Beyond polyclonal antibody responses: dissecting susceptibility to newly emerging SARS-CoV-2 variants

COVID-19疫情继续对全球健康造成巨大影响。SARS-CoV-2编码的表面糖蛋白Spike是自然感染期间引发的中和抗体的主要靶标，也是大多数COVID-19疫苗中使用的抗原。基于祖先Spike的疫苗在减少住院和死亡方面非常成功。当前大流行的最大挑战之一是SARS-CoV-2病毒变体的出现，这些变体编码刺突蛋白的突变。尽管最初有人担心这可能导致疫苗效力降低，但令人欣慰的是，疫苗加强剂计划已被证明成功地继续预防因感染当前流行的关注变异体（VOC）（包括Omicron）而导致的住院和死亡。随着群体免疫力通过疫苗接种和/或SARS-CoV-2突破性感染而增加，抗体将对病毒施加越来越大的压力，以在刺突中产生突变，并且这些突变有可能逃避疫苗引起的抗体应答。虽然我的实验室和其他人已经确定了刺突表面上中和抗体的结合位点（表位），但这些表位对血清中和活性的贡献以及在反复暴露于SARS-CoV-2后这种变化的影响尚未研究。详细了解这些表位对血清中和活性的贡献，以及SARS-CoV-2暴露的不同历史如何影响这一点，对于理解持续的Spike进化至关重要，并为我们对新出现的病毒变体的易感性提供见解。对SARS-CoV-2感染和疫苗接种的中和抗体应答的广泛研究已经在免疫血清上进行，虽然这提供了对SARS-CoV-2的多克隆应答的总体宽度的信息，但它没有提供存在的抗体靶向的表位的信息。在这个项目中，我们将研究接受COVID-19疫苗的个体以及那些在单克隆抗体水平上经历VOC突破性感染的个体的抗体反应。该提案将解决三个基本和转化的生物医学问题：1）个人的SARS-CoV-2暴露史如何影响其中和抗体反应的特异性及其随后对新出现的变体的易感性？2)用编码祖先刺突的疫苗重复免疫如何产生中和抗体应答，从而提供针对VOC的广泛保护？3)基于VOCs的第二代COVID-19疫苗是否会产生上级中和抗体反应？通过解决这些问题，我们将深入了解人群对新出现的SARS-CoV-2变体的易感性，并为选择用作第二代COVID-19疫苗的刺突变体提供信息。

The COVID-19 pandemic continues to have a huge impact on global health. The SARS-CoV-2 encoded surface glycoprotein, Spike, is the primary target for neutralizing antibodies elicited during natural infection and is also the antigen used in most COVID-19 vaccines. Vaccines based on the ancestral Spike are highly successful at reducing hospitalization and death. One of the greatest challenges to the current pandemic has been the emergence of SARS-CoV-2 viral variants which encode mutations in the Spike protein. Although there were initial concerns that this could lead to reduced vaccine efficacy, encouragingly, vaccine booster programmes have proven successful at continuing to prevent hospitalizations and death caused by infection with current circulating variants of concern (VOC), including omicron. As population immunity increases through vaccination and/or SARS-CoV-2 breakthrough infection, antibodies will mount increasing pressure on the virus to generate mutations in Spike and these mutations have the potential to evade vaccine-elicited antibody responses. Although my lab and others have identified the binding sites (epitopes) for neutralizing antibodies on the Spike surface the contribution these epitopes make to the serum neutralizing activity and how this changes upon repeated SARS-CoV-2 exposure has not been studied. A detailed understanding of the contribution these epitopes make to serum neutralization activity, and how different histories of SARS-CoV-2 exposure can impact on this, will be vital for understanding continued Spike evolution and provide insights into our susceptibility to newly emerging viral variants. Extensive research on the neutralizing antibody response to SARS-CoV-2 infection and vaccination has been conducted on immune sera and whilst this provides information on the overall breadth of the polyclonal response to SARS-CoV-2, it does not provide information on the epitopes targeted by the antibodies present. In this project we will study the antibody response in individuals receiving the COVID-19 vaccine as well as those who experience a breakthrough infection with a VOC at the monoclonal antibody level. This proposal will address three basic and translational biomedical questions:1) How does an individual's SARS-CoV-2 exposure history influence the specificity of their neutralizing antibody response and their subsequent susceptibility to newly emerging variants?2) How does repeated immunization with vaccines that encode the ancestral Spike generate a neutralizing antibody response that can provide broad protection against VOCs?3) Will second generation COVID-19 vaccines based on VOCs generate a superior neutralizing antibody response?By addressing these questions, we will gain insights into the population susceptibility to newly emerging SARS-CoV-2 variants and inform on selection of Spike variants to be used as second generation COVID-19 vaccines.