Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins.
Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins.
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DOI：
10.1371/journal.ppat.1000796
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发表时间：
2010-02-26
期刊：
影响因子：
6.7
通讯作者：
Palese P
中科院分区：
文献类型：
--
作者：
Wang TT;Tan GS;Hai R;Pica N;Petersen E;Moran TM;Palese P
作为适应性免疫的目标，流感病毒的特点是其对中和抗体所施加的选择压力作出反应的流动性。这种保护性免疫的结构决定因素的可变性是开发通用流感疫苗的障碍。为了开发此类疫苗和其他免疫疗法，我们的研究旨在确定流感病毒中保守且介导病毒中和的区域。我们特别关注H3N2亚型病毒，自1968年大流行以来，它一直是人类流感相关发病和死亡的主要来源。已经鉴定出三种单克隆抗体，它们对跨越40年的H3流感病毒具有广泛的中和作用。这些抗体与血凝素糖蛋白发生反应，并且似乎结合在对病毒逃避中和所需的结构变异具有抗性的区域。这些抗体在小鼠中对H3N2病毒感染显示出治疗功效，并且有用于治疗人类流感疾病的潜力。通过绘制一种抗体12D1的结合区域，我们已经确定了血凝素的一个连续区域，它可以作为一种免疫原，引发对H3病毒的广泛保护性免疫。抗 - H3单克隆抗体是在用四种不同病毒（A/香港/1/1968、A/阿拉巴马/1/1981、A/北京/47/1992、A/怀俄明/3/2003）的血凝素免疫小鼠后鉴定出来的。这种免疫方案旨在增强针对来自不同抗原簇的血凝素保守区域的B细胞。重要的是，我们的抗体具有天然存在的特异性，而不是从克隆文库中筛选出来的，这表明可以在体内引发对流感病毒的广谱体液免疫。
流感病毒仍然是一个严重的公共卫生威胁。由于流感病毒耐药株的急剧增加以及大流行病毒株的半规律性出现，开发基于抗体的新型疗法和流感疫苗构建体引起了极大的关注。最近，鉴定出了对一系列第1组流感病毒（包括H5和H1亚型）具有广泛中和活性的单克隆抗体；使用这些抗体的研究扩展了我们对病毒血凝素结构方面的理解，血凝素是介导对流感病毒保护性免疫的分子。我们已经鉴定出了针对第2组病毒的首批广泛中和抗体——具体来说，它们对跨越40年的H3流感病毒具有活性。这些抗体与血凝素发生反应，并且似乎结合在对病毒逃避中和所需的结构变异具有抗性的区域。这些抗体在小鼠中对H3N2病毒感染显示出治疗功效，并且有用于治疗人类流感疾病的潜力。通过绘制一种抗体12D1的结合区域，我们已经确定了血凝素的一个连续区域，它可以作为一种免疫原，引发赋予对H3病毒广泛保护的免疫反应。
As targets of adaptive immunity, influenza viruses are characterized by the fluidity with which they respond to the selective pressure applied by neutralizing antibodies. This mutability of structural determinants of protective immunity is the obstacle in developing universal influenza vaccines. Towards the development of such vaccines and other immune therapies, our studies are designed to identify regions of influenza viruses that are conserved and that mediate virus neutralization. We have specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the pandemic of 1968. Three monoclonal antibodies have been identified that are broadly-neutralizing against H3 influenza viruses spanning 40 years. The antibodies react with the hemagglutinin glycoprotein and appear to bind in regions that are refractory to the structural variation required for viral escape from neutralization. The antibodies demonstrate therapeutic efficacy in mice against H3N2 virus infection and have potential for use in the treatment of human influenza disease. By mapping the binding region of one antibody, 12D1, we have identified a continuous region of the hemagglutinin that may act as an immunogen to elicit broadly protective immunity to H3 viruses. The anti-H3 monoclonal antibodies were identified after immunization of mice with the hemagglutinin of four different viruses (A/Hong Kong/1/1968, A/Alabama/1/1981, A/Beijing/47/1992, A/Wyoming/3/2003). This immunization schedule was designed to boost B cells specific for conserved regions of the hemagglutinin from distinct antigenic clusters. Importantly, our antibodies are of naturally occurring specificity rather than selected from cloned libraries, demonstrating that broad-spectrum humoral immunity to influenza viruses can be elicited in vivo. Influenza viruses remain a formidable public health threat. Because of a dramatic increase in drug resistant strains of influenza viruses and due to the semi-regular emergence of pandemic virus strains, the development of novel antibody-based therapies and influenza vaccine constructs is of great interest. Recently, monoclonal antibodies with broad neutralizing activity against an array of Group 1 influenza viruses (including H5 and H1 subtypes) were identified; studies using these antibodies have expanded our understanding of structural aspects of the viral hemagglutinin, the molecule mediating protective immunity to influenza viruses. We have identified the first broadly neutralizing antibodies against viruses in Group 2—specifically, they are active against H3 influenza viruses spanning 40 years. The antibodies react with the hemagglutinin and appear to bind in regions that are refractory to the structural variation required for viral escape from neutralization. The antibodies demonstrate therapeutic efficacy in mice against H3N2 virus infection and have potential for use in the treatment of human influenza disease. By mapping the binding region of one antibody, 12D1, we have identified a continuous region of the hemagglutinin that may act as an immunogen to elicit an immune response conferring broad protection against H3 viruses.
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影响因子：
2.7
作者：
Varecková, E;Mucha, V;Kostolansky, F
通讯作者：
Kostolansky, F
DOI：
10.1073/pnas.031575198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Basler, CF;Reid, AH;Taubenberger, JK
通讯作者：
Taubenberger, JK
影响因子：
64.8
作者：
WILEY, DC;WILSON, IA;SKEHEL, JJ
通讯作者：
SKEHEL, JJ
影响因子：
2.2
作者：
DESTGROTH, SF;SCHEIDEGGER, D
通讯作者：
SCHEIDEGGER, D
DOI：
10.1073/pnas.76.9.4350
发表时间：
1979-01-01
影响因子：
11.1
作者：
TOWBIN, H;STAEHELIN, T;GORDON, J
通讯作者：
GORDON, J