Longitudinal analysis of human humoral responses after vaccination with a live attenuated V. cholerae vaccine

Vibrio cholerae is a bacterial pathogen which causes the severe acute diarrheal disease cholera. Given that a symptomatic incident of cholera can lead to long term protection, a thorough understanding of the immune response to this pathogen is needed to identify parameters critical to the generation and durability of immunity. To approach this, we utilized a live attenuated cholera vaccine to model the response to V. cholerae infection in 12 naïve subjects. We found that this live attenuated vaccine induced durable vibriocidal antibody titers that were maintained at least one year after vaccination. Similar to what we previously reported in infected patients from Bangladesh, we found that vaccination induced plasmablast responses were primarily specific to the two immunodominant antigens lipopolysaccharide (LPS) and cholera toxin (CT). Interestingly, the magnitude of the early plasmablast response at day 7 predicted the serological outcome of vaccination at day 30. However, this correlation was no longer present at later timepoints. The acute responses displayed preferential immunoglobulin isotype usage, with LPS specific cells being largely IgM or IgA producing, while cholera toxin responses were predominantly IgG. Finally, CCR9 was highly expressed on vaccine induced plasmablasts, especially on IgM and IgA producing cells, suggesting a role in migration to the gastrointestinal tract. Collectively, these findings demonstrate that the use of a live attenuated cholera vaccine is an effective tool to examine the primary and long-term immune response following V. cholerae exposure. Additionally, it provides insight into the phenotype and specificity of the cells which likely return to and mediate immunity at the intestinal mucosa. A thorough understanding of these properties both in peripheral blood and in the intestinal mucosae will inform future vaccine development against both cholera and other mucosal pathogens. Trial Registration:NCT03251495.
Author summary Cholera is a severe diarrheal illness which affects millions of people annually. Those most affected reside in developing countries where outbreaks can cause a devastating healthcare crisis. Despite this, much is still unknown regarding the longevity of protective immune responses or how they are generated and maintained. This includes aspects of the mucosal response where immunity is induced, as well as features of the early immune response that could predict long-term immunity. To address these issues, we examined primary humoral immune responses following administration of a live attenuated cholera vaccine to 12 human participants. This study provides insight into the development of humoral immunity and information that may prove valuable for improving cholerae vaccines and treatments.