A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve.
A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve.
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DOI：
10.1038/ncomms12780
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发表时间：
2016-09-13
影响因子：
16.6
通讯作者：
Marasco WA
中科院分区：
文献类型：
--
作者：
Fu Y;Zhang Z;Sheehan J;Avnir Y;Ridenour C;Sachnik T;Sun J;Hossain MJ;Chen LM;Zhu Q;Donis RO;Marasco WA
了解广泛中和抗体（bnAb）开发中涉及的自然进化和结构变化，对于改进预防性流感疫苗的设计具有很大的希望。在这里，我们报告了血凝素（HA）干细胞定向bnAb，3 I14，从人类记忆B细胞中分离，利用IGHV 3 -30种系基因编码的重链。MAb 3 I14结合并中和第1组和第2组甲型流感病毒，并保护小鼠免受致死性攻击。VH和VL种系回复突变体的分析揭示了与H3和H1结合，但不与H5结合，这支持了体细胞超突变在拓宽bnAb应答中的关键作用。此外，单个VLD 94 N突变将3 I14对H5的亲和力提高了近10倍。这些数据提供了证据，记忆B细胞进化可以扩大HA亚型特异性。我们的研究结果进一步表明，建立一个优化的记忆B细胞库应该是“通用”流感疫苗策略的目标。 疫苗设计的一个主要目标是防止广泛的病原体菌株。在这里，作者从人类记忆B细胞中分离出一种新的针对流感血凝素的广泛中和抗体，并鉴定出增加和扩大对H5 HA亚型的中和的突变。
Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal' influenza vaccine strategies. A major goal of vaccine design is to protect against a broad range of pathogen strains. Here the authors isolate a new broadly neutralizing antibody against influenza haemagglutinin from human memory B cells, and identify mutations that increase and broaden the neutralization towards H5 HA subtype.