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Principal Investigator: Ranjit Ray
Organization: SAINT LOUIS UNIVERSITY
Fiscal Year: 2022
Award: $340,875
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
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