Alternating Arenavirus Vector Immunization Generates Robust Polyfunctional Genotype Cross-Reactive Hepatitis B...

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Hepatitis B Virus (HBV) infection is a leading cause of global mortality, necessitating curative therapies.
• Current treatments are insufficient, highlighting the need for strategies that induce immune-mediated viral clearance.
• Effective cure requires both CD8 T cell-mediated clearance of infected hepatocytes and anti-hepatitis B surface antigen (HBsAg) antibodies for viral neutralization.

Purpose of the Study:

• To develop and evaluate a novel therapeutic vaccine strategy for Hepatitis B Virus (HBV) using non-replicating arenavirus vectors.
• To identify HBV antigens that elicit conserved and robust T cell responses across different genotypes.
• To assess the efficacy of alternating immunizations with two distinct arenavirus vectors in preclinical models.

Main Methods:

• Development of recombinant Pichinde virus (PICV, GS-2829) and replication-incompetent lymphocytic choriomeningitis virus (LCMV, GS-6779) vectors encoding selected HBV antigens.
• Screening of antigens for genotype conservation and T cell response magnitude and reactivity.
• Immunization of macaques to optimize dose schedules and assess T cell polyfunctionality and anti-HBs titers.
• Evaluation of vaccine efficacy in AAV-HBV mouse models with low pre-treatment serum HBsAg levels.

Main Results:

• Alternating immunizations with GS-2829 and GS-6779 successfully induced high-magnitude HBV-specific T cell responses and high titers of anti-HBs antibodies.
• Dose schedule optimization in macaques resulted in strong polyfunctional CD8 T cell responses targeting HBV core, HBsAg, and polymerase antigens.
• The therapeutic vaccines (GS-2829 and GS-6779) demonstrated efficacy in clearing HBV in AAV-HBV mice with low baseline HBsAg levels.

Conclusions:

• The novel arenavirus-based therapeutic vaccines (GS-2829 and GS-6779) effectively induce robust HBV-specific cellular and humoral immune responses.
• These vaccines show potential as a core component of future curative regimens for chronic Hepatitis B Virus infection.
• Further development of these therapeutic vaccines is warranted based on their promising preclinical efficacy.