PROJECT SUMMARY Chronic infection with hepatitis B virus (HBV) is a major global problem affecting an estimated 300 million people. HBV-induced immune-mediated progressive liver injury and primary liver cancer led to a WHO-estimated 820,000 deaths in 2019. While clearance of the HBV surface antigen (HBsAg) defines clinical cure and reduces all disease-associated risks, HBsAg clearance is rarely observed and remains therapeutically elusive. As such, there remains a clear and urgent need for finite therapies that safely induce HBsAg clearance, at least in a significant subset of CHB patients. Our mouse models of human HBV reliably mimic HBsAg clearance and persistence in humans. Our published work demonstrates that immune priming to HBV occurs in the liver, and strongly implicate the competency of immune priming in the hepatic environment as a pivotal event that safely promotes HBV-specific T cell diversity and HBsAg clearance. In clinical studies, including here in the United States led by Drs Baron and Cooper (“BeNEG-DO”), CHB patients that stop standard antiviral therapy with nucleos(t)ide analogs after at least 3.7 years of treatment all experience virologic relapse and, in a highly statistically significant subset, remarkably, this HBV re-priming event triggers HBsAg clearance (clinical cure). Liver and longitudinal samples from study patients who clear or fail to clear HBsAg offer an unprecedented opportunity to study immune mechanisms underlying HBsAg clearance and the mechanistic parallels in the mouse model. The Baron/Cooper/Schwartz laboratories at UCSF, CPMC, and Weill Cornell have begun a collaboration to uncover these parallels using a multi-omic approach to identify immune priming mechanisms that facilitate HBsAg clearance in CHB. The complementary suite of studies we propose has strong potential to advance mechanistic understanding of HBsAg clearance, identify new biomarkers with clinical utility, and lead to new treatments for CHB.

NARRATIVE Hepatitis B virus (HBV) remains a major global pathogen and health challenge, and a leading cause of liver disease and liver cancer worldwide; meanwhile, current antiviral therapies (AVT) can suppress but rarely cure infection, emphasizing the need for fresh approaches. We proposed and tested a new approach that demonstrates a clinical cure in a subset of patients with chronic HBV. We now propose to use liver and blood samples from these cured patients, together with samples from a mouse model of HBV, to identify mechanisms that lead to HBV cure.