Feasibility and effectiveness of oral cholera vaccine in an urban endemic setting in Bangladesh: a cluster randomised open-label trial Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study. Efficacy of a Single-Dose, Inactivated Oral Cholera Vaccine in Bangladesh. Field trial of oral cholera vaccines in Bangladesh: results of one year of follow-up. Efficacy of a Low-Cost, Inactivated Whole-Cell Oral Cholera Vaccine: Results from 3 Years of Follow-Up of a Randomized, Controlled Trial Effectiveness of Oral Cholera Vaccine in Haiti: 37-Month Follow-Up. Two-year study of the protective efficacy of the oral whole cell plus recombinant B subunit cholera vaccine in Peru. Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. 5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits FIELD TRIAL OF ORAL CHOLERA VACCINES IN BANGLADESH Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years of follow-up. Safety and immunogenicity of an oral recombinant cholera B subunit-whole cell vaccine in Swedish volunteers. Comparison of immune responses to a killed bivalent whole cell oral cholera vaccine between endemic and less endemic settings. Evidence that inactivated oral cholera vaccines both prevent and mitigate Vibrio cholerae O1 infections in a cholera-endemic area. Immunological response to Vibrio cholerae O1 infection and an oral cholera vaccine among Peruvians. A comparison of heterogeneity variance estimators in combining results of studies. Safety and immunogenicity study of a killed bivalent (O1 and O139) whole-cell oral cholera vaccine Shanchol, in Bangladeshi adults and children as young as 1 year of age. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam
BACKGROUND Cholera is endemic in Bangladesh with epidemics occurring each year . The decision to use a cheap oral killed whole-cell cholera vaccine to control the disease depends on the feasibility and effectiveness of vaccination when delivered in a public health setting . We therefore assessed the feasibility and protective effect of delivering such a vaccine through routine government services in urban Bangladesh and evaluated the benefit of adding behavioural interventions to encourage safe drinking water and h and washing to vaccination in this setting . METHODS We did this cluster-r and omised open-label trial in Dhaka , Bangladesh . We r and omly assigned 90 clusters ( 1:1:1 ) to vaccination only , vaccination and behavioural change , or no intervention . The primary outcome was overall protective effectiveness , assessed as the risk of severely dehydrating cholera during 2 years after vaccination for all individuals present at time of the second dose . This study is registered with Clinical Trials.gov , number NCT01339845 . FINDINGS Of 268,896 people present at baseline , we analysed 267,270 : 94,675 assigned to vaccination only , 92,539 assigned to vaccination and behavioural change , and 80,056 assigned to non-intervention . Vaccine coverage was 65 % in the vaccination only group and 66 % in the vaccination and behavioural change group . Overall protective effectiveness was 37 % ( 95 % CI lower bound 18 % ; p=0·002 ) in the vaccination group and 45 % ( 95 % CI lower bound 24 % ; p=0·001 ) in the vaccination and behavioural change group . We recorded no vaccine-related serious adverse events . INTERPRETATION Our findings provide the first indication of the effect of delivering an oral killed whole-cell cholera vaccine to poor urban population s with endemic cholera using routine government services and will help policy makers to formulate vaccination strategies to reduce the burden of severely dehydrating cholera in such population s. FUNDING Bill & Melinda Gates Foundation BACKGROUND Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2 - 4 weeks between doses . Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera . During a cholera outbreak in May , 2015 , in Juba , South Sudan , the Ministry of Health , Médecins Sans Frontières , and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response . We did a vaccine effectiveness study in conjunction with this large public health intervention . METHODS We did a case-cohort study , combining information on the vaccination status and disease outcomes from a r and om cohort recruited from throughout the city of Juba with that from all the cases detected . Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba . Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1 . We estimated the short-term protection ( direct and indirect ) conferred by one dose of cholera vaccine ( Shanchol , Shantha Biotechnics , Hyderabad , India ) . FINDINGS Between Aug 9 , 2015 , and Sept 29 , 2015 , we enrolled 87 individuals with suspected cholera , and an 898-person cohort from throughout Juba . Of the 87 individuals with suspected cholera , 34 were classified as cholera positive , 52 as cholera negative , and one had indeterminate results . Of the 858 cohort members who completed a follow-up visit , none developed clinical cholera during follow-up . The unadjusted single-dose vaccine effectiveness was 80·2 % ( 95 % CI 61·5 - 100·0 ) and after adjusting for potential confounders was 87·3 % ( 70·2 - 100·0 ) . INTERPRETATION One dose of Shanchol was effective in preventing medically attended cholera in this study . These results support the use of a single-dose strategy in outbreaks in similar epidemiological setting s. FUNDING Médecins Sans Frontières BACKGROUND A single-dose regimen of the current killed oral cholera vaccines that have been prequalified by the World Health Organization would make them more attractive for use against endemic and epidemic cholera . We conducted an efficacy trial of a single dose of the killed oral cholera vaccine Shanchol , which is currently given in a two-dose schedule , in an urban area in which cholera is highly endemic . METHODS Nonpregnant residents of Dhaka , Bangladesh , who were 1 year of age or older were r and omly assigned to receive a single dose of oral cholera vaccine or oral placebo . The primary outcome was vaccine protective efficacy against culture-confirmed cholera occurring 7 to 180 days after dosing . Prespecified secondary outcomes included protective efficacy against severely dehydrating culture-confirmed cholera during the same interval , against cholera and severe cholera occurring 7 to 90 versus 91 to 180 days after dosing , and against cholera and severe cholera according to age at baseline . RESULTS A total of 101 episodes of cholera , 37 associated with severe dehydration , were detected among the 204,700 persons who received one dose of vaccine or placebo .  The vaccine protective efficacy was 40 % ( 95 % confidence interval [ CI ] , 11 to 60 % ; 0.37 cases per 1000 vaccine recipients vs. 0.62 cases per 1000 placebo recipients ) against all cholera episodes , 63 % ( 95 % CI , 24 to 82 % ; 0.10 vs. 0.26 cases per 1000 recipients ) against severely dehydrating cholera episodes , and 63 % ( 95 % CI , -39 to 90 % ) , 56 % ( 95 % CI , 16 to 77 % ) , and 16 % ( 95 % CI , -49 % to 53 % ) against all cholera episodes among persons vaccinated at the age of 5 to 14 years , 15 or more years , and 1 to 4 years , respectively , although the differences according to age were not significant ( P=0.25 ) . Adverse events occurred at similar frequencies in the two groups . CONCLUSIONS A single dose of the oral cholera vaccine was efficacious in older children ( ≥5 years of age ) and in adults in a setting with a high level of cholera endemicity . ( Funded by the Bill and Melinda Gates Foundation and others ; Clinical Trials.gov number , NCT02027207 . ) We assessed the protective efficacy ( PE ) of three doses of B subunit-killed whole cell ( BS-WC ) and killed whole cell-only ( WC ) oral cholera vaccines in a r and omized , double-blind trial among 62,285 children and women residing in rural Bangladesh . After one complete year of surveillance , 110 cases of cholera were detected in the placebo group , 52 in the WC group ( PE , 53 % ; P less than .0001 ) , and 41 in the BS-WC group ( PE , 62 % ; P less than .0001 ) . Protection was greater for BS-WC recipients than for WC recipients only during the initial eight months of observation . Both vaccines conferred equivalent protection against cholera associated with life-threatening dehydration and against less severe cholera . High- grade , sustained protection was observed in persons vaccinated when older than five years ; in younger persons protection was transient . We conclude that BS-WC and WC vaccines confer significant protection against cholera , particularly in persons vaccinated when older than five years Background Killed oral cholera vaccines ( OCVs ) have been licensed for use in developing countries , but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in r and omized , clinical trials . Methods /Principal Findings We conducted a cluster-r and omized , placebo-controlled trial of a two-dose regimen of a low-cost killed whole cell OCV in residents 1 year of age and older living in 3,933 clusters in Kolkata , India . The primary endpoint was culture-proven Vibrio cholerae O1 diarrhea episodes severe enough to require treatment in a health care facility . Of the 66,900 fully dosed individuals ( 31,932 vaccinees and 34,968 placebo recipients ) , 38 vaccinees and 128 placebo-recipients developed cholera during three years of follow-up ( protective efficacy 66 % ; one-sided 95%CI lower bound = 53 % , p<0.001 ) . Vaccine protection during the third year of follow-up was 65 % ( one-sided 95%CI lower bound = 44 % , p<0.001 ) . Significant protection was evident in the second year of follow-up in children vaccinated at ages 1–4 years and in the third year in older age groups . Conclusions / Significance The killed whole-cell OCV conferred significant protection that was evident in the second year of follow-up in young children and was sustained for at least three years in older age groups . Continued follow-up will be important to establish the vaccine 's duration of protection . Trial Registration Clinical Trials.gov NCT00289224 The first oral cholera vaccine ( OCV ) campaign , since its prequalification by the World Health Organization , in response to an ongoing cholera epidemic ( reactive vaccination ) was successfully conducted in a poor urban slum of approximately 70,000 inhabitants in Port-au-Prince , Haiti , in 2012 . Vaccine coverage was 75 % of the target population . This report documents the impact of OCV in reducing the number of culture-confirmed cases of cholera  admitted to the Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes ( GHESKIO ) cholera treatment center from that community in the 37 months postvaccination ( April 2012-April 30 , 2015 ) . Of 1,788 patients with culture-confirmed cholera , 1,770 ( 99 % ) were either from outside the vaccine area ( 1,400 cases ) or from the vaccinated community who had not received OCV ( 370 cases ) . Of the 388 people from the catchment area who developed culture-confirmed cholera , 370 occurred among the 17,643 people who had not been vaccinated ( 2.1 % ) and the remaining 18 occurred among the 52,357 people ( 0.034 % ) who had been vaccinated ( P < 0.001 ) , for an efficacy that approximates 97.5 % . Despite not being design ed as a r and omized control trial , the very high efficacy is a strong evidence for the effectiveness of OCV as part of an integrated package for the control of cholera in outbreak setting The protective efficacy of an oral inactivated whole cell Vibrio cholerae plus recombinant B subunit cholera vaccine was determined against El Tor cholera among Peruvian children and adults ( 2 - 65 years old ) in a r and omized , double-blind manner . Study subjects received 2 doses of vaccine or placebo 2 weeks apart , followed by a booster dose 10 months later . Surveillance for cholera was performed actively , with 2 visits per week to each household , and passively , at a local hospital . Stool sample s were collected during diarrhea episodes and were cultured for V. cholerae . A total of 17,799 persons received 2 doses of vaccine or placebo , and 14,997 of these persons received the booster dose . After 2 doses ( first surveillance period ) , V. cholerae biotype O1 was isolated from 17 vaccinees and 16 placebo recipients , demonstrating vaccine efficacy ( VE ) of -4 % . After 3 doses ( second surveillance period ) , V. cholerae O1 was isolated from 13 vaccinees and 32 placebo recipients , demonstrating VE of 61 % ( 95 % confidence interval ¿ CI , 28%-79 % ) . In the second surveillance period , the VE for illness requiring hospitalization was 82 % ( 95 % CI , 27%-96 % ) . VE was also higher for persons > 15 years old ( VE , 72 % ; 95 % CI , 28%-89 % ) BACKGROUND Zanzibar , in east Africa , has been severely and repeatedly affected by cholera since 1978 . We assessed the effectiveness of oral cholera vaccination in high-risk population s in the archipelago to estimate the indirect ( herd ) protection conferred by the vaccine and direct vaccine effectiveness . METHODS We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites . To estimate vaccine direct protection , we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables . To estimate indirect effects , we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood , after controlling for potential confounding variables . This study is registered with Clinical Trials.gov , number NCT00709410 . FINDINGS Of 48,178 individuals eligible to receive the vaccine , 23,921 ( 50 % ) received two doses . Between February , 2009 , and May , 2010 , there was an outbreak of cholera , enabling us to assess vaccine effectiveness . The vaccine conferred 79 % ( 95 % CI 47 - 92 ) direct protection against cholera in participants who received two doses . Indirect ( herd ) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household 's neighbourhood as the vaccine coverage in that neighbourhood increased . INTERPRETATION Our findings suggest that the oral cholera vaccine offers both direct and indirect ( herd ) protection in a sub-Saharan African setting . Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use . Because this is an internationally-licensed vaccine , we could not undertake a r and omised placebo-controlled trial , but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias . FUNDING Bill & Melinda Gates Foundation , Swedish International Development Cooperation Agency , and the South Korean Government BACKGROUND Efficacy and safety of a two-dose regimen of bivalent killed whole-cell oral cholera vaccine ( Shantha Biotechnics , Hyderabad , India ) to 3 years is established , but long-term efficacy is not . We aim ed to assess protective efficacy up to 5 years in a slum area of Kolkata , India . METHODS In our double-blind , cluster-r and omised , placebo-controlled trial , we assessed incidence of cholera in non-pregnant individuals older than 1 year residing in 3933 dwellings ( clusters ) in Kolkata , India . We r and omly allocated participants , by dwelling , to receive two oral doses of modified killed bivalent whole-cell cholera vaccine or heat-killed Escherichia coli K12 placebo , 14 days apart . R and omisation was done by use of a computer-generated sequence in blocks of four . The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for patients to seek treatment in a health-care facility . We identified culture-confirmed cholera cases among participants seeking treatment for diarrhoea at a study clinic or government hospital between 14 days and 1825 days after receipt of the second dose . We assessed vaccine protection in a per- protocol population of participants who had completely ingested two doses of assigned study treatment . FINDINGS 69 of 31 932 recipients of vaccine and 219 of 34 968 recipients of placebo developed cholera during 5 year follow-up ( incidence 2·2 per 1000 in the vaccine group and 6·3 per 1000 in the placebo group ) . Cumulative protective efficacy of the vaccine at 5 years was 65 % ( 95 % CI 52 - 74 ; p<0·0001 ) , and point estimates by year of follow-up suggested no evidence of decline in protective efficacy . INTERPRETATION Sustained protection for 5 years at the level we reported has not been noted previously with other oral cholera vaccines . Established long-term efficacy of this vaccine could assist policy makers formulate rational vaccination strategies to reduce overall cholera burden in endemic setting s. FUNDING Bill & Melinda Gates Foundation and the governments of South Korea and Sweden The protective efficacy ( PE ) of B subunit killed whole-cell ( BS-WC ) and killed whole-cell-only ( WC ) oral cholera vaccines was assessed in a r and omised double-blind field trial among children aged 2 - 15 years and women over 15 years in rural Bangladesh . Among the 62 285 subjects who received three doses of  BS-WC , WC , or Escherichia coli K12 strain placebo , cumulative PE at 3 years of follow-up was 50 % for BS-WC and 52 % for WC . PE was similar against severe and non-severe cholera , but was significantly lower in children who were vaccinated at 2 - 5 years ( 26 % for BS-WC ; 23 % for WC ) than in older persons ( 63 % for BS-WC ; 68 % for WC ) . Among persons vaccinated at 2 - 5 years , protection at 4 - 6 months of follow-up was similar to that for older persons , but rapidly waned thereafter and was not evident during the third year of follow-up . In contrast , persons vaccinated at older ages were protected even in the third year of follow-up ( PE 40 % for BS-WC ; 62 % for WC ) . PE was substantially higher against classical cholera ( 58 % for BS-WC ; 60 % for WC ) than against El Tor cholera ( 39 % and 40 % ) The cholera epidemic in South America has reinforced the need for safe and effective oral vaccines . In a r and omised , double-blind , placebo-controlled efficacy trial among 1563 Peruvian military recruits we have investigated the protective efficacy of an oral inactivated whole-cell/recombinant-B-subunit ( WC/rBS ) cholera vaccine .  Participants were given two oral doses of cholera vaccine or Escherichia coli K12 placebo , with an interval of 7 - 14 days . 1426 ( 91 % ) subjects received the two prescribed doses and were followed up for a mean of 18 weeks ( median 21 weeks ) . After vaccination , Vibrio cholerae O1 El Tor Ogawa was isolated from 17 subjects with diarrhoea . 16 of the cholera cases occurred 2 weeks or longer after the second dose of vaccine ( 14 placebo recipients , 2 vaccinees ) . We also detected 14 symptomless infections ( 11 [ 7 placebo recipients , 4 vaccinees ] ) 2 weeks or longer after the second dose . The vaccine had significant protective efficacy against cholera ( 86 % [ 95 % CI 37 - 97 ] , p < 0.01 ) but not against symptomless infection ( 42 % [ -96 to 85 ] ) . All cholera cases were in people of blood group O , who made up 76 % of the study population ( p < 0.01 ) . Two doses of WC/rBS vaccine , given 1 to 2 weeks apart , provide rapid , short-term protection against symptomatic cholera in adult South Americans , who are predominantly of blood group O. Long-term efficacy studies in Peruvian adults and children are under way The protective efficacy of oral B subunit killed whole-cell ( BS-WC ) and killed whole-cell ( WC ) cholera vaccines was assessed in 63 498 Bangladeshi children aged 2 - 15 years and women aged over 15 years . Each received three doses of BS-WC , WC , or placebo in a r and omised , double-blinded fashion . Surveillance for cases seeking medical care up to six months after the third dose revealed 26 cases of confirmed cholera in the placebo group , 4 cases in the BS-WC group ( protective efficacy 85 % ; p less than 0.0001 ) , and 11 cases in the WC group ( protective efficacy 58 % ; p less than 0.01 ) . For each vaccine protective efficacy was consistent in different age-groups ( 2 - 10 years versus greater than 10 years ) and for different severities of cholera BACKGROUND Oral cholera vaccines consisting of killed whole cells have been available for many years , but they have not been used extensively in population s with endemic disease . An inexpensive , locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam . To exp and the use of this vaccine , it was modified to comply with WHO st and ards . We assessed the efficacy and safety of this modified vaccine in a population with endemic cholera . METHODS In this double-blind trial , 107 774 non-pregnant residents of Kolkata , India , aged 1 year or older , were cluster-r and omised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine ( n=52 212 ; 1966 clusters ) or heat-killed Escherichia coli K12 placebo ( n=55 562 ; 1967 clusters ) , both delivered orally . R and omisation was done by computer-generated sequence in blocks of four . The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for the patient to seek treatment in a health-care facility . We undertook an interim , per- protocol analysis at 2 years of follow-up that included individuals who received two completely ingested doses of vaccine or placebo . We assessed first episodes of cholera that occurred between 14 days and 730 days after receipt of the second dose . This study is registered with Clinical Trials.gov , number NCT00289224 . FINDINGS 31 932 participants assigned to vaccine ( 1721 clusters ) and 34 968 assigned to placebo  ( 1757 clusters ) received two doses of study treatment . There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group ( protective efficacy 67 % ; one-tailed 99 % CI , lower bound 35 % , p<0.0001 ) . The vaccine protected individuals in age-groups 1.0 - 4.9 years , 5.0 - 14.9 years , and 15 years and older , and protective efficacy did not differ significantly between age-groups ( p=0.28 ) . We recorded no vaccine-related serious adverse events . INTERPRETATION This modified killed-whole-cell oral vaccine , compliant with WHO st and ards , is safe , provides protection against clinical ly significant cholera in an endemic setting , and can be used in children aged 1.0 - 4.9 years , who are at highest risk of developing cholera in endemic setting s. FUNDING Bill & Melinda Gates Foundation , Swedish International Development Cooperation Agency , Governments of South Korea , Sweden , and Kuwait To determine the protective efficacy ( PE ) of three doses of oral B subunit-killed whole cell ( BS-WC ) or killed whole cell-only ( WC ) vaccines against cholera , a clinical trial was conducted among 62285 children over 2 years and adult women in rural Bangladesh . During 5 years of follow-up , there were 144 cases of cholera in the BS-WC group ( PE = 49 % ; P < 0.001 ) , 150 in the WC group ( PE = 47 % ; P < 0.001 ) , and 283 in the K12 group . Protection by each vaccine was evident only during the first three years of follow-up ; long-term protection of young children was observed only against classical but not El Tor cholera ; 3-year protection against both cholera biotypes occurred among older persons , but at a higher level against classical cholera The safety and immunogenicity of a ' new ' oral B subunit-whole cell ( B-WC ) cholera vaccine based on recombinantly produced B subunit was evaluated in Swedish volunteers . The recombinant B-WC vaccine was comparable to the ' old ' type of B-WC vaccine in inducing IgA and IgG antitoxin antibody responses as well as vibriocidal antibody responses in serum , which are known to be good serological correlates of the gut mucosal IgA antitoxic and antibacterial immune responses after oral immunization with B-WC vaccine . Neither of the two B-WC vaccines was associated with any significant side-effects . The results indicate that the more easily and cheaply produced recombinant B subunit can replace the ' old ' type of B subunit isolated from cholera toxin for use in the oral B-WC cholera vaccine Studies on safety , immunogenicity and efficacy of the killed , bivalent whole cell oral cholera vaccine ( Shanchol ) have been conducted in historically endemic setting s of Asia . Recent cholera vaccination campaigns in Haiti and Guinea have also demonstrated favourable immunogenicity and effectiveness in nonendemic outbreak setting s. We performed a secondary analysis , comparing immune responses of  Shanchol from two r and omised controlled trials performed in an endemic and a less endemic area ( Addis Ababa ) during a nonoutbreak setting . While Shanchol may offer some degree of immediate protection in primed population s living in cholera endemic areas , as well as being highly immunogenic in less endemic setting s , underst and ing the characteristics of immune responses in each of these areas is vital in determining ideal dosing strategies that offer the greatest public health impact to population s from areas with varying degrees of cholera endemicity In a r and omized , placebo-controlled field trial of B subunit-killed whole cell ( BS-WC ) and killed whole cell only ( WC ) inactivated oral cholera vaccines in rural Bangladesh , active surveillance of selected neighborhoods during the first year after vaccination identified 127 Vibrio cholerae O1 infections among 3285 three-dose recipients . For each vaccine , protective efficacy was greater against symptomatic ( 57 % , P < .05 for BS-WC ; 58 % , P < .05 for WC ) than against asymptomatic infections ( 46 % , P < .05 for BS-WC ; 32 % , P = .09 for WC ) , and protection against each grade of infection was demonstrable for both the classical and El Tor biotypes . Although vaccine protection against symptomatic infections was evident in both young children and older persons , only persons vaccinated at age > 5 years were protected against asymptomatic infections . These results suggest that the inactivated oral vaccines acted both to protect against intestinal colonization by V. cholerae O1 and to interrupt the pathogenic sequence of established infections A ' double-blind ' , r and omized , placebo controlled study of an oral inactivated whole cell plus recombinant B subunit ( WC/rBS ) cholera vaccine was conducted during February-March 1992 in Peru in 346 military recruits , 307 ( 89 % ) of whom received 2 oral doses of vaccine or Escherichia coli K12 placebo , 2 weeks apart . Paired serum sample s were obtained from 155 ( 50 % ) of the recipients of 2 doses . An epidemic of cholera took place between doses . No difference in cholera attack rates was detected between vaccine and placebo recipients after one dose ( 8 % versus 14 % ) . Seroconversion ( 4-fold or higher increase in vibriocidal antibody titres ) was detected in 90 % and 80 % of vaccine and placebo recipients , respectively , with low pre-existing vibriocidal titres ( < 0.01 ) . The anti-cholera toxin seroconversion rate among those with low pre-existing titres was higher in vaccinated subjects ( 97 % ) than in placebo recipients ( 68 % ) ( P < 0.01 ) . Administration of 2 doses of WC/rBS vaccine concomitantly with natural V. cholerae O1 infection enhanced the serum anti-cholera toxin response . The immune response to the whole cell component of the vaccine was reduced by high pre-existing vibriocidal antibody titres For r and om effects meta- analysis , seven different estimators of the heterogeneity variance are compared and assessed using a simulation study . The seven estimators are the variance component type estimator ( VC ) , the method of moments estimator ( MM ) , the maximum likelihood estimator ( ML ) , the restricted maximum likelihood estimator ( REML ) , the empirical Bayes estimator ( EB ) , the model error variance type estimator ( MV ) , and a variation of the MV estimator ( MVvc ) . The performance of the estimators is compared in terms of both bias and mean squared error , using Monte Carlo simulation . The results show that the REML and especially the ML and MM estimators are not accurate , having large biases unless the true heterogeneity variance is small . The VC estimator tends to overestimate the heterogeneity variance in general , but is quite accurate when the number of studies is large . The MV estimator is not a good estimator when the heterogeneity variance is small to moderate , but it is reasonably accurate when the heterogeneity variance is large . The MVvc estimator is an improved estimator compared to the MV estimator , especially for small to moderate values of the heterogeneity variance . The two estimators MVvc and EB are found to be the most accurate in general , particularly when the heterogeneity variance is moderate to large BACKGROUND Safety and immunogenicity study of an oral , killed , bivalent whole-cell , cholera vaccine , Shanchol was carried out in Bangladeshi participants . This study was conducted prior to initiating a feasibility study in Bangladesh . STUDY PARTICIPANTS The double-blind , r and omized placebo controlled study was carried out in adults ( 18 - 45 years ) , toddlers ( 2 - 5 years ) and younger children ( 12 - 23 months ) . Two doses of the vaccine/placebo were given 14 days apart . RESULTS Shanchol did not elicit major adverse events in any age group . Vibriocidal antibody responses in adults were 60 % against Vibrio cholerae O1 Inaba , 72 % against V. cholerae O1 Ogawa and 21 % against V. cholerae O139 . In toddlers , responses were 84 % , 75 % and 64 % and in younger children it was 74 % , 78 % and 54 % against Inaba , Ogawa and O139 serotypes . The responses in all ages were higher in vaccinees compared to pre-immune titers or to responses in placebo recipients ( P<0.001 ) . Plasma IgA antibody response to O1 Inaba LPS was seen in 61 % , 73 % and 45 % of adults , toddlers and younger children , respectively . CONCLUSIONS The safety and immunogenicity data for Shanchol is promising and warrants future use in large scale trial in cholera endemic areas , high risk Bangladeshi population and in other countries in the region BACKGROUND Several studies have shown that orally administered killed cholera vaccines are safe and protective in population s at risk of cholera in developing countries . However , these vaccines have not been adopted for use in developing countries because of their expense and limited efficacy in young children . We have tested an inexpensive , killed whole-cell cholera vaccine developed and produced in Vietnam . METHODS The efficacy of the vaccine was assessed in a large-scale , open field trial in people at least 1 year old residing in 22,653 households in the central coastal city of Hue . Alternate households were assigned vaccine ( 67,395 people ; two doses per person ) or no vaccine ( 67,058 people ) . Surveillance for cholera was conducted in all Ministry of Health facilities serving this population . Analysis was by intention to treat . FINDINGS During an outbreak of El Tor cholera 8 - 10 months after vaccination , 37 cases of cholera requiring inpatient care occurred among age-eligible people allocated to the vaccine group , and 92 cases among age-eligible people allocated to the no-vaccine group ( protective impact 60 % [ 95 % CI 40 - 73 ] ) . Among the 51,975 people who received the complete two-dose vaccine regimen , the protective efficacy was 66 % ( 46 - 79 ) : in this subset , the protective efficacy was similar for children aged 1 - 5 years ( 68 % ) and for older people ( 66 % ) . INTERPRETATION These findings suggest that oral killed whole-cell vaccines can confer substantial protection against El Tor cholera in young children , who are at highest risk of cholera in endemic setting s. An inexpensive , locally produced , and effective oral cholera vaccine may be within reach of the limited health-care budgets of poor countries with endemic cholera , if our findings can be replicated in a r and omised double-blind trial
BACKGROUND Killed whole-cell oral cholera vaccines ( kOCVs ) are becoming a st and ard 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 .