近日，国际知名病毒学杂志Journal of Virology 在线发表了中科院上海巴斯德研究所周保罗研究组关于高致病性禽流感H5N1疫苗的最新成果，这是世界上首次报道能诱导出针对所有高致病性禽流感H5N1亚类和亚亚类广谱中和抗体反应的免疫原。
高致病性禽流感H5N1病毒因其快速演化、基因多样性、宿主广泛、易在鸟类中传播以及潜在的人-人传播隐患而极大地威胁着人类健康。该病毒的多样性对研发出有效的通用疫苗提出了挑战。
在本项研究中，博士研究生周梵、研究助理王桂芹等在周保罗研究员的指导下，在全面的血清学研究基础上开发设计了能够有效地对抗所有高致病性禽流感H5N1亚类和亚亚类的免疫原的新策略。首先，她们构建了涵盖所有高致病性禽流感H5N1亚类和亚亚类代表性流行株的H5HA表达质粒库；利用该质粒库，建立了相应的假病毒库和免疫血清库；然后进行了全面的基于假病毒的血清学试验。研究人员按照试验结果，将高致病性禽流感H5N1亚类和亚亚类归纳成两大抗原群，但亚亚类2.3.2.1和7.2分别独立于这两个抗原群之外。根据上述所得抗原群，她们设计了三价疫苗，并证明其能诱导出针对所有高致病性禽流感H5N1亚类和亚亚类的广谱中和抗体反应（见图1），并对小鼠在高致死量的异源H5N1病毒攻毒下提供有效的保护。
研究人员由此证明了基于全面血清学研究而设计的三价疫苗能诱导出针对所有高致病性禽流感H5N1亚类和亚亚类的广谱中和抗体反应，为下一步在雪貂模型和人体中进行验证和优化此策略奠定了基础。
该研究是与柬埔寨巴斯德研究所Vincent Deubel教授，美国密西西比州立大学Henry Wan教授合作完成的，得到了国家自然科学基金、国家科技重大专项和上海巴斯德健康研究基金会的资助。（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.
