Breakthrough infection risk and immune responses to vaccines associated with human leukocyte antigen alleles

Breakthrough infection risk and immune responses to vaccines associated with human leukocyte antigen alleles


In a recent study published in Nature Medicine, a team of researchers from the United Kingdom (U.K.) used data from clinical trials of the Oxford-AstraZeneca coronavirus disease 2019 (COVID-19) vaccine ChAdOx1 nCoV-19 to understand the genetic factors that contribute to the individual variations in the antibody responses to the vaccine.

Study: Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection. Image Credit: Tong_stocker/Shutterstock


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Accelerated vaccine development has mitigated the severity and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the U.K., the Pfizer-BioNTech (BNT162b2) and Oxford-AstraZeneca (ChAdOx1 nCoV-19; AZD1222) were early vaccines that showed significant efficacy against hospitalization due to infections from the earlier variants. However, despite the effectiveness of the vaccines in reducing COVID-19 morbidity and mortality, breakthrough infections, especially with the new variants of concern, are increasing in frequency.

Increasing levels of neutralizing antibodies, mainly immunoglobulin G (IgG), against the SARS-CoV-2 spike protein and receptor binding domain (RBD) have been associated with reducing COVID-19 risk. Variations in the anti-spike IgG levels are associated with age and other health conditions, but the genetic basis for varied neutralizing antibody responses is not fully understood.

About the study

In the present study, the team used data from five clinical trials conducted in the U.K. All the participants of the trials were also included in genetic studies. The discovery cohort comprised two clinical trials for the ChAdOx1 nCoV-19 vaccine, while the replication cohort consisted of two trials on participants aged 50 years or older testing the intramuscular doses of ChAdOx1 nCoV-19, BNT162b2, or mRNA-1273 vaccines, or the NVX-CoV2373 nanoparticle vaccine, and one trial of ChAdOx1 nCoV-19 vaccine on children between six and 17 years of age.

Breakthrough infections in the discovery cohort were defined based on self-reported symptoms and a positive nucleic acid amplification test (NAAT) after a minimum of 22 days from vaccination, while breakthrough infections in the replication cohort were defined using only self-reported symptoms.

Serological tests were carried out on blood samples on the 28th day from the first vaccination, before the second vaccine dose, and on days 28, 90, and 182 following dose two. Humoral immune responses were measured against the SARS-CoV-2 spike protein, RBD, and nucleocapsid protein. Enzyme-linked immunosorbent assay (ELISA) was also used to measure anti-spike antibodies in the samples from the replication cohort.

Deoxyribonucleic acid (DNA) was extracted from the blood samples and genotyped. Multi-allelic human leukocyte antigen (HLA) alleles were phased, and the ternary structure of the HLA-spike protein-peptide complex was modeled.

Cryopreserved peripheral blood mononuclear cells were used for proliferation assays, such as the T cell activation-induced marker assay. Enzyme-linked immunospot (ELISpot) assay was used to measure IgG responses in antibody-secreting plasma cells differentiated from memory B cells. Various statistical analyses were used to understand the genome and HLA allele associations with humoral immune responses to vaccines.


The results identified correlations between the major histocompatibility complex (MHC) class II alleles and individual variations in neutralizing antibody responses. The HLA-DQB1*06 alleles were associated with higher anti-spike and anti-RBD immune responses after immunization with ChAdOx1 nCoV-19 and BNT162b2 vaccines.

The HLA-DQB1*06 allele carriers were also seen to be at a lower breakthrough infection risk from the early SARS-CoV-2 variants, including the Alpha variant, than individuals not carrying the HLA-DQB1*06 alleles.

Furthermore, the team identified a distinct HLA-spike peptide, indicating that the HLA-DQB1*06 alleles had specific residues that recognized different sites on the spike protein and subsequently increased T cell receptor recognition and memory B cell responses particular to the SARS-CoV-2 spike protein.

The authors highlighted the need to explore the association between HLA alleles and variations in vaccine-induced immune responses across different groups based on ethnicities and comorbidities. Further research is needed to understand the functional mechanisms of HLA-spike protein binding and differences based on emerging SARS-CoV-2 variants of concern.


To summarize, the study used data from vaccine clinical trials in the U.K. to examine the genetic basis for the varying immune responses to vaccines. The researchers found that the HLA alleles, specifically the HLA-DQB1*06 alleles, correlate to higher antibody responses to vaccines and lower breakthrough infection risks.

The study also found that the HLA-DQB1*06 alleles bind differently to the spike-peptide, which could explain the difference in the humoral immune responses in HLA-DQB1*06 allele carriers. Further research on the mechanisms of this association is needed to improve vaccine design and implementation strategies against emergent SARS-CoV-2 variants.

Journal reference:
  • Mentzer, A. J., O’Connor, D., Bibi, S., Chelysheva, I., Clutterbuck, E. A., Demissie, T., Dinesh, T., Edwards, N. J., Felle, S., Feng, S., Flaxman, A. L., Karp-Tatham, E., Li, G., Liu, X., Marchevsky, N., Godfrey, L., Makinson, R., Bull, M. B., Fowler, J., & Alamad, B. (2022). Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection. Nature Medicine. doi:

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Allele, Antibodies, Antibody, Antigen, Assay, B Cell, Blood, Cell, Children, Coronavirus, covid-19, DNA, Efficacy, ELISA, Enzyme, Frequency, Genetic, Genome, Human Leukocyte Antigen, Immunization, Immunoglobulin, Leukocyte, Medicine, Mortality, Nanoparticle, Nucleic Acid, Proliferation, Protein, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine

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Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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