Immunological responses to pan-CoV vaccines

摘要 泛冠状病毒疫苗(PanCoVac)财团将开发新型冠状病毒疫苗，可以 提供针对一系列冠状病毒的保护。研究项目1(RP1，“PAN的设计和评估-- 冠状病毒疫苗)将开发新的冠状病毒抗原，并在临床前动物模型中进行测试。研究 RP2项目将测试“对泛冠状病毒疫苗的免疫反应”，包括对 RP1抗原疫苗免疫小鼠后的B、T细胞反应 站台。在目标1中(‘提供一组特性良好的抗体，这些抗体交叉反应或针对不同的 冠状病毒株)，从新冠肺炎患者的B细胞中克隆的人源单抗 将产生并表征对各种冠状病毒的活性。功能和结构 将与RP1的调查人员合作进行定性。特征化的mAbs将是 提供给RP1以测试新的抗原。目标是找出保持关键交叉反应的新抗原。 而菌株特异的免疫优势表位则丢失。目标2(《B细胞免疫交叉分析》 对SARS-CoV-2和其他冠状病毒株有反应性)，“免疫球蛋白组学”，即允许 高通量分析B细胞反应、表型、免疫球蛋白(Ig)谱系和反应单抗 各种冠状病毒(由RP2研究人员之一开发)将被用于表征B细胞- 候选疫苗抗原诱导的介导性免疫和mAb特异性。这些数据将被比较 利用一项人类队列研究的结果(通过不同的机制资助)来确定候选疫苗 产生广泛的B细胞反应并刺激生发中心和世代的亲和力成熟 长期记忆B细胞和浆细胞。在目标3(‘T细胞免疫对SARS的交叉反应分析-- CoV-2和其他冠状病毒株)，我们将测试新的候选疫苗引发反应的能力 与CD4和CD8表位发生交叉反应。特别是，基于T细胞谱系测序的新方法将 用于表征SARS-CoV-2与其他病毒之间交叉反应的表位特异性反应 人类冠状病毒，以及那些SARS-CoV-2特异性的反应。使用来自持续纵向的数据 对SARS-CoV-2感染者的队列研究(通过不同的机制资助)，我们将能够确定 SARS-CoV-2感染后扩张的幼稚和基线交叉反应T细胞反应。这些数据将是 与接种新型候选疫苗的小鼠的T细胞反应进行比较。总体而言，这些数据 将允许对接种疫苗的动物和人类COVID之间的B和T细胞反应进行深入比较- 19个样本，以求提炼出更具交叉反应的候选疫苗。

Summary The pan-coronavirus vaccine (PanCoVac) consortium will develop novel coronavirus vaccines that can provide protection against a range of coronaviruses. Research Project 1 (RP1, ‘Design and evaluation of pan- CoV vaccines’) will develop novel coronavirus antigens and test them in pre-clinical animal models. Research Project, RP2, will test the ‘Immunological Responses to pan-CoV vaccines’, including a detailed analysis of B and T cell responses in mice immunized with antigens developed in RP1 and formulated into a vaccine platform. In Aim 1 (‘Provide a panel of well-characterized antibodies cross-reacting or specific to various coronavirus strains’), human monoclonal antibodies (mAbs) cloned from the B cells from COVID-19 patients will be generated and characterized for activity against various coronaviruses. The functional and structural characterization will be carried out in collaboration with investigators in RP1. The characterized mAbs will be provided to RP1 to test novel antigens. The goal is to identify novel antigens that maintain key cross-reactive epitopes while strain-specific immunodominant epitopes are lost. In Aim 2 (‘Analysis of B cell immunity cross- reactive to SARS-CoV-2 and other coronavirus strains’), “Ig-omics”, i.e., single-cell technologies allowing high-throughput analysis of B cell responses, phenotypes, immunoglobulin (Ig) repertoires and mAbs that react to various coronaviruses (developed by one of the RP2 investigators) will be utilized for characterizing B cell- mediated immunity and mAb specificity induced by the candidate vaccine antigens. These data will be compared with results from a human cohort study (funded through a different mechanism) to identify vaccine candidates that generate a broad B cell response and stimulate affinity maturation in germinal centers and the generation of long-term memory B cells and plasma cells. In Aim 3 (‘Analysis of T cell immunity cross-reactive to SARS- CoV-2 and other coronavirus strains’), we will test the ability of novel vaccine candidates to elicit responses to cross-reactive CD4 and CD8 epitopes. In particular, novel methods based on T cell repertoire sequencing will be used to characterize epitope-specific responses that are cross-reactive between SARS-CoV-2 and other human coronaviruses, and those responses that are SARS-CoV-2 specific. Using data from ongoing longitudinal cohort study of SARS-CoV-2-infected people (funded through a different mechanism), we will be able to identify naïve and baseline cross-reactive T cell responses that expand after SARS-CoV-2 infection. These data will be compared with the T cell responses in mice vaccinated with the novel vaccine candidates. Overall, these data will allow an in-depth comparison of B and T cell responses between vaccinated animals and human COVID- 19 samples in order to refine vaccine candidates to be more cross-reactive.