Impact of HLA divergence on humoral response to SARS-CoV-2 and HBV vaccines in the liver transplantation setting

BackgroundOrgan transplant recipients are at high risk of viral infections but show lower humoral vaccine responsiveness than immunocompetent individuals. HLA evolutionary divergence (HED) quantifies the sequence differences between homologous HLA alleles and reflects the breadth of the immunopeptidome presented to T lymphocytes. MethodsWe retrospectively investigated the impact of HED on humoral response to SARS-CoV-2 mRNA vaccine in 310 liver transplant recipients (undetectable anti-spike IgG titers considered as no response, [&le;]250 BAU/mL as moderate response, >250 BAU/mL as strong response) and to Hepatitis B virus (HBV) vaccine in 424 liver transplant candidates (anti-HBs IgG <10 mIU/mL considered as no response, 10-100 mIU/mL as moderate reponse, [&ge;]100 mIU/mL as strong response). HED between aligned allele pairs at HLA-A, -B, -DRB1 and- DQB1 loci were measured as a continuous metric using the Grantham distance. The impact of HED on vaccine responses was analyzed through ordinal logistic regression and inverse probability weighting approach based on generalised propensity scores. FindingsFor both vaccines, HED at the DQB1 locus, but not at other loci, was significantly higher in responders than in others, independent of covariates associated to the response (age, time since transplant, hemoglobin levels, combined graft, immunosuppression with steroids or mycophenolate for SARS-CoV-2 vaccine; age, gender, and liver disease for HBV vaccine). InterpretationDQB1 HED is a critical determinant of humoral response to vaccines in liver transplant recipients. This metric could guide the design of future vaccines as it predicts the magnitude of the repertoire of vaccine-derived peptides presented to CD4 helper T cells. FundingInstitut National de la Sante et de la Recherche Medicale (INSERM)