Broad Cross-Protection against H5N1 Avian Influenza Virus Infection by Means of Monoclonal Antibodies that Map to Conserved Viral Epitopes
Broad Cross-Protection against H5N1 Avian Influenza Virus Infection by Means of Monoclonal Antibodies that Map to Conserved Viral Epitopes
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DOI：
10.1086/594374
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发表时间：
2009-01-01
影响因子：
6.4
通讯作者：
Xia, Ningshao
中科院分区：
文献类型：
--
作者：
Chen, Yixin;Qin, Kun;Xia, Ningshao
背景人源H5抗血清或H5特异性单克隆抗体（MAbs）被动免疫治疗急性H5N1流感病毒感染具有潜在的有效性，但其对抗原多样性H5N1病毒的有效性尚未得到证实。在小鼠中评估了H5特异性单克隆抗体对抗原性不同的H5N1毒株的交叉保护作用，该单克隆抗体通过连续免疫抗原性不同的毒株产生。产生并表征了一组52种广泛交叉反应性H5特异性MAb。这些单克隆抗体之一，13D4，已被证明保护小鼠免受致命的攻击，由4个H5N1菌株代表目前的主要遗传群体，分支1，2.1，2.2，和2.3，即使在感染阶段时，H5N1病毒已扩散到肺部系统以外。用13D4处理后24小时，观察到感染动物肺组织中的病毒完全中和。该单克隆抗体与逃逸突变体的定位显示，它与H5N1血凝素的2个保守的、可能是关键的位点152和182结合。可以通过选择靶向血凝素中保守位点的MAb来优化针对H5N1流感病毒的广泛交叉保护性MAb的产生。H5单克隆抗体如13D4可能被证明在控制由当前和未来的H5N1变体引起的感染方面具有治疗价值。
Background. Passive immunization with human H5 antisera or H5-specific monoclonal antibodies (MAbs) has potential as an effective treatment for acute H5N1 influenza virus infection, but its efficacy against antigenically diverse H5N1 viruses is unconfirmed.Methods. Cross-protection against antigenically diverse H5N1 strains with H5-specific MAbs, generated by successive immunization of antigenically distinct strains, was evaluated in mice.Results. A panel of 52 broadly cross-reactive H5 specific MAbs were generated and characterized. One of these MAbs, 13D4, has been demonstrated to protect mice against lethal challenge by 4 H5N1 strains representing the current major genetic populations, clades 1, 2.1, 2.2, and 2.3, even at a stage of infection when H5N1 virus has disseminated beyond the pulmonary system. Complete neutralization of virus in lung tissue of infected animals was observed 24 h after treatment with 13D4. Mapping of this MAb with escape mutants showed it to bind to 2 conserved, possibly critical, sites of H5N1 hemagglutinin, 152 and 182.Conclusion. Generation of broadly cross-protective MAbs against H5N1 influenza virus may be optimized by selecting MAbs that target conserved sites in hemagglutinin. H5 MAbs such as 13D4 may prove to have therapeutic value in controlling infection due to current and future H5N1 variants.