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SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION

选择预防丙型肝炎病毒感染的疫苗抗原

基本信息

批准号：
10207624
负责人：
Ranjit Ray
金额：
$ 34.09万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207624
关键词：
Active immunity Address Adjuvant Antigen-Presenting Cells Antigens Antiviral Agents B-Lymphocytes Binding Sites CD4 Positive T Lymphocytes CD81 gene Cell Culture Techniques Cell physiology Cells Chronic Hepatitis C Country Development Encapsulated Environment Evaluation Generations Genomic Segment Genotype Glycoproteins Health Health Benefit Helper-Inducer T-Lymphocyte Hepatitis C Hepatitis C Incidence Hepatitis C Vaccine Hepatitis C Viremia Hepatitis C virus Human Immune Immune response Immunization Immunize Immunocompetent Impairment Infection Interruption Literature Liver diseases MF59 Macrophage Activation Messenger RNA Mus Mutate Natural Killer Cells Nature Nucleosides Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phenotype Point Mutation Preventive vaccine Proteins Public Health Recombinants Regimen Research Resistance Resources Risk Role Safety T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Vaccinated Vaccine Adjuvant Vaccine Antigen Vaccines Vaccinia virus Viral Antigens Viral Proteins Virus Diseases Work anti-hepatitis C comparative cost effective cross reactivity design experimental study global health healthy volunteer immune function immunogenicity immunoregulation improved lipid nanoparticle low socioeconomic status macrophage mouse model mutant nanoparticle neutralizing antibody novel vaccines pathogen preclinical study protective efficacy response stem transmission process vaccine candidate vaccine delivery vaccine development vaccine efficacy vaccine evaluation viral RNA virology virus envelope volunteer

项目摘要

Abstract Chronic hepatitis C virus (HCV) infection often causes end stage liver disease. Although current anti-HCV drugs are successful in eliminating viral RNA load, they do not prevent reinfection. In addition, eliminating HCV RNA load does not reduce the risk for progression to end stage liver disease. Therefore, the urgent need for the development of a comprehensive strategy to control HCV infection must include a vaccine. HCV envelope glycoproteins are the key components for the initiation of viral infection. Our phase I safety and immunogenicity trial of a recombinant HCV envelope glycoprotein candidate vaccine did not induce a strong immune response in most vaccinated volunteers. Subsequent studies indicated that purified HCV E2 has an immunoregulatory role and biases primary macrophage activation toward the M2 phenotype (via E2-CD81 interactions), impairs DC/CD4+T cell functions, and leads to an environment for a muted response to antigen. Nevertheless, HCV E2 still contains strong cross-genotype specific B- and T-cell epitopes vital to an active immunity. We hypothesize that modifying E2 by discrete point mutations to inhibit interaction with CD81 will improve immune functions and induce robust protective responses in combination with other HCV regions as candidate vaccine, and will generate stronger protective efficacy. Outstanding abilities of nucleoside modified mRNA-lipid nanoparticle (LNP) to elicit potent immune responses against pathogens makes it a viable new cost-effective platform for vaccine development. The incorporation of modified nucleosides in the mRNA will offer advantages for generation of modified antigens to induce a broad effective immune response. The premise and rigor of the study stems from our own work, and information in the literature. Thus, the use of nanoparticle encapsulated mRNA of modified E2 for stronger immunogenicity together with other viral antigens (E1 and non-structural (NS) genomic regions) for prime and boost with proteins/peptides as a candidate vaccine for HCV cross protective efficacy will generate robust B- and T- cell responses for protection against HCV. The results from our study will advance vaccine development against persistent HCV infection.

摘要