Viral infections shape inter-individual immune variability

Lifetime viral exposures shape the human immune system and contribute to inter-individual variability, yet their full impact remains incompletely understood. We profiled serum from 12 healthy adults using VirScan, a high-throughput serological assay covering nearly all vertebrate viruses, and paired this with ex vivo stimulation of TLR3 and TLR7/8 to quantify >90 inflammatory proteins. VirScan revealed unique viral exposure histories for each individual. At the antibody level, we observed strong protein-level immunodominance, with viral surface proteins consistently recognized across individuals, but striking variability at the epitope level, even within immunodominant proteins. At the functional level, differential protein expression analysis showed that prior infection with HSV-1, HSV-2, or norovirus was associated with elevated production of CCL4, MCP-2, and TNF, respectively, following TLR7/8 stimulation, indicating virus-specific imprints on innate immune responses. Together, these findings suggest that both chronic and acute viral infections are major drivers of immune variation and can leave lasting signatures on innate function. To our knowledge, this is the first integration of broad viral serology with systems-level innate profiling to investigate how lifetime exposures shape human immune variability. Larger studies will be needed to validate these findings and inform strategies for vaccine design and immune modulation.