Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10−30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen ‘a-determinant’ segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion. One-Sentence Summary Host genetics underlying hepatitis B vaccine response in Bangladeshi infants identifies mechanisms of viral vaccine escape, and how to prevent it. ### Competing Interest Statement JBR's institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the CEO of 5 Prime Sciences Inc ([www.5primesciences.com][1]). ### Funding Statement GBL received funding for this research from the Canadian Institutes of Health Research (CIHR), the Fonds de Recherche du Québec - Santé (FRQS), and the Royal College of Physicians and Surgeons of Canada. The Richards research group is supported by the CIHR, the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada and the FRQS. This project has received funding from the European Research Council (ERC) under the European union's \[Seventh Framework programme (FP7/2007-2013)\] (grant agreement No 294557) and National Institute for Health (NIH) grants R01 AI043596 and R37 AI026649. This work was supported by the Wellcome Trust grant numbers 064693, 079110, 095778, 217065, 202802 and 098051, through the UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), by the National Institutes of Allergy and Infectious Diseases to WAP (AI043596), by to WAP the Bill & Melinda Gates Foundation (OPP1017093) and the Henske family. Computation used the BMRC facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by the NIHR Oxford BRC. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. These funding agencies had no role in the design, implementation, or interpretation of this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Review Committee and the Research Review Committee of the International Centre for Diarrhoeal Disease Research, Bangladesh gave ethical approval for this work. The Ethics board of the University of Virginia gave ethical approval for this work. The Ethics board of the University of Vermont gave ethical approval for this work. The Oxford Tropical Research Ethics Committee of the University of Oxford gave ethical approval for this work. The ethics board of The Uganda Virus Research Institute gave ethical approval for this work. The ethics board of Uganda National Council for Science and Technology gave ethical approval for this work. The ethics board of London School of Hygiene and Tropical Medicine gave ethical approval for this work. The ethics board of University of Witwatersrand gave ethical approval for this work. North West Multi-centre Research Ethics Committee gave ethical approval for the UK Biobank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All direct genotypes from the Bangladeshi individuals post-quality control alongside imputed data and raw and curated HLA sequence data and calls have been submitted to the European Genome-Phenome Archive under accession EGAS00001000918. Summary statistics for the genome-wide association tests of imputed data for eight vaccine antibody levels are available on the GWAS Catalog. Code to the modified HLA-TAPAS/SNP2HLA software is available on github at . [1]: http://www.5primesciences.com [2]: http://ClinicalTrials.gov