Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.
Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.
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DOI：
10.1371/journal.pone.0003942
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Goudsmit J
中科院分区：
文献类型：
--
作者：
Throsby M;van den Brink E;Jongeneelen M;Poon LL;Alard P;Cornelissen L;Bakker A;Cox F;van Deventer E;Guan Y;Cinatl J;ter Meulen J;Lasters I;Carsetti R;Peiris M;de Kruif J;Goudsmit J
血凝素（HA）糖蛋白是针对流感病毒感染的保护性体液免疫应答的主要靶标，但这种抗体应答仅提供针对给定病毒亚型内的窄谱HA抗原变体的有效保护。禽流感病毒如H5 N1目前是泛动物传染性的，并构成大流行的威胁。这些病毒是抗原多样性和保护策略需要交叉保护不同的病毒进化枝。此外，存在16种不同的HA亚型，并且不确定下一次大流行将由H5亚型引起，因此重要的是开发提供异亚型保护的预防性和治疗性干预。在这里，我们描述了一组13个单克隆抗体（mAb）回收的组合展示库，构建从人IgM+记忆B细胞的最近（季节性）流感疫苗。该mAb对抗原性不同的H1、H2、H5、H6、H8和H9流感亚型具有广泛的异亚型中和活性。高亲和力mAb组中可变重链基因IGHV 1 -69的限制性与HA茎域中保守疏水口袋的结合相关。最有效的抗体（CR 6261）在致命的H5 N1或H1N1攻击之前和之后给予小鼠时具有保护性。本研究中描述的人单克隆CR 6261可被开发用作预防或治疗人或禽流感感染的广谱药物，而无需事先进行菌株表征。此外，CR 6261表位可以应用于靶向疫苗策略或新型抗病毒药物的设计。最后，我们筛选IgM+记忆库的方法可以应用于识别其他快速进化的病原体上的保守和功能相关的靶标。
The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM+ memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens.
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