HLA-A∗03:01 is associated with increased risk of fever, chills, and stronger side effects from Pfizer-BioNTech COVID-19 vaccination

Abstract

COVID-19 vaccines are safe and highly effective, but some individuals experience unpleasant reactions to vaccination. As the majority of adults in the United States have received a COVID-19 vaccine this year, there is an unprecedented opportunity to study the genetics of reactions to vaccination via surveys of individuals who are already part of genetic research studies. Here, we have queried 17,440 participants in the Helix DNA Discovery Project and Healthy Nevada Project about their reactions to COVID-19 vaccination. Our genome-wide association study identifies an association between severe difficulties with daily routine after vaccination and HLA-A∗03:01. This association was statistically significant only for those who received the Pfizer-BioNTech vaccine (BNT162b2; n = 3,694; p = 4.70E-11; OR = 2.07 [95% CI 1.67-2.56]), and showed a smaller effect size in those who received the Moderna vaccine (mRNA-1273; n = 3,610; p = 0.005; OR = 1.32 [95% CI 1.09-1.59]). In Pfizer-BioNTech recipients, HLA-A∗03:01 was associated with a 2-fold increase in risk of self-reported severe difficulties with daily routine following vaccination. The effect was consistent across ages, sexes, and whether the person had previously had a COVID-19 infection. The reactions experienced by HLA-A∗03:01 carriers were driven by associations with chills, fever, fatigue, and generally feeling unwell.

Keywords: COVID; COVID-19; GWAS; HLA; HLA-A; HLA-A∗03:01; SARS-CoV-2; vaccination.

Figure 1

Manhattan plot for main phenotype of severe/extreme difficulties with daily routine against mild or no difficulties following any vaccination event with Pfizer-BioNTech, Moderna, J&J, or other COVID-19 vaccines. The lambda GC was 1.07 (Figure S2).

Figure 2

Risk of vaccine side effects by HLA-A∗03:01 genotype and vaccine type (A and D) Broken down by whether they had COVID-19 prior to vaccination. (B and E) Broken down by sex (COVID-19 prior to vaccine excluded). (C and F) By age (COVID-19 prior to vaccine excluded). Top row (A–C) shows fraction with severe or extreme difficulties. Bottom row (D–F) shows number of vaccine reaction symptoms per person. Only European genetic ancestry with Pfizer-BioNTech or Moderna is shown. Error bars are 95% confidence intervals.

Figure 3

Odds ratios and 95% confidence intervals (CI) for specific vaccine responses in an additive genetic analysis (regenie) of HLA-A∗03:01 in European ancestry individuals (n = 9,636) (A) ∗p < 0.001 (signficant after correction for testing multiple phenotypes) in Pfizer-BioNTech recipients. (B) No associations were significant in Moderna recipients.