PanCorVac (Center for Pan-Coronavirus Vaccine Development)

摘要 目前批准或正在开发的针对大流行SARS-CoV-2(严重急性冠状病毒)的疫苗 呼吸综合征冠状病毒2)病毒靶向SARS-CoV-2中的免疫优势株特异性表位 SPEKE(S)蛋白，因此预计不会对其他冠状病毒产生保护作用。因此， NIAID公布了NOT-AI-21-002，它呼吁“开发预防性疫苗以提供 针对冠状病毒，特别是SARS-CoV-2和其他具有大流行的病毒提供广泛和持久的保护 潜力“。为响应这一号召，我们组建了泛冠状病毒疫苗(PanCoVac)联盟，以 开发和测试新型泛冠状病毒疫苗。研究项目1(RP1；PAN的设计和评估 冠状病毒疫苗)使用两种策略来开发具有广泛保护性的冠状病毒疫苗：(I)焦点免疫 从S头部区域的免疫优势表位转向更保守的表位， S茎区的免疫亚优势表位；以及(Ii)从变异体中重新定位免疫反应 免疫优势表位朝向S的头部区域更保守的表位。对于每个策略，几个 将使用创新的方法。新的抗原将由病毒样颗粒呈现，基于自身的 组装噬菌体外壳蛋白(一个高免疫原性平台)。候选疫苗将接受测试 在动物模型中研究它们对不同冠状病毒的免疫原性和保护效果。已选择 候选者将在第二个动物模型中进行测试，并使用信使核糖核酸脂质纳米颗粒平台。其他内容 研究将测试免疫反应的持久性和疫苗接种对病毒传播的影响。样本 来自接种动物的疫苗将提供给研究项目2(RP2；对泛冠状病毒的免疫反应 疫苗)，以详细评估B细胞和T细胞的反应。首先，RP2将继续努力 生成和鉴定针对S的SARS-CoV特异性mAb板，这些单抗将用于RP1中以帮助鉴定 并确定疫苗候选的优先顺序。此外，“免疫球蛋白组学”，它涉及单细胞技术，允许高度... B细胞反应、表型、免疫球蛋白(Ig)谱系和与之反应的单抗的吞吐量分析 几种冠状病毒(一种由RP2研究人员开发的技术)将被用来表征B 候选疫苗诱导的细胞免疫和单抗特异性。RP2还将测试(和比较 来自人类队列研究的数据)候选疫苗引发交叉反应的能力 CD4和CD8T细胞表位。特别是，最近开发的新方法将被用来表征和 比较感染和接种后的T细胞谱系。一个行政核心将监督和管理 财团的所有财务和行政方面。我们建议的研究从多个方面汲取力量 分子病毒学、结构生物学、纳米生物技术以及B细胞和T细胞专家组成的机构团队 免疫学。

SUMMARY Most of the vaccines currently approved or in development against the pandemic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus target immunodominant, strain-specific epitopes in the SARS-CoV-2 spike (S) protein and are therefore not expected to confer protection against other coronaviruses. Accordingly, the NIAID announced NOT-AI-21-002, which calls for the “development of prophylactic vaccines to provide broad and durable protection against coronaviruses, especially SARS-CoV-2 and others with pandemic potential”. In response to this call, we assembled the Pan-Coronavirus Vaccine (PanCoVac) consortium to develop and test novel pan-coronavirus vaccines. Research Project 1 (RP1; Design and evaluation of pan- CoV vaccines) uses two strategies to develop broadly protective coronavirus vaccines: (i) Focus immune responses away from the immunodominant epitopes in the head region of S and towards the more conserved, immune-subdominant epitopes in the stem region of S; and (ii) Refocus immune responses from the variable immunodominant epitopes towards more conserved epitopes in the head region of S. For each strategy, several innovative approaches will be used. Novel antigens will be presented by virus-like particles based on a self- assembling bacteriophage coat protein (a highly immunogenic platform). The candidate vaccines will be tested for their immunogenicity and protective efficacy against different coronaviruses in an animal model. Selected candidates will be tested in a second animal model, and with an mRNA lipid nanoparticle platform. Additional studies will test the durability of immune responses and the effect of vaccination on virus transmission. Samples from vaccinated animals will be provided to Research Project 2 (RP2; Immunological responses to pan-CoV vaccines) for a detailed assessment of B- and T-cell responses. First, RP2 will continue its ongoing efforts to generate and characterize panels of SARS-CoV S-specific mAbs, which will be used in RP1 to help characterize and prioritize vaccine candidates. Moreover, “Ig-omics”, which involves single-cell technologies allowing high- throughput analysis of B-cell responses, phenotypes, immunoglobulin (Ig) repertoires and mAbs that react to several coronaviruses (a technology developed by one of the RP2 investigators), will be used to characterize B cell-mediated immunity and mAb specificity induced by the candidate vaccines. RP2 will also test (and compare with data from a human cohort study) the ability of the candidate vaccines to elicit responses to cross-reactive CD4 and CD8 T cell epitopes. In particular, recently developed novel methods will be used to characterize and compare the T-cell repertoires upon infection and vaccination. An Administrative Core will oversee and manage all financial and administrative aspects of the consortium. Our proposed research draws strength from a multi- institutional team of experts in molecular virology, structural biology, nanobiotechnology, and B- and T-cell immunology.