A paper in the American Journal of Human Genetics in January 2024 presents the results of a genome-wide association study (GWAS) to understand the human humoral immune responses to SARS-CoV-2 vaccines. The authors note that the “substantial inter-individual variability” and association with vaccine efficacy raise questions about the “underlying mechanism”; they therefore surveyed the anti-spike IgG serostatus of UK Biobank participants who had previously been uninfected by SARS-CoV-2 before first or second doses of COVID-19 vaccines. The study provides insights into the “biological mechanism underlying individual variation in responses to COVID-19 vaccines” and highlights the importance of acknowledging constitutive genetics when designing vaccination strategies across “diverse populations”.
Understanding variations
The authors introduce the importance of their study in the context of the COVID-19 pandemic, which resulted in “more than 772 million confirmed cases worldwide” by November 2023. In attempts to protect populations and minimise the effects of the pandemic, vaccinations strategies were quickly developed, with the “primary approach” being the utilisation of the virus’ spike protein as an antigen to stimulate an immune response.
The effectiveness of the vaccines that were developed “has shown variation”, which leaves “room for improvement”. For example, the ChAdOx1 vaccine exhibits a vaccine efficacy of 62.1% after two standard doses.
“One crucial method to enhance vaccine efficacy is to understand the biological mechanisms underlying the host immune responses, specifically the host immunogenicity. Host immunogenicity can differ among individuals, even for the same vaccine, in terms of production, potency, and duration of antibodies.”
The paper states that host genetic factors, alongside variables such as “sex, age, and ethnicity”, are “significant contributors” to personal immunogenicity. Thus, it is “imperative” that we understand the host genetics perspective and its influence on the antibody response to COVID-19 vaccines. So, what do we know already?
Thanks to previous research, genetic factors have been “implicated in pathways” such as antigen processing and presentation, innate recognition receptors, and cellular signalling to influence immune responses to vaccines against smallpox, rubella, measles, hepatitis, and influenza.
“However, due to financial and logistical challenges, many of these studies have difficulty distinguishing whether antibodies originate from natural infection or vaccines.”
Furthermore, they were “often constrained by limited sample sizes” and a lack of population diversity. Limitations are similar for studies that examine the host response to COVID-19 vaccination.
UK Biobank
The UK Biobank (UKBB) is a “large-scale biomedical database and research resource” that comprises in-depth, de-identified genetic and health information from half a million UK participants. The database is “globally accessible” to approved researchers and scientists in support of “vital research into the most common and life-threatening diseases”. During the pandemic, UKBB took “swift strides” to respond with five major initiative studies.
In this study, the team designed and leveraged serum antibody status data of spike (S) and nucleocapsid (N) proteins from two studies: the Coronavirus self-test antibody study, involving 200k participants, and the Coronavirus infection study, involving 60k participants, along with genetic and health linkage data. Excluding individuals who had previously been infected with SARS-CoV-2, they were able to “dissect the genuine genetic effects” associated with vaccine response, whilst “mitigating the confounding effects of prior SARS-CoV-2 infection”.
What does the study show?
The team primarily examined serostatus in 78,876 individuals after the first dose of vaccination between 20 and 60 days and in 77,232 individuals after the second dose of vaccination between 0 and 300 days using a self-test kit. Individuals with no detectable S-protein IgG level were classified as IgG seronegative (cases), and individuals with detectable S-protein IgG and no detectable N-protein antibody were classified as IgG seropositive (controls). Individuals with positive N-protein antibodies were excluded to “ensure that seropositivity reflected the immune response to the vaccine”.
The analysis identified a “significant role” of the HLA class II genes in affecting the serostatus after the initial dose of vaccination. Four “significant and independent alleles” were discovered and replicated: HLA-DRB1∗13:02, HLA-DQA1∗01:01, HLA-DPB1∗04:01, and HLA-DQB1∗02:01. These account for the variability in IgG response to the vaccine.
Additionally, amino acid residues analysis identified three independent and replicated residues, including the 71Glu/Arg substitution HLA-DRβ1.
“This specific substitution alters the electrostatic potential of pocket 4 and exhibited a significant association with seronegativity following the initial COVID-19 vaccination.”
Furthermore, nine significant and replicated genes with predicted expression levels associated with the serostatus after the first dose of the vaccine in at least one immune cell type were identified.
“This finding implies that both the protein sequence and expression levels of HLA class II genes contribute to the serostatus resulting from the initial COVID-19 vaccine dose.”
The authors suggest that the amino acid residue polymorphism “influences the binding affinity of the antigen peptide of the COVID-19 vaccine to the T cell receptor (TCR)” through “alteration of the electrostatic potential” of the fourth pocket of HLA-DRβ1, which effects the efficiency of the immune response. For further findings and detailed explanations, why not check out the study here?
“In conclusion, this study unravels HLA class II genes as the major genetic determinants influencing the IgG antibody response to COVID-19 vaccination and explored the underlying mechanisms.”
The results offer insights into the variation in response to COVID-19 vaccine and “may have broader implications for understanding humoral responses for other vaccines”. How do you think this study can inform better vaccination strategies, either for COVID-19 or other diseases?
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