Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes

Junqing Xie, Beatriz Mothe, Marta Alcalde Herraiz, Chunxiao Li, Yu Xu, Annika M. Jödicke, Yaqing Gao, Yunhe Wang, Shuo Feng, Jia Wei, Zhuoyao Chen, Shenda Hong, Yeda Wu, Binbin Su, Xiaoying Zheng, Catherine Cohet, Raghib Ali, Nick Wareham and Daniel Prieto Alhambra ()
Additional contact information
Junqing Xie: NDORMS, University of Oxford
Beatriz Mothe: Hospital Universitari Germans Trias i Pujol
Marta Alcalde Herraiz: NDORMS, University of Oxford
Chunxiao Li: University of Cambridge
Yu Xu: University of Cambridge
Annika M. Jödicke: NDORMS, University of Oxford
Yaqing Gao: University of Oxford
Yunhe Wang: University of Oxford
Shuo Feng: University of Oxford
Jia Wei: University of Oxford
Zhuoyao Chen: University of Oxford
Shenda Hong: Peking University
Yeda Wu: The University of Queensland
Binbin Su: Chinese Academy of Medical Sciences/Peking Union Medical College
Xiaoying Zheng: Chinese Academy of Medical Sciences/Peking Union Medical College
Catherine Cohet: European Medicines Agency
Raghib Ali: University of Cambridge
Nick Wareham: University of Cambridge
Daniel Prieto Alhambra: NDORMS, University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

Date: 2024
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DOI: 10.1038/s41467-024-48339-5

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