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Diarrhea caused by Vibrio cholerae O1 (and occasionally O139) remains a notable disease burden in much of the developing world, affecting several million individuals and leaving an estimated toll of 100,000 deaths annually (52). Outbreaks with unacceptably high case fatality rates continue to occur in areas of extreme poverty, overcrowding, and poor sanitary conditions, often accompanying natural disasters, civil disruption, or social unrest (11, 15, 17, 52). It is known from epidemiological studies and experimental challenges in healthy adult volunteers that a prior episode of clinical cholera induces serogroup-specific protection against clinical disease upon subsequent exposure (25, 27). The precise immunological effectors that mediate protection against V. cholerae are not fully understood. Vibriocidal antibodies (mainly, but not entirely directed against lipopolysaccharide [LPS] antigen) are a measure of immunity and have been inversely correlated with susceptibility to infection (13, 29, 31). Studies performed in the 1960s with household contacts of cholera cases showed that vibriocidal titers of 160 were associated with an 86% lower risk of developing cholera infection. Of 59 household contacts with vibriocidal titers of 160, only 1 (1.7%) developed cholera diarrhea and only 1 (1.7%) other developed inapparent infection, compared with 28 (14.7%) of 190 nonimmune individuals (titer, 20) who developed cholera and another 24 (12.6%) who developed inapparent infection (29). Among these household contacts of cholera patients, every 2-fold rise in vibriocidal titer was associated with a 50% decrease in risk of cholera infection. These data mimic what Mosley et al. also found in large population-based surveillance studies accompanied by serosurveys in which every 2-fold rise in geometric mean vibriocidal titer was accompanied by a halving of the annual incidence of clinical cholera cases (30). Two types of oral cholera vaccines consisting of whole killed organisms are commercially available: Dukoral (Crucell, Sweden), which contains V. cholerae O1 serotype Inaba and Ogawa strains of both El Tor and classical biotypes admixed with recombinant cholera toxin B subunit (CTB), and Shanchol (Shantha Biotechnics-Sanofi Pasteur, India) or mORCVAX (VaBiotech; Vietnam), which contain a mix of several V. cholerae O1 strains and an O139 strain, without CTB. In large-scale, randomized controlled field trials, these vaccines (or their prototypes) were found to be safe and immunogenic and conferred 60 to 80% efficacy in preventing cholera in adults and older children (9, 47). The efficacy of the oral inactivated-cholera vaccines is substantially less in children. The protection afforded is also short-lived ( 2 to 3 years) (52). In contrast, clinical cholera due to wild-type infection generally leads to a more robust and durable protection upon reexposure, which is evident in both young and old individuals and lasts up to a decade (2, 10, 25). A thorough understanding of the bacterium-host interactions that lead to disease, the immune responses induced, and the mechanisms that mediate protection against subsequent V. cholerae illness can help guide efforts to develop even more effective vaccines (e.g., requiring only a single dose and more protective in young children). Because humans are the only natural hosts for V. cholerae O1 and O139, an obstacle to this endeavor is having access to infected patients and individuals exposed to V. cholerae. Our current understanding of cholera pathogenicity and immunity comes from studies conducted in areas where the disease is prevalent or through experimental infection of healthy adult volunteers (human challenge models). When human challenge studies were performed in the 1970s, 1980s, and 1990s, some of the most critical techniques to assess immune responses of modern immunology were not available and therefore many relevant questions could not be answered. Although instructive, it could be argued that some results from challenge studies in subjects in industrialized countries may not be generalizable to endemic cholera, since they are performed in a different (nonendemic) population and in a nonnatural environment (2). However, challenge studies in Thai volunteers that used the same virulent cholera strain given to North American volunteers achieved 90% attack rate with a dose that was only 1 log higher (46). Investigation of disease in its natural context is ideal but very difficult. Assembling cohorts, procuring clinical specimens, and performing sophisticated immunological assays during field studies in resource-poor areas where cholera is endemic can be logistically complicated, requiring infrastructure, equipment and expertise, and substantial financial resources. Cultural differences and social and political conflicts can complicate the work further. Undeterred by these difficulties, a group of very talented and committed scientists from the International Centre for Diarrheal Disease Research in Bangladesh (ICDDR,B), and the Massachusetts General Hospital and Harvard Medical School joined efforts to establish a highly successful and productive collaborative research program focused on dissecting host-pathogen interactions and human immune responses to V. cholerae. This work has generated a wealth of new knowledge that has informed the cholera field, while also advancing our understanding of the immunology of enteric diseases in general. In a series of papers published recently in Clinical and Vaccine Immunology (4, 22, 33, 48), including the accompanying article by Johnson et al. (19), as well as in

Insights from Natural Infection-Derived Immunity to Cholera Instruct Vaccine Efforts