Oral Presentation 16th Lorne Infection and Immunity 2026

HLA-A*03:01 association with COVID-19 vaccine side effect is T cell activation independent (132582)

Dimitra SM Chatzileontiadou 1 2 , Anurag Adhikari 1 , Anshika Srivastava 3 , Jill A Hollenbach 3 4 , Stephanie Gras 1 2
  1. Biochemistry and Chemistry, Infection & Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
  2. Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC, Australia
  3. Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
  4. School of Medicine, University of Colorado, Denver, Colorado, US

Vaccination against SARS-CoV-2 remains the most effective strategy for mitigating the COVID-19 pandemic. However, some individuals experience vaccine side effects, potentially limiting vaccine uptake and posing important public health challenges.

Here, we investigated the role of Human Leukocyte Antigens (HLA) in driving side effects following vaccination against SARS-CoV-2. We analysed variation in HLA-A, -B, -C, -DRB1, and -DQB1 for associations with self-reported side effects and identified HLA-A*03:01 as significantly associated with systemic side effects. Mechanistically, we discovered that HLA-A*03:01 acts as an eQTL for Interferon regulatory factor 4 (IRF4), a transcription factor that promotes dendritic cell differentiation and migration to lymph nodes. Furthermore, monocytes (CD14+) emerged as a central population of interest, driving the pro-inflammatory response that correlated with side-effect severity in HLA-A*03:01⁺ donors.

Surprisingly, we observed a high frequency of spike-specific, low-affinity naïve CD8+ T cells, that were not directly involved in producing cytokines, but instead they seem to participate to the inflammatory milieu that likely enhances monocyte-derived cytokine production, contributing to increased reactogenicity in HLA-A*03:01 individuals.

These insights have major public health implications, as they could inform the design and optimization of vaccines and therapeutic strategies, not only for COVID-19 but other viral infections, that would limit side effects.