Ellis Daniel, Dosey Annie, Boyoglu-Barnum Seyhan, Park Young-Jun, Gillespie Rebecca, Syeda Hubza, Tsybovsky Yaroslav, Murphy Michael, Pettie Deleah, Matheson Nick, Chan Sidney, Ueda George, Fallas Jorge A, Carter Lauren, Graham Barney S, Veesler David, Kanekiyo Masaru, King Neil P
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
bioRxiv. 2023 May 24:2023.05.23.541980. doi: 10.1101/2023.05.23.541980.
Immunogen design approaches aim to control the specificity and quality of antibody responses to enable the creation of next-generation vaccines with improved potency and breadth. However, our understanding of the relationship between immunogen structure and immunogenicity is limited. Here we use computational protein design to generate a self-assembling nanoparticle vaccine platform based on the head domain of influenza hemagglutinin (HA) that enables precise control of antigen conformation, flexibility, and spacing on the nanoparticle exterior. Domain-based HA head antigens were presented either as monomers or in a native-like closed trimeric conformation that prevents exposure of trimer interface epitopes. These antigens were connected to the underlying nanoparticle by a rigid linker that was modularly extended to precisely control antigen spacing. We found that nanoparticle immunogens with decreased spacing between closed trimeric head antigens elicited antibodies with improved hemagglutination inhibition (HAI) and neutralization potency as well as binding breadth across diverse HAs within a subtype. Our "trihead" nanoparticle immunogen platform thus enables new insights into anti-HA immunity, establishes antigen spacing as an important parameter in structure-based vaccine design, and embodies several design features that could be used to generate next-generation vaccines against influenza and other viruses.
免疫原设计方法旨在控制抗体反应的特异性和质量，以创造出具有更高效力和更广谱性的下一代疫苗。然而，我们对免疫原结构与免疫原性之间关系的理解仍然有限。在此，我们利用计算蛋白质设计生成了一种基于流感血凝素（HA）头部结构域的自组装纳米颗粒疫苗平台，该平台能够精确控制纳米颗粒表面抗原的构象、灵活性和间距。基于结构域的HA头部抗原以单体形式或类似天然的封闭三聚体构象呈现，后者可防止三聚体界面表位暴露。这些抗原通过刚性连接子与下层纳米颗粒相连，该连接子可模块化扩展以精确控制抗原间距。我们发现，封闭三聚体头部抗原之间间距减小的纳米颗粒免疫原能诱导出具有更高血凝抑制（HAI）活性和中和效力以及对同一亚型内多种HA结合广度的抗体。因此，我们的“三头”纳米颗粒免疫原平台为抗HA免疫提供了新见解，确立了抗原间距作为基于结构的疫苗设计中的一个重要参数，并体现了几种可用于开发针对流感和其他病毒的下一代疫苗的设计特征。
