The genetic basis of the immune response to SARS-CoV-2 infection and vaccination in the Italian municipality of Vo'

Introduction: It is becoming increasingly evident that SARS-CoV-2 infection is here to stay. Therefore, understanding whether genetic variants may impact the response to the virus or vaccination is crucial. Studies on the genetic determinants of immune responses to SARS-CoV-2 have been limited by the scarcity of genetically homogenous populations and longitudinal designs that assess responses to both infection and vaccination in relation to individual genetic variation. Methods: Here we performed genotyping and whole-genome sequencing in a well-annotated and intensively followed population from the municipality of Vo’, which has previously provided critical insights into SARS-CoV-2 transmission, infection dynamics and COVID-19 clinical manifestations. Results: We identified 99 variants within the major histocompatibility complex (MHC) associated with altered T cell response dynamics following infection. These variants clustered into two semi-independent linkage disequilibrium (LD) blocks, respectively tagged by the HLA-A*01:01 allele and by SNP rs1611581. Additionally, when examining the response to vaccination, we identified 617 MHC genetic variants clustering into 27 semi-independent LD blocks that correlated with either increased or decreased TCR responses. We constructed a polygenic risk score (PRS) that comprehensively captures this genetic variation. Finally, structural modelling of selected variants affecting HLA proteins identified specific amino acid residuals most likely to influence interactions with SARS-CoV-2 epitopes, including arginine at position 114, isoleucine at position 97, and alanine at position 152 of the HLA-A molecule. Conclusion: Together, these findings provide robust evidence that genetic profiles modulate the immune response to SARS-CoV-2 in a longitudinal setting, offering insights that may inform further public health interventions.