Defining T and B-cell correlates of viral control for tissue-optimised, vaccine-guided immunotherapy (360G-Wellcome-340674_Z_25_Z)

Sustained adaptive immune control of hepatitis B virus (HBV) is a crucial unmet therapeutic goal and an informative paradigm for overcoming constraints imposed by high antigen load and the tolerogenic liver niche. Research from our lab and others is defining targets to recapitulate spontaneous HBV ‘functional cure’. We hypothesise that consolidating molecular correlates from unique ‘HBV controller’ blood and liver samples will refine selection for mechanistic testing, applying a novel strategy of vaccine-guided, tissue- adapted and antigen-specific immunotherapy. We aim to: (1) Discover functionally-relevant T and B-cell correlates of control in acute and chronic- resolving HBV, exploring distinct liver-compartmentalised contributions; (2) Dissect defective T-B-cell cross-talk in infection, and in lymphoid tissue responses to existing therapeutic vaccines, to direct coordinated immune boosting; (3) Design and refine a novel immunotherapeutic approach using antibody-signposted lipid nanoparticles to co-deliver mRNAs for costimulants and HBV antigens to professional antigen-presenting-cells; we will test the capacity to achieve immunogenic T and B-cell lymphoid priming, and for intravenous boosting to amplify and re-programme intrahepatic responses for long-lived immunosurveillance. This programme will discover functional components of HBV adaptive immune control and test their recapitulation with vaccine-immunogen-guided, tissue-optimised immunotherapy. Conceptual advances will be of broad relevance to hepatotropic pathogens and tumours.