Toll-like receptor (TLR)-7 agonist stimulates interferon-alfa to activate both innate and adaptive immune response. Early data of vesatolimod showed dose-related cytokine and interferon stimulated gene induction. A phase 2 study in untreated patients failed to show any significant HBsAg decline with 12-week course of vesatolimod and tenofovir disoproxil fumarate (TDF) combination. Other newer TLR-7 agonists are still under early clinical development. TLR-8 agonist also induces both innate and adaptive immune system, but through a broader spectrum of immune cells and cytokines including interleukin-12, tumor necrosis factor alfa and interferon-gamma. Phase 2 study of selgantolimod in combination with nucleos(t)ide analogue in virologically suppressed patients showed mild decline of HBsAg in up to 20% of patients after 24 weeks of treatment. Various therapeutic vaccines have been developed based on HBV antigens at X, core, and/or S region to stimulate T-cell response against HBV. Most clinical trials are conducted among virologically suppressed patients. Unfortunately, only minor reduction in HBsAg could be demonstrated with therapeutic vaccines treatment in early phase studies. Retinoic acid inducible protein (RIG-I) agonist has dual effect against HBV polymerase and immune modulation on type III interferon. Phase 1 study on inarigivir showed dose-dependent HBV DNA reduction and HBV RNA reduction after 12-week treatment, and 26% of patients had HBsAg reduction of >0.5 log IU/ml. However, occurrence of unexpected adverse event was found in a phase 2 study and the development of inarigivir in chronic hepatitis B was aborted. Checkpoint inhibitors have been used to rescue T-cells to kill tumor cells in oncology patients. A phase 1 study using low dose nivolumab, a monoclonal antibody blocking PD1, has shown HBsAg decline in virologically suppressed patients with a single patients clearing HBsAg. Newer formula of PD1 and PD L1 blockade using GalNac targeting are under development for liver-specific therapeutic effect against HBV.