Abstract
Hepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suited for vaccines. Therefore, we have designed an E2 protein in which we strategically changed eight cysteines to alanines (E2.C8A). E2.C8A formed predominantly monomers and virtually no aggregates. Furthermore, E2.C8A also interacted more efficiently with broadly neutralizing antibodies than conventional E2. We used mice to evaluate different prime/boost immunization strategies involving a modified vaccinia virus Ankara (MVA) expressing the nearly full-length genome of HCV (MVA-HCV) in combination with either the E2 aggregates or the E2.C8A monomers. The combined MVA-HCV/E2 aggregates prime/boost strategy markedly enhanced HCV-specific effector memory CD4+ T cell responses and antibody levels compared to MVA-HCV/MVA-HCV. Moreover, the aggregated form of E2 induced higher levels of anti-E2 antibodies in vaccinated mice than E2.C8A monomers. These antibodies were cross-reactive and mainly of the IgG1 isotype. Our findings revealed how two E2 viral proteins that differ in their capacity to form aggregates are able to enhance to different extent the HCV-specific cellular and humoral immune responses, either alone or in combination with MVA-HCV. These combined protocols of MVA-HCV/E2 could serve as a basis for the development of a more effective HCV vaccine.
Highlights
Hepatitis C virus (HCV) is a mayor public health problem, with an estimated 71 million people chronically infected and approximately 400,000 annual deaths
We generated two E2 variants to evaluate the impact of the 8 cysteine residues substitutions in their in vitro properties and in vivo immunogenicity
We generated E2MPER protein, which encompasses the complete ectodomain of E2, including the flexible stem region [52] and the hydrophobic MPER
Summary
Hepatitis C virus (HCV) is a mayor public health problem, with an estimated 71 million people chronically infected and approximately 400,000 annual deaths. Vaccines 2020, 8, 440 adopted in 2016 the first-ever global hepatitis strategy, setting 2030 as a deadline to eliminate HCV as a public health threat by reducing new infections by 90% and mortality by 65% [1]. It will be necessary to greatly improve screening programs, surveillance, HCV tests, infection control measures, and rapidly scale up the coverage of HCV treatment. Assuming these interventions would be successful, the total costs of such an effort are around US$ 11.9 billion for the period 2016-21 alone [2]. Vaccination is a proven method for infection prevention and an effective, accessible, and affordable vaccine is probably needed to eliminate HCV as a health threat by 2030 [1]
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