Introduction Hepatitis B Virus (HBV) interaction with the immune system is a key determinant of infection outcome1. However, efforts to identify relevant circulating biomarkers of liver immune status have been disappointing. As the HBV field advances towards novel therapies (including immunoregulatory drugs)2, enhanced risk stratification, and cancer prevention, there is a pressing need to better understand the immunological profiles that underlie diverse disease outcomes3.We set out to compare circulating levels of ten cytokines, alongside host and viral biomarkers, in people living or not with HBV, based in the United Kingdom (UK), in order to develop new approaches to surveillance and risk stratification. Contrasting immune fingerprints of adults living with chronic Hepatitis B Virus infection, compared to non-infected individuals, from the UK Marion Delphin1, Gavin Kelly1, Elizabeth Waddilove1, Joshua Gahir1, Louise O Downs2,3, Sheila Lumley2,3, Catherine De Lara2, Sue Wareing3, Polyxeni Fengou3, Jacqueline Martin4, Tongai Maponga5, Monique Andersson2,3, Emma Wall1, Paul Klenerman2, Eleanor Barnes2,4, Azim Ansari2 and Philippa C Matthews1,6,7 Conclusions Adults living with HBV in the UK have a distinct immune profile that distinguishes them from matched adult controls. GM-CSF, IFNα2a, IL-2 and IL-10, PD-1 and TNFα seems to be the main modulated cytokines, with no covariance with known host parameters. In the CHB cohort, lower IL-2 and IL-10 was associated with a decreased HBV DNA, mostly attributed to treatment status. Further studies wiht increased numbers of individuals are needed to unravel these immune phenotypes. Developing insights into immune biomarkers may help us to develop enhanced understanding of the mechanisms that determine infection outcomes and treatment response, support better patient-stratification and guide evidence-based interventions. 1 The Francis Crick Institute, 1 Midland Way, London, UK 2 Nuffield Department of Medicine, Medawar Building for Pathogen Research, University of Oxford, Oxford, UK 3 Department of Infectious Diseases and Microbiology, John Radcliffe Hospital, Headley Way, Oxford, UK 4 Department of Hepatology, John Radcliffe Hospital, Headley Way, Oxford, UK 5 Division of Medical Virology, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, SA 6 Division of Infection and Immunity, University College London, London, London, UK 7 Department of Infectious Diseases, University College London Hospital, London, London, UK Contact Informations: Marion Delphin: marion.delphin@crick.ac.uk @MarionDelphin Philippa Matthews: philippa.matthews@crick.ac.uk @pippa_matt Methods Cohort description: Adult living with HBV were enrolled at Oxford University Hospitals, UK (n=60), and age/sex matched non-infected adults were enrolled in the Legacy Study, London, UK (n=60) Patient meta-data were recorded at the time of recruit- ment, supported by Electronic Patient Records where available. Serum Sample Analysis: Liver Biomarkers: ALT/Fibroscan score HBV Biomarkers: HBsAg, HBeAg, HBV DNA Cytokines: GM-CSF, IFNα2a, IL-2, IL-6, IL-8, IL-10, IL-21, IP-10, PD-1 and TNF-α (multiplex ELISA, MSD) Statistical Analysis Using a euclidean distance, samples were hierarchically clustered based purely on stand- ardised log-transformed cytokine measure- ments using Ward's method for linkage. P values were calculated using Mann Witney or Chi-Squared test in Prism v. 8.0. **P ≤ 0.01; ***P ≤ 0.001; P ≤ 0.0001. References 1 M.Maini et al, Nat Rev Gastroenterol Hepatol; 2019 2 J.Feld et al, Clin Gastroenterol Hepatol, 2023. 3 A.Gehring et al, J.Hepatol, 2022. Results 3 Figure 2: Log-standardised heatmap representation of NI and CHB individuals Age 70 60 50 40 30 Sex Female Male HBV status CHB NI Color code Results 2: Result 1 We compared the immune profile of two cohorts of CHB and NI individuals that are age and sex-macthed, using quantification of a panel of 10 cytokines. The CHB cohort is dominated by an increase