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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要丙型肝炎病毒 (HCV) 感染超过 7100 万人，并导致肝脏疤痕和癌症。迫切需要疫苗来预防感染，这应该是一个可以实现的目标，因为 25% 的人。自发解决（SR）原发感染产生抗病毒免疫力可能需要有效的疫苗。模拟与 SR 相关的免疫反应，包括诱导抗 HCV 中和实现这一目标的一种方法是使用病毒载体。已出现的疫苗（黑猩猩腺病毒 [ChAd] 和改良安卡拉痘苗 [MVA]）作为产生针对编码免疫原（包括 HCV）的免疫反应的强大工具。病毒遗传多样性是 HCV 疫苗开发的主要挑战，至少有八种不同的遗传多样性最近，一种病毒载体在 HCV 感染者之间和内部进行了基因型 (gt) 和多种亚型的检测。编码单一 gt-1b 序列的疫苗未能预防慢性感染，凸显了开发的必要性使用新型 HCV 免疫原的新方法，可产生针对多种 gts 的 NAb 和 T 细胞 Project 5。检验优化的病毒载体 HCV 疫苗策略可以产生抗 HCV nAb 的假设，并且为了检验这一假设，我们将利用生物信息学来实现三个具体目标。分析并生成 ChAd 和 MVA 中编码的新型 T 细胞免疫原，旨在生成广泛的 T 在近交系、远交系和 (HLA-2) 人源化小鼠中评估的所有 HCV gts 的细胞覆盖率最有希望。然后，T 细胞免疫原将进展至目标 2。目标 2 将增加病毒载体疫苗产生的 T 细胞使用遗传佐剂（包括 II 类不变链的变体）的反应并评估替代方案腺病毒载体可克服人类中可能存在的潜在抗载体免疫力。开发新的疫苗策略来产生抗 HCV 抗体和 T 细胞，这将通过以下方式实现。评估： i) 病毒载体疫苗中编码的不同 B 细胞免疫原（在项目 2 和项目 3 中确定）； ii) 将有前景的 T 细胞候选疫苗与旨在生成 bNAb（包括病毒）的策略相结合类似颗粒 (VLP) 或呈现来自项目 3 的 HCV 包膜 (E2) 或带有 ChAd 的纳米颗粒表达 E 蛋白；以及 iii) 开发编码最佳病毒的单一“二价”病毒载体疫苗重要的是，该项目还将考虑合作伙伴的研究结果。项目应确定与 SR 相关的 T 细胞谱（项目 1）或病毒序列基序（项目 4）。这些目标共同将有助于开发优化的病毒载体 HCV 疫苗策略在恒河猴中进行评估，以期进行未来的人体临床试验。