Table 2. Host factors.

Factors	Targets	Results	Ref.
Innate immunity
PRRs (TLRs)	TLR-7 agonist: GS-9620	Suppression of HBV DNA in both serum and liver of HBV-infected chimpanzees; induction of IFN-α and cytokines Phase I trials in CHB patients	Animal study: [124] Phase I study in healthy volunteers: [125] Phase I trials in CHB (completed) [126,127]
Cytokines	IL-7 Recombinant human IL-7 (rhIL-7)-CYT 107 IL-21 Recombinant IL-21	Preclinical data: Immunorestorative and vaccine adjuvant effect Phase I-II clinical trial on CHB patients ongoing Possible immunorestorative effect when used in combination with antivirals	Small animal study (LCMV mice): [128,129] Small animal study (LCMV mice): [134–135,137]
Adaptive immunity
Inhibitory T lymphocytes	PD-1/PD-L1	Blockade of PD-1/PD-L1 interaction leading to restoration of T-cell function	Small animal study (LCMV mice): [146] Wood chucks (WHV infected): [153,154]
Humoral & adaptive immunity
Therapeutic vaccination	Immunogenic complexes: HBsAg with anti-HBs immunoglobulin)	Priming of HBV-specific CD8+ CTL responses	Clinical trial: [165] Phase 11 b clinical trial: [164] Phase III clinical trial: [166]
	HBsAg and HBcAg Combination: NASVAC	Recombinant HBcAg act as potent Th1 adjuvant to HBsAg and strong immunogen Phase I clinical trial in HVs demonstrated safety and immunologic efficacy Phase III clinical trial is on going in CHB patients	Phase I clinical trial: [169] Phase III clinical trial: [170]
	Whole recombinant yeast- based therapeutic vaccine: tarmogens: GS-4774 (formerly GI-13020)	Antigen-specific T-cell responses; tarmogens elicited HBV-specific T-cell responses ex vivo in samples collected from HVs and donors with CHB; induce both CD4+ and CD8+ T-cell responses in ex vivo model; induce HBV-specific T-cell response	[172,183] Phase I trial in HV completed: [184] Phase II trial in CHB patients: [185]
	Adenovirus-based therapeutic vaccination TG1050	Stimulate polyfunctional, multispecific, robust and long-lasting T cells targeting multiple epitopes from three major viral proteins, expected to control the HBV replication and to elicit viral clearance	[173]
	DNA vaccines	Activate not only the T-cell responses specific to HBV but also natural killer cells	Phase I clinical trial: [175] Proof-of-concept study/CHB carriers: [176]
	T-cell peptide epitope vaccine	String of 30 HBV-derived CTL epitopes linked to 16 Th epitopes presented to T cells by a large number of HLA molecules	Mouse model: [177]

AASLD: American Association for the Study of Liver Diseases; anti-HBs: Hepatitis B surface antibody; CHB: Chronic hepatitis B; CTL: Cytotoxic T lymphocyte; HBcAg: Hepatitis B core antigen; HBsAg: Hepatitis B surface antigen; HV: Healthy volunteer; LCMV:lymphocytic choriomeningitis virus; NASVAC: Nasal HBV vaccine candidate; PD1/PD-L1: Programmed death-1/Programmed death-ligand 1; PRR: Pattern recognition receptor; Th: T helper; TLR: Toll-like receptor.