Table 2.

Immunotherapeutic trials for chronic hepatitis B virus infection in humans

Immunotherapy	Results	Ref.
Peptide vaccination
A vaccine with HBc18-27 peptide comprised of a T-helper cell epitope and two palmitic acid residues	Low levels of CTL activity were induced but no significant changes in liver biochemistry or viral serology were observed	[52]
Protein vaccination
PreS2/S (GenHevac B) or S (Recombivax)	HBe/anti-HBe seroconversion in 13% and HBV DNA negativity in 16% of the treated patients	[53]
Intradermal HBsAg vaccine and laimvudine in combination with IL-2	Induction of significant HBV DNA loss in the serum in two of five the treated patients	[54]
Oral administration of HBV envelope proteins (HBsAg + preS1 + preS2)	Induction of histological improvement in 30%, HBeAg negativity in 26.3% and HBsAg-specific T cell proliferation in 78% of the treated patients	[55]
IFN-α-2b monotherapy (9 mo) or IFN-α-2b plus pre-S2/S vaccine	Greater reduction in HBV DNA in patients with combination HBV therapy than those who received IFN-α-2b monotherapy	[56]
The combination with lamivudune and HBsAg vaccine in HBeAg+ cases	No improvement of HBe seroconversion rate in comparison with lamivudine therapy alone	[57]
Combination of lamivudine and HBsAg vaccine	Induction of sustained negativity of HBV DNA in 1/4 of patients	[58]
Combination of lamivudine and HBsAg vaccine	HBV DNA became undetectable in 64% of the patients, and was decreased in the remaining patients	[59]
DNA immunization
DNA vaccine encoding HBV envelope protein	Induction of an increase in HBV-specific IFN-γ-secreting T cells in nonresponders to conventional therapies, and HBV DNA levels were transiently decreased in 50% of vaccinated patients	[60]
DNA vaccine encoding PreS and S in patients with lamivudine breakthrough	Development of IFN-γ-producing T cells specific for preS or S antigen; Two of 10 patients showed seroconversion to anti-HBe	[61]
DC immunization
Peripheral blood-derived DCs, activated with GM-CSF and IL-4 pulsed with HBsAg	Both patients with normal and elevated ALT responded equally to DC vaccine and 53% of the patients showed induction of HBeAg negativity	[62]
Activated DCs from PBL with GM-CSF and IL-4, pulsed with two peptides, HBc18-27 and PreS2 44-53	Undetectable HBV DNA was achieved in 46.3% and 3.1% of HBeAg- and HBeAg+ patients, respectively. ALT normalization was observed in 69% and 30.5% of HBeAg- and HBeAg+ patients, respectively	[63]
Cytokines
GM-CSF	Safe and tolerable up to 1.0 μg/kg body weight, and induced HBV DNA negativity in 4/8 patients	[64]
Combination therapy with GM-CSF and HBsAg vaccine in HBV carrier children	Significant reduction of serum HBV DNA	[65]
High dose of IL-12 (0.5 μg/kg)	HBV DNA clearance was observed in 25% of the patients	[66]
Combination of IL-12 and lamivudine	Stimulation of T cell response to HBV with IFN-γ production. However, IL-12 was unable to suppress re-elevation of HBV DNA after cessation of lamivudine	[67]
Combination of IL-12 and IL-18	Stimulation of IFN-γ production by CD4+ T cells isolated from peripheral blood in response to HBcAg, and the effect was greater than those observed with either cytokine alone	[68]
α-galactosylceramide	Poorly tolerated and showed no clear suppressive effect on serum HBV DNA or ALT levels	[69]
Tα1
Combination of Tα1 and IFN-α	No statistically significant differences as compared with IFN-α monotherapy with respect to HBeAg seroconversion, changes in histology, normalization of ALT or loss of HBV DNA	[70]
Tα1 alone	At 12 mo after cessation of therapy, 36.4% of patients treated with 1.6 mg of Tα1 achieved ALT normalization, 15% achieved HBV DNA clearance by transcription-mediated amplification, and 22.8% achieved clearance of HBeAg	[71]
Comparative effect of Tα1 and IFN-α	Tα1 treatment was more effective in achieving ALT normalization and HBV DNA negativity at the end of the follow-up period than IFN-α	[72]
Combination of Tα1 and lamivudine	No any additional antiviral effect compared with lamivudine monotherapy as determined by HBe seroconversion and the emergence of viral breakthrough	[73]
Combination therapy with lamivudine and Tα1	Induction of significantly higher rates of ALT normalization, virological response, and HBeAg seroconversion than lamivudine monotherapy	[74]

HBV: Hepatitis B virus; Tα1: Thymosin α1; IFN: Interferon; ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IL: Interleukin; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core antigen; PBL: Peripheral blood lymphocytes.