Elucidation of Dysregulated Immune Profiles via Vaccine-Induced Transcriptomics

Systems vaccinology involves the measurement of genome-wide expression (transcriptomics) in peripheral blood to identify early predictors of vaccine efficacy and to gain mechanistic insight into the biological actions of effective vaccines. Prediction of the degree and duration of immune protection conferred by vaccines is accomplished by identifying patterns of gene expression induced rapidly after vaccination that correlate with downstream antibody or T cell production. These methods were first applied to define molecular signatures of the yellow fever vaccine, YF-17D, and have most recently been applied to study the Covid-19 mRNA vaccines. These studies have demonstrated the value of systems vaccinology in elucidating the biological underpinnings of vaccine-induced immune recruitment and in predicting protective immune responses. While traditional transcriptomic studies have utilized differential gene expression analyses to identify key genes that associate with immune phenotypes, there is growing evidence of the importance of studying the regulatory processes that govern gene expression. This is particularly relevant in the study of the immune system due to its vast, inter-connected system of activating and inhibitory loops that finely tune immunogenic versus tolerogenic balance. Gene networks can thus provide a more holistic characterization of the relationships within this system. In fact, regulatory alterations can define immune phenotypes, even in instances where key regulators do not exhibit differential gene expression levels. Due to the dependence of gene network construction on gene expression variance across samples, a natural extension of this approach is to stimulate and then characterize the resultant networks to enable more sensitive measurement of regulatory interactions. We posited that the widespread gene expression perturbations induced by vaccination can elucidate patterns of immune dysregulation in disease. Thus, we investigated immune-mediated disease using two different systems vaccinology approaches; one in which we characterized vaccine-conferred immune protection and identified transcriptomic correlates of this protection, and one in which we investigated the broader structure and dynamics of gene dysregulation in immune-mediated disease using vaccination as an in vivo stimulus. We applied these approaches to publicly available RNA sequencing data in children at risk for developing asthma, and peripheral blood samples that we collected from healthy controls and immunocompromised patient populations at multiple time points surrounding Covid-19 mRNA vaccination. First, we showed non-allergen-specific immune network dysregulation in peripheral blood mononuclear cells (PBMCs) of children who later developed a clinical diagnosis of allergic asthma. Next, we characterized the BNT162b2 SARS-CoV-2 mRNA vaccine-conferred immune protection from Covid-19 in sarcoidosis and end stage renal disease (ESRD), two immunocompromised patient populations, compared to controls. Finally, we elucidated decreased coupling between immune system components in ESRD, and identified dysregulated blood transcription modules and genes that underlie these altered relationships.