Efficacy of a Single-Dose, Inactivated Oral Cholera Vaccine in Bangladesh.

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 randomly 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; ClinicalTrials.gov number, NCT02027207.).

Feasibility and effectiveness of oral cholera vaccine in an urban endemic setting in Bangladesh: a cluster randomised open-label trial.

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 hand washing to vaccination in this setting. METHODS: We did this cluster-randomised open-label trial in Dhaka, Bangladesh. We randomly 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 ClinicalTrials.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 populations 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 populations. FUNDING: Bill & Melinda Gates Foundation.

Knowledge of, attitudes toward, and preventive practices relating to cholera and oral cholera vaccine among urban high-risk groups: findings of a cross-sectional study in Dhaka, Bangladesh.

BACKGROUND: In endemic countries such as Bangladesh, consequences of cholera place an enormous financial and social burden on patients and their families. Cholera vaccines not only provide health benefits to susceptible populations but also have effects on the earning capabilities and financial stability of the family. Community-based research and evaluations are necessary to understand perceptions about and practices of the community relating to cholera and oral cholera vaccines. This may help identify the ways in which such vaccines may be successfully introduced, and other preventive measures can be implemented. The present study assessed the knowledge of, attitudes toward, and preventive practices relating to cholera and oral cholera vaccine among an urban population residing in a high cholera-prone setting in Dhaka, Bangladesh. METHODS: This cross-sectional study was conducted in an area of high cholera prevalence in 15 randomly-selected clusters in Mirpur, Dhaka city. A study team collected data through a survey and in-depth interviews during December 2010-February 2011. RESULTS: Of 2,830 families included in the final analysis, 23% could recognize cholera as acute watery diarrhea and 16% had ever heard of oral cholera vaccine. About 54% of the respondents had poor knowledge about cholera-related issues while 97% had a positive attitude toward cholera and oral cholera vaccine. One-third showed poor practice relating to the prevention of cholera.The findings showed a significant (p < 0.05) association between the respondents' knowledge and sex, education, occupation, monthly overall household expenditure, attitudes and practice. In the adjusted model, male sex, having a lower monthly overall household expenditure, and having a less positive attitude toward cholera were the significant predictors to having poor knowledge. CONCLUSIONS: The findings suggest the strengthening of health education activities to improve knowledge on cholera, its prevention and treatment and information on cholera vaccination among high-risk populations. The data also underscore the potential of mass cholera vaccination to prevent and control cholera.

Effect of the Integrated Management of Childhood Illness strategy on childhood mortality and nutrition in a rural area in Bangladesh: a cluster randomised trial.

BACKGROUND: WHO and UNICEF launched the Integrated Management of Childhood Illness (IMCI) strategy in the mid-1990s to reduce deaths from diarrhoea, pneumonia, malaria, measles, and malnutrition in children younger than 5 years. We assessed the effect of IMCI on health and nutrition of children younger than 5 years in Bangladesh. METHODS: In this cluster randomised trial, 20 first-level government health facilities in the Matlab subdistrict of Bangladesh and their catchment areas (total population about 350 000) were paired and randomly assigned to either IMCI (intervention; ten clusters) or usual services (comparison; ten clusters). All three components of IMCI-health-worker training, health-systems improvements, and family and community activities-were implemented beginning in February, 2002. Assessment included household and health facility surveys tracking intermediate outputs and outcomes, and nutrition and mortality changes in intervention and comparison areas. Primary endpoint was mortality in children aged between 7 days and 59 months. Analysis was by intention to treat. This study is registered, number ISRCTN52793850. FINDINGS: The yearly rate of mortality reduction in children younger than 5 years (excluding deaths in first week of life) was similar in IMCI and comparison areas (8.6%vs 7.8%). In the last 2 years of the study, the mortality rate was 13.4% lower in IMCI than in comparison areas (95% CI -14.2 to 34.3), corresponding to 4.2 fewer deaths per 1000 livebirths (95% CI -4.1 to 12.4; p=0.30). Implementation of IMCI led to improved health-worker skills, health-system support, and family and community practices, translating into increased care-seeking for illnesses. In IMCI areas, more children younger than 6 months were exclusively breastfed (76%vs 65%, difference of differences 10.1%, 95% CI 2.65-17.62), and prevalence of stunting in children aged 24-59 months decreased more rapidly (difference of differences -7.33, 95% CI -13.83 to -0.83) than in comparison areas. INTERPRETATION: IMCI was associated with positive changes in all input, output, and outcome indicators, including increased exclusive breastfeeding and decreased stunting. However, IMCI implementation had no effect on mortality within the timeframe of the assessment. FUNDING: Bill & Melinda Gates Foundation, WHO's Department of Child and Adolescent Health and Development, and US Agency for International Development.

Invasive pneumococcal disease among children in rural Bangladesh: results from a population-based surveillance.

BACKGROUND: Streptococcus pneumoniae infection is recognized as a global priority public health problem, and conjugate vaccines have been shown to prevent vaccine-type invasive pneumococcal disease (IPD) in children. However, better estimates of the disease burden and reliable population-based data on serotype composition are needed for vaccine development and implementation in developing countries. METHODS: We initiated a population-based surveillance in the rural Bangladesh community of Mirzapur, covering a population of approximately 144,000. Village health care workers made weekly visits to approximately 12,000 children 1-59 months of age in the study area. Children with reported fever, cough, or difficulty breathing were assessed by the village health care workers using a clinical algorithm and were referred to the hospital if required. Children from the study area who were seen in the hospital underwent clinical examination and laboratory testing if they met standardized case definitions. IPD was confirmed by blood and/or cerebrospinal fluid culture results. Isolates were identified, tested for susceptibility to antibiotics, and serotyped in accordance with standard laboratory methods. We present here the results from the first 3 years of the surveillance (July 2004-June 2007). RESULTS: Village health care workers identified 5020 cases of possible severe pneumonia and/or very severe disease (165 cases per 1000 child-years)and 9411 cases of possible pneumonia (310 cases per 1000 child-years) as well as 2029 cases of suspected meningitis and/or very severe disease (67 cases per 1000 child-years) and 8967 cases of high fever and/or possible bacteremia (295 cases per 1000 child-years). Pneumonia was the single most common form of illness observed among 2596 hospitalizations (found in 977 [38%] of cases). We recovered 26 S. pneumoniae isolates (25 isolates from 6925 blood cultures and 1 isolate from 41 cerebrospinal fluid cultures), which gave an overall IPD incidence of 86 cases per 100,000 child-years. Invasive pneumococcal infection was common during infancy (with infants accounting for 23 of the 26 cases), and 50% of the total isolates were obtained from nonhospitalized patients who received a diagnosis of upper respiratory tract infection and fever. The most prevalent pneumococcal serotypes were serotypes 1, 5, 14, 18C, 19A, and 38. Ten of the 26 isolates were completely resistant to trimethoprim-sulfamethoxazole, and another 10 isolates had intermediate resistance. CONCLUSIONS: IPD contributes substantially to childhood morbidity in rural Bangladesh. S. pneumoniae can cause invasive but nonsevere disease in children, and IPD incidence can be seriously under reported if such cases are overlooked. The emerging high resistance to trimethoprim-sulfamethoxazole should be addressed. Data on serotype distribution would help to guide appropriate pneumococcal conjugate vaccine formulation.

Care at first-level facilities for children with severe pneumonia in Bangladesh: a cohort study.

BACKGROUND: Guidelines on integrated management of childhood illness (IMCI) for severe pneumonia recommend referral to hospitals. However, in many settings, children who are referred do not actually attend hospital, which severely limits appropriate care. We aimed to assess the safety and effectiveness of modified guidelines that allowed most children with severe pneumonia to be treated locally in first-level facilities, with referral only for those with danger signs or other severe classifications. METHODS: We did an observational cohort study in ten first-level health facilities in Matlab, rural Bangladesh that had implemented IMCI guidelines. We assessed children with severe pneumonia who were aged between 2 and 59 months, and for whom we could obtain complete information, in two cohorts: 261 children who presented to these facilities between May, 2003, and April, 2004 (before implementation of the modified guidelines) and 1271 children between September, 2004, and August, 2005 (after full implementation). We obtained information about the characteristics and management of their illness, including referrals and admissions to hospital, from facility records. Staff visited households to obtain details of treatment, socioeconomic information, and final outcome, including mortality data. FINDINGS: 245 (94%) of 261 children who had severe pneumonia were referred to hospital before the guidelines were modified, compared with 107 (8%) of 1271 after implementation (p<0.0001). 94 (36%) children with severe pneumonia received correct management before the guidelines were modified, compared with 1145 (90%) children after implementation (p<0.0001). Before modification of the guidelines, three children with severe pneumonia who presented at first-level facilities died, with a case-fatality rate of 1.1%; after modification, seven children died, with a case-fatality rate of 0.6% (p=0.39). INTERPRETATION: Local adaptation of the IMCI guidelines, with appropriate training and supervision, could allow safe and effective management of severe pneumonia, especially if compliance with referral is difficult because of geographic, financial, or cultural barriers.

Post-vaccination campaign coverage evaluation of oral cholera vaccine, oral polio vaccine and measles-rubella vaccine among Forcibly Displaced Myanmar Nationals in Bangladesh.

Background: The new influx of Forcibly Displaced Myanmar Nationals (FDMNs) into Bangladesh started in August 2017 through different entry points of Bangladesh. Considering the imminent threat of infectious diseases outbreaks, the Government of Bangladesh (GoB) decided to vaccinate children against three deadly diseases (measles, rubella and poliomyelitis) and oral cholera vaccine (OCV) for all except <1 year children. After completion of the campaigns, post-vaccination campaign evaluation was carried out to assess the coverage of OCV, OPV and MR vaccines during campaigns.Methods: Post-vaccination campaign evaluation was conducted after completion of the 2nd dose of oral cholera vaccine (OCV2) and oral polio vaccine (OPV2) through a cross-sectional survey. The evaluation was conducted in the Balukhali camps under Ukhiya upazilla. Precision-based sample size was calculated to estimate the vaccine coverage. Ninety-two trained interviewers were involved to collect data from the target of approximately 40000 FDMNs between 18 and 25 November 2017.Results: Data were collected from 39,438 FDMNs during the survey period. The highest coverage was observed for OCVs (94% for OCV1 and 92% for OCV2). On the other hand, lower coverage was observed for the other vaccines; the coverage for OPV1, OPV2 and MR were 75%, 88% and 38%, respectively. Unawareness (30.7% did not know about the campaign) was the most notable cause of lowering down MR vaccine coverage.Conclusion: The experience in Bangladesh demonstrates that vaccine campaigns can be successfully implemented as part of a comprehensive response toward disease outbreak among high-risk populations in humanitarian crisis.

Feasibility of engaging "Village Doctors" in the Community-based Integrated Management of Childhood Illness (C-IMCI): experience from rural Bangladesh.

BACKGROUND: Informal health care providers particularly "village doctors" are the first point of care for under-five childhood illnesses in rural Bangladesh. We engaged village doctors as part of the Multi-Country Evaluation (MCE) of Integrated Management of Childhood Illness (IMCI) and assessed their management of sick under-five children before and after a modified IMCI training, supplemented with ongoing monitoring and supportive supervision. METHODS: In 2003-2004, 144 village doctors across 131 IMCI intervention villages in Matlab Bangladesh participated in a two-day IMCI training; 135 of which completed pre- and post-training evaluation tests. In 2007, 38 IMCI-trained village doctors completed an end-of-project knowledge retention test. Village doctor prescription practices for sick under-five children were examined through household surveys, and routine monitoring visits. In-depth interviews were done with mothers seeking care from village doctors. RESULTS: Village doctors' knowledge on the assessment and management of childhood illnesses improved significantly after training; knowledge of danger signs of pneumonia and severe pneumonia increased from 39% to 78% (P < 0.0001) and from 17% to 47% (P < 0.0001) respectively. Knowledge on the correct management of severe pneumonia increased from 62% to 84% (P < 0.0001), and diarrhoea management improved from 65% to 82% (P = 0.0005). Village doctors retained this knowledge over three years except for home management of pneumonia. No significant differences were observed in prescribing practices for diarrhoea and pneumonia management between trained and untrained village doctors. Village doctors were accessible to communities; 76% had cell phones; almost all attended home calls, and did not charge consultation fees. Nearly all (91%) received incentives from pharmaceutical representatives. CONCLUSIONS: Village doctors have the capacity to learn and retain knowledge on the appropriate management of under-five illnesses. Training alone did not improve inappropriate antibiotic prescription practices. Intensive monitoring and efforts to target key actors including pharmaceutical companies, which influence village doctors dispensing practices, and implementation of mechanisms to track and regulate these providers are necessary for future engagement in management of under-five childhood illnesses.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Bill & Melinda Gates Foundation to the International Vaccine Institute.