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Mechanisms of spontaneous and vaccine mediated hepatitis C virus control to direct rational development of a novel HCV vaccine

自发和疫苗介导的丙型肝炎病毒控制机制指导新型丙型肝炎疫苗的合理开发

基本信息

批准号：
10205729
负责人：
ANDREA L COX
金额：
$ 263.27万
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/10205729
关键词：
Acute Acute Hepatitis C Adjuvant Animals Antibodies Antibody Response Antibody-mediated protection Antigens Antiviral Agents B cell repertoire B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cellular Immunity Cessation of life Characteristics Chronic Hepatitis C Clinical Cohort Studies Collaborations Complex Country Data Development Epitopes Event Evolution Exposure to Extinction (Psychology)Failure Future Generations Genes Genetic Genotype Goals Gold Hepatitis C Hepatitis C Antibodies Hepatitis C Therapy Hepatitis C Vaccine Hepatitis C virus Human Humoral Immunities Immune Immune response Immunity Immunization Income Infection Infection Control Length Liver Failure Mediating Membrane Modeling Molecular Mus Participant Pathway interactions Patients Persons Phenotype Placebos Plasma Population Prevention Primary Infection Primary carcinoma of the liver cells Property Recovery Regimen Research Research Personnel Resolution Resources Risk Sequence Analysis Site Standardization Structure T cell response T-Lymphocyte Testing Time Translating Vaccinated Vaccination Vaccine Antigen Vaccines Viral Viral Antigens Viral Genome Viral Hepatitis Vaccines Viral Vector Viremia Virus Virus-like particle Work acute infection adaptive immune response anti-hepatitis C antibody test antigen test base chronic infection clinical trial participant cross reactivity design efficacy study efficacy trial env Gene Products genome sequencing healthy volunteer high risk high risk population human data immunogenicity memory CD4 T lymphocyte nanoparticle neutralizing antibody nonhuman primate novel novel vaccines pre-clinical assessment preclinical study prevent programs recruit repository response vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine trial vector vaccine viral RNA virus envelope

项目摘要

Overall Project Summary Hepatitis C virus (HCV) infects ~70 million people worldwide and is a major cause of hepatocellular carcinoma and liver failure. Even with highly effective HCV treatment, recent data show that 80% of high-income countries are not on target to meet the WHO goals of elimination of HCV. In most countries, the annual number of new infections remains higher than the number cured by treatment. A vaccine for HCV should be possible because 25% of people resolve primary infection with effective anti-viral T cells and the generation of broadly neutralizing antibodies (bNAbs). Recently, we have identified people who are repeatedly exposed to HCV with reinfection and control of up to six distinct HCV infections, often of more than one HCV genotype. To date, one candidate vaccine has been tested in an at-risk human population. This vaccine was designed to induce robust T cell responses and was evaluated by proposal investigators for immunogenicity in healthy volunteers and for efficacy in the prevention of HCV persistence in people at high risk of HCV infection. Although not protective against chronic infection, vaccinated participants had significantly reduced mean peak HCV RNA compared to placebo recipients. Our overarching hypothesis is that defining HCV-specific T cell and antibody mediated immunity in effective control of HCV infection can be directly translated into more effective vaccine strategies. Therefore, we plan an integrated analysis of T cell and B-cell/Ab mediated immunity alongside an assessment of viral antigen sequences in resolved infection and vaccinees. This will inform the design and pre-clinical assessment of novel vaccine strategies. In Project 1, CD4 and CD8 T cell responses will be compared between people who are repeatedly exposed to and spontaneously control HCV and HCV clinical trial participants, both to define T cell properties associated with HCV control, but also to identify the reasons for vaccine failure. NAbs also contribute to successful control of repeated HCV exposure and work across several projects will identify and test novel vaccine antigens and platforms with potential to induce anti-HCV bNAbs. Binding (Project 2) and structural (Project 3) studies of bNAbs in complex with envelope proteins (E2 or E1E2) selected through a collaboration between projects 2 and 4 will identify a panel of potential vaccine antigens with unique structural characteristics that favor bNAb induction and maturation. Project 3 will develop nanoparticle (NP) and virus-like particle (VLP)- based vaccines to present these E2 or E1E2 antigens and test them in mice. Project 5 will assess new T cell immunogens in viral vectored vaccines, with viral vectored E2 or E1E2, NPs, or VLPs in mice, aiming to generate both anti-E1E2 antibodies and the effective, genotype cross-reactive T cell responses defined in Project 1. We will then test the two most successful vaccine candidates in non-human primates. The proposed integrative research will provide a precise molecular description of infection events and the comprehensive characterization of adaptive immune responses underlying effective HCV immune control, with new vaccine candidates assessed in pre-clinical studies to identify the best vaccine antigens and strategy to advance to future human trials.

整体项目总结