Highlights
- PreS1 antigen concentrations correlate positively with HBV replication markers and are highest in HBeAg-positive chronic hepatitis B patients.
- Anti-preS1 IgG antibodies are detectable throughout disease phases and inversely correlate with viral loads, indicating an endogenous immune response linked to viral control.
- Sera characterized by low preS1 antigen and high anti-preS1 IgG exhibit potent neutralising capacity against HBV and HDV through inhibition of viral entry and blockade of preS1-NTCP interaction.
- High baseline anti-preS1 IgG levels predict sustained virological suppression following nucleos(t)ide analogue therapy withdrawal, suggesting a functional biomarker for personalized treatment strategies.
Background
Chronic hepatitis B virus (HBV) infection remains a worldwide health challenge, with over 296 million people chronically infected and at risk of cirrhosis, hepatocellular carcinoma (HCC), and liver failure. Despite effective antiviral nucleos(t)ide analogue (NUC) therapies, functional cure—defined as HBsAg loss with sustained viral suppression—is rarely achieved. The HBV large surface antigen (L-HBsAg) comprises the preS1, preS2, and S domains, with the preS1 region playing a pivotal role in viral entry by binding the hepatocyte receptor sodium taurocholate cotransporting polypeptide (NTCP). Understanding the serological dynamics and functional roles of circulating preS1 antigen and corresponding antibodies may reveal novel biomarkers of viral control and targets for immunotherapeutic intervention.
Key Content
Serological Characterisation of preS1 Antigen and anti-preS1 IgG Across Chronic HBV Infection
The study by Wang et al. (2026) used novel ELISA assays to quantify serum preS1 antigen and anti-preS1 IgG in a large cohort including 549 chronic HBV-infected individuals, 107 functionally cured patients, and 110 vaccinated healthy controls. Results demonstrated that preS1 antigen levels were significantly elevated in HBeAg-positive patients, correlating strongly with HBV DNA, HBsAg, and HBeAg titers. This reflects active viral replication and antigen secretion. Conversely, anti-preS1 IgG was present in all clinical phases, albeit at variable levels, showing a strong inverse correlation with HBV DNA, suggesting that these antibodies may arise as part of the host’s immune response to control viral replication. Furthermore, anti-preS1 IgG levels positively correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers of hepatic inflammation, indicating immune activation concurrent with antibody production.
Interestingly, anti-preS1 IgG remained detectable in a subset of individuals achieving functional cure, implying persistence of these antibodies may contribute to or reflect long-term viral control.
Functional Neutralising Activity of Anti-preS1 Antibodies
Neutralisation assays using in vitro models of HBV and hepatitis D virus (HDV) infection revealed that sera with low preS1 antigenaemia but high anti-preS1 IgG effectively inhibited viral entry. Mechanistically, the antibodies competitively blocked preS1 binding to NTCP on hepatocytes, a critical step governing HBV/HDV infection. Peptide microarray epitope mapping localized dominant linear antibody epitopes within the preS1 domain essential for NTCP interaction, underscoring their functional relevance.
These results affirm that anti-preS1 IgG antibodies have potent neutralising capabilities, not merely serving as serological markers but as effectors in preventing viral spread.
Clinical Relevance and Predictive Value for Treatment Discontinuation
A significant translational insight arose from analyzing 51 patients discontinuing NUC therapy. Those with higher baseline anti-preS1 IgG levels demonstrated a greater probability of sustained virological suppression off-therapy. This suggests that quantification of anti-preS1 IgG could serve as a predictive biomarker to guide safe NUC withdrawal, potentially reducing the risk of viral relapse.
Such biomarkers are urgently needed to personalize treatment duration and improve functional cure rates, given that indefinite antiviral therapy carries burden and cost.
Integration with Prior Literature and Guidelines
Previous studies established the importance of preS1 in HBV entry and as a vaccine target component; however, serological profiling of endogenous anti-preS1 antibodies in chronic infection has been limited. This study by Wang et al. bridges this gap by combining quantitative serology with functional assays and clinical correlates. Current HBV management guidelines (e.g., EASL 2017, AASLD 2018) recommend monitoring viral replication and serum markers but do not yet incorporate anti-preS1 antibody testing. The evidence presented justifies further incorporation of such immunological markers in HBV management algorithms.
Expert Commentary
The demonstration of functionally active anti-preS1 antibodies in chronic HBV provides compelling evidence for their role as endogenous viral neutralisers. Unlike neutralising antibodies targeting the small HBsAg domain, anti-preS1 IgG targets the entry mechanism at the receptor-binding interface, a critical vulnerability of HBV and HDV.
While high preS1 antigenaemia reflects active replication, the rise of anti-preS1 IgG signifies host immune engagement. The inverse correlation of anti-preS1 IgG with viral load and its predictive capacity for post-NUC viral suppression highlight its potential utility as a biomarker.
Nevertheless, limitations include the observational nature of the study and the need for validation in diverse populations and clinical settings. Future research should explore whether therapeutic vaccination or passive immunisation to boost anti-preS1 antibodies can enhance functional cure rates.
The translational impact is notable, as measuring anti-preS1 IgG may refine patient stratification for treatment cessation and provide a surrogate marker for immune control, facilitating more personalized, immunologically informed management of chronic hepatitis B.
Conclusion
The evolving landscape of chronic hepatitis B management benefits from insights into host-virus interactions at the molecular and immunological levels. Wang and colleagues’ work elucidates distinct serological patterns of circulating preS1 antigen and anti-preS1 IgG, correlating with viral load, liver inflammation, and functional cure states.
Functionally, anti-preS1 IgG antibodies exert potent neutralising activity by blocking preS1-NTCP interaction, preventing viral entry and propagation. Their presence and concentration may inform prognosis and guide antiviral therapy discontinuation safely.
Overall, this research expands understanding of endogenous immune responses in chronic hepatitis B and unveils promising biomarkers for viral control and treatment stratification, paving the way for novel immunotherapeutic approaches and precision medicine in HBV infection.
References
- Wang B, Li Y, Li F, Feng Y, Hao M, Hua T, Wu M, He M, Luo F, Lu M, Wang Q, Zhang J, Yuan Z, Zhang M, Chen J. Functional anti-preS1 antibody responses associated with viral control in chronic hepatitis B. Gut. 2026 Jun 22. PMID: 42331615. https://pubmed.ncbi.nlm.nih.gov/42331615/
- European Association for the Study of the Liver (EASL). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. PMID: 28427875.
- Terrault NA, Lok ASF, McMahon BJ, et al. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology. 2018 Apr;67(4):1560-1599. PMID: 29427912.
- Xia Y, Chen DS. The molecular biology of HBV preS/S proteins and viral entry. J Viral Hepat. 2011 May;18(5):261-275. PMID: 20961393.
