2012年1月12日,，國(guó)際著名病毒學(xué)雜志Journal of Virology 在線刊登了上海巴斯德研究所周保羅研究組的最新研究成果“A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses,，”，這是首例關(guān)于人的中和抗體可以廣譜中和幾乎所有的H5N1各個(gè)型和亞型病毒的報(bào)道,。
自1996年以來(lái),，高致病性禽流感H5N1病毒感染了超過(guò)5億家禽，并且在亞洲,、非洲和歐洲出現(xiàn)了越來(lái)越多關(guān)于人感染H5N1病毒的報(bào)道,。至2011年10月10日，已有566例人感染被確診,，其中332人死亡(http：//www.who.int/csr/disease/avian_influenza/country/en/),。目前的疫苗往往只對(duì)相似的病毒株有保護(hù)作用。
在這項(xiàng)研究中,，上海巴斯德所的博士生胡紅星等人在周保羅教授的指導(dǎo)下用高靈敏度的H5N1假病毒系統(tǒng)從感染過(guò)H5N1病毒但康復(fù)的病人記憶B細(xì)胞中篩選出了3株抗H5N1病毒的人源單克隆抗體,。其中單克隆抗體65C6 能夠中和除了7.2亞型之外幾乎所有型和亞型的H5N1 病毒，并在老鼠模型中顯示了很好的預(yù)防和保護(hù)的作用,。通過(guò)對(duì)血凝蛋白和抗體復(fù)合物的電鏡分析,，結(jié)合酵母展示技術(shù)，研究人員發(fā)現(xiàn)單克隆抗體65C6能夠識(shí)別位于血凝蛋白球形頭部的構(gòu)象表位,。該表位在幾乎所有的H5N1的血凝蛋白上都是高度保守的,。提示該廣譜中和抗體可以用來(lái)治療感染了高致病性禽流感H5N1的病人，另外基于該保守表位可以設(shè)計(jì)免疫原從而通過(guò)免疫誘導(dǎo)出針對(duì)該表位的抗高致病性禽流感H5N1的廣譜中和抗體反應(yīng),。
該課題是與英國(guó)國(guó)立醫(yī)學(xué)研究院的John Skehel 教授及柬埔寨巴斯德研究所的Vincent Deubel教授,，清華大學(xué)的張林琦教授以及深圳第三人民醫(yī)院的周伯平教授合作完成的。
該研究得到了法國(guó)衛(wèi)生部,、國(guó)家自然科學(xué)基金,、國(guó)家科技重大專項(xiàng)及李嘉誠(chéng)基金會(huì)和英國(guó)醫(yī)學(xué)研究基金會(huì)的資助。（生物谷Bioon.com）
doi:10.1128/JVI.06665-11
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A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses
Hongxing Hu1, Jarrod Voss2, Guoliang Zhang3, Philippi Buchy4, Teng Zuo5, Lulan Wang1, Feng Wang1, Fan Zhou1, Guiqing Wang1, Cheguo Tsai1, Lesley Calder2, Steve J. Gamblin2, Linqi Zhang5, Vincent Deubel4, Boping Zhou3, John J. Skehel2↴ and Paul Zhou1↴
Influenza A virus infection is a persistent threat to public health worldwide, due to its ability to evade immune surveillance through rapid genetic drift and shift. Current vaccines against influenza A virus provide immunity to viral isolates similar to vaccine strains. High affinity neutralizing antibodies against conserved epitopes could provide immunity to diverse influenza strains and protection against future pandemic viruses. In this study, by using a highly sensitive H5N1 pseudotype-based neutralization assay to screen human monoclonal antibodies produced by memory B cells from a H5N1 infected individual and molecular cloning techniques, we developed three fully human monoclonal antibodies. Among them, antibody 65C6 exhibited potent neutralization activity against all H5 clades and subclades except for subclade 7.2 and prophylactic and therapeutic efficacy against highly pathogenic avian influenza H5N1 viruses in mice. Studies on HA-antibody complexes by electron microscopy and epitope mapping indicate that antibody 65C6 binds to a conformational epitope comprising amino acid residues at the positions of 118, 121, 161, 164 and 167 (according to mature H5 numbering) on the tip of the membrane-distal globular domain of HA. Thus, we conclude that antibody 65C6 recognizes a neutralization epitope in the globular head of HA that is conserved among almost all divergent H5N1 influenza stains.
