PanCorVac (Center for Pan-Coronavirus Vaccine Development)

总结 目前批准或正在开发的大多数针对大流行性SARS-CoV-2（严重急性 呼吸综合征冠状病毒2）病毒靶向SARS-CoV-2中的免疫显性、毒株特异性表位 刺突（S）蛋白，因此预计不会提供针对其他冠状病毒的保护。因此，委员会认为， NIAID宣布了NOT-AI-21-002，呼吁“开发预防性疫苗， 广泛和持久的保护，防止冠状病毒，特别是SARS-CoV-2和其他大流行 潜力”。为了响应这一呼吁，我们组建了泛冠状病毒疫苗（PanCoVac）联盟， 开发和测试新型泛冠状病毒疫苗。研究项目1（RP 1;泛- CoV疫苗）使用两种策略来开发广泛保护性的冠状病毒疫苗： 反应远离S的头部区域中的免疫显性表位并朝向更保守的， S的茎区中的免疫亚显性表位;以及（ii）从可变的免疫亚显性表位重新聚焦免疫应答。 免疫显性表位对更保守的表位在S的头部区域。对于每种策略， 将采用创新办法。新的抗原将由病毒样颗粒提出， 组装噬菌体外壳蛋白（一种高免疫原性平台）。将对候选疫苗进行测试 它们在动物模型中对不同冠状病毒的免疫原性和保护功效。选择 候选物将在第二动物模型中进行测试，并使用mRNA脂质纳米颗粒平台。额外 研究将测试免疫反应的持久性和接种疫苗对病毒传播的影响。样品 将向研究项目2（RP 2;对泛CoV的免疫应答）提供来自接种疫苗动物的 疫苗）以详细评估B细胞和T细胞应答。第一，区域方案2将继续努力， 生成并表征SARS-CoV S特异性mAb组，其将用于RP 1以帮助表征 优先考虑候选疫苗此外，“免疫球蛋白组学”，其中涉及单细胞技术，允许高， B细胞应答、表型、免疫球蛋白（IG）库和与以下反应的mAb的通量分析： 几种冠状病毒（由RP 2研究人员之一开发的技术）将用于表征B 候选疫苗诱导的细胞介导的免疫和mAb特异性。RP 2还将测试（并比较 来自人类群组研究的数据）候选疫苗引起对交叉反应性免疫应答的能力， CD 4和CD 8 T细胞表位。特别是，最近开发的新方法将用于表征和 比较感染和接种后的T细胞库。一个行政核心将监督和管理 联合体的所有财务和行政方面。我们提出的研究从多方面汲取力量- 分子病毒学、结构生物学、纳米生物技术以及B和T细胞 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.