Preclinical development of a prophylactic genotype 1A/1B consensus hepatitis C virus DNA vaccine

Brian Paul Latimer

doi:10.17918/00008526

Chronic hepatitis C virus (HCV) infections can progress to liver cirrhosis and hepatocellular carcinoma. Currently, 170-185 million individuals are infected, and 3-4 million new infections occur annually. Medications are too costly to meaningfully control HCV. Vaccination is the most cost-effective means to control disease. However, an effective HCV vaccine remains an unmet need. A prophylactic HCV vaccine is necessary to impact HCV-associated disease burden globally. Because a minority of acute infections resolve spontaneously, a prophylactic vaccine strategy is feasible. Viral clearance is associated with early, strong, and durable CD4+ and cytolytic CD8+ T cell responses that are broadly reactive to multiple nonstructural viral proteins. These correlates of acute resolution have provided immunological benchmarks for vaccine development. To address an urgent need, we have formulated a prophylactic HCV DNA vaccine candidate designed to achieve acute resolution immune correlates. Our vaccine encodes four synthetic consensus nonstructural antigens of genotype 1a/1b HCV, which maximizes the opportunity to mount a broadly reactive HCVspecific T cell response. In both mice and Rhesus macaques, immunization followed by in vivo electroporation elicited broadly reactive HCV-specific CD4+ and CD8+ T cells. In mice, durable memory T cells demonstrated rapid recall and functional killing of antigen-expressing hepatocytes in vivo. In Rhesus macaques, immunization induced cytolytic CD8+ T cells, and HCV-specific T cells exhibiting phenotypes associated with immune memory. Additionally, our collaborators at lnovio Pharmaceuticals have initiated a Phase I clinical trial to test our HCV vaccine candidate for safety, tolerability, and immunogenicity in human volunteers. Taken together, we are the first to (1) formulate a multi-antigenic HCV DNA vaccine candidate using consensus antigens to combat the genetic diversity of HCV, (2) deliver our HCV DNA vaccine candidate using the CELLECTRA® 2000 in vivo electroporation device, which has been extensively tested in clinical studies, (3) demonstrate strong DNA vaccine-induced T cell responses reactive to multiple HCV antigens, (4) establish an animal model with chronic hepatocyterestricted expression of an HCV antigen, (5) demonstrate a self-limiting recall of HCV DNA vaccine-induced memory T cells that rapidly killed antigen-expressing hepatocytes, and (6) achieve acute resolution correlates with our vaccine candidate in non-human primates.

Preclinical development of a prophylactic genotype 1A/1B consensus hepatitis C virus DNA vaccine

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Preclinical development of a prophylactic genotype 1A/1B consensus hepatitis C virus DNA vaccine

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