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: 10205550
• 负责人: Christopher M. Walker
• 金额: $ 35.31万
• 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/10205550
• 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 该程序的一个核心假设是体液和细胞自适应免疫协同控制以控制 HCV感染。项目2的目的是开发引起泛型型的HCV疫苗成分 CD4+和CD8+ T细胞存储器。当与旨在引起广泛中和的疫苗成分结合使用时 抗体（项目1），我们期望产生相等或超过受保护的适应性反应的免疫学 通过赞助急性HCV感染而自然获得。 几种观察结果表明，疫苗诱导的T细胞免疫对于保护至关重要。初始控制 急性HCV复制的暂时与功能性T细胞反应的发作有关。感染解决 只有这种反应得以维持。耐用的T细胞记忆发展，可能会阻止重新持续 感染。再感染之前，来自免疫黑猩猩的CD8+或CD4+ T细胞的抗体介导的部署 引起长时间或持续感染。最后，对异源HCV基因型的保护一直是 在免疫黑猩猩中观察到，但可能会失败，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）缺乏评估疫苗效率的动物挑战模型。为了提供广泛的T细胞免疫，A 从HCV GT1A，1B，GT2和GT3完成保守的HCV非结构蛋白的四疫苗疫苗 序列将被评估。 NS抗原将根据大量可用的计算设计 HCV序列，导致镶嵌物，使得包含不常见的氨基酸，否则 引起较少的生产性疫苗或病毒特异性T细胞反应。马赛克与自然没有区别 HCV蛋白在序列和加工HLA向T细胞中的处理。将交付马赛克转基因 通过两个病毒载体AD48（一种罕见的人类亚型）和MVA，可以进行人类疫苗接种。 一个关键的未解决的问题是疫苗是否会产生组织居住的记忆T细胞，以及它们是否是 相当于由赞助感染引起的那些。我们将进行第一个特征 来自黑猩猩的肝居民CD4+和CD8+ T细胞种群赞助了HCV感染。 该分析将使用在暂停之前用NIH支撑收集的冷冻保存的肝单核细胞 关于黑猩猩在生物医学研究中的使用。质量的关键度量（广度，频率和功能）将是 建立并与四卫星猕猴中的组织居民T细胞进行了比较 疫苗。在与项目3的合作中，T细胞还将通过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测量 在没有病毒挑战模型的情况下，疫苗生化的T细胞的功效。