Perspective
Focus on Research
H5N1 Influenza — Continuing Evolution and Spread
N Engl J Med 2006; 355:2174-2177November 23, 2006
- Article
There is no question that there will be another influenza pandemic someday. We simply don't know when it will occur or whether it will be caused by the H5N1 avian influenza virus. But given the number of cases of H5N1 influenza that have occurred in humans to date (251 as of late September 2006) and the rate of death of more than 50%, it would be prudent to develop robust plans for dealing with such a pandemic.
The epicenters of both the Asian influenza pandemic of 1957 and the Hong Kong influenza pandemic of 1968 were in Southeast Asia, and it is in this region that multiple clades of H5N1 influenza virus have already emerged. The Asian H5N1 virus was first detected in Guangdong Province, China, in 1996, when it killed some geese, but it received little attention until it spread through live-poultry markets in Hong Kong to humans in May 1997, killing 6 of 18 infected persons (see map and time line
The Spread of H5N1 Influenza Virus and Time Line Showing Its Emergence.). The culling of all poultry in Hong Kong ended the first wave of H5N1, but the virus continued to circulate among apparently healthy ducks in the coastal provinces of China.From 1997 to May 2005, H5N1 viruses were largely confined to Southeast Asia, but after they had infected wild birds in Qinghai Lake, China, they rapidly spread westward. The deaths of swans and geese marked H5N1's spread into Europe, India, and Africa. Infections with highly pathogenic H5N1 viruses were confirmed in poultry in Turkey in mid-October 2005, and the first confirmed human cases in Turkey occurred in early January 2006. Thus, H5N1 influenza viruses continue to emerge from the epicenter.
The H5N1 viruses can be divided into clade 1 and clade 2; the latter can be further subdivided into three subclades. The bad news is that these clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines. Studies in ferrets suggest that vaccine against one clade will not protect against infection with another clade, though it will protect against influenza-associated death.1 Thus, the available information supports the notion that a vaccine against H5N1 is worth stockpiling as a “prepandemic” vaccine, since very few persons have been immunologically exposed to H5 antigens and priming with one clade may be beneficial.
Another key question is whether these clades and subclades vary in sensitivity to available anti-influenza drugs. The majority of H5N1 clade 1 viruses (e.g., A/Vietnam/1203/2004) are resistant to the adamantanes (amantadine and rimantadine), but the majority of clade 2 viruses (e.g., A/Indonesia/5/2005) are sensitive. All H5N1 viruses that have been tested are sensitive to the neuraminidase inhibitors; these drugs may be effective when used prophylactically, but the window for effective treatment will probably be limited to 1 to 2 days after initial infection. Kandun et al. make clear in their report in this issue of the Journal (pages 2186–2194) on three clusters of patients with H5N1 infection in Indonesia that the difficulty with the use of a neuraminidase inhibitor (oseltamivir) in those cases was that treatment began 5 to 7 days after initial infection. Such delayed administration of the drug limits its value in decreasing the viral load and might lead to the selection of resistant strains.
The use of rapid diagnostics for H5N1 virus infection can permit specific antiviral treatments to be initiated early. Oner et al. report in this issue of the Journal (pages 2179–2185) that in a human outbreak of H5N1 in Turkey, it was difficult to detect H5N1 virus infection with standard techniques; the authors found that a real-time polymerase-chain-reaction assay performed on nasopharyngeal specimens had the best diagnostic value.
The continuing evolution of H5N1 viruses and the clusters of human infections in Indonesia and Turkey raise important questions. First, can the source of H5N1 be eliminated? And second, is the increasing number of clusters of human infection an indicator of evolution toward consistent human-to-human transmission?
Controlling H5N1 influenza by eradicating it at the source in domestic poultry has worked for some wealthy countries: in 2003, Japan and South Korea eradicated H5N1 through a strategy of quarantine and culling of poultry and implementation of improved biosecurity measures for poultry facilities. In Thailand, however, the same strategy resulted in only a temporary respite; after nearly a year with no H5N1 activity, new cases in humans in July 2006 heralded the resurgence of H5N1 in domestic poultry.
An alternative strategy adopted by China, Indonesia, and Vietnam has been to vaccinate uninfected poultry in conjunction with the quarantine and culling of infected birds. This approach has failed, however, and its critics explain that poultry vaccines are largely of poor quality, do not provide sterilizing immunity, and promote antigenic drift. Yet vaccines against H5N1 influenza virus have been used successfully since 2004 on all poultry sold in Hong Kong, where no H5N1 virus has been isolated from fowl in live-bird markets despite extensive prospective surveillance.
Perhaps the most important experiment in controlling H5N1 is one that is ongoing in Vietnam. Since the country adopted a strategy of vaccinating all poultry with inactivated, oil-emulsion H5N1 vaccine, there have been no additional cases in humans and no reported H5N1 infections in chickens. But in September 2006, H5N1 was reported to have reemerged in ducks and geese in Vietnam. Thus, H5N1 influenza vaccine seems to protect chickens and, indirectly, humans, but probably not waterfowl.
Given that the vaccine predominantly used in Vietnam is prepared in China, where the policy is to vaccinate all poultry, some have questioned why H5N1 is not under control in China. The problem may be the lack of protection in waterfowl. Ducks may be the stealth carriers (the Trojan horses of H5N1 influenza), for wild mallard ducks do not always show signs of disease when infected with any of a range of highly pathogenic H5N1 viruses.2 Our knowledge about the efficacy of H5N1 influenza vaccines in domestic waterfowl is limited, and highly pathogenic H5N1 viruses continue to be isolated from waterfowl in the epicenter of the epidemic. If the reservoir of highly pathogenic H5N1 virus is domestic waterfowl, the virus should theoretically be eradicable, but eliminating it would require improved vaccines for waterfowl and draconian prospective surveillance and culling.
Meanwhile, the number of infections in humans continues to increase. By mid-August, 97 humans had been infected in 2006 — the same number as in all of 2005. Perhaps the most surprising thing about highly pathogenic H5N1 is that although more than 230 million domestic birds have died or been killed, only 251 humans have become ill from H5N1 infection, and there has been little or no evidence of subclinical infection in humans. The current H5N1 virus is apparently not well “fitted” to replication in humans, although the genetic makeup of a small proportion of humans supports attachment and replication of the virus, if not its transmission. The specific receptor for the current avian influenza virus (α2-3 sialic acid) is found deep in the respiratory tract of humans,3 but it seems likely that only a minority of people have receptors for avian influenza viruses in their upper respiratory tracts. Moreover, receptor specificity is only one of the requirements for human infection; the virus must also find compatible enzyme systems in the infected human cells if the viral polymerase complex is to function. Currently, these conditions are apparently met in only a few persons. But the virus is always changing, and mutations that make it more compatible with human transmission may occur at any time.
The seasonality of H5N1 influenza seems similar to that of human influenza: the virus has apparently been more transmissible among chickens, and consequently to humans, during the cooler months. The cases in humans in Turkey, Iraq, and Egypt occurred during the cooler months and coincided with explosive outbreaks of the disease in wild and domestic poultry. In the tropical areas of Asia, there have been two resurgences of H5N1 during the warmer months of the year — a pattern that resembles that followed by human influenza in the tropics, with its multiple peaks of activity. With winter approaching in the northern hemisphere, H5N1 may spread further. Will it cross from Eurasia to the Americas? Will wild migratory birds carry it from their breeding sites in northern Europe and Siberia to commercial poultry in Europe, Africa, and America? If it is endemic in wild migratory birds that are not rapidly killed by it, then spread to domestic backyard poultry is inevitable. The intermittent spread to humans will continue, and the virus will continue to evolve.
Clearly, we must prepare for the possibility of an influenza pandemic. If H5N1 influenza achieves pandemic status in humans — and we have no way to know whether it will — the results could be catastrophic.
Drs. Webster and Govorkova report receiving research funding from Hoffmann–La Roche and BioCryst Pharmaceuticals. Dr. Webster reports receiving consulting fees from GlaxoSmithKline; and Dr. Govorkova, consulting fees from BioCryst Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
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
References
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
CrossRef | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
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
CrossRef | Web of Science | Medline
- Citing Articles (82)
Citing Articles
1
Kaifa Wei, Yanfeng Chen, Juan Chen, Lingjuan Wu, Daoxin Xie. (2012) Evolution and adaptation of hemagglutinin gene of human H5N1 influenza virus. Virus Genes
CrossRef2
Joseph J. Jablonski, Dipwanita Basu, Daniel A. Engel, H. Mario Geysen. (2012) Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. Bioorganic & Medicinal Chemistry 20:1, 487-497
CrossRef3
Akira Sakurai, Namiko Nomura, Reiko Nanba, Takayuki Sinkai, Tsunehito Iwaki, Taminori Obayashi, Kazuhiro Hashimoto, Michiya Hasegawa, Yoshihiro Sakoda, Akihiro Naito, Yoshihito Morizane, Mitsugu Hosaka, Kunio Tsuboi, Hiroshi Kida, Akemi Kai, Futoshi Shibasaki. (2011) Rapid typing of influenza viruses using super high-speed quantitative real-time PCR. Journal of Virological Methods 178:1-2, 75-81
CrossRef4
Takashi Ohkura, Yuji Kikuchi, Naoko Kono, Shigeyuki Itamura, Katsuhiro Komase, Fumitaka Momose, Yuko Morikawa. (2011) Epitope mapping of neutralizing monoclonal antibody in avian influenza A H5N1 virus hemagglutinin. Biochemical and Biophysical Research Communications
CrossRef5
Timo Vesikari, Aino Forstén, Karl-Heinz Herbinger, Giovanni Della Cioppa, Jenny Beygo, Astrid Borkowski, Nicola Groth, Mariaviviana Bennati, Frank von Sonnenburg. (2011) Safety and immunogenicity of an MF59®-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly. Vaccine
CrossRef6
L. T. DAUM, S. A. WORTHY, K. C. YIM, M. NOGUERAS, R. F. SCHUMAN, Y. W. CHOI, G. W. FISCHER. (2011) A clinical specimen collection and transport medium for molecular diagnostic and genomic applications. Epidemiology and Infection 139:11, 1764-1773
CrossRef7
Trang Truc Nguyen, Binh Khanh Mai, Mai Suan Li. (2011) Study of Tamiflu Sensitivity to Variants of A/H5N1 Virus Using Different Force Fields. Journal of Chemical Information and Modeling 51:9, 2266-2276
CrossRef8
G.G.U. Rohde. (2011) Influenza. Der Internist 52:9, 1047-1052
CrossRef9
Juine-Ruey Chen, Che Ma, Chi-Huey Wong. (2011) Vaccine design of hemagglutinin glycoprotein against influenza. Trends in Biotechnology 29:9, 426-434
CrossRef10
Zhijie Zhang, Dongmei Chen, Yue Chen, Tilman M. Davies, Jean-Pierre Vaillancourt, Wenbao Liu. (2011) Risk signals of an influenza pandemic caused by highly pathogenic avian influenza subtype H5N1: Spatio-temporal perspectives. The Veterinary Journal
CrossRef11
Binh Khanh Mai, Mai Suan Li. (2011) Neuraminidase inhibitor R-125489 – A promising drug for treating influenza virus: Steered molecular dynamics approach. Biochemical and Biophysical Research Communications 410:3, 688-691
CrossRef12
Mohamed E. El Zowalaty, Martha Abin, Yogesh Chander, Patrick T. Redig, Sagar M. Goyal. (2011) Isolation of H5 Avian Influenza Viruses from Waterfowl in the Upper Midwest Region of the United States. Avian Diseases 55:2, 259-262
CrossRef13
Ye Liu, Hong Chen, Yajiao Sun, Fuhui Chen. (2011) Antiviral role of toll-like receptors and cytokines against the new 2009 H1N1 virus infection. Molecular Biology Reports
CrossRef14
Peng Cui, Yuansheng Hou, Zhi Xing, Yubang He, Tianxian Li, Shan Guo, Ze Luo, Baoping Yan, Zuohua Yin, Fumin Lei. (2011) Bird Migration and Risk for H5N1 Transmission into Qinghai Lake, China. Vector-Borne and Zoonotic Diseases 11:5, 567-576
CrossRef15
Eiji Miyagawa, Hiroyuki Kogaki, Yoshiaki Uchida, Nobuyuki Fujii, Takashi Shirakawa, Yoshihrio Sakoda, Hiroshi Kida. (2011) Development of a novel rapid immunochromatographic test specific for the H5 influenza virus. Journal of Virological Methods 173:2, 213-219
CrossRef16
Brendan M. Giles, Ted M. Ross. (2011) A computationally optimized broadly reactive antigen (COBRA) based H5N1 VLP vaccine elicits broadly reactive antibodies in mice and ferrets. Vaccine 29:16, 3043-3054
CrossRef17
E. J. Kasowski, R. J. Garten, C. B. Bridges. (2011) Influenza Pandemic Epidemiologic and Virologic Diversity: Reminding Ourselves of the Possibilities. Clinical Infectious Diseases 52:Supplement 1, S44-S49
CrossRef18
Shoji KAWACHI. (2011) THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA 31:4, 620-628
CrossRef19
Peng Cui, Yuansheng Hou, Mingjie Tang, Haiting Zhang, Yuanchun Zhou, Zuohua Yin, Tianxian Li, Shan Guo, Zhi Xing, Yubang He, Diann J. Prosser, Scott H. Newman, John Y. Takekawa, Baoping Yan, Fumin Lei. (2011) Movement patterns of Bar-headed Geese Anser indicus during breeding and post-breeding periods at Qinghai Lake, China. Journal of Ornithology 152:1, 83-92
CrossRef20
Bryan Corrin, Andrew G. Nicholson. 2011. Infectious diseases. , 155-262.
CrossRef21
Jiri Beran, Ibrahim A. Abdel-Messih, Jolana Raupachova, Lenka Hobzova, Elena Fragapane. (2010) A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses. Clinical Therapeutics 32:13, 2186-2197
CrossRef22
Saori Sakabe, Kiyoko Iwatsuki-Horimoto, Taisuke Horimoto, Chairul A. Nidom, Mai thi Quynh Le, Ryo Takano, Ritsuko Kubota-Koketsu, Yoshinobu Okuno, Makoto Ozawa, Yoshihiro Kawaoka. (2010) A cross-reactive neutralizing monoclonal antibody protects mice from H5N1 and pandemic (H1N1) 2009 virus infection. Antiviral Research 88:3, 249-255
CrossRef23
Catherine Moore, Jean-Noel Telles, Sally Corden, Rong-Bao Gao, Guy Vernet, Pierre Van Aarle, Yue-Long Shu. (2010) Development and validation of a commercial real-time NASBA assay for the rapid confirmation of influenza A H5N1 virus in clinical samples. Journal of Virological Methods 170:1-2, 173-176
CrossRef24
J. Herington. (2010) Securitization of infectious diseases in Vietnam: the cases of HIV and avian influenza. Health Policy and Planning 25:6, 467-475
CrossRef25
Aeron C. Hurt, Sue Lowther, Deborah Middleton, Ian G. Barr. (2010) Assessing the development of oseltamivir and zanamivir resistance in A(H5N1) influenza viruses using a ferret model. Antiviral Research 87:3, 361-366
CrossRef26
Haiyan Chang, Xiaoman Li, Yong Teng, Yan Liang, Bo Peng, Fang Fang, Ze Chen. (2010) Comparison of Adjuvant Efficacy of Chitosan and Aluminum Hydroxide for Intraperitoneally Administered Inactivated Influenza H5N1 Vaccine. DNA and Cell Biology 29:9, 563-568
CrossRef27
Liwen Ju, Lufang Jiang, Jixing Yang, Qing Shi, Qingwu jiang, Huiguo Shen, Yiyun Tan, Yuanan Lu. (2010) Co-infection with influenza A/H1N1 and A/H3N2 viruses in a patient with influenza-like illness during the winter/spring of 2008 in Shanghai, China. Journal of Medical Virology 82:8, 1299-1305
CrossRef28
Richard Y Kao, Dan Yang, Lai-Shan Lau, Wayne H W Tsui, Lihong Hu, Jun Dai, Mei-Po Chan, Che-Man Chan, Pui Wang, Bo-Jian Zheng, Jian Sun, Jian-Dong Huang, Jason Madar, Guanhua Chen, Honglin Chen, Yi Guan, Kwok-Yung Yuen. (2010) Identification of influenza A nucleoprotein as an antiviral target. Nature Biotechnology 28:6, 600-605
CrossRef29
Nikolai Kaverin. (2010) Postreassortment amino acid substitutions in influenza A viruses. Future Microbiology 5:5, 705-715
CrossRef30
Guillermo Ruiz-Carrascoso, Inmaculada Casas, Francisco Pozo, Carmen Pérez-González, Jordi Reina, Pilar Pérez-Breña. (2010) Development and implementation of influenza a virus subtyping and detection of genotypic resistance to neuraminidase inhibitors. Journal of Medical Virology 82:5, 843-853
CrossRef31
Gunnar Gunnarsson, Elsa Jourdain, Jonas Waldenström, Björn Helander, Peter Lindberg, Johan Elmberg, Neus Latorre-Margalef, Björn Olsen. (2010) Zero Prevalence of Influenza A Virus in Two Raptor Species by Standard Screening. Vector-Borne and Zoonotic Diseases 10:4, 387-390
CrossRef32
Da-Yuan Chen, Jui-Hung Shien, Laurence Tiley, Shyan-Song Chiou, Sheng-Yang Wang, Tien-Jye Chang, Ya-Jane Lee, Kun-Wei Chan, Wei-Li Hsu. (2010) Curcumin inhibits influenza virus infection and haemagglutination activity. Food Chemistry 119:4, 1346-1351
CrossRef33
Jennifer Pfeiffer, David L. Suarez, Luciana Sarmento, Thanh Long To, Tung Nguyen, Mary J. Pantin-Jackwood. (2010) Efficacy of Commercial Vaccines in Protecting Chickens and Ducks Against H5N1 Highly Pathogenic Avian Influenza Viruses from Vietnam. Avian Diseases 54:s1, 262-271
CrossRef34
Tommy Tsan-Yuk Lam, Chung-Chau Hon, Julian W. Tang. (2010) Use of phylogenetics in the molecular epidemiology and evolutionary studies of viral infections. Critical Reviews in Clinical Laboratory Sciences 47:1, 5-49
CrossRef35
Jane Baer, Felix Santiago, Hongmei Yang, Hulin Wu, Jeanne Holden-Wiltse, John Treanor, David J. Topham. (2010) B cell responses to H5 influenza HA in human subjects vaccinated with a drifted variant. Vaccine 28:4, 907-915
CrossRef36
Fanny LeBouder, Khaled Khoufache, Catherine Menier, Yassmina Mandouri, Mahmoud Keffous, Nathalie Lejal, Irène Krawice-Radanne, Edgardo D. Carosella, Nathalie Rouas-Freiss, Béatrice Riteau. (2009) Immunosuppressive HLA-G molecule is upregulated in alveolar epithelial cells after influenza A virus infection. Human Immunology 70:12, 1016-1019
CrossRef37
Jing-Fang Wang, Dong-Qing Wei, Kuo-Chen Chou. (2009) Insights from investigating the interactions of adamantane-based drugs with the M2 proton channel from the H1N1 swine virus. Biochemical and Biophysical Research Communications 388:2, 413-417
CrossRef38
GORDON CONWAY. (2009) Presidential Address: Geographical crises of the twenty-first century. Geographical Journal 175:3, 221-228
CrossRef39
Pan Tao, Mengcheng Luo, Dandan Zhu, Sanfu Qu, Zhenhua Yang, Meng Gao, Deyin Guo, Zishu Pan. (2009) Virus-Like Particle Vaccine Comprised of the HA, NA, and M1 Proteins of an Avian Isolated H5N1 Influenza Virus Induces Protective Immunity Against Homologous and Heterologous Strains in Mice. Viral Immunology 22:4, 273-281
CrossRef40
Marguerite Pappaioanou. (2009) Highly pathogenic H5N1 avian influenza virus: Cause of the next pandemic?. Comparative Immunology, Microbiology and Infectious Diseases 32:4, 287-300
CrossRef41
DIANN J. PROSSER, JOHN Y. TAKEKAWA, SCOTT H. NEWMAN, BAOPING YAN, DAVID C. DOUGLAS, YUANSHENG HOU, ZHI XING, DEHAI ZHANG, TIANXIAN LI, YONGDONG LI, DELONG ZHAO, WILLIAM M. PERRY, ERIC C. PALM. (2009) Satellite-marked waterfowl reveal migratory connection between H5N1 outbreak areas in China and Mongolia. Ibis 151:3, 568-576
CrossRef42
Prasert Auewarakul, Sunisa Chatsurachai, Alita Kongchanagul, Pumaree Kanrai, Sikarin Upala, Prapat Suriyaphol, Pilaipan Puthavathana. (2009) Codon volatility of hemagglutinin genes of H5N1 avian influenza viruses from different clades. Virus Genes 38:3, 404-407
CrossRef43
Michel Weïwer, Chi-Chang Chen, Melissa M. Kemp, Robert J. Linhardt. (2009) Synthesis and Biological Evaluation of Non-Hydrolyzable 1,2,3-Triazole-Linked Sialic Acid Derivatives as Neuraminidase Inhibitors. European Journal of Organic Chemistry 2009:16, 2611-2620
CrossRef44
Junbao Yang, John A. Gebe, Laurie Huston, Eddie James, Venus Tan, Betty B. Yue, Gerald T. Nepom, William W. Kwok. (2009) H5N1 strain-specific Hemagglutinin CD4+ T cell epitopes restricted by HLA DR4. Vaccine 27:29, 3862-3869
CrossRef45
J. Pfeiffer, M. Pantin-Jackwood, T.L. To, T. Nguyen, D.L. Suarez. (2009) Phylogenetic and biological characterization of highly pathogenic H5N1 avian influenza viruses (Vietnam 2005) in chickens and ducks. Virus Research 142:1-2, 108-120
CrossRef46
Sawyin Oh, Paul Selleck, Nigel J. Temperton, Paul K.S. Chan, Barbara Capecchi, Jim Manavis, Geoff Higgins, Christopher J. Burrell, Tuckweng Kok. (2009) Neutralizing monoclonal antibodies to different clades of Influenza A H5N1 viruses. Journal of Virological Methods 157:2, 161-167
CrossRef47
Holly Brodzinski, Richard M. Ruddy. (2009) Review of New and Newly Discovered Respiratory Tract Viruses in Children. Pediatric Emergency Care 25:5, 352-360
CrossRef48
Isabel Leroux-Roels, Geert Leroux-Roels. (2009) Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Review of Vaccines 8:4, 401-423
CrossRef49
Yoshinao Yamazaki, Mikio Doy, Nobuhiko Okabe, Yoshinori Yasui, Kazutoshi Nakashima, Takashi Fujieda, Shin-ichi Yamato, Yuichi Kawata, Tsuyoshi Ogata. (2009) Serological survey of avian H5N2-subtype influenza virus infections in human populations. Archives of Virology 154:3, 421-427
CrossRef50
Quanjiao Chen, Haimen Kuang, Huadong Wang, Fang Fang, Zhongdong Yang, Zhiping Zhang, Xianen Zhang, Ze Chen. (2009) Comparing the ability of a series of viral protein-expressing plasmid DNAs to protect against H5N1 influenza virus. Virus Genes 38:1, 30-38
CrossRef51
S. Spitsin, V. Andrianov, N. Pogrebnyak, Y. Smirnov, N. Borisjuk, C. Portocarrero, V. Veguilla, H. Koprowski, M. Golovkin. (2009) Immunological assessment of plant-derived avian flu H5/HA1 variants. Vaccine 27:9, 1289-1292
CrossRef52
Joel R. Haynes, Leslie Dokken, James A. Wiley, Andrew G. Cawthon, John Bigger, Allen G. Harmsen, Charles Richardson. (2009) Influenza-pseudotyped Gag virus-like particle vaccines provide broad protection against highly pathogenic avian influenza challenge. Vaccine 27:4, 530-541
CrossRef53
Henju Marjuki, Ulrich Wernery, Hui-Ling Yen, John Franks, Patrick Seiler, David Walker, Scott Krauss, Robert G. Webster. (2009) Isolation of Highly Pathogenic Avian Influenza H5N1 Virus from Saker Falcons (Falco cherrug) in the Middle East. Advances in Virology 2009, 1-7
CrossRef54
Benoit Baras, Nancy Bouveret, Jeanne-Marie Devaster, Louis Fries, Paul Gillard, Roland Sänger, Emmanuel Hanon. (2008) A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses. Influenza and Other Respiratory Viruses 2:6, 251-260
CrossRef55
Pathumwadee Intharathep, Chittima Laohpongspaisan, Thanyada Rungrotmongkol, Arthorn Loisruangsin, Maturos Malaisree, Panita Decha, Ornjira Aruksakunwong, Krit Chuenpennit, Nopphorn Kaiyawet, Pornthep Sompornpisut, Somsak Pianwanit, Supot Hannongbua. (2008) How amantadine and rimantadine inhibit proton transport in the M2 protein channel. Journal of Molecular Graphics and Modelling 27:3, 342-348
CrossRef56
Linhui Hao, Akira Sakurai, Tokiko Watanabe, Ericka Sorensen, Chairul A. Nidom, Michael A. Newton, Paul Ahlquist, Yoshihiro Kawaoka. (2008) Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454:7206, 890-893
CrossRef57
Junwei Li, Hui Cai, Qingzhen Liu, Deyin Guo. (2008) Molecular and pathological characterization of two H5N1 avian influenza viruses isolated from wild ducks. Virus Genes 37:1, 88-95
CrossRef58
Jan Willem van der Laan, Carla Herberts, Robert Lambkin-Williams, Alison Boyers, Alexander J Mann, John Oxford. (2008) Animal models in influenza vaccine testing. Expert Review of Vaccines 7:6, 783-793
CrossRef59
Matthew J. Memoli, David M. Morens, Jeffery K. Taubenberger. (2008) Pandemic and seasonal influenza: therapeutic challenges. Drug Discovery Today 13:13-14, 590-595
CrossRef60
Shixia Wang, Chris Parker, Jessica Taaffe, Alicia Solórzano, Adolfo García-Sastre, Shan Lu. (2008) Heterologous HA DNA vaccine prime—inactivated influenza vaccine boost is more effective than using DNA or inactivated vaccine alone in eliciting antibody responses against H1 or H3 serotype influenza viruses. Vaccine 26:29-30, 3626-3633
CrossRef61
D. M. FLEMING, A. J. ELLIOT. (2008) Lessons from 40 years' surveillance of influenza in England and Wales. Epidemiology and Infection 136:07,
CrossRef62
S. L. Kosakovsky Pond, A. F.Y. Poon, A. J. Leigh Brown, S. D.W. Frost. (2008) A Maximum Likelihood Method for Detecting Directional Evolution in Protein Sequences and Its Application to Influenza A Virus. Molecular Biology and Evolution 25:9, 1809-1824
CrossRef63
Maturos Malaisree, Thanyada Rungrotmongkol, Panita Decha, Pathumwadee Intharathep, Ornjira Aruksakunwong, Supot Hannongbua. (2008) Understanding of known drug-target interactions in the catalytic pocket of neuraminidase subtype N1. Proteins: Structure, Function, and Bioinformatics 71:4, 1908-1918
CrossRef64
Hans C. Rümke, José-María Bayas, José-Ramón de Juanes, Covadonga Caso, Jan Hendrik Richardus, Magda Campins, Lars Rombo, Xavier Duval, Viktor Romanenko, Tino F. Schwarz, Rustem Fassakhov, Francisco Abad-Santos, Frank von Sonnenburg, Mamadou Dramé, Roland Sänger, W. Ripley Ballou. (2008) Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine 26:19, 2378-2388
CrossRef65
J. G. Bartlett, L. Borio. (2008) The Current Status of Planning for Pandemic Influenza and Implications for Health Care Planning in the United States. Clinical Infectious Diseases 46:6, 919-925
CrossRef66
Alex J Elliot, Douglas M Fleming. (2008) Influenza and respiratory syncytial virus in the elderly. Expert Review of Vaccines 7:2, 249-258
CrossRef67
Timothy M. UYEKI. (2008) Global epidemiology of human infections with highly pathogenic avian influenza A (H5N1) viruses. Respirology 13:s1, S2-S9
CrossRef68
Mizgerd, Joseph P., . (2008) Acute Lower Respiratory Tract Infection. New England Journal of Medicine 358:7, 716-727
Full Text69
Jeffery K. Taubenberger, David M. Morens. (2008) The Pathology of Influenza Virus Infections. Annual Review of Pathology: Mechanisms of Disease 3:1, 499-522
CrossRef70
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. (2008) Update on Avian Influenza A (H5N1) Virus Infection in Humans. New England Journal of Medicine 358:3, 261-273
Full Text71
Kevin C. Worley, Scott W. Roberts, Roger E. Bawdon. (2008) The Metabolism and Transplacental Transfer of Oseltamivir in the Ex Vivo Human Model. Infectious Diseases in Obstetrics & Gynecology 2008, 1-5
CrossRef72
Petr O. Ilyinskii, Galini Thoidis, Alexander M. Shneider. (2008) Development of a Vaccine Against Pandemic Influenza Viruses: Current Status and Perspectives. International Reviews of Immunology 27:6, 392-426
CrossRef73
Muhiuddin Haider, Shamsun Nahar Ahamed, Teresa Leslie. (2008) Challenges for Bangladesh to conquer avian influenza. International Journal of Pharmaceutical and Healthcare Marketing 2:4, 273-283
CrossRef74
Michael E. Bose, John C. Littrell, Andrew D. Patzer, Andrea J. Kraft, Jacob A. Metallo, Jiang Fan, Kelly J. Henrickson. (2008) The Influenza Primer Design Resource: a new tool for translating influenza sequence data into effective diagnostics. Influenza and Other Respiratory Viruses 2:1, 23-31
CrossRef75
Folorunso O Fasina, Shahn P Bisschop, Robert G Webster. (2007) Avian influenza H5N1 in Africa: an epidemiological twist. The Lancet Infectious Diseases 7:11, 696-697
CrossRef76
Katja Höschler, Robin Gopal, Nick Andrews, Melanie Saville, Stephanie Pepin, John Wood, Maria C. Zambon. (2007) Cross-neutralisation of antibodies elicited by an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine in healthy adults against H5N1 clade 2 strains. Influenza and Other Respiratory Viruses 1:5-6, 199-206
CrossRef77
Susan Shoshana Weisberg. (2007) Influenza. Disease-a-Month 53:9, 435-446
CrossRef78
Jindrich Cinatl jr, Martin Michaelis, Hans W. Doerr. (2007) The threat of avian influenza A (H5N1). Part IV: development of vaccines. Medical Microbiology and Immunology 196:4, 213-225
CrossRef79
Jindrich Cinatl, Martin Michaelis, Hans W. Doerr. (2007) The threat of avian influenza A (H5N1). Part III: antiviral therapy. Medical Microbiology and Immunology 196:4, 203-212
CrossRef80
Jindrich Cinatl, Martin Michaelis, Hans W. Doerr. (2007) The threat of avian influenza a (H5N1): part II: Clues to pathogenicity and pathology. Medical Microbiology and Immunology 196:4, 191-201
CrossRef81
Prasert Auewarakul, Prasert Thongcharoen. (2007) Vaccines for a potential influenza pandemic. Future Microbiology 2:3, 345-349
CrossRef82
(2007) Human H5N1 Influenza. New England Journal of Medicine 356:13, 1375-1377
Full Text
- Letters
