Correlates of protective immunity to HCV and rational vaccine design

HCV 保护性免疫与合理疫苗设计的相关性

• 批准号: 10205764
• 负责人: Arash Grakoui
• 金额: $ 201.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205764
• 关键词: Acute Hepatitis C; Adolescent and Young Adult; Adoption; Antibody Response; Antigens; Antiviral Agents; Antiviral Therapy; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Chronic Hepatitis C; DNA; Direct Costs; Egypt; Engineering; Epidemic; Exposure to; Frequencies; Generations; Goals; Government; Hepatitis C; Hepatitis C virus; High Prevalence; Human; Immune response; Immunity; Individual; Infection; Injecting drug user; Knowledge; Liver; Longevity; Memory; Methods; Modality; Modeling; Modified Vaccinia Virus Ankara; Monitor; Outcome; Participant; Patients; Pharmaceutical Preparations; Phenotype; Prevention; Primary Infection; Production; Proteins; Public Health; Regimen; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Signal Pathway; Signaling Molecule; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Time; Vaccine Design; Vaccines; Viral; Viral Proteins; Virus; base; chronic infection; cohort; cytotoxic CD8 T cells; design; high risk; human subject; memory CD4 T lymphocyte; neutralizing antibody; nonhuman primate; novel vaccines; prevent; programs; recruit; response; screening; stem; success; transcription factor; vaccination strategy; vaccine development; vaccine trial

Abstract Prevention of HCV infection remains an important public health objective even with the recent adoption of highly effective antiviral therapies. Importantly, treatment with direct acting antivirals (DAAs) does not prevent reinfection in those who have successfully been treated. A vaccine to prevent HCV persistence is needed to stem an emerging epidemic of infection in adolescents and young adults who inject drugs that have limited access to screening and treatment. Only twenty five percent of acute HCV infections resolve spontaneously. Resolution does, however, sharply reduce the risk of persistent infection upon re-exposure to the virus. Memory CD4+ T helper and CD8+ cytotoxic T cell responses contribute to accelerated clearance of a second infection. However, the role of neutralizing antibodies during reinfection is less clear. Importantly, vaccines to generate an equivalent T cell response failed to thwart off the rate of persistence in naïve recipients. Here, we will test the central hypothesis that memory CD4+ T cells contribute significantly to HCV reinfection outcome by promoting expansion of HCV-specific B cells and production of broadly neutralizing antibodies that contribute to viral clearance. Unique features of this proposal are (i) the use of longitudinal samples from the Montreal cohort of high- risk people who inject drugs. Participants are monitored prior to, during, and after HCV infection and then subsequently followed again when they have been re-exposed to HCV a second time after resolving their primary infection. (ii) We have assembled a team of investigators in Cairo, Egypt who will assist us with recruiting and treating subjects undergoing DAA treatment. Egypt has the highest prevalence of HCV infection in the world. In 2014, Egypt's government has made DAA treatment affordable and 2.5 million subjects have started treatment. Understanding the immune responses in these two cohorts will provide us with valuable information to develop an efficacious vaccine regimen that would emulate the successful responses generated during a natural challenge with HCV. Three highly interactive Projects are proposed. Project 1 (N. Shoukry, PI) will compare the frequency, breadth, function, and phenotype of CD4+ T cells in HCV reinfections that either resolve or become persistent. Project 2 (A. Grakoui, PI) will use new state of the art technology to isolate and characterize antigen-specific B cells during HCV reinfection and post DAA treatment. Project 3 (R. Amara, PI) will develop vaccine modalities to induce both a CD4+ T helper response and a robust antigen-specific antibody response in blood and liver using DNA, modified vaccinia Ankara (MVA) and protein-based vaccines against HCV proteins in non-human primates.

摘要