Differential proteomic signatures of host responses following COVID-19 vaccination in individuals with or without prior SARS-CoV-2 infection

The goal of this study is to characterize how proteomic signatures differ following COVID-19 vaccination in individuals naïve to SARS-CoV-2 infection (CoV-N) and those with a prior history of infection (CoV-P) to better understand the influence of pre-infection on host responses to vaccination. A subset of individuals (n = 63) enrolled in our IRB-approved, longitudinal cohort (COVID-19 Immunity Study [CITY]) were included in this study. Serum samples collected at baseline and ≤ 14 days following two doses of primary vaccination (PV) were analyzed with the proteomic aptamer-based SomaScan assay across 1500 targets. Significant (α ≤ 0.05) differentially expressed proteins (DEPs) were those with ≥ 2.5 log₂-adjusted fold changes following PV among both CoV-P and CoV-N. Proteins identified in both groups were utilized in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to elucidate biological regulation following PV. Twenty DEPs were identified in the CoV-P group and 91 DEPs in the CoV-N group. CoV-P displayed downregulation of fibrinogen, the active compound in fibrin clot synthesis. CoV-N displayed increased activation of C3, the essential activator of the alternative complement pathway, and downregulation of alternate pathway inhibitors CR1 and complement decay acceleration factor. The significant activation of complement pathways in CoV-N indicates an enhanced innate immunoprotected effect following vaccination not observed in CoV-P individuals.