Role of the gut microbiota and cell-mediated immunity in vaccine-induced mucosal immunity to Polio Virus

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PROJECT SUMMARY: Jessica Crothers, MD, Research Project Leader (RPL) Paralytic Polio is a devastating cause of flaccid paralysis, and its eradication is a major initiative of the World Health Organization (WHO). Critical to eradication efforts is control of viral shedding and environmental transmission of poliovirus (PV). While live attenuated oral poliovirus vaccines (OPV) have been widely effective in establishing sterilizing mucosal immunity and limiting human to human transmission, viral strains used can revert to neurovirulence while being shed in the feces of vaccinees such that its use perpetuates the existence of an environmental reservoir of disease. Alternatively, inactivated polio vaccines (IPV) do little to establish mucosal immunity and limit viral shedding despite their ability to generate protective antibody responses. If polio eradication efforts are to be realized, new PV vaccine strategies and enhanced understanding of the immunologic mechanisms responsible for effective mucosal immunity to PV are critically needed. Dr. Crothers will maximize evaluation of existing data and biospecimens from key clinical PV vaccine-challenge studies to characterize the immunologic target profile of PV mucosal immunity and investigate whether leveraging immune-microbiota interactions, including through use of a novel mucosal vaccine adjuvant, offer a path forward in the fight to eradicate polio. In addition to protective immunity to prevent disease, mucosal immunity is an important vaccination goal to limit pathogen transmission. This project will seek to comprehensively characterize the immune responses of human subjects during PV challenge and compare those of individuals with and without effective mucosal immunity to identify immunologic target profiles associated with effective mucosal immunity to PV. The immunologic impact of a novel mucosal adjuvant (dmLT) combined with IPV will be evaluated to assess its ability to stimulate target immune profiles. Lastly, the impact of the gut microbiota on PV replication and transmission dynamics will be investigated during PV challenge. Altogether, this work will provide a critical step in understanding the role of adjuvants and the gut microbiome in the development of mucosal immunity to PV. This work aligns with the NIAID 2018 strategic plan on vaccine adjuvants which highlights development of mucosal adjuvants with an emphasis on maximizing evaluation of clinical trial data to enhance understanding of their mode of action.