The Fatal Clinical Outcome of Severe COVID-19 in Hospitalized Patients: Findings from a Prospective Cohort Study in Dhaka, Bangladesh.

Background and Objectives: The morbidity and mortality associated with COVID-19 have burdened worldwide healthcare systems beyond their capacities, forcing them to promptly investigate the virus characteristics and its associated outcomes. This clinical analysis aimed to explore the key factors related to the fatal outcome of severe COVID-19 cases. Materials and Methods: Thirty-five adult severe COVID-19 patients were enrolled from two COVID-19 hospitals in Dhaka, Bangladesh. Clinical manifestation, comorbid conditions, medications, SARS-CoV-2 RT-PCR related cycle threshold (CT) value, hematology, biochemical parameters with SARS-CoV-2 specific IgG and IgM responses at enrollment were compared between the survivors and deceased participants. Results: Total 27 patients survived and 8 patients died within 3 months of disease onset. Deceased patients suffered longer from shortness of breath than the survived (p = 0.049). Among the severe cases, 62% of the deceased patients had multiple comorbid condition compared to 48% of those who survived. Interestingly, the anti-viral was initiated earlier among the deceased patients [median day of 1 (IQR: 0, 1.5) versus 6.5 (IQR: 6.25, 6.75)]. Most of the survivors (55%) received a combination of anticoagulant (p = 0.034). Liver enzymes, creatinine kinase, and procalcitonin were higher among the deceased patients during enrollment. The median CT value among the deceased was significantly lower than the survivors (p = 0.025). A significant difference for initial IgG (p = 0.013) and IgM (p = 0.030) responses was found between the survivor and the deceased groups. Conclusions: The factors including older age, male gender, early onset of respiratory distress, multiple comorbidities, low CT value, and poor antibody response may contribute to the fatal outcome in severe COVID-19 patients. Early initiation of anti-viral and a combination of anticoagulant treatment may prevent or lower the fatality among severe COVID-19 cases.

Prevention of Typhoid by Vi Conjugate Vaccine and Achievable Improvements in Household Water, Sanitation, and Hygiene: Evidence From a Cluster-Randomized Trial in Dhaka, Bangladesh.

BACKGROUND: Typhoid fever contributes to approximately 135 000 deaths annually. Achievable improvements in household water, sanitation, and hygiene (WASH) combined with vaccination using typhoid conjugate vaccines (TCVs) may be an effective preventive strategy. However, little is known about how improved WASH and vaccination interact to lower the risk of typhoid. METHODS: A total of 61 654 urban Bangladeshi children aged 9 months to <16 years, residing in 150 clusters with a baseline population of 205 760 residents, were randomized 1:1 by cluster to Vi-tetanus toxoid TCV or Japanese encephalitis (JE) vaccine. Surveillance for blood culture-confirmed typhoid fever was conducted over 2 years. Existing household WASH status was assessed at baseline as Better or Not Better using previously validated criteria. The reduction in typhoid risk among all residents associated with living in TCV clusters, Better WASH households, or both was evaluated using mixed-effects Poisson regression models. RESULTS: The adjusted reduced risk of typhoid among all residents living in the clusters assigned to TCV was 55% (95% confidence interval [CI], 43%-65%; P < .001), and that of living in Better WASH households, regardless of cluster, was 37% (95% CI, 24%-48%; P < .001). The highest risk of typhoid was observed in persons living in households with Not Better WASH in the JE clusters. In comparison with these persons, those living in households with Better WASH in the TCV clusters had an adjusted reduced risk of 71% (95% CI, 59%-80%; P < .001). CONCLUSIONS: Implementation of TCV programs combined with achievable and culturally acceptable household WASH practices were independently associated with a significant reduction in typhoid risk. CLINICAL TRIALS REGISTRATION: ISRCTN11643110.

Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial.

BACKGROUND: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. METHODS: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110. FINDINGS: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. INTERPRETATION: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. FUNDING: The study was funded by the Bill & Melinda Gates Foundation.

Sexual and reproductive health experiences of adolescent girls and women in marginalised communities in Bangladesh.

Participatory research was conducted with adolescent girls and women in three isolated rural communities of Bangladesh to assess their perspectives and the role of social and gender norms on the construction of knowledge regarding menstruation, pregnancy and abortion. Norms of privacy and silence, local beliefs and a culture of shame held that the human body is 'natural' and does not require formal sexual and reproductive health care. Instead, participants sought out traditional healers and used herbal plants as natural remedies. Participants reported being restricted in performing religious activities, cooking and food consumption during menstruation. Because sanitary protection was expensive, women used old cloths to soak up menstrual blood and used them repeatedly without washing with soap or drying in the open air, due to shame and the fear of evil spirits. The local incidence of child marriage was high, which also limited women's agency and voice. Contraceptive use was irregular and inappropriate; none of participants or their husbands used contraceptives, resulting in unwanted pregnancy often followed by unsafe abortion. Programmes and interventions are needed that engage with women's experiences within the sociocultural context of studied communities.

Acute Watery Diarrhea Surveillance During the Rohingya Crisis 2017-2019 in Cox's Bazar, Bangladesh.

BACKGROUND: Forcibly Displaced Myanmar Nationals (FDMNs) fled into Cox's Bazar, Bangladesh due to internal conflict. Considering the public health situation, a surveillance network was established to identify the enteric pathogens and early detection of cholera epidemics. The purpose of this manuscript is to report the clinical, epidemiological determinants of cholera and other enteric pathogens among hospitalized diarrheal patients from FDMNs and host community. METHODS: A total of 11 sentinel surveillance sites were established around the camps in Ukhia and Teknaf Upazila, Cox's Bazar. Rapid diagnostic testing was conducted for immediate detection of cholera cases. Stool samples were transferred to the Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b) laboratory for culture. RESULTS: A total of 8134 participants with diarrhea were enrolled from 2017 to 2019: 4881 were FDMNs and 3253 were from the Bangladeshi host community. Among the FDMNs, the proportion of Vibrio cholerae was 0.7%, the proportion of enterotoxigenic Escherichia coli (ETEC) was 4.9%, and the proportion of Shigella was 1.5%. The distributions from host community were 1.2% V cholerae, 1.8% ETEC, and 1.1% Shigella. Similar risk factors have been identified for the diarrheal pathogens for both communities. CONCLUSIONS: This surveillance helped to monitor the situation of diarrheal diseases including cholera in refugee camps as well as in the neighboring host community. These findings lead policymakers to take immediate preventive measures.

Can Existing Improvements of Water, Sanitation, and Hygiene (WASH) in Urban Slums Reduce the Burden of Typhoid Fever in These Settings?

BACKGROUND: Sustained investments in water, sanitation, and hygiene (WASH) have lagged in resource-poor settings; incremental WASH improvements may, nonetheless, prevent diseases such as typhoid in disease-endemic populations. METHODS: Using prospective data from a large cohort in urban Kolkata, India, we evaluated whether baseline WASH variables predicted typhoid risk in a training subpopulation (n = 28 470). We applied a machine learning algorithm to the training subset to create a composite, dichotomous (good, not good) WASH variable based on 4 variables, and evaluated sensitivity and specificity of this variable in a validation subset (n = 28 470). We evaluated in Cox regression models whether residents of "good" WASH households experienced a lower typhoid risk after controlling for potential confounders. We constructed virtual clusters (radius 50 m) surrounding each household to evaluate whether a prevalence of good WASH practices modified the typhoid risk in central household members. RESULTS: Good WASH practices were associated with protection in analyses of all households (hazard ratio [HR] = 0.57; 95% confidence interval [CI], .37-.90; P = .015). This protection was evident in persons ≥5 years old at baseline (HR = 0.47; 95% CI, .34-.93; P = .005) and was suggestive, though not statistically significant, in younger age groups (HR = 0.61; 95% CI, .27-1.38; P = .235). The level of surrounding household good WASH coverage was also associated with protection (HR = 0.988; 95% CI, .979-.996; P = .004, for each percent coverage increase). However, collinearity between household WASH and WASH coverage prevented an assessment of their independent predictive contributions. CONCLUSIONS: In this typhoid-endemic setting, natural variation in household WASH was associated with typhoid risk. If replicated elsewhere, these findings suggest that WASH improvements may enhance typhoid control, short of major infrastructural investments.

Women's attitudes and beliefs towards specific contraceptive methods in Bangladesh and Kenya.

BACKGROUND: Missing from the huge literature on women's attitudes and beliefs concerning specific contraceptive methods is any detailed quantitative documentation for all major methods in low- and middle-income countries. The objectives are to provide such a documentation for women living in Matlab (rural Bangladesh), Nairobi slums and Homa Bay (rural Kenya) and to compare the opinions and beliefs of current, past and never users towards the three most commonly used methods (oral contraceptives, injectables and implants). METHODS: In each site, 2424 to 2812 married women aged 15-39 years were interviewed on reproduction, fertility preferences, contraceptive knowledge and use, attitudes and beliefs towards family planning in general and specific methods. We analysed the data from round one of the prospective cohort study. RESULTS: While current users typically expressed satisfaction and held more positive beliefs about their method than past or never users, nevertheless appreciable minorities of current users thought the method might pose serious damage to health, might impair fertility and was unsafe for prolonged use without taking a break. Larger proportions, typically between 25% and 50%, associated their method with unpleasant side effects. Past users of pills and injectables outnumbered current users and their beliefs were similar to those of never users. In all three sites, about half of past injectable users reported satisfaction with the method and the satisfaction of past implant users was lower. CONCLUSIONS: High levels of contraceptive use can clearly co-exist with widespread misgivings about methods, even those that are widely used. Serious concerns about damage to health, long term fertility impairment, and dangers of prolonged use without taking a break were particularly common in the Kenyan sites and these beliefs may explain the high levels of discontinuation observed in Kenya and elsewhere in Africa. This documentation of beliefs provides useful guidance for counselling and informational campaigns. The generally negative views of past users imply that programmes may need not only to improve individual counselling but also strengthen community information campaign to change the overall climate of opinion which may have been influenced by dissatisfaction among past users.

Do Oral Cholera Vaccine and Water, Sanitation, and Hygiene Combine to Provide Greater Protection Against Cholera? Results From a Cluster-Randomized Trial of Oral Cholera Vaccine in Kolkata, India.

Background: Oral cholera vaccine (OCV) and incremental improvements in household water, sanitation, and hygiene (WASH) within cholera-endemic areas can reduce cholera risk. However, we lack empiric evaluation of their combined impact. Methods: We evaluated a cluster-randomized, placebo-controlled trial of OCV (Shanchol) in Kolkata, India. The study population included 108 777 individuals, and 106 879 nonpregnant individuals >1 year of age were eligible to receive 2 doses of OCV or placebo. We measured cholera risk in all household members assigned to OCV vs placebo and in all members of households with "Better" vs "Not Better" WASH, where WASH was classified according to validated criteria. Protection was measured by Cox proportional hazard models. Results: Residence in an OCV household was associated with protective effectiveness (PE) of 54% (95% CI, 42%-64%; P < .001) and was similar regardless of Better (PE, 57%; 95% CI, 26%-75%; P = .002) or Not Better (PE, 53%; 95% CI, 40%-64%; P < .001) household WASH. Better WASH household residence was associated with PE of 30% (95% CI, 5%-48%; P = .023) and was similar in OCV (PE, 24%; 95% CI, -26% to 54%; P = .293) and placebo (PE, 29%; 95% CI, -3% to 51%; P = .069) households. When assessed conjointly, residence in OCV households with Better WASH was associated with the greatest PE against cholera at 69% (95% CI, 49%-81%; P < .001). Conclusions: These findings suggest that the combination of a vaccine policy and improved WASH reduces cholera risk more than either would alone, although the magnitude of either intervention was not affected by the other. Future randomized trials investigating OCV and WASH interventions separately and together are recommended to further understand the interaction between OCV and WASH.

Spatial and temporal clustering of typhoid fever in an urban slum of Dhaka City: Implications for targeted typhoid vaccination.

BACKGROUND: Salmonella enterica serotype Typhi (Salmonella Typhi) causes severe and occasionally life-threatening disease, transmitted through contaminated food and water. Humans are the only reservoir, inadequate water, sanitation, and hygiene infrastructure increases risk of typhoid. High-quality data to assess spatial and temporal relationships in disease dynamics are scarce. METHODS: We analyzed data from a prospective cohort conducted in an urban slum area of Dhaka City, Bangladesh. Passive surveillance at study centers identified typhoid cases by microbiological culture. Each incident case (index case) was matched to two randomly selected index controls, and we measured typhoid incidence in the population residing in a geographically defined region surrounding each case and control. Spatial clustering was evaluated by comparing the typhoid incidence in residents of geometric rings of increasing radii surrounding the index cases and controls over 28 days. Temporal clustering was evaluated by separately measuring incidence in the first and second 14-day periods following selection. Incidence rate ratios (IRRs) were calculated using Poisson regression models. RESULTS: We evaluated 141 typhoid index cases. The overall typhoid incidence was 0.44 per 100,000 person-days (PDs) (95% CI: 0.40, 0.49). In the 28 days following selection, the highest typhoid incidence (1.2 per 100,000 PDs [95% CI: 0.8, 1.6]) was in the innermost cluster surrounding index cases. The IRR in this innermost cluster was 4.9 (95% CI: 2.4, 10.3) relative to the innermost control clusters. Neither typhoid incidence rates nor relative IRR between index case and control populations showed substantive differences in the first and second 14-day periods after selection. CONCLUSION: In the absence of routine immunization programs, geographic clustering of typhoid cases suggests a higher intensity of typhoid risk in the population immediately surrounding identified cases. Further studies are needed to understand spatial and temporal trends and to evaluate the effectiveness of targeted vaccination in disrupting typhoid transmission.

A phase 3 non-inferiority trial of locally manufactured Meningococcal ACWY vaccine 'Ingovax ACWY' among Bangladeshi adults.

Meningococcal disease is caused by Neisseria meningitidis or meningococcus. Every year globally around 1.2 million people are affected and approximately 120,000 deaths occur due to meningitis. The disease can be prevented by a single dose of meningococcal vaccine. We carried out a randomized observer-blinded non-inferiority trial to evaluate and compare the immunogenicity and safety of a local meningococcal polysaccharide vaccine 'Ingovax ACWY' (test) with Quadri MeningoTM (comparator), an approved meningococcal polysaccharide vaccine in India. A total of 88 healthy adults (18-45 years old) were randomized at a 1:1 ratio in two vaccine groups receiving a single dose vaccine subcutaneously. All participants were followed until three months post-vaccination. Blood for clinical parameters (hematology and biochemistry) and serum bactericidal assay (SBA) was collected prior to vaccination and one-month post-vaccination. Solicited adverse events (AEs) were assessed up to 6 days following vaccination and unsolicited AEs were monitored throughout the follow-up period. There was no significant difference in rates of AE between the two groups. The commonest solicited AE was injection site pain. No serious AEs were reported. There was no significant difference (p<0.05) in seroconversion rate as well as pre and post-vaccination SBA geometric mean titers (GMT)between test and comparator vaccine. The post-vaccination GMT ratio (GMR) of the test and comparator vaccine was found to be 0.9, 1, 1.29, and 0.85 for serogroup A, C, W135, and Y respectively. For all the serogroups, lower limit of 95% CI of the GMR was found to be greater than the pre-defined 0.5 non-inferiority margin suggesting that Ingovax ACWY is similar to Quadri MeningoTM vaccine. We observed the immunogenicity and safety of Ingovax ACWY is non-inferior to comparator vaccine. The development of facilities for manufacturing polysaccharide ACWY vaccines locally will further lead to capacity building in the field of vaccines for Bangladesh.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in Bangladesh.

Background: Shigella is an important cause of diarrhea in Bangladeshi children <5 years of age, with an incidence rate of 4.6 per 100 person-years. However, the report was more than a decade old, and data on Shigella consequences are similarly outdated and heterogeneously collected. Methods: Facility-based disease surveillance is planned to be carried out under the Enterics for Global Health (EFGH) Shigella Surveillance Study consortium for 2 years with aims to optimize and standardize laboratory techniques and healthcare utilization and coverage survey, clinical and anthropometric data collection, safety monitoring and responsiveness, and other related activities. The EFGH is a cohesive network of multidisciplinary experts, capable of operating in concert to conduct the study to generate data that will pave the way for potential Shigella vaccine trials in settings with high disease burden. The study will be conducted within 7 country sites in Asia, Africa, and Latin America. Conclusions: We outline the features of the Bangladesh site as part of this multisite surveillance network to determine an updated incidence rate and document the consequences of Shigella diarrhea in children aged 6-35 months, which will help inform policymakers and to implement the future vaccine trials.

A snap-shot of a diarrheal epidemic in Dhaka due to enterotoxigenic Escherichia coli and Vibrio cholerae O1 in 2022.

Background: Enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae O1 are most common bacterial causes of diarrheal diseases in Bangladesh. This analysis projected distribution of ETEC and V. cholerae O1 among diarrheal patients of icddr,b, Dhaka hospital in two diarrheal peaks of 2022. Methodology: Under the 2% systematic surveillance system, stool samples collected from diarrheal patients of icddr,b hospital were cultured and diagnostic testing was done for ETEC and V. cholerae O1. Comparison of positive cases was done between first peak (March-April) and second peak (October-November) in 2022. Results: A total of 2,937 stool specimens were tested of which 12% were ETEC and 20% were V. cholerae O1. About 40% of the severe dehydration cases were infected with V. cholerae O1. Predominant ETEC enterotoxin type was 'LT/ST' (41%). The LT enterotoxin significantly increased from 13% to 28% in the second peak (p = 0.015). The predominant colonization factors (CFs) on ETEC were CS5 + CS6 (23%), followed by CS6 (15%). CF-positive isolates was significantly higher in the second peak (36%) than in the first peak (22%) (p = 0.043). Total 14% cases were co-infected with ETEC and V. cholerae O1. Significant differences in the distribution of enterotoxin types were observed (p = 0.029) among the co-infection cases. Conclusion: Changing patterns of enterotoxin and CFs observed in ETEC pathogens should be taken into consideration for ETEC vaccine development. Considering cholera and ETEC biannual trends in causing diarrheal epidemics and outbreaks, emphasizes the need for thoughts on combination vaccine strategies for preventing acute watery diarrhea due to the two major bacterial pathogens.

National Hospital-Based Sentinel Surveillance for Cholera in Bangladesh: Epidemiological Results from 2014 to 2021.

Despite focusing on cholera burden, epidemiologic studies in Bangladesh tend to be limited in geographic scope. National-level cholera surveillance data can help inform cholera control strategies and assess the effectiveness of preventive measures. Hospital-based sentinel surveillance among patients with suspected diarrhea in different sites across Bangladesh has been conducted since 2014. We selected an age-stratified sample of 20 suspected cholera cases each week from each sentinel site, tested stool for the presence of Vibrio cholerae O1/O139 by culture, and characterized antibiotic susceptibility in a subset of culture-positive isolates. We estimated the odds of being culture positive among suspected cholera cases according to different potential risk factors. From May 4, 2014 through November 30, 2021, we enrolled 51,414 suspected cases from our sentinel surveillance sites. We confirmed V. cholerae O1 in 5.2% of suspected cases through microbiological culture. The highest proportion of confirmed cholera cases was from Chittagong (9.7%) and the lowest was from Rangpur Division (0.9%). Age, number of purges, duration of diarrhea, occupation, and season were the most relevant factors in distinguishing cholera-positive suspected cases from cholera-negative suspected cases. Nationwide surveillance data show that cholera is circulating in Bangladesh and the southern region is more affected than the northern region. Antimicrobial resistance patterns indicate that multidrug resistance (resistance to three or more classes of antibiotics) of V. cholerae O1 could be a major threat in the future. Alignment of these results with Bangladesh's cholera-control program will be the foundation for future research into the efficacy of cholera-control initiatives.

The interplay between WASH practices and vaccination with oral cholera vaccines in protecting against cholera in urban Bangladesh: Reanalysis of a cluster-randomized trial.

The current global initiative to end Cholera by 2030 emphasizes the use of oral cholera vaccine (OCV) combined with feasible household Water-Sanitation-Hygiene (WASH) interventions. However, little is known about how improved WASH practices and behaviors and OCV interact to reduce the risk of cholera. We reanalyzed two arms of a cluster-randomized trial in urban Bangladesh, to evaluate the effectiveness of OCV given as a 2-dose regimen. One arm (30 clusters, n = 94,675) was randomized to vaccination of persons aged one year and older with OCV, and the other arm (30 clusters, n = 80,056) to no intervention. We evaluated the prevention of cholera by household WASH, classified at baseline using a previously validated rule, and OCV over 2 years of follow-up. When analyzed by assignment to OCV clusters rather than receipt of OCV, in comparison to persons living in "Not Better WASH" households in the control clusters, reduction of severe cholera (the primary outcome) was similar for persons in "Not Better WASH" households in vaccine clusters (46%, 95% CI:24,62), for persons in "Better WASH" households in the control clusters (48%, 95% CI:25,64), and for persons in "Better WASH" households in the vaccine clusters (48%, 95% CI:16,67). In contrast, when analyzed by actual receipt of a complete OCV regimen, , in comparison to persons in "Not Better WASH" households in the control clusters, protection against severe cholera increased steadily from 39% (95% CI:13,58) in residents of "Better WASH" households in the control clusters to 57% (95% CI:35,72) in vaccinated persons in "Not Better WASH" households to 63% (95% CI:21,83) in vaccinated persons in "Better WASH" households. This analysis suggests that improved household WASH and OCV received may interact to provide greater protection against cholera. However, the divergence between findings related to intent to vaccinate versus those pertaining to actual receipt of OCV underscores the need for further research on this topic.

Association Among Household Water, Sanitation, and Hygiene (WASH) Status and Typhoid Risk in Urban Slums: Prospective Cohort Study in Bangladesh.

BACKGROUND: Typhoid fever, or enteric fever, is a highly fatal infectious disease that affects over 9 million people worldwide each year, resulting in more than 110,000 deaths. Reduction in the burden of typhoid in low-income countries is crucial for public health and requires the implementation of feasible water, sanitation, and hygiene (WASH) interventions, especially in densely populated urban slums. OBJECTIVE: In this study, conducted in Mirpur, Bangladesh, we aimed to assess the association between household WASH status and typhoid risk in a training subpopulation of a large prospective cohort (n=98,087), and to evaluate the performance of a machine learning algorithm in creating a composite WASH variable. Further, we investigated the protection associated with living in households with improved WASH facilities and in clusters with increasing prevalence of such facilities during a 2-year follow-up period. METHODS: We used a machine learning algorithm to create a dichotomous composite variable ("Better" and "Not Better") based on 3 WASH variables: private toilet facility, safe drinking water source, and presence of water filter. The algorithm was trained using data from the training subpopulation and then validated in a distinct subpopulation (n=65,286) to assess its sensitivity and specificity. Cox regression models were used to evaluate the protective effect of living in "Better" WASH households and in clusters with increasing levels of "Better" WASH prevalence. RESULTS: We found that residence in households with improved WASH facilities was associated with a 38% reduction in typhoid risk (adjusted hazard ratio=0.62, 95% CI 0.49-0.78; P<.001). This reduction was particularly pronounced in individuals younger than 10 years at the first census participation, with an adjusted hazard ratio of 0.49 (95% CI 0.36-0.66; P<.001). Furthermore, we observed an inverse relationship between the prevalence of "Better" WASH facilities in clusters and the incidence of typhoid, although this association was not statistically significant in the multivariable model. Specifically, the adjusted hazard of typhoid decreased by 0.996 (95% CI 0.986-1.006) for each percent increase in the prevalence of "Better" WASH in the cluster (P=.39). CONCLUSIONS: Our findings demonstrate that existing variations in household WASH are associated with differences in the risk of typhoid in densely populated urban slums. This suggests that attainable improvements in WASH facilities can contribute to enhanced typhoid control, especially in settings where major infrastructural improvements are challenging. These findings underscore the importance of implementing and promoting comprehensive WASH interventions in low-income countries as a means to reduce the burden of typhoid and improve public health outcomes in vulnerable populations.

Better Existing Water, Sanitation, and Hygiene Can Reduce the Risk of Cholera in an Endemic Setting: Results From a Prospective Cohort Study From Kolkata, India.

Background: Global cholera control efforts rely heavily on effective water, sanitation, and hygiene (WASH) interventions in cholera-endemic settings. Methods: Using data from a large, randomized controlled trial of oral cholera vaccine conducted in Kolkata, India, we evaluated whether natural variations in WASH in an urban slum setting were predictive of cholera risk. From the control population (n = 55 086), baseline WASH data from a randomly selected "training subpopulation" (n = 27 634) were analyzed with recursive partitioning to develop a dichotomous ("better" vs "not better") composite household WASH variable from several WASH features collected at baseline, and this composite variable was then evaluated in a mutually exclusive "validation population" (n = 27 452). We then evaluated whether residents of better WASH households in the entire population (n = 55 086) experienced lower cholera risk using Cox regression models. Better WASH was defined by a combination of 4 dichotomized WASH characteristics including safe source of water for daily use, safe source of drinking water, private or shared flush toilet use, and always handwashing with soap after defecation. Results: Residence in better WASH households was associated with a 30% reduction in risk of cholera over a 5-year period (adjusted hazard ratio, 0.70 [95% confidence interval, .49-.99]; P = .048). We also found that the impact of better WASH households on reducing cholera risk was greatest in young children (0-4 years) and this effect progressively declined with age. Conclusions: The evidence suggests that modest improvements in WASH facilities and behaviors significantly modify cholera risk and may be an important component of cholera prevention and elimination strategies in endemic settings. Clinical Trials Registration. NCT00289224.

Appearance of tolerance-induction and non-inflammatory SARS-CoV-2 spike-specific IgG4 antibodies after COVID-19 booster vaccinations.

Background: Understanding the characteristics of the humoral immune responses following COVID-19 vaccinations is crucial for refining vaccination strategies and predicting immune responses to emerging SARS-CoV-2 variants. Methods: A longitudinal analysis of SARS-CoV-2 spike receptor binding domain (RBD) specific IgG antibody responses, encompassing IgG subclasses IgG1, IgG2, IgG3, and IgG4 was performed. Participants received four mRNA vaccine doses (group 1; n=10) or two ChAdOx1 nCoV-19 and two mRNA booster doses (group 2; n=19) in Bangladesh over two years. Results: Findings demonstrate robust IgG responses after primary Covishield or mRNA doses; declining to baseline within six months. First mRNA booster restored and surpassed primary IgG responses but waned after six months. Surprisingly, a second mRNA booster did not increase IgG levels further. Comprehensive IgG subclass analysis showed primary Covishield/mRNA vaccination generated predominantly IgG1 responses with limited IgG2/IgG3, Remarkably, IgG4 responses exhibited a distinct pattern. IgG4 remained undetectable initially but increased extensively six months after the second mRNA dose, eventually replacing IgG1 after the 3rd/4th mRNA doses. Conversely, initial Covishield recipients lack IgG4, surged post-second mRNA booster. Notably, mRNA-vaccinated individuals displayed earlier, robust IgG4 levels post first mRNA booster versus Covishield counterparts. IgG1 to IgG4 ratios decreased with increasing doses, most pronounced with four mRNA doses. This study highlights IgG response kinetics, influenced by vaccine type and doses, impacting immunological tolerance and IgG4 induction, shaping future vaccination strategies. Conclusions: This study highlights the dynamics of IgG responses dependent on vaccine type and number of doses, leading to immunological tolerance and IgG4 induction, and shaping future vaccination strategies.

Are better existing WASH practices in urban slums associated with a lower long-term risk of severe cholera? A prospective cohort study with 4 years of follow-up in Mirpur, Bangladesh.

OBJECTIVE: To investigate the association between existing household water quality, sanitation and hygiene (WASH) practices and severe cholera risk in a dense urban slum where cholera is highly endemic. DESIGN, SETTING AND PARTICIPANTS: We assembled a large prospective cohort within a cluster randomised trial evaluating the effectiveness of oral cholera vaccine. Our dynamic cohort population (n=193 576) comprised individuals living in the 'non-intervention' clusters of the trial, and were followed over 4 years. This study was conducted in a dense urban slum community of Dhaka, Bangladesh and cholera surveillance was undertaken in 12 hospitals serving the study area. PRIMARY OUTCOME MEASURE: First severe cholera episode detected during follow-up period. METHODS: We applied a machine learning algorithm on a training subpopulation (n=96 943) to develop a binary ('better', 'not better') composite WASH variable predictive of severe cholera. The WASH rule was evaluated for performance in a separate validation subpopulation (n=96 633). Afterwards, we used Cox regression models to evaluate the association between 'better' WASH households and severe cholera risk over 4 years in the entire study population. RESULTS: The 'better' WASH rule found that water quality and access were the most significant factors associated with severe cholera risk. Members of 'better' WASH households, constituting one-third of the population, had a 47% reduced risk of severe cholera (95% CI: 29 to 69; p<0.001), after adjusting for covariates. The protective association between living in a 'better' WASH household and severe cholera persisted in all age groups. CONCLUSIONS: Salutary existing household WASH practices were associated with a significantly reduced long-term risk of severe cholera in an urban slum of Dhaka. These findings suggest that WASH adaptations already practised in the community may be important for developing and implementing effective and sustainable cholera control programmes in similar settings. TRIAL REGISTRATION NUMBER: This article is a re-analysis of data from a cluster randomized trial; can be found on ClinicalTrials.gov NCT01339845.

Prevention of Typhoid Fever by Existing Improvements in Household Water, Sanitation, and Hygiene, and the Use of the Vi Polysaccharide Typhoid Vaccine in Poor Urban Slums: Results from a Cluster-Randomized Trial.

Modest improvements in household water, sanitation, and hygiene (WASH) and typhoid vaccination can reduce typhoid risk in endemic settings. However, empiric evaluation of their combined impact is lacking. A total of 62,756 persons residing in 80 clusters in a Kolkata slum were allocated randomly 1:1 to either the typhoid Vi polysaccharide (ViPS) vaccine or hepatitis A (Hep A) vaccine. Surveillance was conducted for 2 years before and 2 years after vaccination. We classified households as having "better" or "not better" WASH, and calculated the prevalence of better WASH households in clusters using previously validated criteria. We evaluated the protection by better household WASH, better household WASH prevalence, and ViPS vaccination against typhoid in all cluster members present at baseline using Cox proportional hazard models. Overall, ViPS vaccination was associated with a 55% (P < 0.001; 95% CI, 35-69) reduction of typhoid risk and was similar regardless of better WASH in the residence. Living in a better WASH household was associated with a typhoid risk reduction of 31% (P = 0.16; 95% CI, -16 to 59) overall. The reduction was 48% (P = 0.05; 95% CI, -1 to 73) in Hep A clusters, 6% (P = 0.85; 95% CI, -82 to 51) in ViPS clusters, and 57% (P < 0.05; 95% CI, 15-78) in the population during the 2 years preceding the trial. These findings demonstrate a preventive association of better household WASH in the non-ViPS population, but, unexpectedly, an absence of additional protection from ViPS by better WASH in the ViPS population. This analysis highlights the importance of assessing the combination of WASH in conjunction with typhoid vaccines, and has implications for the evaluation of new-generation typhoid conjugate vaccines.

Cost of oral cholera vaccine delivery in a mass immunization program for children in urban Bangladesh.

Cholera poses a substantial health burden in the developing world due to both epidemic and endemic diseases. The World Health Organization recommends oral cholera vaccines for mass vaccination campaigns in addition to traditional prevention practices and treatments in resource-poor settings. In many developing countries like Bangladesh, the major challenge behind implementing mass vaccination campaigns concerns the affordability of the oral cholera vaccine (OCV). Vaccination of children with OCV is not only an impactful approach for controlling cholera at the population level and reducing childhood morbidity but is also considered more cost-effective than vaccinating all ages. The aim of the study was to estimate the cost of an OCV campaign for children from a societal perspective using empirical study. A total of 66,311 children aged 1 to 14 years old were fully vaccinated with two doses of the OCV Shanchol while 9,035 individuals received one dose of this vaccine. The estimated societal cost per individual for full vaccination was US$ 6.11, which includes the cost of vaccine delivery estimated at US$ 1.95. The cost per single dose was estimated at US$ 2.86. The total provider cost for full vaccination was estimated at US$ 6.01 and the recipient cost at US$ 0.10. Our estimation of OCV delivery costs for children was relatively higher than what was found in a similar mass OCV campaign for all age groups, indicating that there may be additional cost factors to consider in targeted vaccine campaigns. This analysis provides useful benchmarks for the possible costs related to delivery of OCV to children and future OCV cost-effectiveness models should factor in these possible cost disparities. Attempts to reduce the cost per dose are likely to have a greater impact on the cost of similar vaccination campaigns in many resource-poor settings.