BackgroundThe mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection.MethodologyIn this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2).Principle findingsThe presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses.ConclusionThese results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1.

Cholera infection can result in severe dehydration that may lead to death within a short period of time if not treated immediately. Vaccination is an important strategy to prevent the disease.

Background Oral cholera vaccine (OCV) containing killed Vibrio cholerae O1 and O139 organisms (Bivalent-OCV; Biv-OCV) are playing a central role in global cholera control strategies. OCV is currently administered in a 2-dose regimen (day 0 and 14). There is a growing body of evidence that immune responses targeting the O-specific polysaccharide (OSP) of V . cholerae mediate protection against cholera. There are limited data on anti-OSP responses in recipients of Biv-OCV. We assessed serum antibody responses against O1 OSP, as well as antibody secreting cell (ASC) responses (a surrogate marker for mucosal immunity) and memory B cell responses in blood of adult recipients of Biv-OCV in Dhaka, Bangladesh. Methodology/Principal findings We enrolled 30 healthy adults in this study and administered two doses of OCV (Shanchol) at days 0 and 14. Blood samples were collected before vaccination (day 0) and 7 days after each vaccination (day 7 and day 21), as well as on day 44. Serum responses were largely IgA with minimal IgG and IgM responses in this population. There was no appreciable boosting following day 14 vaccination. There were significant anti-OSP IgA ASC responses on day 7 following the first vaccination, but none after the second immunization. Anti-OSP IgA memory B cell responses were detectable 30 days after completion of the vaccination series, with no evident induction of IgG memory responses. In this population, anti-Ogawa OSP responses were more prominent than anti-Inaba responses, perhaps reflecting impact of previous exposure. Serum anti-OSP responses returned to baseline within 30 days of completing the vaccine series. Conclusion Our results call into question the utility of the 2-dose regimen separated by 14 days in adults in cholera endemic areas, and also suggest that Biv-OCV-induced immune responses targeting OSP are largely IgA in this highly endemic cholera area. Studies in children in cholera-endemic areas need to be performed. Protective efficacy that extends for more than a month after vaccination presumably is mediated by direct mucosal immune response which is not assessed in this study. Our results suggest a single dose of OCV in adults in a cholera endemic zone may be sufficient to mediate at least short-term protection.

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BackgroundOral cholera vaccines (OCVs) are an important tool for reduction of the worldwide cholera burden, but some individuals who receive an OCV do not develop protective immune responses. The gut microbiota is a potential explanation for these differences. Components of the gut microbiota associated with differences in OCV response have not been identified.ResultsWe used metagenomic sequencing to identify predicted protein-coding genes in the gut microbiota at the time of OCV administration, and then measured immune responses to vaccination. Vaccine recipients were classified as OCV “responders” if they developed a post­vaccination increase in memory B cell populations that produce IgA or IgG specific for cholera toxin and the V. cholerae O-specific polysaccharide. We next analyzed microbial genes seen at similar abundances across individual samples and classified these into co-abundant gene groupings (CAGs), and correlated CAGs with OCV responses. Next, to identify specific bacterial strains associated with OCV responses, we mapped CAGs to bacterial genomes and generated a “priority score” for each strain detected in the study population. This score reflects both the number of CAGs aligning to a specific bacterial genome and the strength of the association between the CAGs and the vaccine response. This strain-level analysis revealed relationships between the gut microbiota and immune response to OCV that were not detected at the genus or species level. Bacterial strains which produce short-chain fatty acids and those with sphingolipid-containing cell membranes were correlated with more robust immune responses to vaccination.ConclusionOur study demonstrates a method for translating metagenomic sequencing data into strain-specific results associated with a biological outcome. Using this approach, we identified strains for the study of bacterial-derived molecules or metabolites associated with immune responses; such agents might have potential utility as vaccine adjuvants.