21:2174:3" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE -->
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- (2006). Avian Flu: Deadly, and Difficult to Diagnose. Journal Watch (General) 2006: 1-1 <NOBR>[Full Text] </NOBR>
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