近日,，國(guó)際知名病毒學(xué)雜志Journal of Virology 在線發(fā)表了中科院上海巴斯德研究所周保羅研究組關(guān)于高致病性禽流感H5N1疫苗的最新成果，這是世界上首次報(bào)道能誘導(dǎo)出針對(duì)所有高致病性禽流感H5N1亞類和亞亞類廣譜中和抗體反應(yīng)的免疫原,。
高致病性禽流感H5N1病毒因其快速演化、基因多樣性,、宿主廣泛,、易在鳥類中傳播以及潛在的人-人傳播隱患而極大地威脅著人類健康。該病毒的多樣性對(duì)研發(fā)出有效的通用疫苗提出了挑戰(zhàn),。
在本項(xiàng)研究中,，博士研究生周梵、研究助理王桂芹等在周保羅研究員的指導(dǎo)下,，在全面的血清學(xué)研究基礎(chǔ)上開發(fā)設(shè)計(jì)了能夠有效地對(duì)抗所有高致病性禽流感H5N1亞類和亞亞類的免疫原的新策略,。首先，她們構(gòu)建了涵蓋所有高致病性禽流感H5N1亞類和亞亞類代表性流行株的H5HA表達(dá)質(zhì)粒庫(kù),；利用該質(zhì)粒庫(kù),，建立了相應(yīng)的假病毒庫(kù)和免疫血清庫(kù)；然后進(jìn)行了全面的基于假病毒的血清學(xué)試驗(yàn),。研究人員按照試驗(yàn)結(jié)果,，將高致病性禽流感H5N1亞類和亞亞類歸納成兩大抗原群，但亞亞類2.3.2.1和7.2分別獨(dú)立于這兩個(gè)抗原群之外,。根據(jù)上述所得抗原群,，她們?cè)O(shè)計(jì)了三價(jià)疫苗，并證明其能誘導(dǎo)出針對(duì)所有高致病性禽流感H5N1亞類和亞亞類的廣譜中和抗體反應(yīng)（見圖1）,，并對(duì)小鼠在高致死量的異源H5N1病毒攻毒下提供有效的保護(hù),。
研究人員由此證明了基于全面血清學(xué)研究而設(shè)計(jì)的三價(jià)疫苗能誘導(dǎo)出針對(duì)所有高致病性禽流感H5N1亞類和亞亞類的廣譜中和抗體反應(yīng)，為下一步在雪貂模型和人體中進(jìn)行驗(yàn)證和優(yōu)化此策略奠定了基礎(chǔ),。
該研究是與柬埔寨巴斯德研究所Vincent Deubel教授,，美國(guó)密西西比州立大學(xué)Henry Wan教授合作完成的，得到了國(guó)家自然科學(xué)基金,、國(guó)家科技重大專項(xiàng)和上海巴斯德健康研究基金會(huì)的資助,。（生物谷Bioon.com）
doi:10.1128/JVI.06930-11
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A Tri-Clade DNA Vaccine Designed on the Basis of a Comprehensive Serologic Study Elicits Neutralizing Antibody Responses against All Clades and Subclades of HPAI H5N1 Viruses
Fan Zhou1, Guiqing Wang1, Philippe Buchy2, Zhipeng Cai3, Honglin Chen4, Zhiwei Chen5, Genhong Cheng6, Xiu-Feng Wan3, Vincent Deubel2 and Paul Zhou1,*
Because of their rapid evolution, genetic diversity, broad host range, ongoing circulation in birds and potential human-to-human transmission, H5N1 influenza viruses remain a major global health concern. High degree of genetic diversity also poses enormous burdens and uncertainties in developing effective vaccines. To overcome this, in this study we took a new approach, i.e. development of immunogens based on a comprehensive serologic study. We constructed DNA plasmids encoding codon-optimized HA from 17 representative strains covering all reported clades and subclades of HPAI H5N1 viruses. Using DNA plasmids we generated corresponding H5N1 pseudotypes and immune sera. We performed an across-board pseudotype-based neutralization assay and determined antigenic clusters by cartography. We then designed a tri-clade DNA vaccine and evaluated its immunogenicity and protection in mice. Here we report that (sub)clades 0, 1, 3, 4, 5, 6, 7.1 and 9 were grouped into antigenic cluster 1; (sub)clades 2.1.3.2, 2.3.4, 2.4, 2.5 and 8 into another with subclade 2.2.1 loosely connected to it; and subclades 2.3.2.1 and 7.2 each by itself. Importantly, the tri-clade DNA vaccine encoding HA of (sub)clades 0, 2.3.2.1 and 7.2 elicited broadly neutralizing antibody responses against all H5 clades and subclades and protected mice against high lethal dose heterologous H5N1 challenge. Thus, we conclude that broadly neutralizing antibodies against all H5 clades and subclades can indeed be elicited with immunogens on the basis of a comprehensive serologic study. Further evaluation and optimization of such an approach in ferrets and in humans is warranted.
