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 HCV感染。项目2的目标是开发一种HCV疫苗成分， CD 4+和CD 8 + T细胞记忆。当与设计用于引起广泛中和的疫苗组分组合时， 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感染的自发消退而自然获得。 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 急性丙型肝炎病毒复制与功能性T细胞应答的发生有时间相关性。感染消退 只有这种反应持续下去。持久的T细胞记忆的发展，并可能防止持久性后，重新 感染再次感染前抗体介导的免疫黑猩猩CD 8+或CD 4 + T细胞耗竭 引起长期或持续感染的。最后，针对异源HCV基因型的保护已经被证实是有效的。 在免疫黑猩猩中观察到，但可能失败，这表明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， (ii)缺乏评估疫苗效力的动物攻击模型。为了提供广泛的T细胞免疫， 包含来自HCV gt 1a、1b、gt 2和gt3的保守HCV非结构蛋白的四价疫苗 将评估序列。NS抗原将从大量可用的抗原中通过计算来设计。 HCV序列，导致镶嵌，不利于包括不常见的氨基酸，否则 引起生产性较低的疫苗或病毒株特异性T细胞应答。马赛克与自然的 HCV蛋白质的序列和加工用于HLA呈递给T细胞。嵌合转基因将被传递到 通过两种病毒载体，Ad 48（一种罕见的人类亚型）和MVA，可以翻译用于人类疫苗接种。 一个关键的未回答的问题是，疫苗是否产生组织驻留记忆T细胞，以及它们是否 相当于感染自发消退引起的那些。我们将首先对 来自黑猩猩的肝脏驻留的CD 4+和CD 8 + T细胞群，其自发地解决了HCV感染。 这项分析将使用在暂停前在NIH支持下收集的冷冻保存的肝脏单核细胞 黑猩猩在生物医学研究中的应用质量的主要衡量标准（广度、频率和功能）将是 建立，并与用四价嵌合体在恒河猴中引发的组织驻留T细胞进行比较。 疫苗在与项目3的合作中，T细胞也将通过Cite-Seq进行比较，以提供整合的细胞免疫学。 蛋白质和转录组测量。这些比较预计将提供一个替代措施， 在不存在病毒攻击模型的情况下，疫苗致敏的T细胞的功效。