Immunological responses to pan-CoV vaccines

对泛冠状病毒疫苗的免疫反应

• 批准号: 10841734
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 155.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10841734
• 关键词: 2019-nCoV; Affinity; Animal Model; Animals; Antibodies; Antibody Specificity; Antigens; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 patient; Cell Maturation; Cells; Cellular Immunity; Cohort Studies; Collaborations; Collection; Coronavirus; Coronavirus Infections; Cross Reactions; Cytotoxic T-Lymphocytes; Data; Development; Disease; Ensure; Epitopes; Evaluation; Funding; Funding Opportunities; Generations; Goals; Head; Human; Immune; Immune response; Immune system; Immunity; Immunize; Immunodominant Epitopes; Immunoglobulins; Immunologic Tests; Infection; Influenza; Laboratories; Longitudinal cohort study; Mediating; Memory B-Lymphocyte; Methods; Middle East Respiratory Syndrome Coronavirus; Monoclonal Antibodies; Mus; Outcome; Persons; Phase I Clinical Trials; Phenotype; Plasma Cells; Polysaccharides; Proteins; Reaction; Research Personnel; Research Project Grants; SARS coronavirus; Sampling; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccinated; Vaccine Antigen; Vaccines; Variant; Viral; adaptive immune response; candidate validation; cell killing; coronavirus vaccine; cross immunity; cross reactivity; cytotoxic; design; high throughput analysis; human coronavirus; human monoclonal antibodies; long term memory; novel; novel coronavirus; novel vaccines; post SARS-CoV-2 infection; pre-clinical; programs; reconstruction; response; single cell technology; stem; universal coronavirus vaccine; vaccine candidate; vaccine development; vaccine platform

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.

总结 泛冠状病毒疫苗（PanCoVac）联盟将开发新型冠状病毒疫苗， 提供对一系列冠状病毒的保护。研究项目1（RP 1，"泛- CoV疫苗将开发新型冠状病毒抗原，并在临床前动物模型中进行测试。研究 RP 2项目将测试“泛冠状病毒疫苗的免疫反应”，包括详细分析 用在RP 1中开发并配制成疫苗的抗原免疫的小鼠中的B和T细胞应答 平台在目标1中（“提供一组充分表征的抗体，其与各种抗体交叉反应或特异性， 冠状病毒株），从COVID-19患者的B细胞克隆的人单克隆抗体（mAb） 将产生并表征针对各种冠状病毒的活性。功能和结构 将与RP 1中的研究者合作进行表征。特征化的mAb将是 提供给RP 1以测试新抗原。目标是鉴定维持关键交叉反应性的新抗原， 表位，而菌株特异性免疫显性表位丢失。在目的2（"B细胞免疫交叉分析“）中， 对SARS-CoV-2和其它冠状病毒株具有反应性），“Ig组学”，即，单细胞技术， B细胞应答、表型、免疫球蛋白（IG）库和与免疫球蛋白反应的mAb的高通量分析 各种冠状病毒（由RP 2研究者之一开发）将用于表征B细胞- 介导的免疫和候选疫苗抗原诱导的mAb特异性。这些数据将被比较 来自人类队列研究（通过不同的机制资助）的结果，以确定候选疫苗 其产生广泛的B细胞应答并刺激生发中心的亲和力成熟， 长时记忆B细胞和浆细胞。在目标3（“对SARS交叉反应的T细胞免疫的分析- CoV-2和其他冠状病毒株），我们将测试新型候选疫苗引发反应的能力 交叉反应的CD 4和CD 8表位。特别是，基于T细胞库测序的新方法将 可用于表征SARS-CoV-2和其他病毒之间交叉反应的表位特异性应答， 人类冠状病毒，以及SARS-CoV-2特异性反应。使用正在进行的纵向数据 SARS-CoV-2感染者的队列研究（通过不同的机制资助），我们将能够识别 SARS-CoV-2感染后扩增的初始和基线交叉反应性T细胞应答。这些数据将 与用新的候选疫苗接种的小鼠中的T细胞应答相比。总的来说，这些数据 将允许深入比较接种疫苗的动物和人类COVID之间的B和T细胞反应， 19个样本，以改进候选疫苗，使其更具交叉反应性。