Preventing cholera outbreaks through early targeted interventions.

In a Perspective, Lorenz von Seidlein and Jacqueline L. Deen discuss the implications of Andrew Azman and colleagues' accompanying study for management of cholera outbreaks.

Affordable house designs to improve health in rural Africa: a field study from northeastern Tanzania.

BACKGROUND: The population of sub-Saharan Africa is currently estimated to be 1245 million and is expected to quadruple by the end of the century, necessitating the building of millions of homes. Malaria remains a substantial problem in this region and efforts to minimise transmission should be considered in future house planning. We studied how building elements, which have been successfully employed in southeast Asia to prevent mosquitos from entering and cooling the house, could be integrated in a more sustainable house design in rural northeastern Tanzania, Africa, to decrease mosquito density and regulate indoor climate. METHODS: In this field study, six prototype houses of southeast Asian design were built in in the village of Magoda in Muheza District, Tanga Region, Tanzania, and compared with modified and unmodified, traditional, sub-Saharan African houses. Prototype houses were built with walls made of lightweight permeable materials (bamboo, shade net, or timber) with bedrooms elevated from the ground and with screened windows. Modified and unmodified traditional African houses, wattle-daub or mud-block constructions, built on the ground with poor ventilation served as controls. In the modified houses, major structural problems such as leaking roofs were repaired, windows screened, open eaves blocked with bricks and mortar, cement floors repaired or constructed, and rain gutters and a tank for water storage added. Prototype houses were randomly allocated to village households through a free, fair, and transparent lottery. The lottery tickets were deposited in a bucket made of transparent plastic. Each participant could draw one ticket. Hourly measurements of indoor temperature and humidity were recorded in all study houses with data loggers and mosquitoes were collected indoors and outdoors using Furvela tent traps and were identified with standard taxonomic keys. Mosquitoes of the Anopheles gambiae complex were identified to species using PCR. Attitudes towards the new house design were assessed 6-9 months after the residents moved into their new or modified homes through 15 in-depth interviews with household heads of the new houses and five focus group discussions including neighbours of each group of prototype housing. FINDINGS: Between July, 2014, and July, 2015, six prototype houses were constructed; one single and one double storey building with each of the following claddings: bamboo, shade net, and timber. The overall reduction of all mosquitoes caught was highest in the double-storey buildings (96%; 95% CI 92-98) followed closely by the reduction found in single-storey buildings (77%; 72-82) and lowest in the modified reference houses (43%; 36-50) and unmodified reference houses (23%; 18-29). The indoor temperature in the new design houses was 2·3°C (95% CI 2·2-2·4) cooler than in the reference houses. While both single and two-storey buildings provided a cooler indoor climate than did traditional housing, two-story buildings provided the biggest reduction in mosquito densities (96%, 95% CI 89-100). Seven people who moved into the prototype houses and seven of their neighbours (three of whom had their houses modified) participated in in-depth interviews. After living in their new prototype houses for 6-9 months, residents expressed satisfaction with the new design, especially the second-storey sleeping area because of the privacy and security of upstairs bedrooms. INTERPRETATION: The new design houses had fewer mosquitoes and were cooler than modified and unmodified traditional homes. New house designs are an underused intervention and hold promise to reduce malaria transmission in sub-Saharan Africa and keep areas malaria-free after elimination. FUNDING: Ruth W Jensens Foundation, Copenhagen and Hanako Foundation, Singapore.

Assessing different measures of population-level vaccine protection using a case-control study.

BACKGROUND: Case-control studies have not been examined for their utility in assessing population-level vaccine protection in individually randomized trials. METHODS: We used the data of a randomized, placebo-controlled trial of a cholera vaccine to compare the results of case-control analyses with those of cohort analyses. Cases of cholera were selected from the trial population followed for three years following dosing. For each case, we selected 4 age-matched controls who had not developed cholera. For each case and control, GIS was used to calculate vaccine coverage of individuals in a surrounding "virtual" cluster. Specific selection strategies were used to evaluate the vaccine protective effects. RESULTS: 66,900 out of 108,389 individuals received two doses of the assigned regimen. For direct protection among subjects in low vaccine coverage clusters, we observed 78% (95% CI: 47-91%) protection in a cohort analysis and 84% (95% CI: 60-94%) in case-control analysis after adjusting for confounding factors. Using our GIS-based approach, estimated indirect protection was 52% (95% CI: 10-74%) in cohort and 76% (95% CI: 47-89%) in case control analysis. Estimates of total and overall effectiveness were similar for cohort and case-control analyses. CONCLUSION: The findings show that case-control analyses of individually randomized vaccine trials may be used to evaluate direct as well as population-level vaccine protection.

5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial.

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 aimed to assess protective efficacy up to 5 years in a slum area of Kolkata, India. METHODS: In our double-blind, cluster-randomised, 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 randomly 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. Randomisation 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 settings. FUNDING: Bill & Melinda Gates Foundation and the governments of South Korea and Sweden.

Risk map of cholera infection for vaccine deployment: the eastern Kolkata case.

BACKGROUND: Despite advancement of our knowledge, cholera remains a public health concern. During March-April 2010, a large cholera outbreak afflicted the eastern part of Kolkata, India. The quantification of importance of socio-environmental factors in the risk of cholera, and the calculation of the risk is fundamental for deploying vaccination strategies. Here we investigate socio-environmental characteristics between high and low risk areas as well as the potential impact of vaccination on the spatial occurrence of the disease. METHODS AND FINDINGS: The study area comprised three wards of Kolkata Municipal Corporation. A mass cholera vaccination campaign was conducted in mid-2006 as the part of a clinical trial. Cholera cases and data of the trial to identify high risk areas for cholera were analyzed. We used a generalized additive model (GAM) to detect risk areas, and to evaluate the importance of socio-environmental characteristics between high and low risk areas. During the one-year pre-vaccination and two-year post-vaccination periods, 95 and 183 cholera cases were detected in 111,882 and 121,827 study participants, respectively. The GAM model predicts that high risk areas in the west part of the study area where the outbreak largely occurred. High risk areas in both periods were characterized by poor people, use of unsafe water, and proximity to canals used as the main drainage for rain and waste water. Cholera vaccine uptake was significantly lower in the high risk areas compared to low risk areas. CONCLUSION: The study shows that even a parsimonious model like GAM predicts high risk areas where cholera outbreaks largely occurred. This is useful for indicating where interventions would be effective in controlling the disease risk. Data showed that vaccination decreased the risk of infection. Overall, the GAM-based risk map is useful for policymakers, especially those from countries where cholera remains to be endemic with periodic outbreaks.

Herd protection by a bivalent killed whole-cell oral cholera vaccine in the slums of Kolkata, India.

BACKGROUND: We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches: cluster design and geographic information system (GIS) design. METHODS: Residents living in 3933 dwellings (clusters) in Kolkata, India, were cluster-randomized to receive either cholera vaccine or oral placebo. Nonpregnant residents aged≥1 year were invited to participate in the trial. Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered. In the cluster design, indirect protection was assessed by comparing the incidence of cholera among nonparticipants in vaccine clusters vs those in placebo clusters. In the GIS analysis, herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population. RESULTS: Among 107 347 eligible residents, 66 990 received 2 doses of either cholera vaccine or placebo. In the cluster design, the 3-year data showed significant total protection (66% protection, 95% confidence interval [CI], 50%-78%, P<.01) but no evidence of indirect protection. With the GIS approach, the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage, and the trend was highly significant (P<.01). This relationship held in multivariable models that also controlled for potentially confounding demographic variables (hazard ratio, 0.94 [95% CI, .90-.98]; P<.01). CONCLUSIONS: Indirect protection was evident in analyses using the GIS approach but not the cluster design approach, likely owing to considerable transmission of cholera between clusters, which would vitiate herd protection in the cluster analyses. CLINICAL TRIALS REGISTRATION: NCT00289224.

Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy.

INTRODUCTION: Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy should cholera occur in these women, as well as the lack of expected adverse events from a killed oral bacterial vaccine. METHODOLOGY/PRINCIPAL FINDINGS: From January to February 2009, a mass rBS-WC vaccination campaign of persons over two years of age was conducted in an urban and a rural area (population 51,151) in Zanzibar. Pregnant women were advised not to participate in the campaign. More than nine months after the last dose of the vaccine was administered, we visited all women between 15 and 50 years of age living in the study area. The outcome of pregnancies that were inadvertently exposed to at least one oral cholera vaccine dose and those that were not exposed was evaluated. 13,736 (94%) of the target women in the study site were interviewed. 1,151 (79%) of the 1,453 deliveries in 2009 occurred during the period when foetal exposure to the vaccine could have occurred. 955 (83%) out of these 1,151 mothers had not been vaccinated; the remaining 196 (17%) mothers had received at least one dose of the oral cholera vaccine. There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies. CONCLUSIONS/SIGNIFICANCE: We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial vaccine, are reassuring but the study had insufficient power to detect infrequent events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00709410.

Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial.

BACKGROUND: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. METHODS: African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. RESULTS: Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. CONCLUSIONS: Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.

Efficacy of a low-cost, inactivated whole-cell oral cholera vaccine: results from 3 years of follow-up of a randomized, controlled trial.

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 randomized, clinical trials. METHODS/PRINCIPAL FINDINGS: We conducted a cluster-randomized, 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: ClinicalTrials.gov NCT00289224.

Assessment and comparative analysis of a rapid diagnostic test (Tubex®) for the diagnosis of typhoid fever among hospitalized children in rural Tanzania.

BACKGROUND: Typhoid fever remains a significant health problem in many developing countries. A rapid test with a performance comparable to that of blood culture would be highly useful. A rapid diagnostic test for typhoid fever, Tubex®, is commercially available that uses particle separation to detect immunoglobulin M directed towards Salmonella Typhi O9 lipopolysaccharide in sera. METHODS: We assessed the sensitivity and specificity of the Tubex test among Tanzanian children hospitalized with febrile illness using blood culture as gold standard. Evaluation was done considering blood culture confirmed S. Typhi with non-typhi salmonella (NTS) and non - salmonella isolates as controls as well as with non-salmonella isolates only. RESULTS: Of 139 samples tested with Tubex, 33 were positive for S. Typhi in blood culture, 49 were culture-confirmed NTS infections, and 57 were other non-salmonella infections. Thirteen hemolyzed samples were excluded. Using all non - S. Typhi isolates as controls, we showed a sensitivity of 79% and a specificity of 89%. When the analysis was repeated excluding NTS from the pool of controls we showed a sensitivity of 79% and a specificity of 97%. There was no significant difference in the test performance using the two different control groups (p > 0.05). CONCLUSION: This first evaluation of the Tubex test in an African setting showed a similar performance to those seen in some Asian settings. Comparison with the earlier results of a Widal test using the same samples showed no significant difference (p > 0.05) for any of the performance indicators, irrespective of the applied control group.

The case for reactive mass oral cholera vaccinations.

INTRODUCTION: The outbreak of cholera in Zimbabwe intensified interest in the control and prevention of cholera. While there is agreement that safe water, sanitation, and personal hygiene are ideal for the long term control of cholera, there is controversy about the role of newer approaches such as oral cholera vaccines (OCVs). In October 2009 the Strategic Advisory Group of Experts advised the World Health Organization to consider reactive vaccination campaigns in response to large cholera outbreaks. To evaluate the potential benefit of this pivotal change in WHO policy, we used existing data from cholera outbreaks to simulate the number of cholera cases preventable by reactive mass vaccination. METHODS: Datasets of cholera outbreaks from three sites with varying cholera endemicity--Zimbabwe, Kolkata (India), and Zanzibar (Tanzania)--were analysed to estimate the number of cholera cases preventable under differing response times, vaccine coverage, and vaccine doses. FINDINGS: The large cholera outbreak in Zimbabwe started in mid August 2008 and by July 2009, 98,591 cholera cases had been reported with 4,288 deaths attributed to cholera. If a rapid response had taken place and half of the population had been vaccinated once the first 400 cases had occurred, as many as 34,900 (40%) cholera cases and 1,695 deaths (40%) could have been prevented. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. A brisk response is required for outbreaks with the majority of cases occurring during the early weeks. Even a delayed response can save a substantial number of cases and deaths in long, drawn-out outbreaks. If circumstances prevent a rapid response there are good reasons to roll out cholera mass vaccination campaigns well into the outbreak. Once a substantial proportion of a population is vaccinated, outbreaks in subsequent years may be reduced if not prevented. A single dose vaccine would be of advantage in short, small outbreaks. CONCLUSIONS: We show that reactive vaccine use can prevent cholera cases and is a rational response to cholera outbreaks in endemic and non-endemic settings. In large and long outbreaks a reactive vaccination with a two-dose vaccine can prevent a substantial proportion of cases. To make mass vaccination campaigns successful, it would be essential to agree when to implement reactive vaccination campaigns and to have a dynamic and determined response team that is familiar with the logistic challenges on standby. Most importantly, the decision makers in donor and recipient countries have to be convinced of the benefit of reactive cholera vaccinations.

Use of verbal autopsy to determine mortality patterns in an urban slum in Kolkata, India.

OBJECTIVE: To define mortality patterns in an urban slum in Kolkata, India, in the context of a cholera and typhoid fever project. METHODS: In a well-defined population that was under surveillance for 18 months, we followed a dynamic cohort of 63 788 residents whose households were visited monthly by community health workers to identify deaths. Trained physicians performed verbal autopsies and experienced senior physicians assigned the primary cause of death according to the International classification of diseases, 10th edition. We tabulated causes of death in accordance with Global Burden of Disease 2000 categories and assessed overall and cause-specific mortality rates per age group and gender. FINDINGS: During 87 921 person-years of follow-up, we recorded 544 deaths. This gave an overall mortality rate of 6.2 per 1000 person-years. We assigned a cause to 89% (482/544) of the deaths. The leading causes of death, in descending order, were cardiovascular diseases (especially among adults aged over 40 years), cancer, respiratory ailments and digestive disorders. Most deaths in children under 5 years of age were caused by tuberculosis, respiratory infections and diarrhoeal diseases. CONCLUSION: Although the most common causes of death in children were infectious, non-communicable diseases were predominant among adults. There is a need for continuing interventions against infectious diseases in addition to new and innovative strategies to combat non-infectious conditions.

Evaluation of the Widal tube agglutination test for the diagnosis of typhoid fever among children admitted to a rural hdospital in Tanzania and a comparison with previous studies.

BACKGROUND: The diagnosis of typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi (S. typhi). However, a more rapid, simpler, and cheaper diagnostic method would be very useful especially in developing countries. The Widal test is widely used in Africa but little information exists about its reliability. METHODS: We assessed the performance of the Widal tube agglutination test among febrile hospitalized Tanzanian children. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various anti-TH and -TO titers using culture-confirmed typhoid fever cases as the "true positives" and all other febrile children with blood culture negative for S. typhi as the "true negatives." RESULTS: We found that 16 (1%) of 1,680 children had culture-proven typhoid fever. A single anti-TH titer of 1:80 and higher was the optimal indicator of typhoid fever. This had a sensitivity of 75%, specificity of 98%, NPV of 100%, but PPV was only 26%. We compared our main findings with those from previous studies. CONCLUSION: Among febrile hospitalized Tanzanian children with a low prevalence of typhoid fever, a Widal titer of > or = 1:80 performed well in terms of sensitivity, specificity, and NPV. However a test with improved PPV that is similarly easy to apply and cost-efficient is desirable.

Invasive salmonellosis among children admitted to a rural Tanzanian hospital and a comparison with previous studies.

BACKGROUND: The importance of invasive salmonellosis in African children is well recognized but there is inadequate information on these infections. We conducted a fever surveillance study in a Tanzanian rural hospital to estimate the case fraction of invasive salmonellosis among pediatric admissions, examine associations with common co-morbidities and describe its clinical features. We compared our main findings with those from previous studies among children in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: From 1 March 2008 to 28 Feb 2009, 1,502 children were enrolled into the study. We collected clinical information and blood for point of care tests, culture, and diagnosis of malaria and HIV. We analyzed the clinical features on admission and outcome by laboratory-confirmed diagnosis. Pathogenic bacteria were isolated from the blood of 156 (10%) children, of which 14 (9%) were S. typhi, 45 (29%) were NTS and 97 (62%) were other pathogenic bacteria. Invasive salmonellosis accounted for 59/156 (38%) bacteremic children. Children with typhoid fever were significantly older and presented with a longer duration of fever. NTS infections were significantly associated with prior antimalarial treatment, malarial complications and with a high risk for death. CONCLUSIONS/SIGNIFICANCE: Invasive salmonellosis, particularly NTS infection, is an important cause of febrile disease among hospitalized children in our rural Tanzanian setting. Previous studies showed considerable variation in the case fraction of S. typhi and NTS infections. Certain suggestive clinical features (such as older age and long duration of fever for typhoid whereas concomitant malaria, anemia, jaundice and hypoglycemia for NTS infection) may be used to distinguish invasive salmonellosis from other severe febrile illness.

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.

BACKGROUND: Oral cholera vaccines consisting of killed whole cells have been available for many years, but they have not been used extensively in populations with endemic disease. An inexpensive, locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam. To expand the use of this vaccine, it was modified to comply with WHO standards. 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-randomised 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. Randomisation 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 ClinicalTrials.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 standards, is safe, provides protection against clinically 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 settings. FUNDING: Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, Governments of South Korea, Sweden, and Kuwait.