Suppression of Indoleamine 2,3-Dioxygenase Enhances Immune Responses to the Therapeutic Vaccine for Chronic Hepatitis B

Aim: Chronic hepatitis B virus (HBV) infection remains a major cause of liver cirrhosis and hepatocellular carcinoma. NASVAC is a therapeutic vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg), which has shown clinical potential to induce loss of HBsAg and acquisition of anti-HBs antibodies. Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan into kynurenine, plays a key role in viral persistence by suppressing effector T cell activity and promoting immunoregulatory pathways. This study aimed to elucidate the role of IDO in modulating immune responses to NASVAC. Methods: Wild-type and IDO knockout (KO) mice were immunized with NASVAC, and some wild-type mice received an IDO inhibitor. Serum amino acids and anti-HBc and anti-HBs titers, cellular immune responses, splenic CD4/CD8 T cell ratios, and IL-2 production from splenocytes were assessed. Additionally, pretreatment and posttreatment serum samples from NASVAC clinical trial were analyzed for tryptophan and kynurenine levels to assess their association with the efficacy of vaccination. Results: Genetic deletion of IDO markedly enhanced NASVAC-induced humoral and cellular immune responses in mice, whereas pharmacological inhibition partially increased cellular responses. NASVAC treatment modulated the splenic CD4/CD8 ratio, with more pronounced effects in IDO-KO mice. In human participants, lower pretreatment serum kynurenine level was associated with successful acquisition of anti-HBs following NASVAC administration. Conclusions: These findings suggest that IDO activity negatively regulates both humoral and cellular immune responses to NASVAC. Modulation or suppression of IDO may potentially enhance the therapeutic efficacy of NASVAC, and serum kynurenine may represent a predictive biomarker for treatment outcomes in chronic HBV infection. Registry and the Registration No. of the study/trial: The clinical trial was registered in the UMIN Clinical Trials Registry (no. UMIN000027442) and the Japan Registry of Clinical Trials (no. jRCTs061180100).