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Gene Linked to Better COVID-19 Vaccine Response

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A new study from the University of Oxford explores how genetic variants can influence the immune response to COVID-19 vaccines. The findings are published in Nature Medicine.

Individual responses to pathogens and vaccines

The SARS-CoV-2 pandemic has emphasized how important individual differences can be in the human immune response. While COVID-19 infection has sadly proven fatal for some, symptoms have been mild – if at all apparent – in others. Ensuring that this individuality is explored and considered when developing diagnostics, therapeutics and preventives is a cornerstone of precision medicine.

Researchers at the University of Oxford investigated how differences in the genetic code could impact a person’s immune response (immunogenicity) to a COVID-19 vaccine. “Significant variation in immune responses, including antibody levels and T cell responses, has been reported among vaccinated individuals,” the authors write. “We sought to investigate the contribution of genetic factors to the observed variation in response to vaccination with ChAdOx1 nCoV-19.”

What is immunogenicity?

Immunogenicity refers to the ability of a molecule or substance to generate an immune response. The molecule or substance may be an antigen or a protein from a vaccine formulation, for example.

The team, led by Julian Knight, professor of Genomic Medicine at the University’s Wellcome Centre for Human Genetics, analyzed DNA samples from a range of clinical trial and research program participants, including:

  • Samples from 1,190 participants recruited to the University of Oxford’s COVID-19 vaccine clinical trials
  • DNA from 1,677 adults recruited to the Oxford’s Com-COV research program
  • DNA samples from children that participated in clinical trials for the Oxford–AstraZeneca vaccine

The researchers conducted a genome-wide association study (GWAS). This is a commonly adopted method in genetics research that probes the genome of large populations to look for variations – such as single nucleotide polymorphisms (SNPs) – in genes. If a variation is observed frequently in populations presenting with a specific phenotype – such as a certain immune response profile – this is described as an association. However, an association does not prove causation, an important limitation to note.

Gene variation linked to stronger antibody response post-vaccination

Participants carrying the HLA-DQB1*06 allele were able to generate a stronger antibody response to the Oxford–AstraZeneca vaccine 28 days after administration of the first dose. In addition, participants carrying this allele (approximately two in every five from the sample) were less likely to contract COVID-19 post-vaccination compared to non-carriers. 

HLA-DQB1*06 is a variation of the human leukocyte antigen (HLA) gene that is important for the induction and regulation of the immune response, including the body’s ability to distinguish between its own proteins and those produced by foreign substances. The HLA region of the genome is highly polymorphic, meaning there is a lot of variation going on, and has been linked to many diseases, such as autoimmune conditions and cancer.

“Further work is needed to better understand the clinical significance of this specific association, and more broadly what identifying this gene variant can tell us about how effective immune responses are generated and ways to continue to improve vaccines for everyone,” said Knight.

Towards precision vaccines?

Discussing how the study’s findings can be applied to vaccine R&D, Professor Adam Finn who was not involved in the study but contributes to vaccine policy advisory work for the World Health Organization, said: “It’s a small but important step in increasing our understanding of how vaccines work. Ultimately it could lead to vaccines designed to give stronger protection to people whose responses might otherwise be too weak.” It is possible that, in the future, vaccines could be designed for individuals or populations based on the genetic make-up of their immune system.

The Oxford researchers behind the study propose that the impact of human genetics should be prioritized in vaccine design and implementation to “deliver translational outputs for the long-term benefit of populations worldwide”.

Reference: Mentzer AJ, O’Connor D, Bibi S, et al. Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection. Nat Med. 2022. doi: 10.1038/s41591-022-02078-6.