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Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. However, little is known about pre-treatment HBsAg levels as an indicator of HBV immune potential. Here, we compared the phenotypes and HBV-specific response of lymphocytes in CHB patients stratified by serum HBsAg levels <500 (HBs^lo) or >50,000 IU/ml (HBs^hi) using immunological assays (flow cytometry, ICS, ELISPOT). HBs^hi patients had significantly higher expression of inhibitory PD-1 on CD4⁺ T cells, particularly among TEMRA subset, and higher FcRL5 expression on B cells. Upon HBcAg(core) or HBsAg(env)-stimulation, 85% and 60% of HBs^lo patients had IFNγ⁺TNFα⁺ and IFNγ⁺ IL2⁺ CD4⁺ T cell responses respectively, in …