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

Severe acute respiratory syndrome coronavirus 2 (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 found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after 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 replicated 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 to non-carriers (hazard ratio = 0.63, 0.42–0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (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. Mentzer1,36, Daniel O’Connor2,3,36, 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. Pollard2,3,36, Teresa Lambe2,3,5,36 & Julian C. Knight1,3,5,36

Novel Coronavirus SARS-CoV-2


Nature - Medicine