Whole-cell Oral Cholera Vaccine Research Articles

Effectiveness of a killed whole-cell oral cholera vaccine in Bangladesh: further follow-up of a cluster-randomised trial

Killed whole-cell oral cholera vaccines (OCVs) are widely used for prevention of cholera in developing countries. However, few studies have evaluated the protection conferred by internationally recommended OCVs for durations beyond 2 years of follow-up. In this study, we followed up the participants of a cluster-randomised controlled trial for 2 years after the end of the original trial. Originally, we had randomised 90 geographical clusters in Dhaka slums in Bangladesh in equal numbers (1:1:1) to a two-dose regimen of OCV alone (targeted to people aged 1 year or older), a two-dose regimen of OCV plus a water-sanitation-hygiene (WASH) intervention, or no intervention. There was no masking of group assignment. The WASH intervention conferred little additional protection to OCV and was discontinued at 2 years of follow-up. Surveillance for severe cholera was continued for 4 years. Because of the short duration and effect of the WASH intervention, we combined the two OCV intervention groups. The primary outcomes were OCV overall protection (protection of all members of the intervention clusters) and total protection (protection of individuals who got vaccinated in the intervention clusters) against severe cholera, which we assessed by multivariable survival models appropriate for cluster-randomised trials. This trial is registered on ClinicalTrials.gov, NCT01339845. The study was done between April 17, 2011, and Nov 1, 2015. 268 896 participants were present at the time of the first dose, with 188 206 in the intervention group and 80 690 in the control group. OCV coverage of the two groups receiving OCV was 66% (123 659 of 187 214 participants). During 4 years of follow-up, 441 first episodes of severe cholera were detected (243 episodes in the vaccinated groups and as 198 episodes in the unvaccinated group). Overall OCV protection was 36% (95% CI 19 to 49%) and total OCV protection was 46% (95% CI 32 to 58). Cumulative total vaccine protection was notably lower for people vaccinated before the age of 5 years (24%; -30 to 56) than for people vaccinated at age 5 years or older (49%; 35 to 60), although the differences in protection for the two age groups were not significant (p=0·3308). Total vaccine protection dropped notably (p=0·0115) after 3 years in children vaccinated at 1-4 years of age. These findings provide further evidence of long-term effectiveness of killed whole-cell OCV, and therefore further support for the use of killed whole-cell OCVs to control endemic cholera, but indicate that protection is shorter-lived in children vaccinated before the age of 5 years than in people vaccinated at the age of 5 years or older. Bill & Melinda Gates Foundation. For the Bengali translation of the abstract see Supplementary Materials section.

Assessing Vaccine Herd Protection by Killed Whole-Cell Oral Cholera Vaccines Using Different Study Designs.

The population level effectiveness of a vaccine may arise as the result of direct protection of vaccinees and vaccine herd protection, which may protect non-vaccinees, vaccinees, or both. Indirect, total, enhanced, and overall vaccine protection are measures of vaccine herd protection. The level of population level effectiveness induced by a vaccine is driven by several factors, including known vaccine-induced protective efficacy, the magnitude, and distribution of vaccine coverage at a point in time and the extent to which different groups mix with one another in the community. Data on vaccine herd protection are valuable in understanding the importance and cost-effectiveness in deploying the e vaccine in public health program. Killed whole-cell (WC) oral cholera vaccines (OCVs) have been evaluated for herd protection in various study settings, leveraging geographic information system (GIS) tools for the analyses. This article provides a brief description of the herd protective effects of killed WC OCVs measured using various study deigns that include (a) individually randomized, controlled clinical trials, (b) cluster randomized clinical trials, (c) observational cohort studies, and (d) observational case-control studies. In all of the study designs, significant herd protection was observed in unvaccinated persons as well as in the community as a whole. The findings of these studies suggest that using killed WC OCV as a public health tool for controlling cholera is impactful and cost-effective.

Fishing for vaccines against Vibrio cholerae using in silico pan-proteomic reverse vaccinology approach.

BackgroundCholera, an acute enteric infection, is a serious health challenge in both the underdeveloped and the developing world. It is caused by Vibrio cholerae after ingestion of fecal contaminated food or water. Cholera outbreaks have recently been observed in regions facing natural calamities (i.e., earthquake in Haiti 2010) or war (i.e., ongoing civil war in Yemen 2016) where healthcare and sanitary setups have been disrupted as a consequence. Whole-cell oral cholera vaccines (OCVs) have been in market but their regimen efficacy has been questioned. A reverse vaccinology (RV) approach has been applied as a successful anti-microbial measure for many infectious diseases.MethodologyWith the aim of finding new protective antigens for vaccine development, the V. cholerae O1 (biovar eltr str. N16961) proteome was computationally screened in a sequential prioritization approach that focused on determining the antigenicity of potential vaccine candidates. Essential, accessible, virulent and immunogenic proteins were selected as potential candidates. The predicted epitopes were filtered for effective binding with MHC alleles and epitopes binding with greater MHC alleles were selected.ResultsIn this study, we report lipoprotein NlpD, outer membrane protein OmpU, accessory colonization factor AcfA, Porin, putative and outer membrane protein OmpW as potential candidates qualifying all the set criteria. These predicted epitopes can offer a potential for development of a reliable peptide or subunit vaccine for V. cholerae.

Safety of a bivalent, killed, whole-cell oral cholera vaccine in pregnant women in Bangladesh: evidence from a randomized placebo-controlled trial

BackgroundCholera increases the risk of harmful effects on foetuses. We prospectively followed pregnant women unaware of their pregnancy status who received a study agent in a clinical trial evaluating the association between exposure to an oral cholera vaccine (OCV) and foetal survival.MethodsStudy participants were selected from a randomized placebo-controlled trial conducted in Dhaka, Bangladesh. The vaccination campaign was conducted between January 10 and February 4, 2014. We enrolled women who were exposed to an OCV or placebo during pregnancy (Cohort 1) and women who were pregnant after the vaccination was completed (Cohort 2). Our primary endpoint was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were preterm delivery and low birth weight. We employed a log-binomial regression to calculate the relative risk of having adverse outcomes among OCV recipients compared to that among placebo recipients.ResultThere were 231 OCV and 234 placebo recipients in Cohort 1 and 277 OCV and 299 placebo recipients in Cohort 2. In Cohort 1, the incidence of pregnancy loss was 113/1000 and 115/1000 among OCV and placebo recipients, respectively. The adjusted relative risk for pregnancy loss was 0.97 (95% CI: 0.58–1.61; p = 0.91) in Cohort 1. We did not observe any variation in the risk of pregnancy loss between the two cohorts. The risks for preterm delivery and low birth weight were not significantly different between the groups in both cohorts.ConclusionsOur study provides additional evidence that exposure to an OCV during pregnancy does not increase the risk of pregnancy loss, preterm delivery, or low birth weight, suggesting that pregnant women in cholera-affected regions should not be excluded in a mass vaccination campaign.Trial registrationThe study is registered at (http://clinicaltrials.gov). Identifier: NCT02027207.

Unmasking herd protection by an oral cholera vaccine in a cluster-randomized trial.

BackgroundSeveral studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection on vaccinees and herd protection on populations. Because our earlier cluster-randomized effectiveness trial (CRT) in urban Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis.MethodsA total of 267 270 persons were randomized to 90 approximately equal-sized clusters. In 60 clusters persons aged 1 year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesized that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households.ResultsDuring 2 years of follow-up of all residents of the clusters, total protection (protection of OCV recipients relative to control residents) was 58% [95% confidence interval (CI): 43%, 70%; P<0.0001], indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: –20%, 41%; P=0.35) and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI: 30%, 59%; P<0.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI: 50%, 87%, P<0.0001), indirect protection 52% (95% CI: –9%, 79%; P=0.08) and overall protection 72% (95% CI: 49%, 84%; P<0.0001) for the innermost 25% households.ConclusionConsistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines.

Bivalent oral cholera vaccination induces a memory B cell response to the V. cholerae O1-polysaccharide antigen in Haitian adults

The bivalent killed whole-cell oral cholera vaccine (BivWC) is being increasingly used to prevent cholera. The presence of O-antigen-specific memory B cells (MBC) has been associated with protective immunity against cholera, yet MBC responses have not been evaluated after BivWC vaccination. To address this knowledge gap, we measured V. cholerae O1-antigen MBC responses following BivWC vaccination. Adults in St. Marc, Haiti, received 2 doses of the BivWC vaccine, Shanchol, two weeks apart. Participants were invited to return at days 7, 21, 44, 90, 180 and 360 after the initial vaccination. Serum antibody and MBC responses were assessed at each time-point before and following vaccination. We observed that vaccination with BivWC resulted in significant O-antigen specific MBC responses to both Ogawa and Inaba serotypes that were detected by day 21 and remained significantly elevated over baseline for up to 12 months following vaccination. The BivWC oral cholera vaccine induces durable MBC responses to the V. cholerae O1-antigen. This suggests that long-term protection observed following vaccination with BivWC could be mediated or maintained by MBC responses.

622. Increased IgA Coating of Gut Microbes After Administration of Killed, Whole-Cell Oral Cholera Vaccine

BackgroundCholera vaccines are recommended for use in outbreaks to prevent infections and reduce severity of disease. Variable immune responses are observed after administration of killed, whole-cell cholera vaccines, and limited data suggest that the gut microbiome may be one factor influencing immune responses to vaccination. Methods. We used microbial DNA sequencing of stool and serum vibriocidal titers to examine the gut microbiome and immune responses to vaccination at day 0, 7, 17 and 44 in adult vaccine recipients in Dhaka, Bangladesh. Using flow cytometry-based bacterial cell sorting, we identified IgA-coated gut microbes in stool before and after vaccination in a subset of patients. Results. Vibriocidal titer magnitude and kinetics were used to classify participants. Within 17 days of vaccination, 86/89 (96%) adults developed a four-fold rise in vibriocidal titer. Gut microbial diversity was not significantly changed after vaccination. Rate of seroconversion (four-fold increase in vibriocidal titer by Day 3 after vaccination) was faster in participants with increased bacteria from the genus Prevotella (multivariate analysis using linear models, q value 0.04). The gut microbes of participants with higher peak vibriocidal titers was characterized by increased Prevotella (3% vs. <0.1% of the total microbiome, P < 0.001 unpaired t-test, linear discriminant analysis score >3.5), particularly the species Prevotella copri (P < 0.001, unpaired t-test, linear discriminant analysis score >3.5). Lipopolysaccharide from Prevotella species is known to increase vaccination-associated antigen-specific antibody titers in animal models. Additionally, IgA coating of gut microbes in stool increased after vaccination, from 8.9% IgA coated at baseline to a peak level of 19% during follow-up (Wilcoxon signed rank test, P < 0.01). Conclusion. Certain microbiome profiles are correlated with greater immune responses to cholera vaccination, and IgA coating of gut bacteria indicates which commensal species may be participating in the mucosal immune response. The potential for modulation of mucosal immune responses based on gut microbial species warrants further study.Disclosures All authors: No reported disclosures.

Unmasking Herd Protection by an Oral Cholera Vaccine in a Cluster-Randomised Trial: A Reanalysis

Background: Several studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection to vaccinees and herd protection to populations. Because our earlier cluster randomised, effectiveness trial (CRT) in urban, Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis. Methods: 267,270 persons were randomised to 90 approximately equal-sized clusters. In 60 clusters persons aged one year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesised that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households. Findings: During two years of follow-up of all residents of the clusters total protection (protection of OCV recipients relative to control residents) was 58% (95% CI: 43%, 70%; P<.0001), indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: -20%, 41%; P=.35), and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI:30%,59%; P<.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI:50%,87%, P<.0001), indirect protection 52% (95% CI:-9%,79%; P=.08), and overall protection 72% (95% CI:49%,84%; P<.0001) for the innermost 25% households. Interpretation: Consistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines. Trial Registration Number: Clinical Trials.gov NCT01339845 Funding: Bill and Melinda Gates Foundation Declaration of Interest: We declare no competing interests. Ethical Approval: The study protocol was approved by the Research Review Committee and the Ethical Review Committee of the icddr,b, Dhaka, Bangladesh and the Institutional Review Board of the International Vaccine Institute. Written informed consent was obtained from residents 18 years and older and from the parents or guardians of residents aged 1 to 17 years of age. Additional assent was obtained from residents aged 11 to 17 years.

Long-term effectiveness of one and two doses of a killed, bivalent, whole-cell oral cholera vaccine in Haiti: an extended case-control study.

SummaryBackgroundNo study of long-term protection following killed oral cholera vaccination has been done outside of the historically cholera-endemic areas of south Asia, or has examined protection after a single-dose vaccination regimen. To address this, we examined the duration of protection of the standard two-dose regimen and an incomplete regimen of one dose up to 4 years after vaccination in Haiti.MethodsIn the setting of two-dose vaccination campaigns with a killed, bivalent, whole-cell oral cholera vaccination, we did a case-control study from October, 2012 through November, 2016. Eligible participants were required to be resident in the vaccine catchment area (Artibonite Department or Central Department) where they were recruited at the start of the study; and be eligible for the vaccination campaign (ie, aged ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign). Patients with cholera had a positive stool culture and were recruited from cholera treatment centres. Community controls were matched to people with cholera by age group, time, and neighbourhood. We did adjusted matched regression analyses to calculate vaccine effectiveness and examine heterogeneity in effectiveness over time. The primary outcome was the effectiveness of one and two oral cholera doses as compared with zero doses from 2 months to 48 months after vaccination, measured by self reporting.FindingsAmong 178 people assigned to the case group and 706 people assigned to the control group, we found no evidence that two-dose effectiveness decreased during follow-up. In adjusted analyses, the average cumulative 4 year effectiveness for two doses was 76% (95% CI 59–86). In contrast, single-dose effectiveness decreased over time in a log-linear fashion, with a predicted vaccine effectiveness of 79% at the end of 12 months (95% CI 43–93), which declined to zero before the end of the second year.InterpretationIn a setting of epidemic and newly endemic cholera in Haiti, single-dose vaccination with killed, bivalent, whole-cell oral cholera vaccination provided short-term protection; however, vaccination with two doses was required for long-term protection, which lasted up to 4 years after vaccination. These results add to the evidence in support of the use of killed, bivalent, whole-cell oral cholera vaccination as part of comprehensive cholera control plans.FundingUS National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Bill & Melinda Gates Foundation.

A randomized, observer-blinded, equivalence trial comparing two variations of Euvichol®, a bivalent killed whole-cell oral cholera vaccine, in healthy adults and children in the Philippines

BackgroundTo contribute to the global demand for oral cholera vaccine (OCV), the production of Euvichol® was scaled up with elimination of thimerosal. To demonstrate the equivalence of the variations, a study was carried out in the Philippines. MethodsHealthy male and female adults and children in Manila were randomized to receive two doses of Euvichol® two weeks apart from either the 100L (Comparator) or the 600L (Test) variation. Primary and secondary immunogenicity endpoints were respectively geometric mean titer (GMT) of vibriocidal antibodies (two weeks post second dose) and seroconversion rate (two weeks after each dose) against O1 Inaba, Ogawa, and O139 serogroups. The GMT of vibriocidal antibodies against O1 Inaba, Ogawa, and O139 two weeks post first dose was also measured. To show the equivalence of two variations of Euvichol®, the ratio of GMT and the difference of seroconversion rate between Test and Comparator vaccines were tested with equivalence margin of [0.5, 2.0] for GMT ratio and of 15% for seroconversion rate, respectively. Safety assessment included solicited reactogenicity within 6 days after each dose and unsolicited and serious adverse events. ResultsA total of 442 participants were enrolled. For the overall population, equivalence between Test and Comparator was demonstrated for vibriocidal antibody response against O1 Inaba and Ogawa serotypes and O139 serogroup in both modified intention-to-treat (mITT) and per protocol analysis, since the 95% confidence intervals (CI) of GMT to any serotypes were within the lower and upper boundary [0.5, 2.0]. Seroconversion rates after two doses also showed equivalence for O1 Inaba, Ogawa, and O139. The vaccine was safe and well tolerated, similarly between the two groups. ConclusionThe study results support the equivalence of the 600L Euvichol® to the 100L formulation in healthy children and adults. The 600L Euvichol® is safe and immunogenic in adults and children.ClinicalTrials.gov registration number: NCT02502331.

Efficacy of a single-dose regimen of inactivated whole-cell oral cholera vaccine: results from 2 years of follow-up of a randomised trial

A single-dose regimen of inactivated whole-cell oral cholera vaccine (OCV) is attractive because it reduces logistical challenges for vaccination and could enable more people to be vaccinated. Previously, we reported the efficacy of a single dose of an OCV vaccine during the 6 months following dosing. Herein, we report the results of 2 years of follow-up. In this placebo-controlled, double-blind trial done in Dhaka, Bangladesh, individuals aged 1 year or older with no history of receipt of OCV were randomly assigned to receive a single dose of inactivated OCV or oral placebo. The primary endpoint was a confirmed episode of non-bloody diarrhoea for which the onset was at least 7 days after dosing and a faecal culture was positive for Vibrio cholerae O1 or O139. Passive surveillance for diarrhoea was done in 13 hospitals or major clinics located in or near the study area for 2 years after the last administered dose. We assessed the protective efficacy of the OCV against culture-confirmed cholera occurring 7-730 days after dosing with both crude and multivariable per-protocol analyses. This trial is registered at ClinicalTrials.gov, number NCT02027207. Between Jan 10, 2014, and Feb 4, 2014, 205 513 people were randomly assigned to receive either vaccine or placebo, of whom 204 700 (102 552 vaccine recipients and 102 148 placebo recipients) were included in the per-protocol analysis. 287 first episodes of cholera (109 among vaccine recipients and 178 among placebo recipients) were detected during the 2-year follow-up; 138 of these episodes (46 in vaccine recipients and 92 in placebo recipients) were associated with severe dehydration. The overall incidence rates of initial cholera episodes were 0·22 (95% CI 0·18 to 0·27) per 100 000 person-days in vaccine recipients versus 0·36 (0·31 to 0·42) per 100 000 person-days in placebo recipients (adjusted protective efficacy 39%, 95% CI 23 to 52). The overall incidence of severe cholera was 0·09 (0·07 to 0·12) per 100 000 person-days versus 0·19 (0·15 to 0·23; adjusted protective efficacy 50%, 29 to 65). Vaccine protective efficacy was 52% (8 to 75) against all cholera episodes and 71% (27 to 88) against severe cholera episodes in participants aged 5 years to younger than 15 years. For participants aged 15 years or older, vaccine protective efficacy was 59% (42 to 71) against all cholera episodes and 59% (35 to 74) against severe cholera. The protection in the older age groups was sustained throughout the 2-year follow-up. In participants younger than 5 years, the vaccine did not show protection against either all cholera episodes (protective efficacy -13%, -68 to 25) or severe cholera episodes (-44%, -220 to 35). A single dose of the inactivated whole-cell OCV offered protection to older children and adults that was sustained for at least 2 years. The absence of protection of young children might reflect a lesser degree of pre-existing natural immunity in this age group. Bill & Melinda Gates Foundation to the International Vaccine Institute.

Bivalent oral cholera vaccine in participants aged 1 year and older in the Dominican Republic: A phase III, single-arm, safety and immunogenicity trial

ABSTRACTThe Dominican Republic, historically non-endemic for cholera, is experiencing an ongoing cholera epidemic. We assessed the safety and immunogenicity of two doses of the killed bivalent (O1 and O139) whole-cell oral cholera vaccine (OCV) on day (D)0 and D14 in healthy participants aged ≥1 year. Immediate unsolicited systemic adverse events (AEs) were monitored up to 30 minutes and solicited systemic reactions, up to 7 days after each vaccination. Unsolicited AEs were recorded up to D14 (post-dose 1) and 30 days post-dose 2. A vibriocidal antibody assay with microtiter technique was used to measure serum antibodies to V. cholerae strains (O1 El Tor Inaba, O1 El Tor Ogawa, O139) on D0, D14 and D28. Geometric mean titers (GMTs) and seroconversion (≥4-fold increase from D0) rates were calculated. We recruited 336 participants; 112 in three age groups (1–4, 5–14 and ≥15 years). No safety concerns were observed. GMTs increased from baseline for all serotypes, with marked increases for O1 Inaba and Ogawa post-dose 1. Post-dose 2 GMTs tended to be equal or slightly lower, with ranges: O1 Inaba, 283 (95% confidence interval 191–419) to 612 (426–880); O1 Ogawa, 346 (223–536) to 754 (553–1028); and O139, 20.3 (13.5–30.6) to 43.8 (30.1–63.7). Seroconversion rates post-dose 2 for O1 Inaba and Ogawa were high (≥87%) for all age groups. OCV demonstrated an acceptable safety profile and robust immunogenicity in these participants, in-line with previous observations in epidemic and endemic settings.This study is registered on www.clinicaltrials.gov (NCT02434822).

Killed Whole-Cell Oral Cholera Vaccine Induces CCL20 Secretion by Human Intestinal Epithelial Cells in the Presence of the Short-Chain Fatty Acid, Butyrate

Short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, modulate immune responses in the gut. However, the effect of SCFAs on mucosal vaccine-induced immune cell migration is poorly understood. Here, we investigated whether SCFAs modulate chemokine expression induced by the killed whole-cell oral cholera vaccine, Shanchol™, in human intestinal epithelial cells. Shanchol™ induced expression of CCL2, CCL5, CCL20, and CXCL10 at the mRNA level, but not at the protein level. Interestingly, CCL20 secretion was substantially increased by co-stimulation with Shanchol™ and butyrate, while neither acetate nor propionate showed such effect. Enhanced CCL20 secretion was associated with GPR109A activation, and histone deacetylase (HDAC) inhibition. In addition, co-treatment with Shanchol™ and butyrate synergistically increased the secretion of adenosine triphosphate (ATP). Moreover, CCL20 secretion was decreased by inhibiting the extracellular ATP receptor P2X7. However, neither inflammasomes nor caspases were involved in CCL20 production. The culture supernatant of cells treated with Shanchol™ and butyrate augmented human immature dendritic cell migration. Collectively, these results suggest that butyrate enhances Shanchol™-induced CCL20 production in human intestinal epithelial cells via HDAC inhibition and ATP-P2X7 signaling by activating GPR109A. These effects potentially enhance the mucosal immune responses in the gut induced by this oral cholera vaccine.

Protection against cholera from killed whole-cell oral cholera vaccines: a systematic review and meta-analysis

SummaryBackgroundKilled whole-cell oral cholera vaccines (kOCVs) are becoming a standard cholera control and prevention tool. However, vaccine efficacy and direct effectiveness estimates have varied, with differences in study design, location, follow-up duration, and vaccine composition posing challenges for public health decision making. We did a systematic review and meta-analysis to generate average estimates of kOCV efficacy and direct effectiveness from the available literature.MethodsFor this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Review Library on July 9, 2016, and ISI Web of Science on July 11, 2016, for randomised controlled trials and observational studies that reported estimates of direct protection against medically attended confirmed cholera conferred by kOCVs. We included studies published on any date in English, Spanish, French, or Chinese. We extracted from the published reports the primary efficacy and effectiveness estimates from each study and also estimates according to number of vaccine doses, duration, and age group. The main study outcome was average efficacy and direct effectiveness of two kOCV doses, which we estimated with random-effect models. This study is registered with PROSPERO, number CRD42016048232.FindingsSeven trials (with 695 patients with cholera) and six observational studies (217 patients with cholera) met the inclusion criteria, with an average two-dose efficacy of 58% (95% CI 42–69, I2=58%) and effectiveness of 76% (62–85, I2=0). Average two-dose efficacy in children younger than 5 years (30% [95% CI 15–42], I2=0%) was lower than in those 5 years or older (64% [58–70], I2=0%; p<0·0001). Two-dose efficacy estimates of kOCV were similar during the first 2 years after vaccination, with estimates of 56% (95% CI 42–66, I2=45%) in the first year and 59% (49–67, I2=0) in the second year. The efficacy reduced to 39% (13 to 57, I2=48%) in the third year, and 26% (−46 to 63, I2=74%) in the fourth year.InterpretationTwo kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control.FundingThe Bill & Melinda Gates Foundation.

Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults.

BackgroundThe bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination.Methodology/Principal FindingsWe enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety.Conclusions/SignificanceImmunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a cholera-endemic area.

Clinical Review of Shanchol™ (a WHO pre-qualified oral cholera vaccine)

Background: Cholera caused by Vibrio cholerae of the O1 or O139 serogroup is an important cause of severe dehydrating diarrhea in adults and children. It continues to be a major global health problem. The WHO estimates that 3-5 million cases and 100,000–130,000 deaths occur per year globally, predominantly in Asia and Africa. The WHO recommends that in cholera-endemic countries, vaccination should be used as an additional tool to control cholera along with longer term interventions of improving water and sanitation. It recommends pre-emptive vaccination to help prevent potential outbreaks or the spread of current outbreaks. Shanchol™ is a ready-to-use killed bivalent (O1 and O139) whole-cell oral cholera vaccine administered as 2 doses 14 days apart in individuals aged 1 year and above. There is no need for buffer or water for its administration. It is currently licensed in India and 17 other countries in Asia, Africa and Latin America. It is prequalified for international use by the WHO. The vaccine is the basis for the WHO stockpile which is used to help control cholera epidemics. Methods & Materials: Clinical analysis of safety, immunogenicity and efficacy studies of Shanchol™ Results: Overall, ∼66,000 doses have been administered to subjects during the clinical development of the vaccine. Shanchol™ was observed to provide sustained protective efficacy level of 65% for at least 5 years in a clinical trial conducted in over 69,000 subjects in India. The herd effect conferred by Shanchol™ was evident with minimum vaccine coverage of 38% and was sustained for at least 3 years. Safety and immunogenicity clinical trials conducted in India, Bangladesh, Ethiopia, Philippines and Haiti showed that the vaccine is safe and provides good immune responses in different endemic populations. Results from a clinical study showed that flexible dosing schedule of Shanchol™ as 2 doses 14 to 28 days apart is possible. A modeling study observed that single-dose vaccination may prevent more deaths during outbreaks than 2-dose vaccination. Shanchol™ was also observed to be highly effective in mass vaccination campaigns in Guinea, Haiti, Odisha (India) and Bangladesh. Conclusion: Shanchol™ vaccine is safe and effective for control of cholera in endemic countries

Pregnancy Outcomes after a Mass Vaccination Campaign with an Oral Cholera Vaccine in Guinea: A Retrospective Cohort Study.

IntroductionSince 2010, WHO has recommended oral cholera vaccines as an additional strategy for cholera control. During a cholera episode, pregnant women are at high risk of complications, and the risk of fetal death has been reported to be 2–36%. Due to a lack of safety data, pregnant women have been excluded from most cholera vaccination campaigns. In 2012, reactive campaigns using the bivalent killed whole-cell oral cholera vaccine (BivWC), included all people living in the targeted areas aged ≥1 year regardless of pregnancy status, were implemented in Guinea. We aimed to determine whether there was a difference in pregnancy outcomes between vaccinated and non-vaccinated pregnant women.Methods and FindingsFrom 11 November to 4 December 2013, we conducted a retrospective cohort study in Boffa prefecture among women who were pregnant in 2012 during or after the vaccination campaign. The primary outcome was pregnancy loss, as reported by the mother, and fetal malformations, after clinical examination. Primary exposure was the intake of the BivWC vaccine (Shanchol) during pregnancy, as determined by a vaccination card or oral history. We compared the risk of pregnancy loss between vaccinated and non-vaccinated women through binomial regression analysis. A total of 2,494 pregnancies were included in the analysis. The crude incidence of pregnancy loss was 3.7% (95%CI 2.7–4.8) for fetuses exposed to BivWC vaccine and 2.6% (0.7–4.5) for non-exposed fetuses. The incidence of malformation was 0.6% (0.1–1.0) and 1.2% (0.0–2.5) in BivWC-exposed and non-exposed fetuses, respectively. In both crude and adjusted analyses, fetal exposure to BivWC was not significantly associated with pregnancy loss (adjusted risk ratio (aRR = 1.09 [95%CI: 0.5–2.25], p = 0.818) or malformations (aRR = 0.50 [95%CI: 0.13–1.91], p = 0.314).ConclusionsIn this large retrospective cohort study, we found no association between fetal exposure to BivWC and risk of pregnancy loss or malformation. Despite the weaknesses of a retrospective design, we can conclude that if a risk exists, it is very low. Additional prospective studies are warranted to add to the evidence base on OCV use during pregnancy. Pregnant women are particularly vulnerable during cholera episodes and should be included in vaccination campaigns when the risk of cholera is high, such as during outbreaks.

A Randomized, Placebo-Controlled Trial Evaluating Safety and Immunogenicity of the Killed, Bivalent, Whole-Cell Oral Cholera Vaccine in Ethiopia.

Killed whole-cell oral cholera vaccine (OCV) has been a key component of a comprehensive package including water and sanitation measures for recent cholera epidemics. The vaccine, given in a two-dose regimen, has been evaluated in a large number of human volunteers in India, Vietnam, and Bangladesh, where it has demonstrated safety, immunogenicity, and clinical efficacy. We conducted a double-blind randomized placebo-controlled trial in Ethiopia, where we evaluated the safety and immunogenicity of the vaccine in 216 healthy adults and children. OCV was found to be safe and elicited a robust immunological response against Vibrio cholerae O1, with 81% adults and 77% children demonstrating seroconversion 14 days after the second dose of vaccine. This is the first study to evaluate safety and immunogenicity of the vaccine in a population outside Asia using a placebo-controlled, double-blind, randomized study design.

Effectiveness of oral cholera vaccine in Haiti.

Although killed, whole-cell oral cholera vaccines (OCVs) have been known to be efficacious since 1986,1 and the bivalent whole-cell vaccine Shanchol has been licensed in India since 2009,2 OCV was not regarded as useful for controlling cholera outbreaks until recently.2 Many public health officials questioned the use of OCV,3 including concerns about its cost, the feasibility of undertaking large campaigns, the acceptability of OCV among vaccinated communities, and the possibility of diverting resources from other interventions.

Effectiveness of reactive oral cholera vaccination in rural Haiti: a case-control study and bias-indicator analysis.

Between April and June, 2012, a reactive cholera vaccination campaign was done in Haiti with an oral inactivated bivalent whole-cell vaccine. We aimed to assess the effectiveness of the vaccine in a case-control study and to assess the likelihood of bias in that study in a bias-indicator study. Residents of Bocozel or Grand Saline who were eligible for the vaccination campaign (ie, age ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign) were included. In the primary case-control study, cases had acute watery diarrhoea, sought treatment at one of three participating cholera treatment units, and had a stool sample positive for cholera by culture. For each case, four control individuals who did not seek treatment for acute watery diarrhoea were matched by location of residence, enrolment time (within 2 weeks of the case), and age (1-4 years, 5-15 years, and >15 years). Cases in the bias-indicator study were individuals with acute watery diarrhoea with a negative stool sample for cholera. Controls were selected in the same manner as in the primary case-control study. Trained staff used standard laboratory procedures to do rapid tests and stool cultures from study cases. Participants were interviewed to collect data on sociodemographic characteristics, risk factors for cholera, and self-reported vaccination. Data were analysed by conditional logistic regression, adjusting for matching factors. From Oct 24, 2012, to March 9, 2014, 114 eligible individuals presented with acute watery diarrhoea and were enrolled, 25 of whom were subsequently excluded. 47 participants were analysed as cases in the vaccine effectiveness case-control study and 42 as cases in the bias-indicator study. 33 (70%) of 47 cholera cases self-reported vaccination versus 167 (89%) of 188 controls (vaccine effectiveness 63%, 95% CI 8-85). 27 (57%) of 47 cases had certified vaccination versus 147 (78%) of 188 controls (vaccine effectiveness 58%, 13-80). Neither self-reported nor verified vaccination was significantly associated with non-cholera diarrhoea (vaccine effectiveness 18%, 95% CI -208 to 78 by self-report and -21%, -238 to 57 by verified vaccination). Bivalent whole-cell oral cholera vaccine effectively protected against cholera in Haiti from 4 months to 24 months after vaccination. Vaccination is an important component of efforts to control cholera epidemics. National Institutes of Health, Delivering Oral Vaccines Effectively project, and Department of Global Health and Social Medicine at Harvard Medical School.