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Research Project 1

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Protective Immune Mechanisms to S. dysenteriae 1 Vaccines in Macaques & Humans

Project Leader: Marcelo B. Sztein, MD 

Given the potential of S. dysenteriae 1, a Category B priority pathogen, to cause devastating pandemics with high case fatality rates, the development of a Shigella vaccine is a high priority.

However, the development of effective Shigella vaccines has been hampered by a considerable lack of information of the specific determinants of protective immunity to Shigella infection, particularly in the gut microenvironment. To advance this goal we propose to perform an in-depth analysis to identify the systemic and mucosal immunological mechanisms of protection following oral immunization with attenuated strains of S. dysenteriae 1 in a wt S. dysenteriae 1 challenge model in cynomolgus macaques recently developed in the PI's laboratory.

These studies will provide the first indication of the similarities and differences observed between systemic and mucosal antibodies, and memory B and T immunity elicited following oral administration of an attenuated gram negative vaccine organism. Moreover, we will investigate the effects of immunization of monkeys with attenuated S. dysenteriae 1 strains on the colonic microbiota in stools of monkeys and the impact of the existing microbiota on the observed immune responses and protection from challenge. Finally, we will take advantage of an upcoming trial with the attenuated S. dysenteriae 1 strain CVD 1256 to evaluate the hypothesis that the immune responses observed systemically and locally in humans, as well as the perturbations of the stool microbiome, are similar to those that correlate with protection in cynomolgus macaques.

These studies will provide valuable insights that might accelerate the development of attenuated vaccines for S. dysenteriae 1.