Individuals with inborn errors of immunity often mount suboptimal responses to vaccination, yet the molecular determinants underlying their variable responses to mRNA vaccines remain poorly defined. The present study aimed to identify baseline immune transcriptional signatures predictive of humoral responses to the BNT162b2 (Comirnaty) mRNA vaccine in individuals with inborn errors of immunity. Twenty-one SARS-CoV-2-naïve participants with diverse inborn errors of immunity were stratified as high or low responders to the BNT162b2 vaccine based on anti-SARS-CoV-2 spike IgG titers at day 28 post-vaccination. Although vaccine-induced T cell responses were broadly comparable, low responders had significantly lower frequencies of switched memory B cells ( = .014). Transcriptional profiling revealed 41 differentially expressed genes between groups at baseline. Activated memory B cells and peripheral T follicular helper cells from high responders exhibited greater induction of activation and memory-related genes, including NFKB1, CD69, TIGIT, CD40L, and BATF, indicating greater intrinsic readiness to support coordinated antibody production. These findings demonstrate that distinct pre-vaccination gene expression patterns within specific immune subsets are associated with differential humoral responses to mRNA vaccination in individuals with inborn errors of immunity. More broadly, the study highlights that baseline molecular immune features substantially influence vaccine efficacy and suggests that pre-vaccination transcriptional profiling may enable more personalized vaccination strategies for individuals with impaired immunity. p
