Oral immunization with a probiotic cholera vaccine induces broad protective immunity against Vibrio cholerae colonization and disease in mice

Oral cholera vaccines (OCVs) are being increasingly employed, but current killed formulations generally require multiple doses and lack efficacy in young children. We recently developed a new live-attenuated OCV candidate (HaitiV) derived from a Vibrio cholerae strain isolated during the 2010 Haiti cholera epidemic. HaitiV exhibited an unexpected probiotic-like activity in infant rabbits, preventing intestinal colonization and disease by wild-type V. cholerae before the onset of adaptive immunity. However, it remained unknown whether HaitiV would behave similarly to other OCVs to stimulate adaptive immunity against V. cholerae. Here, we orally immunized adult germ-free female mice to test HaitiV's immunogenicity. HaitiV safely and stably colonized vaccinated mice and induced known adaptive immune correlates of cholera protection within 14 days of administration. Pups born to immunized mice were protected against lethal challenges of both homologous and heterologous V. cholerae strains. Cross-fostering experiments revealed that protection was not dependent on vaccine colonization in or transmission to the pups. These findings demonstrate the protective immunogenicity of HaitiV and support its development as a new tool for limiting cholera. Author summary Oral cholera vaccines are increasingly used as public health tools for prevention of cholera and curtailing the spread of outbreaks. However, current killed vaccines provide minimal protection in young children, who are especially susceptible to this diarrheal disease, and require similar to 7-14 days between vaccination and development of protective immunity. We recently created HaitiV, a live-attenuated oral cholera vaccine candidate derived from a clinical isolate from the Haiti cholera outbreak. Unexpectedly, HaitiV protected against cholera-like illness in infant rabbits within 24 hours of administration, before the onset of adaptive immunity. However, HaitiV's capacity to stimulate adaptive immune responses against the cholera pathogen were not investigated. Here, we report that HaitiV induces immunological correlates of protection against cholera in adult germ-free mice and leads to protection against disease in their offspring. Protection against disease was transferable through the milk of the immunized mice and was not due to transmission or colonization of HaitiV in this model. Coupling the immunogenicity data presented here with our previous observation that HaitiV can protect from cholera prior to the induction of adaptive immunity, we propose that HaitiV may provide both rapid-onset short-term protection from disease while eliciting stable and long-lasting immunity against cholera.