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

Oxford COVID Vaccine Trial Genetics Study Team Group

doi:10.1038/s41591-022-02078-6

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

Oxford COVID Vaccine Trial Genetics Study Team Group

Research output: Contribution to journal › Article (Academic Journal) › peer-review

44 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	147-157
Number of pages	11
Journal	Nature Medicine
Volume	29
Issue number	1
Early online date	13 Oct 2022
DOIs	https://doi.org/10.1038/s41591-022-02078-6
Publication status	Published - 1 Jan 2023

Bibliographical note

Funding Information:
This study is funded by the University of Oxford COVID-19 Research Response Fund and UK Research and Innovation. The ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy trials were funded by the UK National Institute for Health Research (NIHR), UK Research and Innovation, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation and the South African Medical Research Council. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors are grateful to the volunteers who participated in this study. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. J.C.K. is supported by a Wellcome Trust Investigator Award (grant no. 204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. A.J.M. is an NIHR Academic Clinical Lecturer. The research was supported by the Wellcome Trust Core Award (grant no. 203141/Z/16/Z), with additional support from the NIHR Oxford Biomedical Research Centre and an Academy of Medical Sciences Starter Grant awarded to A.J.M. (SGL024\1096).

Publisher Copyright:
© 2023, The Author(s).

Keywords

Humans
Alleles
Antibodies, Viral
Breakthrough Infections
ChAdOx1 nCoV-19
COVID-19/genetics
COVID-19 Vaccines/immunology
Histocompatibility Antigens Class II
Immunogenicity, Vaccine
SARS-CoV-2
Vaccination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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

abstract = "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.",

keywords = "Humans, Alleles, Antibodies, Viral, Breakthrough Infections, ChAdOx1 nCoV-19, COVID-19/genetics, COVID-19 Vaccines/immunology, Histocompatibility Antigens Class II, Immunogenicity, Vaccine, SARS-CoV-2, Vaccination",

author = "{Oxford COVID Vaccine Trial Genetics Study Team Group} and Mentzer, {Alexander J} and Daniel O'Connor and Sagida Bibi and Irina Chelysheva and Clutterbuck, {Elizabeth A} and Tesfaye Demissie and Tanya Dinesh and Edwards, {Nick J} and Sally Felle and Shuo Feng and Flaxman, {Amy L} and Eleanor Karp-Tatham and Grace Li and Xinxue Liu and Natalie Marchevsky and Leila Godfrey and Rebecca Makinson and Bull, {Maireid B} and Jamie Fowler and Bana Alamad and Tomas Malinauskas and Chong, {Amanda Y} and Katherine Sanders and Shaw, {Robert H} and Merryn Voysey and Snape, {Matthew D} and Pollard, {Andrew J} and Teresa Lambe and Knight, {Julian C}",

note = "Funding Information: This study is funded by the University of Oxford COVID-19 Research Response Fund and UK Research and Innovation. The ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy trials were funded by the UK National Institute for Health Research (NIHR), UK Research and Innovation, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D{\textquoteright}OR, the Brava and Telles Foundation and the South African Medical Research Council. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors are grateful to the volunteers who participated in this study. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. J.C.K. is supported by a Wellcome Trust Investigator Award (grant no. 204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. A.J.M. is an NIHR Academic Clinical Lecturer. The research was supported by the Wellcome Trust Core Award (grant no. 203141/Z/16/Z), with additional support from the NIHR Oxford Biomedical Research Centre and an Academy of Medical Sciences Starter Grant awarded to A.J.M. (SGL024\1096). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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doi = "10.1038/s41591-022-02078-6",

language = "English",

volume = "29",

pages = "147--157",

journal = "Nature Medicine",

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TY - JOUR

T1 - Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

AU - Oxford COVID Vaccine Trial Genetics Study Team Group

AU - Mentzer, Alexander J

AU - O'Connor, Daniel

AU - Bibi, Sagida

AU - Chelysheva, Irina

AU - Clutterbuck, Elizabeth A

AU - Demissie, Tesfaye

AU - Dinesh, Tanya

AU - Edwards, Nick J

AU - Felle, Sally

AU - Feng, Shuo

AU - Flaxman, Amy L

AU - Karp-Tatham, Eleanor

AU - Li, Grace

AU - Liu, Xinxue

AU - Marchevsky, Natalie

AU - Godfrey, Leila

AU - Makinson, Rebecca

AU - Bull, Maireid B

AU - Fowler, Jamie

AU - Alamad, Bana

AU - Malinauskas, Tomas

AU - Chong, Amanda Y

AU - Sanders, Katherine

AU - Shaw, Robert H

AU - Voysey, Merryn

AU - Snape, Matthew D

AU - Pollard, Andrew J

AU - Lambe, Teresa

AU - Knight, Julian C

N1 - Funding Information: This study is funded by the University of Oxford COVID-19 Research Response Fund and UK Research and Innovation. The ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy trials were funded by the UK National Institute for Health Research (NIHR), UK Research and Innovation, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation and the South African Medical Research Council. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors are grateful to the volunteers who participated in this study. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. J.C.K. is supported by a Wellcome Trust Investigator Award (grant no. 204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. A.J.M. is an NIHR Academic Clinical Lecturer. The research was supported by the Wellcome Trust Core Award (grant no. 203141/Z/16/Z), with additional support from the NIHR Oxford Biomedical Research Centre and an Academy of Medical Sciences Starter Grant awarded to A.J.M. (SGL024\1096). Publisher Copyright: © 2023, The Author(s).

PY - 2023/1/1

Y1 - 2023/1/1

N2 - 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.

AB - 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.

KW - Humans

KW - Alleles

KW - Antibodies, Viral

KW - Breakthrough Infections

KW - ChAdOx1 nCoV-19

KW - COVID-19/genetics

KW - COVID-19 Vaccines/immunology

KW - Histocompatibility Antigens Class II

KW - Immunogenicity, Vaccine

KW - SARS-CoV-2

KW - Vaccination

U2 - 10.1038/s41591-022-02078-6

DO - 10.1038/s41591-022-02078-6

M3 - Article (Academic Journal)

C2 - 36228659

SN - 1078-8956

VL - 29

SP - 147

EP - 157

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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