The development and pre-clinical assessment of novel HCV vaccines to generate T and B cell immunity

产生 T 和 B 细胞免疫的新型 HCV 疫苗的开发和临床前评估

• 批准号: 10205736
• 负责人: Eleanor Barnes
• 金额: $ 28.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205736
• 关键词: Acute; Address; Adenovirus Vector; Adjuvant; Antibody Response; Antigens; B-Lymphocytes; Bioinformatics; CD8-Positive T-Lymphocytes; COVID-19 vaccine; Chad; Cicatrix; Clinical Trials; Conserved Sequence; Data; Detection; Development; E protein; Epitopes; Future; Genetic; Genetic Variation; Genotype; Goals; HLA A*0201 antigen; HLA Antigens; HLA-A3 Antigen; Head; Hepatitis C; Hepatitis C Antiviral; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune response; Immunity; Immunization; Immunology; Inbreeding; Individual; Infection; Infection prevention; Length; Link; Liver; Macaca mulatta; Malignant Neoplasms; Mediating; Methods; Modeling; Modified Vaccinia Virus Ankara; Mosaicism; Mus; Pan Genus; Primary Infection; Proteins; Proteome; Regimen; T cell response; T memory cell; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Transgenic Mice; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Vector; World Health Organization; anti-hepatitis C; antiviral immunity; chronic infection; cross reactivity; design; efficacy trial; humanized mouse; immunogenic; immunogenicity; in silico; invariant chain; memory recall; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel strategies; novel vaccines; particle; pre-clinical; pre-clinical assessment; preclinical study; prevent; secondary infection; tool; transgene expression; vaccination strategy; vaccine candidate; vector; vector vaccine; viral RNA; virus envelope; virus genetics

PROJECT SUMMARY Hepatitis C virus (HCV) infects more than 71 million people and causes liver scarring and cancer. An effective vaccine to prevent infection is urgently required. This should be an achievable goal, since 25% of individuals spontaneously resolve (SR) primary infection generating anti-viral immunity. An effective vaccine may need to mimic the immune responses associated with SR including the induction of anti-HCV neutralizing antibodies (NAbs) and HCV-specific T cells. One method to achieve this, is through the use of viral vectored vaccines (both chimpanzee Adenoviral [ChAd] and modified vaccinia Ankara [MVA]), which have emerged as powerful tools to generate immune responses against an encoded immunogen, including HCV. However, viral genetic diversity is a major challenge for the development of HCV vaccines, with at least eight distinct genotypes (gt) and multiple subtypes between and within HCV infected people. Recently, a viral vectored vaccine encoding a single gt-1b sequence failed to prevent chronic infection, highlighting the need to develop new approaches with novel HCV immunogens that generate NAbs and T cells against multiple gts. Project 5 tests the hypothesis that an optimized viral vectored HCV vaccine strategy can generate anti-HCV nAbs and cross-reactive T cells. To test this hypothesis, we will pursue three specific aims. Aim 1 uses bioinformatic analysis and generates novel T cell immunogens encoded in ChAd and MVA, designed to generate broad T cell coverage to all HCV gts assessed in inbred, outbred and (HLA-2) humanised mice. The most promising T cell immunogen(s) will then progress to aim 2. Aim 2 will increase viral vectored vaccine generated T cell responses using genetic adjuvants (including variants of class II invariant chain) and assess alternative adenovirus vectors to overcome potential anti-vector immunity, that may be present in humans. Aim 3 will develop new vaccine strategies to generate both anti-HCV Abs and also T cells. This will be achieved through assessing: i) Different B cell immunogens (identified in project 2 and 3) encoded in viral vectored vaccines; ii) Combining promising T cell vaccine candidates with strategies designed to generate bNAbs including Viral Like Particles (VLP) or nanoparticles that present the HCV envelope (E2) from Project 3 or with a ChAd expressing E proteins; and iii) developing a single ‘bivalent’ viral vectored vaccine that encodes the optimal B cell and T cell immunogens together. Importantly, the project will also take account of findings in partner projects should T cell profiles (project 1) or viral sequence motifs (project 4) linked to SR be identified. Together the aims will contribute to developing an optimized viral vectored HCV vaccine strategy for assessment in Rhesus monkeys with a view to future human clinical trials.

项目摘要 丙型肝炎病毒（HCV）感染超过7100万人，并引起肝脏疤痕和癌症。有效 迫切需要防止感染的疫苗。这应该是一个可以实现的目标，因为25％的个人 赞助解析（SR）产生抗病毒免疫力的原发性感染。有效的疫苗可能需要 模仿与SR相关的免疫反应，包括抗HCV中和 抗体（NABS）和HCV特异性T细胞。一种实现这一目标的方法是通过使用病毒量 出现的疫苗（黑猩猩腺病毒[Chad]和改良的vercinia ankara [MVA]） 作为针对包括HCV在内的编码免疫原生成免疫调查的强大工具。然而， 病毒遗传多样性是HCV疫苗开发的主要挑战，至少有八种不同 HCV感染者之间和内部的基因型（GT）和多个亚型。最近，病毒载体 编码单个GT-1B序列的疫苗无法防止慢性感染，强调了发展的需求 新的HCV免疫原子的新方法，可针对多个GT产生NAB和T细胞。项目5 检验了优化的病毒载体HCV疫苗策略可以产生抗HCV NAB的假设，并且 交叉反应T细胞。为了检验这一假设，我们将追求三个具体目标。 AIM 1使用生物信息学 分析并生成编码在乍得和MVA中的新型T细胞免疫原，旨在产生广泛的T 在近交，近交和（HLA-2）人类化的小鼠中评估的所有HCV GTS的细胞覆盖率。最有前途的 T细胞免疫原（S）将发展为AIM 2。AIM 2将增加病毒矢量的疫苗产生的T细胞 使用遗传调节器（包括II类不变链的变体）的响应，并评估替代方案 腺病毒载体克服了潜在的抗载体免疫，可能存在于人类中。目标3意志 制定新的疫苗策略来产生抗HCV ABS和T细胞。这将通过 评估：i）用病毒矢量疫苗编码的不同B细胞免疫（在项目2和3中鉴定）； ii）将承诺T细胞疫苗候选物与旨在产生包括病毒在内的BNAB的策略相结合 像颗粒（VLP）或纳米颗粒，这些粒子呈现项目3或乍得的HCV包膜（E2） 表达E蛋白； iii）开发一种编码最佳的单个“二价”病毒载体疫苗 B细胞和T细胞免疫原。重要的是，该项目还将考虑合作伙伴的发现 项目应确定与SR相关的T细胞概况（项目1）或病毒序列基序（项目4）。 目的共同有助于开发优化的病毒量HCV疫苗策略 对恒河猴的评估，以期为未来的人类临床试验。