Anti-Vibrio cholerae responses in the human periphery and intestine following a live-attenuated vaccine

Abstract

Abstract Vibrio cholerae is a prototypical mucosal pathogen that causes cholera, a severe diarrheal disease. Cholera affects an estimated 3 to 5 million people annually, resulting in over 100,000 deaths. Infection leads to serotype-specific immunity that can last for up to ten years. Immunity is likely mediated by intestinal antibodies, which primarily target the immunodominant antigens lipopolysaccharide (LPS) and cholera toxin (CT). However, how immunity is generated and maintained is not well understood. Here we have used the live-attenuated cholera vaccine, Vaxchora, to characterize the primary immune response in both the periphery and the human duodenum. Previously, this vaccine showed 80% protective efficacy 90 days after vaccination of naïve volunteers, and induced early antibody responses in levels similar to infection. We developed new technology to identify and characterize V. cholerae-specific plasmablasts and plasma cells by flow cytometry, and found that antigen-specific plasmablasts in peripheral blood quickly expand and upregulate mucosal trafficking markers CCR9 and CCR10. These B cells either develop locally or home to the small intestine, where anti-LPS and anti-CT antibody-secreting cells are present by day 28. Surprisingly, our preliminary data shows that vaccinees may exhibit robust anti-CT responses in the duodenum even when peripheral anti-CT antibody secreting cells are not detected, which provides novel insight into the generation of sustained protection. These data will help us understand not only protective immunity to V. cholerae, but also how the human mucosal plasma cell compartment is developed and maintained.