Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P = 3.2 × 10−9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha-variant waves compared with non-carriers (HR 0.63, 0.42–0.93, P = 0.02). We identify a distinct S-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared with other similar alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days following first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

Author list



  1. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 
  2. Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; 
  3. NIHR Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 
  4. The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 
  5. Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford, UK; 
  6. Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.


Alexander J Mentzer1, Daniel O’Connor2,3, Sagida Bibi2,3, Irina Chelysheva2,3, Elizabeth A Clutterbuck2,3, Tesfaye Demissie2,3, Tanya Dinesh2,3, Nick J Edwards4, Sally Felle2,3, Shuo Feng2,3, Amy L Flaxman2,3, Eleanor Karp-Tatham1, Grace Li2,3, Xinxue Liu2,3, Natalie Marchevsky2,3, Leila Godfrey2,3, Rebecca Makinson4, Maireid B Bull2,5, Jamie Fowler4, Bana Alamad1, Tomas Malinauskas6, Amanda Y Chong1, Katherine Sanders2,3, Robert H Shaw2,3, Merryn Voysey2,3, Oxford COVID Vaccine Trial Genetics Study Team Group†, Matthew D Snape2,3, Andrew J Pollard2,3, Teresa Lambe2,3,5, Julian C Knight1,3,5

Novel Coronavirus SARS-CoV-2


Nature - Medicine