Therapeutic HBV vaccine efficacy through ancestral mismatched T cell epitopes

Abstract Therapeutic vaccines for the treatment of chronic viral infections, such as HBV, have been mainly designed to target conserved viral regions and to preferentially restore dysfunctional virus-specific CD8 T cells. Such vaccines have failed to deliver clinical benefit, but a recent trial combining siRNA Elabsiran and PEG-IFN-α reported a remarkable ~50% HBsAg loss rate in chronic HBV patients who responded to the therapeutic vaccine BRII-179 administered prior to the trial. To define the underlying immunological mechanisms leading to the increased HBsAg loss rate, we longitudinally characterized vaccine-induced T and B cell responses using functional assays, persistence tracking, epitope mapping, phenotyping, and analysis of vaccine and infecting HBV sequences. We found that BRII-179-mediated modulation of HBV-specific immunity did not result from recovery of pre-existing dysfunctional T cells. Instead, the vaccine primed novel IL-2-producing CD4⁺ T cells targeting epitopes that were largely mismatched to patients’ infecting HBV strains. These responses were driven by a PreS1 N-terminal domain sequence within the vaccine’s large S protein that shows high homology to HBV genotype G—a rare genotype thought to represent a remnant of an extinct prehistoric HBV lineage. These vaccine-induced CD4⁺ T cells were detected in most vaccinated patients across diverse HLA class II backgrounds and persisted with stable functionality for more than two years. Despite their lack of cross-reactivity with contemporary HBV genotypes, the presence of these epitope-mismatched CD4⁺ T cells was associated with marked, progressive maturation of HBs-specific B cells during PEG-IFN-α/siRNA treatment, consistent with intramolecular T cell help. We conclude that the ability of BRII-179 to increase HBsAg loss is associated with the expansion of epitope-mismatched CD4⁺ T cells that promote HBs-specific B cell maturation during PEG-IFN-α treatment. These findings challenge current therapeutic vaccine strategies focused on conserved viral regions and CD8⁺ T cell responses, and suggest that ancestral HBV epitopes lost during viral evolution may represent potent targets for inducing therapeutically effective antiviral immunity.