High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response

How human genetic variation contributes to vaccine immunogenicity and effectiveness is unclear, particularly in infants from Africa. We undertook genome-wide association analyses of eight vaccine antibody responses in 2,499 infants from three African countries and identified significant associations across the human leukocyte antigen (HLA) locus for five antigens spanning pertussis, diphtheria and hepatitis B vaccines. Using high-resolution HLA typing in 1,706 individuals from 11 African populations we constructed a continental imputation resource to fine-map signals of association across the class II HLA observing genetic variation explaining up to 10% of the observed variance in antibody responses. Using follicular helper T-cell assays, in silico binding, and immune cell eQTL datasets we find evidence of HLA-DRB1 expression correlating with serological response and inferred protection from pertussis following vaccination. This work improves our understanding of molecular mechanisms underlying HLA associations that should support vaccine design and development across Africa with wider global relevance. Teaser High-resolution typing of HLA diversity provides mechanistic insights into differential potency and inferred effectiveness of vaccines across Africa. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project has received funding from the European Research Council (ERC) under the European Unions \[Seventh Framework Programme (FP7/2007-2013)\] (grant agreement No 294557). This work was supported by the Wellcome Trust grant numbers 064693, 079110, 095778, 217065, 202802 and 098051. AJM was supported by an Oxford University Clinical Academic School Transitional Fellowship and a Wellcome Trust Clinical Research Training Fellowship reference 106289/Z/14/Z and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC\_UU\_00011) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). 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. Computational support and infrastructure was also provided by the Centre for Information and Media Technology (ZIM) at the University of Dusseldorf (Germany). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and NJT will serve as guarantor for the contents of this paper. GWAS data for ALSPAC was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.The cellular immunology studies were supported by National Institute of Health grants U19 AI118626 (AS) and U01 AI141995 (AS/BP). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ### 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: Uganda Virus Research Institute (reference GC/127/12/07/32) gave ethical approval for this work Uganda National Council for Science and Technology (MV625) gave ethical approval for this work London School of Hygiene and Tropical Medicine (A340) gave ethical approval for this work Oxford Tropical Research Ethics Committees (39-12 and 42-14) gave ethical approval for this work University of Witwatersrand Human Research Ethics Committee (reference M130714) gave ethical approval for this work Oxford Tropical Research Ethics Committee (1042-13 and 42-14) gave ethical approval for this work Ministere de la Recherche Scientifique et de Innovation in Burkina Faso (reference 2014-12-151) gave ethical approval for this work 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. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics are available as part of the submission or on Zonodo (https://doi.org/10.5281/zenodo.7357687). Direct genotypes will be available through managed access through the European Genome-Phenome Archive under accession EGAS00001000918.