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Principal Investigator: Amit Kapoor
Organization: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
Fiscal Year: 2024
Award: $614,828
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Although direct acting antivirals can cure Hepatitis C virus (HCV) infection, a vaccine is necessary to stop new
infections, and to prevent re-infections in the cured individuals. Studies in humans and chimpanzees suggest
that both T cells and neutralizing antibodies (nAb) can play an important role in the clearance of HCV infection.
However, further progress on HCV vaccine development has been stymied by a lack of animal models. Notably,
the nature, breadth, and relative contribution of humoral and cellular immunity in determining the outcomes
of HCV infection remain poorly understood. We recently showed that a rat hepacivirus (HCV-like virus),
RHV, shares the hallmarks of HCV infection and immunity. A majority of fully-immunocompetent rats develop
lifelong viral persistence, and thus rats are appropriate models for “proof-of-concept” vaccination studies to
prevent HCV- like viral persistence, the desired goal of HCV vaccines. We further validated this model by
determining that like reported from HCV studies in chimpanzees, rats vaccinated using an Adenovirus
expressing RHV non-structural (NS) proteins develop partial protection against persistence of a
homologous RHV strain (Nature communications, PMC6405742). Interestingly, we observed that the
vaccinated rats that cleared a homologous virus developed more efficient and broader immunity for
homologous and heterologous viruses, and T cell escape variants. These results suggest that the short-
term viral infection either enhances T cell immunity or generates nAbs, or both, to confer effective immunity
against heterologous viruses. Most importantly, these results are promising for defining the nature of
immunity that confers effective protection against persistent infection of genetically diverse viruses, like HCV
variants. The overall goal of this project is to define the immune correlates of protection against hepacivirus
persistence. Specific aim-1 is to define the T cell correlates of protection against hepacivirus persistence.
Our hypothesis is that the nature and breadth of virus-specific T cells determines the fate of hepacivirus
infections. Specific aim-2 is to study the role of envelope proteins (E1/E2) induced immunity and importance
of nAbs in virus clearance. Our hypothesis is that a vaccination approach using a combination of NS and
E1E2 vaccines will increase the immunity against viral persistence. Specific Aim- 3 is to define the breadth of
vaccine induced immunity, and to identify the viral determinants of vaccine failure. Our hypothesis is that
vaccination can prevent persistence of genetically diverse viruses that share only a few T cell epitopes. The
proposed dissection of vaccine and short-term viral infection conferred immunity is necessary to understand
the relative contributions of T and B cells in hepacivirus clearance, and this knowledge can help in
conceptualizing an effective vaccination strategy for HCV. Finally, the proposed characterization of T and B
cell immunity in this unique model of life-long persistent RNA virus infection will pave the way for testing of newer
vaccination approaches (like RNA vaccines) to prevent chronic virus infection.
Terms: <Acceleration><Ad vector><Address><Adenoviral Vector><Adenoviridae><Adenovirus Vector><Adenoviruses><Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Antigens><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological Assay><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Mediated Immunology><Cell surface><Cell-Mediated Immunity><Cellular Immunity><Chimp><Chimpanzee><Chronic><Common Rat Strains><Communication><Data><Dissection><E1 protein><Envelope Protein><Epitope Mapping><Escape Mutant><Failure><Future><Genetic Diversity><Genetic Variation><Goals><HCV><HCV Vaccine><HCV infection><HPV-16 E1 protein><HPV16 E1 protein><Hepacivirus><Hepatitis C><Hepatitis C Vaccine><Hepatitis C virus><Hepatitis C virus infection><Hepatitis C-Like Viruses><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Human><Human papilloma virus 16 E1 protein><Human papillomavirus 16 E1 protein><Humoral Immunities><Immune><Immunes><Immunity><Immunocompetent><Individual><Infection><Knowledge><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nature><Non-structural Protein><Nonstructural Protein><Outcome><Pan Genus><Pan Species><Paper><Phenotype><Play><Proteins><RNA Virus Infections><RNA vaccine><RNA viral infection><RNA-based vaccine><Rat><Rats Mammals><Rattus><Reporting><Rodent><Rodentia><Rodents Mammals><Role><Staining method><Stains><Structural Protein><T-Cell Depletion><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Vaccinated><Vaccination><Vaccination acquired immunity><Vaccination induced immunity><Vaccines><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><adeno vector><adenovector><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody-based immunity><cell killing><chronic infection><cytokine><develop a vaccine><develop vaccines><development of a vaccine><env Antigens><env Gene Products><env Polyproteins><env Protein><experiment><experimental research><experimental study><experiments><global gene expression><global transcription profile><hep C><hepatitis C virus vaccine><hepatitis non A non B><immune competent><immunization strategy><immunogen><in vivo><infection by hepatitis c virus><innovate><innovation><innovative><insight><mRNA vaccine><mRNA-based vaccine><model of animal><neutralizing antibody><non A, non B hepatitis><non-A, non-B hepatitis><novel><persistent infection><prevent><preventing><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><transcriptome><vaccination strategy><vaccination study><vaccination trial><vaccine acquired immunity><vaccine associated immunity><vaccine development><vaccine failure><vaccine study><vaccine trial><vaccine-induced immunity><vaccine-induced protection><viral infection><virus infection><virus-induced disease>