Strategies to enhance vaccine-primed T cell immunity against HCV

增强针对 HCV 的疫苗引发 T 细胞免疫的策略

• 批准号: 10409761
• 负责人: Christopher M. Walker
• 金额: $ 63.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409761
• 关键词: Acute; Adjuvant; Alleles; Amino Acids; Animals; Antibodies; Antigens; Archives; B-Cell Development; B-Lymphocytes; Biomedical Research; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chimeric Proteins; Computer Analysis; Cryopreservation; Development; Ethnic Origin; Failure; Family; Frequencies; Genetic Variation; Genotype; Geographic Locations; Goals; Haplotypes; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immune response; Immunity; Infection; Link; Liver; Macaca mulatta; Measurement; Measures; Mediating; Modeling; Mononuclear; Mosaicism; Nonstructural Protein; Outcome; Pan Genus; Pathway interactions; Pattern; Phenotype; Polyvalent Vaccine; Population; Proteins; Resolution; Sampling; Site; Structure; T cell response; T memory cell; T-Lymphocyte; Tissues; Transgenes; Transgenic Mice; Translating; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral Vector; Virus; adaptive immune response; base; chronic infection; cross reactivity; design; improved; neutralizing antibody; operation; prevent; programs; response; transcriptome; vaccine development; vaccine efficacy; vector

ABSTRACT – PROJECT 2 A central hypothesis of this Program is that humoral and cellular adaptive immune responses synergize to control HCV infection. The objective of Project 2 is to develop an HCV vaccine component that elicits pan-genotypic CD4+ and CD8+ T cell memory. When combined with a vaccine component designed to elicit broadly neutralizing antibodies (Project 1), we expect to generate immunity equaling or exceeding protective adaptive responses acquired naturally by spontaneous resolution of acute HCV infection. Several observations indicate that vaccine-induced T cell immunity will be essential for protection. Initial control of acute HCV replication is temporally associated with onset of a functional T cell response. Infections resolve only if this response is sustained. Durable T cell memory develops and may prevent persistence upon re- infection. Antibody-mediated depletion of CD8+ or CD4+ T cells from immune chimpanzees before re-infection caused prolonged or persistent infection. Finally, protection against heterologous HCV genotypes has been observed in immune chimpanzees, but can fail suggesting that HCV genetic diversity limits protective T cell memory. Two major challenges for vaccine development are (i) the tremendous genetic diversity of HCV genotypes and (ii) the lack of an animal challenge model to assess vaccine efficacy. To provide broad T cell immunity, a tetravalent vaccine comprised of conserved HCV non-structural proteins from HCV gt1a, 1b, gt2, and gt3 sequences will be assessed. NS antigens will be designed computationally from a large number of available HCV sequences, resulting in Mosaics that disfavor inclusion of uncommon amino acids that would otherwise elicit less productive vaccine- or virus strain-specific T cell responses. Mosaics are indistinguishable from natural HCV proteins in sequence and processing for HLA presentation to T cells. Mosaic transgenes will be delivered by two viral vectors, Ad48 (a rare human subtype) and MVA, that can be translated for human vaccination. A key unanswered question is whether vaccines generate tissue-resident memory T cells, and whether they are equivalent to those elicited by spontaneous resolution of infection. We will undertake the first characterization of liver-resident CD4+ and CD8+ T cell populations from chimpanzees that spontaneously resolved HCV infection. This analysis will use cryopreserved liver mononuclear cells collected with NIH support before the moratorium on chimpanzee use in biomedical research. Key measures of quality (breadth, frequency and function) will be established, and compared with tissue-resident T cells primed in rhesus macaques with the tetravalent Mosaic vaccine. In co-operation with Project 3, T cells will also be compared by Cite-Seq to provide integrated cellular protein and transcriptome measurements. These comparisons are expected to provide a surrogate measure of efficacy for vaccine-primed T cells in the absence of a virus challenge model.

摘要 – 项目 2 该计划的一个中心假设是体液和细胞适应性免疫反应协同控制 丙肝病毒感染。项目2的目标是开发一种可引发泛基因型的HCV疫苗成分 CD4+ 和 CD8+ T 细胞记忆。当与旨在引发广泛中和的疫苗成分结合使用时 抗体（项目1），我们期望产生等于或超过保护性适应性反应的免疫力 通过急性 HCV 感染的自然消退而自然获得。 一些观察结果表明，疫苗诱导的 T 细胞免疫对于保护至关重要。初始控制 HCV 急性复制的发生与功能性 T 细胞反应的发生暂时相关。感染解决 只要这种反应持续下去。持久的 T 细胞记忆会发展，并且可能会阻止重新记忆后的持久性。 感染。在再次感染之前抗体介导的免疫黑猩猩 CD8+ 或 CD4+ T 细胞的消耗 造成长期或持续感染。最后，针对异源 HCV 基因型的保护已得到证实。 在免疫黑猩猩中观察到，但可能无法表明 HCV 遗传多样性限制了保护性 T 细胞 记忆。 疫苗开发的两个主要挑战是（i）HCV 基因型的巨大遗传多样性和 (ii) 缺乏评估疫苗功效的动物攻击模型。为了提供广泛的 T 细胞免疫， 四价疫苗由来自 HCV gt1a、1b、gt2 和 gt3 的保守 HCV 非结构蛋白组成 将评估序列。 NS 抗原将根据大量可用的抗原通过计算设计出来 HCV 序列，导致嵌合体不利于包含不常见的氨基酸，否则会 引起生产力较低的疫苗或病毒株特异性 T 细胞反应。马赛克与天然马赛克没有区别 HCV 蛋白的序列和 HLA 呈递给 T 细胞的处理。嵌合转基因将被交付 由两种病毒载体 Ad48（一种罕见的人类亚型）和 MVA 组成，可转化为人类疫苗接种。 一个尚未解答的关键问题是疫苗是否会产生组织驻留记忆 T 细胞，以及它们是否 相当于感染自发消退引起的症状。我们将进行第一次表征 来自黑猩猩肝脏的 CD4+ 和 CD8+ T 细胞群可自发解决 HCV 感染。 该分析将使用在暂停之前由 NIH 支持收集的冷冻保存的肝脏单核细胞 关于黑猩猩在生物医学研究中的使用。质量的关键衡量标准（广度、频率和功能）将是 建立，并与用四价 Mosaic 在恒河猴中引发的组织驻留 T 细胞进行比较 疫苗。与 Project 3 合作，T 细胞也将通过 Cite-Seq 进行比较，以提供集成的细胞 蛋白质和转录组测量。这些比较预计将提供替代衡量标准 在没有病毒攻击模型的情况下疫苗引发的 T 细胞的功效。