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

 

Affiliations:

  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.

Authors:

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

10.1038/s41591-022-02078-6

Nature - Medicine

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