Nature communicationsJun 18, 2026

A two-part mRNA vaccine designed to help the immune system control chronic hepatitis B

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 19, 2026

Abstract

The dual-antigen mRNA vaccine combining preS1 and HBsAg leads to near-complete viral genome clearance in chronic hepatitis B mouse models.

The preS1-HBsAg combination was identified as the optimal pairing for inducing immune responses against hepatitis B.
Robust HBV-specific immune responses were elicited, resulting in a significant reduction of multiple HBV antigens.
preS1 was found to be the primary driver of T cell responses specific to HBV.
HBsAg contributed to anti-HBsAg seroconversion and enhanced immune cell activation.
When combined with interferon-α, the preS1-HBsAg vaccine improved antiviral effectiveness and immune memory without compromising safety.

Simplified

Therapeutic vaccination for chronic hepatitis B (CHB) remains challenging, as persistent immune tolerance to hepatitis B surface antigen (HBsAg) impedes anti-HBsAg seroconversion. Here we show that screening antigen combinations incorporating HBsAg identifies preS1-HBsAg as the optimal pairing. The resulting dual-antigen mRNA vaccine elicits robust hepatitis B virus (HBV)-specific immune responses in chronic HBV mouse models, leading to near-complete viral genome clearance, marked reduction of multiple HBV antigens, and serological conversion. Mechanistic analyses reveal that preS1 serves as the primary driver of HBV-specific T cell responses, while HBsAg contributes to both anti-HBsAg seroconversion and intrinsic adjuvant activity. Specifically, when delivered in mRNA form, HBsAg promotes antigen-presenting cell (APC) activation, enhances antigen presentation, and amplifies preS1-specific CD8⁺ T cell responses. Furthermore, combining the preS1-HBsAg vaccine with interferon-α (IFN-α) enhances antiviral efficacy and immune memory while maintaining a favorable safety profile. These findings establish preS1-HBsAg mRNA vaccination as a promising and translatable therapeutic strategy for functional cure of CHB.

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A two-part mRNA vaccine designed to help the immune system control chronic hepatitis B

Abstract

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