Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2200821119. doi: 10.1073/pnas.2200821119. Epub 2022 May 20.
Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
流感病毒血凝素 (HA) 一直是流感疫苗开发的主要目标。针对 HA 保守区域的广泛保护性抗体为开发通用流感免疫提供了可能。先前设计了两种 2 类流感 A 嵌合 HA，cH4/3 和 cH15/3，以诱导针对保守 HA 茎的抗体。在这里，我们通过 X 射线晶体学和负染电子显微镜显示，一种广泛保护性抗茎抗体可以稳定地结合到 cH4/3 和 cH15/3 HAs 上，从而验证了它们作为通用疫苗免疫原的潜力。此外，嵌合 HA 结构的头部结构域表现出灵活性，表明抗体也可能与头部接口表位相互作用。我们的结构和结合研究表明，一种广泛保护性的抗三聚体接口抗体确实可以靶向 cH15/3 HA 三聚体更开放的头部结构域。因此，除了诱导针对保守 HA 茎的广泛保护性抗体外，嵌合 HA 还可能能够诱导针对 HA 头部域中保守三聚体接口的抗体，从而提高疫苗的功效。
