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After the large influx of Rohingya nationals (termed Forcibly Displaced Myanmar National; FDMN) from Rakhine State of Myanmar to Cox’s Bazar in Bangladesh, it was apparent that outbreaks of cholera was very likely in this setting where people were living under adverse water and sanitation conditions. Large campaigns of oral cholera vaccine (OCV) were carried out as a preemptive measure to control cholera epidemics. The aim of the study was to evaluate the immune responses of healthy adults and children after administration of two doses of OCV at 14 days interval in FDMN population and compare with the response observed in Bangladeshi’s vaccinated earlier. A cross-sectional immunogenicity study was conducted among FDMNs of three age cohort; in adults (18+years; n = 83), in older children (6–17 years; n = 63) and in younger children (1–5 years; n = 80). Capillary blood was collected at three time points to measure vibriocidal antibodies using either plasma or dried blood spot (DBS) specimens. There was a significant increase of responder frequency of vibriocidal antibody titer at day 14 in all groups for Vibrio cholerae O1 (Ogawa/Inaba: adults-64%/64%, older children-70%/89% and younger children-51%/75%). There was no overall difference of vibriocidal antibody titer between FDMN and Bangladeshi population at baseline (p = 0.07–0.08) and at day 14, day 28 in all age groups for both serotypes. The seroconversion rate and geometric mean titer (GMT) of either serotype were comparable using both plasma and DBS specimens. These results showed that OCV is capable of inducing robust immune responses in adults and children among the FDMN population which is comparable to that seen in Bangladeshi participants in different age groups or that reported from other cholera endemic countries. Our results also suggest that the displaced population were exposed to V. cholerae prior to seeking shelter in Bangladesh., Author summary Oral cholera vaccines (OCV) are now on the WHO stockpile and targeted for use for countries with outbreaks and epidemics but also for control of endemic cholera. In Bangladesh many studies have been carried out to assess the safety, immunogenicity as well as feasibility of vaccination in the endemic settings of the country. However, with the large recent influx of displaced Rohingya nationals from Myanmar (termed Forcibly Displace Myanmar National; FDMN), mass campaigns with OCV were conducted between October 2017-December 2018. However, no data is available of the previous exposure to cholera of this population, prior to their arrival in Bangladesh. An assessment of immunogenicity status of FDMN is needed to find out if OCV is able to elicit comparable immune response and whether the same dose regimen of OCV was immunogenic among the FDMNs. In this study, we have measured the immune responses to the OCV, Shanchol, in adults (18 years and above), older children (6–17 years), and younger children (1–5 years). The results of this study shows that the oral cholera vaccine capable of inducing an immune response in adults and children among this FDMN population and the responses were comparable to that seen in Bangladeshi participants in earlier studies.

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., Author summary Cholera, which can be a severe watery diarrheal illness caused by the non-invasive bacterium Vibrio cholerae, remains a global public health concern for many developing countries. Immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. Evidence suggests that inactivated whole-cell oral cholera vaccine (OCV) that includes killed V. cholerae O1 and O139 organisms provides protection against cholera caused by V. cholerae O1, but the immune correlates of this protection are not fully defined. In this study, we specifically assessed induction of immune responses targeting V. cholerae O1 OSP following vaccination with the OCV in adults in a cholera endemic area, Bangladesh. Our results show that OCV induces serum, mucosal and memory anti-OSP responses, and that these responses are maximal following the first dose of vaccination, without evident boosting with the second dose. This result calls into question the day 0 and day 14 two dose regimen currently used among adults in a cholera-endemic zone.

Background Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans. Methodology We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera. Principal findings We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter. Conclusions Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations. Trial registration number ClinicalTrials.gov NCT01895855., Author summary Cholera is an acute, secretory diarrheal disease caused by Vibrio cholerae O1. There is a growing body of evidence that immune responses targetting the O-specific polysaccharide (OSP) of V. cholerae are associated with protecton against cholera. Despite this, little is known about immune responses targeting OSP in immunologically naive individals. Cholera affects populations in severely resource-limited areas. To address this, we assessed anti-OSP immune responses in North American volunteers experimentally infected with wild type V. cholerae O1 El Tor Inaba strain N16961. We found that antibody responses were largely IgM and IgA, cross-reacted to both Inaba and Ogawa serotypes, and correlated with vibriocidal responses. We found no association of responses to severity of disease, but did find that blood group O individuals mounted lower IgA fold-changes to OSP than did non-blood group O individuals. Individuals with blood group O are at particular risk for severe cholera, and are less well protected against cholera following oral vaccination. We also compared anti-OSP responses in previously unexposed individuals to responses in matched endemic zone patients, and found a number of significant differences. Such differences may explain in part the varying degrees of protective efficacy afforded by cholera vaccination between these two populations.

Background Household contacts of cholera patients are at a 100 times higher risk of developing cholera than the general population. The objective of this study was to examine the incidence of V. cholerae infections among household contacts of cholera patients in a rural setting in Bangladesh, to identify risk factors for V. cholerae infections among this population, and to investigate transmission pathways of V. cholerae using multilocus variable-number tandem-repeat analysis (MLVA). Methodology/Principal findings Stool from household contacts, source water and stored water samples were collected from cholera patient households on Day 1, 3, 5, and 7 after the presentation of the index patient at a health facility. Two hundred thirty clinical and water V. cholerae isolates were analyzed by MLVA. Thirty seven percent of households had at least one household contact with a V. cholerae infection. Thirteen percent of households had V. cholerae in their water source, and 27% had V. cholerae in stored household drinking water. Household contacts with V. cholerae in their water source had a significantly higher odds of symptomatic cholera (Odds Ratio (OR): 5.49, 95% Confidence Interval (CI): 1.07, 28.08). Contacts consuming street vended food had a significantly higher odds of a V. cholerae infection (OR: 9.45, 95% CI: 2.14, 41.72). Older age was significantly associated with a lower odds of a V. cholerae infection (OR: 0.96, 95% CI: 0.93, 0.99). Households with both water and clinical V. cholerae-positive samples all had isolates that were closely related by MLVA. Conclusions/Significance These findings emphasize the need for interventions targeting water treatment and food hygiene to reduce V. cholerae infections., Author summary Household members of cholera patients are at a 100 times higher risk of developing cholera infections than the general population. This risk is highest during the seven days after the cholera patient presents at a health facility. In this study we investigated the rate of cholera transmission within cholera patient households, identified risk factors for household cholera transmission, and performed genetic characterization of cholera strains collected. Stool was collected from patients, their household members, and from water sources and stored water during the seven days after the cholera patient presented at the health facility. A total of 230 human and water V. cholerae strains were collected and analyzed. Thirty seven percent of households had at least one household member with a V. cholerae infection. Thirteen percent of households had V. cholerae in their water source, and 27% had V. cholerae in stored drinking water. A water source with V. cholerae, consuming street vended food, and younger age were risk factors for cholera infections for household members of cholera patients. All strains from within households with water and human samples were closely related. These results demonstrate the importance of interventions focusing on water treatment and food hygiene for prevention of cholera.

Background The 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. Methodology In 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 findings The 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. Conclusion These 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., Author summary Vibrio cholerae is a non-invasive pathogen which causes watery diarrheal diseases both in adults and children. Natural infection with Vibrio cholerae provides protection against subsequent diseases and protection against cholera is serogroup specific. Serogroup specificity is defined by O-specific polysaccharide (OSP) of V. cholerae. In this study, we have found that uninfected household contacts had higher baseline OSP-specific plasma IgA, IgG and IgM antibody responses than infected contacts. These observations demonstrate those plasma antibodies responses against OSP are associated with a decrease of the risk of infection of household contacts of cholera patients. We also found that OSP-specific IgG memory B cells are associated with a decrease in the risk of infection in contacts of cholera patients. This result further supports the hypothesis that immune responses targeting V. cholerae OSP is a prime mediator of protection against cholera, and suggests that future work should focus on more detailed analysis of mucosal immune responses targeting OSP, as well as evaluation of potential mechanisms of how antibodies targeting V. cholerae OSP might mediate protection against cholera.

Close interpersonal contact likely drives spatial clustering of cases of cholera and diarrhea, but spatial clustering of risk factors may also drive this pattern. Few studies have focused specifically on how exposures for disease cluster at small spatial scales. Improving our understanding of the micro-scale clustering of risk factors for cholera may help to target interventions and power studies with cluster designs. We selected sets of spatially matched households (matched-sets) near cholera case households between April and October 2013 in a cholera endemic urban neighborhood of Tongi Township in Bangladesh. We collected data on exposures to suspected cholera risk factors at the household and individual level. We used intra-class correlation coefficients (ICCs) to characterize clustering of exposures within matched-sets and households, and assessed if clustering depended on the geographical extent of the matched-sets. Clustering over larger spatial scales was explored by assessing the relationship between matched-sets. We also explored whether different exposures tended to appear together in individuals, households, and matched-sets. Household level exposures, including: drinking municipal supplied water (ICC = 0.97, 95%CI = 0.96, 0.98), type of latrine (ICC = 0.88, 95%CI = 0.71, 1.00), and intermittent access to drinking water (ICC = 0.96, 95%CI = 0.87, 1.00) exhibited strong clustering within matched-sets. As the geographic extent of matched-sets increased, the concordance of exposures within matched-sets decreased. Concordance between matched-sets of exposures related to water supply was elevated at distances of up to approximately 400 meters. Household level hygiene practices were correlated with infrastructure shown to increase cholera risk. Co-occurrence of different individual level exposures appeared to mostly reflect the differing domestic roles of study participants. Strong spatial clustering of exposures at a small spatial scale in a cholera endemic population suggests a possible role for highly targeted interventions. Studies with cluster designs in areas with strong spatial clustering of exposures should increase sample size to account for the correlation of these exposures., Author Summary While clustering of cholera incidence had been previously described, the relative role of similar risk behaviors versus transmission dynamics is not well understood. We explored how risk factors for cholera clustered at the sub-community scale, and found significant more correlation in risk behaviors among spatially matched households than the community as a whole. We found clustering of single risk factors, and co-occurrence of different risk factors. Our results indicated that the distribution of risk behaviors may play a role in the clustering of cholera cases at very small (e.g.

Environmental enteropathy (EE) is a poorly understood condition that refers to chronic alterations in intestinal permeability, absorption, and inflammation, which mainly affects young children in resource-limited settings. Recently, EE has been linked to suboptimal oral vaccine responses in children, although immunological mechanisms are poorly defined. The objective of this study was to determine host factors associated with immune responses to an oral cholera vaccine (OCV). We measured antibody and memory T cell immune responses to cholera antigens, micronutrient markers in blood, and EE markers in blood and stool from 40 Bangladeshi children aged 3–14 years who received two doses of OCV given 14 days apart. EE markers included stool myeloperoxidase (MPO) and alpha anti-trypsin (AAT), and plasma endotoxin core antibody (EndoCab), intestinal fatty acid binding protein (i-FABP), and soluble CD14 (sCD14). We used multiple linear regression analysis with LASSO regularization to identify host factors, including EE markers, micronutrient (nutritional) status, age, and HAZ score, predictive for each response of interest. We found stool MPO to be positively associated with IgG antibody responses to the B subunit of cholera toxin (P = 0.03) and IgA responses to LPS (P = 0.02); plasma sCD14 to be positively associated with LPS IgG responses (P = 0.07); plasma i-FABP to be positively associated with LPS IgG responses (P = 0.01) and with memory T cell responses specific to cholera toxin (P = 0.01); stool AAT to be negatively associated with IL-10 (regulatory) T cell responses specific to cholera toxin (P = 0.02), and plasma EndoCab to be negatively associated with cholera toxin-specific memory T cell responses (P = 0.02). In summary, in a cohort of children 3–14 years old, we demonstrated that the majority of biomarkers of environmental enteropathy were positively associated with immune responses after vaccination with an OCV., Author Summary Cholera is a life-threatening diarrheal disease that affects millions of people worldwide. Currently available oral cholera vaccines are less effective in young children, and some have hypothesized that this is related to environmental enteropathy, a problem in the gut characterized by alterations in intestinal permeability, absorption, and inflammation, which mainly affects young children in resource-limited settings. We measured cholera-specific immune responses in 40 Bangladeshi children aged 3–14 who received an oral cholera vaccine. We then identified host factors, such as enteropathy biomarkers, sex, age, and micronutrient status, associated with each immune response. Unexpectedly, we found enteropathy biomarkers to be positively associated with immune responses to vaccine, underlining the complexity of the interaction between enteropathy and oral vaccine immunogenicity.