Hepatitis B Virus is a major driver of infectious disease mortality. Curative therapies are needed and ideally should induce CD8 T cell-mediated clearance of infected hepatocytes plus anti-surface antigen antibodies (anti-HBs) to neutralize residual virus. We developed a novel therapeutic vaccine using non-replicating arenavirus vectors. Antigens were screened for genotype conservation and magnitude and genotype reactivity of T cell response, then cloned into Pichinde virus vectors (rPICV, GS-2829) and lymphocytic choriomeningitis virus vectors (rLCMV, GS-6779). Alternating immunizations with rPICV and rLCMV induced high magnitude HBV T cell responses, with PICV vectors driving high anti-HBs titers. Dose schedule optimization in macaques achieved strong polyfunctional CD8 T cell responses with balanced specificity for core, HBsAg, and polymerase and high titer anti-HBs. In AAV-HBV mice, GS-2829 and GS-6779 were efficacious in animals with low pre-treatment serum HBsAg. Based on these results, GS-2829 and GS-6779 could become central components of cure regimens.© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
