Therapeutic nucleic acid vaccine for chronic hepatitis B in HIV/HBV co-infected individuals

PROJECT SUMMARY Over 300 million people are living with chronic hepatitis B virus infections (CHB) across the world with an estimated 1.5 million new HBV infections and 800,000 deaths per year. CHB often leads to chronic cirrhosis, end stage liver disease, and hepatocellular carcinomas. CHB remains the leading cause of end-stage liver disease and liver cancer especially among HIV infected individuals co-infected with HBV due to persistent immune dysfunction caused by both infections. Currently licensed non-nucleic acid prophylactic HBV vaccines are not effective therapeutically (i.e., they do not provide a functional cure for persons with CHB). A functional cure for persons with CHB is highly desired and it is generally believed that immunotherapies including therapeutic vaccines hold great promise for a functional cure. Nucleic acid (NA) vaccines, including RNA and DNA, emerged as leading vaccine strategies during the COVID-19 pandemic, and they are now showing significant promise as therapeutic vaccines for chronic viral infections and cancers due to their ability to overcome immune dysfunction and tolerance and their capacity to induce neutralizing antibody and CD8+ T cell responses. Orlance has developed a next-generation gene gun called MACH-1TM, that delivers room temperature stable DNA and RNA vaccines. MACH-1 efficiently delivers DNA and RNA directly into the cells of the highly immunocompetent epidermis, leading to robust immune responses with substantially lower doses than other DNA or RNA delivery technologies. We and others have also found that immunizing the epidermis elicits both systemic immunity and tissue resident T cell responses that we hypothesize could provide more effective targeting of persistent HBV viral reservoirs in the liver. Early clinical trials of a prophylactic HBV DNA vaccine delivered by a predecessor of the MACH-1 induced strong T cell responses and protective levels of antibodies in vaccinated humans. Studies in our lab have also shown that gene gun delivery of a therapeutic HIV DNA vaccine in SIV-infected macaques induces strong polyfunctional T cell responses. When formulated with novel genetic adjuvants, this vaccine was also highly effective in the induction of tissue resident CD8+ T cell responses that correlated with a reduction of the viral reservoir. These results support the feasibility of developing a MACH- 1 delivered NA vaccine for treatment of CHB in HIV-infected and non-infected individuals. Under this phase I STTR, our goal is to optimize the immunogenicity of a MACH-1 adjuvanted NA (DNA or RNA) HBV vaccine. We will first compare MACH-1 delivered DNA and RNA with and without genetic adjuvants for the ability to induce systemic and liver-resident B and T cells (Aim 1). The lead formulations from this study will then be compared to a currently marketed HBV vaccine and to licensed LNP-delivered mRNA and self-amplifying RNA vaccine delivery platforms in mice to determine if MACH-1 delivery offers advantages (Aim 2). If successful, these studies will support advancing our lead approach to testing in HBV-infected macaques with and without SIV co-infection in a future phase II STTR.