Systems Vaccinology Approaches to Define and Predict Immunity in Response to Nontyphoidal Salmonella Conjugate Vaccines - PROJECT SUMMARY This proposal is for a Mentored Research Scientist Development Award (K01) for Scott Baliban, Ph.D. Training: My long-term career goal is to become an independent investigator in systems vaccinology, focusing on defining the elements that support protective immune responses to pediatric bacterial infections and using this knowledge to predict infection and vaccination outcomes. My current research expertise involves developing mouse models of bacterial infectious disease and exploring functional and protective aspects of vaccine-induced antibody responses. This application presents a five-year career development program meant to expand my vaccinology toolkit with new areas of expertise in bioinformatics and computational biology. Specifically, I will receive training in analyzing rich and complex data sets using multi-omics data integration and machine learning. My mentoring and advising team are experts in all areas of my proposed research, and I have designed a rigorous training plan that will ensure my success throughout the award. Research: The global rise in pediatric infections caused by invasive nontyphoidal Salmonella (iNTS) serovars Typhimurium and Enteritidis has created an urgent public health crisis. We have developed novel glycoconjugate vaccines consisting of the iNTS surface polysaccharide (core-O-polysaccharide [COPS]) linked to the flagellar monomer protein (FliC). COPS:FliC conjugates are immunogenic and protective in animal models; however, less is known about the mechanisms that support successful immunization as well as the in vivo effector function of protective vaccine-induced antibodies. My preliminary data demonstrate that infant mice respond sub-optimally to COPS:FliC immunization as compared to adult vaccine recipients and that COPS:FliC-induced antibodies are sufficient for robust protection against lethal iNTS challenge. In Aim 1, using S. Enteritidis COPS:FliC as an exemplar conjugate vaccine, I will build a predictive model of vaccine responsiveness based on both gene expression and metabolite perturbations after vaccination. In Aim 2, I will decipher the in vivo functionality of human anti-COPS:FliC antibodies using the infant mouse model of fatal iNTS challenge. Outlook: This study will identify vaccine-induced molecular pathways that correlate with COPS:FliC vaccination outcomes. It will also establish the in vivo importance of specific antibody effector functions for protection against in infant mice. These findings will support an R01 application where I will derive more accurate predictive models of COPS:FliC response quality by assessing the temporal dynamics of metabolomic and transcriptomic responses to vaccination in mice. This approach will be extended to S. Typhimurium COPS:FliC conjugates, and ultimately the predictive models will be verified in vaccinated human infants. I will also investigate mechanistic antibody correlates of protection in the infant mouse model with the goal of developing serological assays to measure anti-microbial functions. At the completion of the K01, I will be uniquely positioned for an independent career where I will apply systems vaccinology approaches to develop novel conceptual frameworks for infant immunology and the vaccination process.
