Bangaru Sandhya, Jackson Abigail M, Copps Jeffrey, Fernández-Quintero Monica L, Torres Jonathan L, Richey Sara T, Nogal Bartek, Sewall Leigh M, de la Peña Alba Torrents, Rehman Asma, Guebre-Xabier Mimi, Girard Bethany, Das Rituparna, Corbett-Helaire Kizzmekia S, Seder Robert A, Graham Barney S, Edwards Darin K, Patel Nita, Smith Gale, Ward Andrew B
Dept. of Integrative Structural and Computational Biology, The Scripps Research Institute; La Jolla, CA, 92037, USA.
Novavax, Inc; 21 Firstfield Road, Gaithersburg, MD, 20878, USA.
bioRxiv. 2024 Dec 12:2024.12.11.628030. doi: 10.1101/2024.12.11.628030.
Current COVID-19 vaccines are largely limited in their ability to induce broad, durable immunity against emerging viral variants. Design and development of improved vaccines utilizing existing platforms requires an in-depth understanding of the antigenic and immunogenic properties of available vaccines. Here we examined the antigenicity of two of the original COVID-19 vaccines, mRNA-1273 and NVX-CoV2373, by electron microscopy-based polyclonal epitope mapping (EMPEM) of serum from immunized non-human primates (NHPs) and clinical trial donors. Both vaccines induce diverse polyclonal antibody (pAb) responses to the N-terminal domain (NTD) in addition to the receptor-binding domain (RBD) of the Spike protein, with the NTD supersite being an immunodominant epitope. High-resolution cryo-EMPEM studies revealed extensive pAb responses to and around the supersite with unique angles of approach and engagement. NTD supersite pAbs were also the most susceptible to variant mutations compared to other specificities, indicating that ongoing Spike ectodomain-based vaccine design strategies should consider immuno-masking this site to prevent induction of these strain-specific responses.
目前的新冠疫苗在诱导针对新出现的病毒变体产生广泛、持久免疫力方面存在很大局限性。利用现有平台设计和开发改进型疫苗需要深入了解现有疫苗的抗原性和免疫原性特性。在此，我们通过基于电子显微镜的多克隆表位图谱分析（EMPEM），对免疫后的非人类灵长类动物（NHP）血清和临床试验捐赠者血清进行检测，研究了两种原始新冠疫苗mRNA-1273和NVX-CoV2373的抗原性。两种疫苗除了诱导针对刺突蛋白受体结合域（RBD）的多克隆抗体（pAb）反应外，还诱导了针对N端结构域（NTD）的多种多克隆抗体反应，其中NTD超位点是一个免疫显性表位。高分辨率冷冻EMPEM研究揭示了针对超位点及其周围区域的广泛pAb反应，且具有独特的接近和结合角度。与其他特异性抗体相比，NTD超位点pAb对变体突变也最为敏感，这表明基于刺突蛋白胞外域的现有疫苗设计策略应考虑对该位点进行免疫掩蔽，以防止诱导这些菌株特异性反应。
