Decreased efficacy of a COVID-19 vaccine due to mutations present in early SARS-CoV-2 variants of concern.
Decreased efficacy of a COVID-19 vaccine due to mutations present in early SARS-CoV-2 variants of concern.
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由于早期 SARS-CoV-2 变体中存在突变，导致 COVID-19 疫苗的功效降低。
DOI：
10.1101/2023.06.27.546764
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kim,PeterS
中科院分区：
文献类型：
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作者：
Weidenbacher,PaytonA-B;Friedland,Natalia;Sanyal,Mrinmoy;Morris,MaryKate;Do,Jonathan;Hanson,Carl;Kim,PeterS
由于SARS-CoV-2病毒仍在传播和进化，仍然存在一个悬而未决的问题，即变异特异性疫苗是否代表最佳的前进道路，或者其他策略是否可能更有效地提供针对新出现的变异的广泛保护。在这里，我们研究了我们以前报道的泛Sarbecovirus疫苗候选物DCFHP-明矾的菌株特异性变体的功效，DCFHP-明矾是一种用SARS-CoV-2刺突蛋白的工程形式功能化的铁蛋白纳米颗粒。在非人类灵长类动物中，DCFHP-明矾可激发针对迄今为止出现的所有已知VOC和SARS-CoV-1的中和抗体。在DCFHP抗原的开发过程中，我们研究了迄今为止出现的主要VOC的菌株特异性突变的掺入：D 614 G，Epidermal，Alpha，Beta和Gamma。在这里，我们报告的生化和免疫学特性，使我们选择祖先武汉-1序列作为基础的最终DCFHP抗原设计。具体来说，我们显示，通过尺寸排阻色谱法和差示扫描荧光法，在挥发性有机化合物的突变不利地改变抗原的结构和稳定性。更重要的是，我们确定了没有菌株特异性突变的DCFHP在假病毒和活病毒中和试验中均产生了最稳健的交叉反应。我们的数据表明，在蛋白质纳米颗粒疫苗的开发中，变体追踪方法存在潜在的局限性，但也对其他方法（包括基于mRNA的疫苗）具有影响。
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.