Understanding the Development of Mucosal Immunity to Poliovirus: Adjuvants and Modulation of the Enteric Microbiota

Project Summary Paralytic Polio is a devastating cause of flaccid paralysis, and its eradication is a major initiative of the World Health Organization (WHO). Eradication requires control of viral shedding and environmental transmission of poliovirus (PV). Inactivated polio vaccines (IPVs) fail to establish mucosal immunity and viral shedding despite generating protective antibody responses. Live attenuated oral poliovirus vaccines (OPVs) stimulate mucosal immunity and limit transmission, but the viral strains used can revert to neurovirulence when shed in the feces of vaccinees, thus sustaining a viral reservoir for environmental transmission. The candidate will maximize evaluation of existing data and biospecimens from key clinical PV vaccine-challenge studies using vaccine shedding as a gold standard assessment of effective antigen-specific mucosal immunity. Through the analyses described, Dr. Crothers will characterize human immune responses during OPV infection to identify immunologic target profiles associated with effective mucosal immunity, investigate the relative impact of two modifiable variables (vaccine priming and the gut microbiota), and evaluate the potential of a novel mucosal adjuvant (dmLT) to stimulate target immune profiles. This work aligns with the NIAID 2018 strategic plan on vaccine adjuvants which highlights development of mucosal adjuvants and emphasizes maximizing evaluation of clinical trial data to enhance our understanding of their mode of action. Through this K23 Mentored Clinical Scientist Research Career Development Award, Dr. Crothers will pursue advanced training in clinical research and computational techniques with a focus on data integration across clinical trials and data types. This work will build on the candidate’s background of doctoral research training in immunology and microbiology and build new skills in microbiome data analysis, bioinformatics, and novel computational approaches through formal coursework and practical application. Situated in the stimulating environment of her primary mentor (Dr. B. Kirkpatrick) at the University of Vermont Translational Global Infectious Diseases Research Group and Vaccine Testing Center with easy access to the research groups of her co-mentor (Dr. P. Wright) and key advisor (Dr. A. Hoen) at Dartmouth College, her work will be guided by a team of experts in poliovirus immunology, computational methodologies, and translational research. This work will position the candidate to launch her career as an independent physician scientist at the intersection of enteric infectious diseases and mucosal immunology with a focus on harnessing the clinical potential of the human microbiome to prevent and treat enteric diseases.