Weidenbacher Payton A-B, Friedland Natalia, Sanyal Mrinmoy, Morris Mary Kate, Do Jonathan, Hanson Carl, Kim Peter S
Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Department of Chemistry, Stanford University, Stanford, CA, USA.
bioRxiv. 2023 Jun 29:2023.06.27.546764. doi: 10.1101/2023.06.27.546764.
With the SARS-CoV-2 virus still circulating and evolving, there remains an outstanding question if variant-specific vaccines represent the optimal path forward, or if other strategies might be more efficacious towards providing broad protection against emerging variants. Here, we examine the efficacy of strain-specific variants of our previously reported, pan-sarbecovirus vaccine candidate, DCFHP-alum, a ferritin nanoparticle functionalized with an engineered form of the SARS-CoV-2 spike protein. In non-human primates, DCFHP-alum elicits neutralizing antibodies against all known VOCs that have emerged to date and SARS-CoV-1. During development of the DCFHP antigen, we investigated the incorporation of strain-specific mutations from the major VOCs that had emerged to date: D614G, Epsilon, Alpha, Beta, and Gamma. Here, we report the biochemical and immunological characterizations that led us to choose the ancestral Wuhan-1 sequence as the basis for the final DCFHP antigen design. Specifically, we show by size exclusion chromatography and differential scanning fluorimetry that mutations in the VOCs adversely alter the antigen's structure and stability. More importantly, we determined that DCFHP without strain-specific mutations elicits the most robust, cross-reactive response in both pseudovirus and live virus neutralization assays. Our data suggest potential limitations to the variant-chasing approach in the development of protein nanoparticle vaccines, but also have implications for other approaches including mRNA-based vaccines.
随着SARS-CoV-2病毒仍在传播和演变，一个悬而未决的问题是，针对特定变体的疫苗是否代表了最佳的前进方向，或者其他策略是否可能在提供针对新出现变体的广泛保护方面更有效。在这里，我们研究了我们之前报道的泛沙贝病毒疫苗候选物DCFHP-alum（一种用工程化形式的SARS-CoV-2刺突蛋白功能化的铁蛋白纳米颗粒）的菌株特异性变体的效力。在非人类灵长类动物中，DCFHP-alum可引发针对所有已知的迄今出现的VOCs和SARS-CoV-1的中和抗体。在DCFHP抗原的研发过程中，我们研究了纳入迄今出现的主要VOCs的菌株特异性突变：D614G、Epsilon、Alpha、Beta和Gamma。在这里，我们报告了生化和免疫学特征，这些特征使我们选择了原始的武汉-1序列作为最终DCFHP抗原设计的基础。具体而言，我们通过尺寸排阻色谱法和差示扫描荧光法表明，VOCs中的突变会不利地改变抗原的结构和稳定性。更重要的是，我们确定没有菌株特异性突变的DCFHP在假病毒和活病毒中和试验中引发的反应最为强烈且具有交叉反应性。我们的数据表明了在蛋白质纳米颗粒疫苗开发中追踪变体方法的潜在局限性，但也对包括基于mRNA的疫苗在内的其他方法具有启示意义。
