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Vaccine clinical trials are necessary in low- and middle-income countries (LMICs) because new vaccine candidates are developed against diseases found mainly in these settings, the results of trials done in industrialized countries may not be generalizable to LMICs and more institutions in middle-income countries are producing vaccines for use in LMICs.We searched PubMed and conducted a narrative review on standard, newer and proposed approaches toward obtaining data supportive for vaccine licensure, with a special focus in LMICs.Of the vaccine trials done worldwide, only a small proportion is conducted in LMICs, but this is likely to increase as more research experience and infrastructure is developed. At present, the majority of vaccine trials follows the standard paradigm of fixed phase 1 to 3 trials, the latter with clinical endpoints, or immunobridging studies when a valid immunocorrelate of vaccine protection exists. Other study designs may help facilitate the generation of data toward licensure of and recommendations for needed vaccines. Increased international collaboration is needed for local capacity building and regulatory oversight to ensure that all studies are conducted under good clinical practice.

Bangladesh remains cholera endemic with biannual seasonal peaks causing epidemics. At least 300,000 severe cases and over 4,500 deaths occur each year. The available oral cholera vaccineshave not yet been adopted for cholera control in Bangladesh due to insufficient number of doses available for endemic control. With a public private partnership, icddr,b initiated a collaboration between vaccine manufacturers in Bangladesh and abroad. A locally manufactured Oral Cholera Vaccine (OCV) named Cholvax became available for testing in Bangladesh. We evaluated the safety and immunogenicity of this locally produced Cholvax (Incepta Vaccine Ltd) inexpensive OCV comparatively to Shanchol (Shantha Biotechnics-Sanofi Pasteur) which is licensed in several countries. We conducted a randomized non-inferiority clinical trial of bivalent, killed oral whole-cell cholera vaccine Cholvax vs. Shanchol in the cholera-endemic area of Mirpur, Dhaka, among three different age cohorts (1-5, 6-17 and 18-45 years) between April 2016 and April 2017. Two vaccine doses were given at 14 days apart to 2,052 healthy participants. No vaccine-related serious adverse events were reported. There were no significant differences in the frequency of solicited (7.31% vs. 6.73%) and unsolicited (1.46% vs. 1.07%) adverse events reported between the Cholvax and Shanchol groups. Vibriocidal antibody responses among the overall population for O1 Ogawa (81% vs. 77%) and O1 Inaba (83% vs. 84%) serotypes showed that Cholvax was non-inferior to Shanchol, with the non-inferiority margin of -10%. For O1 Inaba, GMT was 462.60 (Test group), 450.84 (Comparator group) with GMR 1.02(95% CI: 0.92, 1.13). For O1 Ogawa, GMT was 419.64 (Test group), 387.22 (Comparator group) with GMR 1.12 (95% CI: 1.02, 1.23). Cholvax was safe and non-inferior to Shanchol in terms of immunogenicity in the different age groups. These results support public use of Cholvax to contribute for reduction of the cholera burden in Bangladesh. ClinicalTrials.gov number: NCT027425581.

Funder: New faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0049)., Two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID-19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID-19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID-19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID-19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47-65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62-24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines.

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.

Coronavirus disease 2019 (COVID-19) is a protean disease causing different degrees of clinical severity including fatality. In addition to humoral immunity, antigen-specific T cells may play a critical role in defining the protective immune response against SARS-CoV-2, the virus that causes this disease. As a part of a longitudinal cohort study in Bangladesh to investigate B and T cell-specific immune responses, we sought to evaluate the activation-induced marker (AIM) and the status of different immune cell subsets during a COVID-19 infection. We analyzed a total of 115 participants, which included participants with asymptomatic, mild, moderate, and severe clinical symptoms. We observed decreased mucosal-associated invariant T (MAIT) cell frequency on the initial days of the COVID-19 infection in symptomatic patients compared to asymptomatic patients. However, natural killer (NK) cells were found to be elevated in symptomatic patients just after the onset of the disease compared to both asymptomatic patients and healthy individuals. Moreover, we found a significant increase of AIM+ (both OX40+CD137+ and OX40+CD40L+) CD4+ T cells in moderate and severe COVID-19 patients in response to SARS-CoV-2 peptides (especially spike peptides) compared to pre-pandemic controls who are unexposed to SARS-CoV-2. Notably, we did not observe any significant difference in the CD8+ AIMs (CD137+CD69+), which indicates the exhaustion of CD8+ T cells during a COVID-19 infection. These findings suggest that patients who recovered from moderate and severe COVID-19 were able to mount a strong CD4+ T-cell response against shared viral determinants that ultimately induced T cells to mount further immune responses to SARS-CoV-2.

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, pInterpretation 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.

The World Health Organization (WHO) recommends the use of oral cholera vaccines (OCVs) as part of an integrated control program, both in highly endemic settings and during cholera epidemics. The available and internationally recommended WHO-prequalified OCVs (Dukoral, Shanchol, Euvichol) contain multiple heat and formalin-killed V. cholerae strains of Inaba and Ogawa serotypes. MSD Wellcome Trust Hilleman Laboratories Pvt. Ltd. in technical collaboration with University of Gothenburg, Sweden has developed a new single strain OCV, Hillchol. This vaccine consists of formaldehyde-inactivated whole cell El Tor V. cholerae O1 bacteria engineered into the Hikojima serotype for stable expression of both the Ogawa (AB) and Inaba (AC) LPS antigens on the bacterial surface. We evaluated the safety and immunogenicity of this novel and potentially much less expensive OCV in comparison with Shanchol.We conducted a randomized, non-inferiority, age-descending clinical trial of OCV (Hillchol vs. Shanchol) in the Mirpur area of Dhaka city from July 2016 to May 2017. This study was carried out in three different age cohorts (1-5, 5-17 and ≥18 years old). Two doses of vaccine were given at 14 days intervals to 560 healthy participants.No serious adverse events were reported. There were no significant differences in the rates of adverse events between the test vaccine (Hillchol) and the comparator (Shanchol) group. Serum vibriocidal antibody responses in all age groups combined were comparable for all the O1 Ogawa (59% vs. 67%; 90% CI of difference: -14.55, -0.84) and Inaba (70% vs. 71%; 90% CI of difference: -7.24, 5.77) serotypes, showing that the Hillchol vaccine was non-inferior to Shanchol. This new vaccine was also non-inferior to Shanchol in the different age strata.The safety and immunogenicity profile of the new OCV Hillchol is comparable to Shanchol in persons residing in a cholera-endemic setting. ClinicalTrials.gov number: NCT02823899.

Background Inadequate treatment of hypertension is a widespread problem, especially in South Asian countries where cardiovascular disease mortality rates are high. We aimed to explore the effect of a multicomponent intervention (MCI) on antihypertensive medication intensification among rural South Asians with hypertension. Methods A post hoc analysis of a 2-year cluster-randomized controlled trial including 2,645 hypertensives aged ≥40 years from 30 rural communities, 10 each, in Bangladesh, Pakistan, and Sri Lanka. Independent assessors collected information on participants’ self-reports and physical inspection of medications. The main outcomes were the changes from baseline to 24 months in the following: (i) the therapeutic intensity score (TIS) for all (and class-specific) antihypertensive medications; (ii) the number of antihypertensive medications in all trial participants. Results At 24 months, the mean increase in the TIS score of all antihypertensive medications was 0.11 in the MCI group and 0.03 in the control group, with a between-group difference in the increase of 0.08 (95% confidence interval (CI, 0.03, 0.12); P = 0.002). In MCI compared with controls, a greater increase in the TIS of renin–angiotensin–aldosterone system blockers (0.05; 95% CI (0.02, 0.07); P < 0.001) and calcium channel blockers (0.03; 95% CI (0.00, 0.05); P = 0.031), and in the number of antihypertensive medications (0.11, 95% CI (0.02, 0.19); P = 0.016) was observed. Conclusions In rural communities in Bangladesh, Pakistan, and Sri Lanka, MCI led to a greater increase in antihypertensive medication intensification compared with the usual care among adults with hypertension. Clinical trials registration Trial Number NCT02657746.

Summary Background COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multi-component hypertension management programme that is led by community health workers, has been shown to be efficacious at reducing systolic blood pressure in rural communities in Bangladesh, Pakistan, and Sri Lanka. In this study, we aimed to assess the budget required to scale up the programme and the incremental cost-effectiveness ratios. Methods In a cluster-randomised trial of COBRA-BPS, individuals aged 40 years or older with hypertension who lived in 30 rural communities in Bangladesh, Pakistan, and Sri Lanka were deemed eligible for inclusion. Costs were quantified prospectively at baseline and during 2 years of the trial. All costs, including labour, rental, materials and supplies, and contracted services were recorded, stratified by programme activity. Incremental costs of scaling up COBRA-BPS to all eligible adults in areas covered by community health workers were estimated from the health ministry (public payer) perspective. Findings Between April 1, 2016, and Feb 28, 2017, 11 510 individuals were screened and 2645 were enrolled and included in the study. Participants were examined between May 8, 2016, and March 31, 2019. The first-year per-participant costs for COBRA-BPS were US$10·65 for Bangladesh, $10·25 for Pakistan, and $6·42 for Sri Lanka. Per-capita costs were $0·63 for Bangladesh, $0·29 for Pakistan, and $1·03 for Sri Lanka. Incremental cost-effectiveness ratios were $3430 for Bangladesh, $2270 for Pakistan, and $4080 for Sri Lanka, per cardiovascular disability-adjusted life year averted, which showed COBRA-BPS to be cost-effective in all three countries relative to the WHO-CHOICE threshold of three times gross domestic product per capita in each country. Using this threshold, the cost-effectiveness acceptability curves predicted that the probability of COBRA-BPS being cost-effective is 79·3% in Bangladesh, 85·2% in Pakistan, and 99·8% in Sri Lanka. Interpretation The low cost of scale-up and the cost-effectiveness of COBRA-BPS suggest that this programme is a viable strategy for responding to the growing cardiovascular disease epidemic in rural communities in low-income and middle-income countries where community health workers are present, and that it should qualify as a priority intervention across rural settings in south Asia and in other countries with similar demographics and health systems to those examined in this study. Funding The UK Department of Health and Social Care, the UK Department for International Development, the Global Challenges Research Fund, the UK Medical Research Council, Wellcome Trust.

ObjectiveTo identify factors associated with COVID-19 positivity among staff and their family members of icddr,b, a health research institute located in Bangladesh.SettingDhaka, Bangladesh.ParticipantsA total of 4295 symptomatic people were tested for SARS-CoV-2 by reverse-transcription PCR between 19 March 2020 and 15 April 2021. Multivariable logistic regression was done to identify the factors associated with COVID-19 positivity by contrasting test positives with test negatives.ResultForty-three per cent of the participants were tested positive for SARS-CoV-2. The median age was high in positive cases (37 years vs 34 years). Among the positive cases, 97% were recovered, 2.1% had reinfections, 24 died and 41 were active cases as of 15 April 2021. Multivariable regression analysis showed that age more than 60 years (adjusted OR (aOR)=2.1, 95% CI 1.3 to 3.3; pConclusionsThe study findings suggest that older age, fever, cough and anosmia were associated with COVID-19 among the study participants.

Highlights • Serum IgG antibody responses developed in 95% of mildly symptomatic individuals by day 14 and all subjects had seroconverted by day 30. • Serum IgM and IgA antibody responses were lower and less frequent than corresponding IgG responses, and peaked and declined earlier 100% of mild symptomatic individuals developed an IgG antibody response by day 30. • Fewer than 45% of asymptomatic infected individuals had seroconverted by day 30 post-PCR diagnosis. • Impact on modeling of herd immunity., Objectives Studies on serologic responses following COVID-19 have been published primarily in individuals who are moderately or severely symptomatic, but there are few data from individuals who are mildly symptomatic or asymptomatic. Methods We measured IgG, IgM, and IgA to the receptor-binding domain of SARS-CoV-2 by ELISA in mildly symptomatic (n = 108) and asymptomatic (n = 63) on days 1, 7, 14, and 30 following RT-PCR confirmation in Bangladesh, and compared with pre-pandemic samples, including healthy controls (n = 73) and individuals infected with other viruses (n = 79). Results Mildly symptomatic individuals developed IgM and IgA responses by day 14 in 72% and 83% of individuals, respectively, while 95% of individuals developed IgG response, and rose to 100% by day 30. In contrast, individuals infected with SARS-CoV-2 but who remained asymptomatic developed antibody responses significantly less frequently, with only 20% positive for IgA and 22% positive for IgM by day 14, and 45% positive for IgG by day 30 after infection. Conclusions These results confirm immune responses are generated following COVID-19 who develop a mildly symptomatic illness. However, those with the asymptomatic infection do not respond or have lower antibody levels. These results will impact modeling needed for determining herd immunity generated by natural infection or vaccination.

Blood cultures (BCs) detect an estimated 50% of typhoid fever cases. There is need for validated clinical criteria to define cases that are BC negative, both to help direct empiric antibiotic treatment and to better evaluate the magnitude of protection conferred by typhoid vaccines. To derive and validate a clinical rule for defining BC-negative typhoid fever, we assessed, in a cluster-randomized effectiveness trial of Vi-polysaccharide (ViPS) typhoid vaccine in Kolkata, India, 14,797 episodes of fever lasting at least 3 days during 4 years of comprehensive, BC-based surveillance of 70,865 persons. A recursive partitioning algorithm was used to develop a decision rule to predict BC-proven typhoid cases with a diagnostic specificity of 97–98%. To validate this rule as a definition for BC-negative typhoid fever, we assessed whether the rule defined culture-negative syndromes prevented by ViPS vaccine. In a training subset of individuals, we identified the following two rules: rule 1: patients aged < 15 years with prolonged fever accompanied by a measured body temperature ≥ 100°F, headache, and nausea; rule 2: patients aged ≥ 15 years with prolonged fever accompanied by nausea and palpable liver but without constipation. The adjusted protective efficacy of ViPS against clinical typhoid defined by these rules in persons aged ≥ 2 years in a separate validation subset was 33% (95% CI: 4–53%). We have defined and validated a clinical rule for predicting BC-negative typhoid fever using a novel vaccine probe approach. If validated in other settings, this rule may be useful to guide clinical care and to enhance typhoid vaccine evaluations.

Highlights • Matlab, Bangladesh was a well-documented cholera ‘hotspot’ – an area of regularly recurrent cholera with a high annual incidence – for many decades. • In recent years, cholera has declined to negligible levels in Matlab, despite persistently high rates in many areas of Bangladesh and despite increasing local ambient and sea surface temperatures, which favor a high cholera incidence. • The decline occurred following the provision of low-cost tubewells for the supply of water and inexpensive sanitary latrines to a high proportion of the population. • These observations lend optimism to the success of the World Health Organization current global initiative to end preventable cholera by 2030., Background Cholera remains a major public health threat in low- and middle-income countries. The World Health Organization (WHO) has recently launched a global initiative to end preventable cholera by 2030. Key to the success of this initiative will be the elimination of cholera transmission in cholera ‘hotspots’ with regularly recurrent disease; this can be achieved via improved surveillance to define hotspot populations, through the use of oral cholera vaccines, and through the implementation of improved water, sanitation, and hygiene (WASH). Methods This study was performed to analyze the trend in cholera incidence during the years 1974–2018 in Matlab, Bangladesh (defined population of about 200 000) that has been recognized as one of the world’s cholera hotspots. During this period, Matlab has maintained a demographically defined population and comprehensive, culture-based surveillance for cholera, supplemented by periodic surveys to characterize the socioeconomic status of the population, as well as water sources and facilities for defecation. Results Cholera transmission has nearly been eliminated in Matlab, despite a continuing high cholera burden in many other parts of Bangladesh and despite trends of increasing ambient and sea surface temperatures, which are known to increase cholera incidence. Concomitantly, the socioeconomic status of the population has increased modestly, and the use of simple tubewells for drinking water has reached 95% and the installation of sanitary latrines has reached 85%. Conclusions The factors responsible for the decline in cholera are difficult to pinpoint precisely, but this decline has occurred with the installation of inexpensive improvements in water sources and latrines and despite environmental factors that should have augmented cholera incidence. These observations lend optimism to the current global initiative to end preventable cholera by 2030.

Cholera causes substantial morbidity and mortality in the world's poorest populations. For nearly a decade, an inactivated oral cholera vaccine (OCV) stockpile has been available to control and prevent outbreaks. In 2017, WHO launched a bold global initiative to reduce mortality from cholera by 90% by 2030, a cornerstone of which is deployment of OCVs from the global stockpile. The current production of OCVs for the stockpile falls well short of the doses needed to accomplish this goal. Besides efforts to enlist additional manufacturers of the current OCVs in the stockpile, inclusion of new-generation inactivated OCVs already in clinical development might offer advantages of enlarged production, improved performance, simplified logistics, and reduced costs. However, logistical, scientific, and ethical barriers make conventional, randomised, phase 3 clinical efficacy trials towards licensure of such new-generation OCVs problematic. The serum vibriocidal antibody response, the traditional immunological surrogate of protection against cholera, is imperfect for use as a standalone outcome. In this Personal View, we describe the need for new thinking on approaches for licensure and recommendations for new-generation inactivated OCVs, and suggest a pathway based on a sequential combination of immunogenicity and effectiveness observational studies.

Background In low and middle-income countries (LMICs), severe pneumonia with hypoxemia is the leading cause of child deaths, even with the provision of WHO-recommended antibiotic therapy, oxygen therapy and other supportive care. Previous studies found positive outcomes from the use of bubble continuous positive airway pressure (bCPAP) for treating these children compared to the standard oxygen therapy. Due to lack of data on the perceptions and experiences of hospital health care workers and caregivers of children on the feasibility and acceptability of bCPAP in treating children with severe pneumonia and hypoxemia in real-life settings, we examined these issues in tertiary and general hospitals in Ethiopia. Methods As part of a three-stages clinical trial, this qualitative study was conducted in two tertiary (stage I) and two general (stage II) hospitals from September 2019 to July 2020. During stages I and II, we have consecutively enrolled children with severe pneumonia and hypoxemia and put them on bCPAP to examine its feasibility and acceptability by clinicians and parents. A total of 89 children were enrolled (49 from two tertiary and 40 from two general hospitals). Then qualitative data were collected through 75 repeated in-depth interviews by social-science experts with purposively selected 30 hospital health workers and 15 parents of 12 children who received bCPAP oxygen therapy in the hospitals. Interview data were supplemented by 6 observations in the hospitals. Data were analyzed using a thematic approach. Results Identified structural and functional challenges for the introduction of bCPAP in treating childhood severe pneumonia and hypoxemia in the study hospitals include: inadequate number of pulse oximeters; unavailability of nasal prongs with age-specific size; inadequate and non-functioning oxygen flow meters, concentrator, and cylinders; disruption in power-supply; and inadequate number of staff. The opportunities in introducing bCPAP oxygen therapy included the availability of a dedicated corner for the study patients situated in front of nurse’s station, required medicines and satisfactory level of clinicians’ knowledge and skills for treating severe pneumonia patients. Additionally, the identified operational challenges were occasional lack of bubbling in the water-filled plastic bottle, lack of stand for holding the water-filled plastic bottle, and delayed shifting of oxygen source from an oxygen concentrator to a cylinder, particularly during electricity disruption. Participants (clinicians and parents) expressed their satisfaction as bCPAP oxygen therapy was found to be simple to handle, children had ease of breathing and recovered fast without major ill effects. Conclusion Our study identified some important structural, functional, and operational challenges that need to be addressed before implementation of bCPAP oxygen therapy especially in frontline general hospitals with limited resources. In spite of these observed challenges, the clinicians and caregivers were highly satisfied with the overall performance of bCPAP oxygen therapy.

Background Enteric fever is a serious public health concern in many low-income and middle-income countries. Numerous data gaps exist concerning the epidemiology of Salmonella enterica serotype Typhi (S Typhi) and Salmonella enterica serotype Paratyphi (S Paratyphi), which are the causative agents of enteric fever. We aimed to determine the burden of enteric fever in three urban sites in Africa and Asia. Methods In this multicentre population-based study, we did a demographic census at three urban sites in Africa (Blantyre, Malawi) and Asia (Kathmandu, Nepal and Dhaka, Bangladesh) between June 1, 2016, and Sept 25, 2018. Households were selected randomly from the demographic census. Participants from within the geographical census area presenting to study health-care facilities were approached for recruitment if they had a history of fever for 72 h or more (later changed to >48 h) or temperature of 38·0°C or higher. Facility-based passive surveillance was done between Nov 11, 2016, and Dec 31, 2018, with blood-culture collection for febrile illness. We also did a community-based serological survey to obtain data on Vi-antibody defined infections. We calculated crude incidence for blood-culture-confirmed S Typhi and S Paratyphi infection, and calculated adjusted incidence and seroincidence of S Typhi blood-culture-confirmed infection. Findings 423 618 individuals were included in the demographic census, contributing 626 219 person-years of observation for febrile illness surveillance. 624 S Typhi and 108 S Paratyphi A isolates were collected from the blood of 12 082 febrile patients. Multidrug resistance was observed in 44% S Typhi isolates and fluoroquinolone resistance in 61% of S Typhi isolates. In Blantyre, the overall crude incidence of blood-culture confirmed S Typhi was 58 cases per 100 000 person-years of observation (95% CI 48–70); the adjusted incidence was 444 cases per 100 000 person-years of observation (95% credible interval [CrI] 347–717). The corresponding rates were 74 (95% CI 62–87) and 1062 (95% CrI 683–1839) in Kathmandu, and 161 (95% CI 145–179) and 1135 (95% CrI 898–1480) in Dhaka. S Paratyphi was not found in Blantyre; overall crude incidence of blood-culture-confirmed S Paratyphi A infection was 6 cases per 100 000 person-years of observation (95% CI 3–11) in Kathmandu and 42 (95% CI 34–52) in Dhaka. Seroconversion rates for S Typhi infection per 100 000 person-years estimated from anti-Vi seroconversion episodes in serological surveillance were 2505 episodes (95% CI 1605–3727) in Blantyre, 7631 (95% CI 5913–9691) in Kathmandu, and 3256 (95% CI 2432–4270) in Dhaka. Interpretation High disease incidence and rates of antimicrobial resistance were observed across three different transmission settings and thus necessitate multiple intervention strategies to achieve global control of these pathogens. Funding Wellcome Trust and the Bill & Melinda Gates Foundation.

Background In April 2018, a diarrhea epidemic broke out in Dhaka city and adjoining areas, which continued through May. The Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), a dedicated diarrheal disease hospital, had a large upsurge in patient visits during the epidemic. An enhanced understanding of the epidemiology of this epidemic may help health-related professionals better prepare for such events in the future. This study examined the microbial etiology and non-pathogen factors associated with diarrhea during the epidemic. The study also evaluated the patients’ presentation and clinical course and estimated the potential mortality averted by treating patients during the epidemic. Methodology/Principal findings Data from the patients who were treated at Dhaka Hospital during the diarrhea epidemic between April 2 and May 12, 2018 and were enrolled into the Diarrheal Disease Surveillance System (DDSS) at icddr,b were compared with the DDSS-enrolled patients treated during the seasonally-matched periods in the flanking years using logistic regression. icddr,b Dhaka Hospital treated 29,212 diarrheal patients during the 2018 epidemic period (and 25,950 patients per comparison period on average). Vibrio cholerae was the most common pathogen isolated (7,946 patients; 27%) and associated with diarrhea during the epidemic (adjusted odds ratio [AOR] 1.5, 95% CI: 1.1–2.0). The interaction of Vibrio cholerae with ETEC (AOR 2.7, 95% CI: 1.3–5.9) or Campylobacter (AOR 2.4, 95% CI: 1.1–5.1) was associated with further increased odds of diarrhea during the epidemic. In children under five years old, rotavirus was the most common pathogen (2,029 patients; 26%). Those who were adolescents (AOR 2.0, 95% CI: 1.3–3.1) and young adults (AOR 1.9, 95% CI: 1.4–2.5) compared to children younger than five years, resided within a 10 km radius of Dhaka Hospital (AOR 1.6, 95% CI: 1.1–2.2) compared to those living outside 20 km, borrowed money or relied on aid to pay for the transport to the hospital (AOR 1.6, 95% CI: 1.2–2.0), used tap water (AOR 1.8, 95% CI: 1.4–2.4) for drinking compared to tubewell water, and disposed of the solid waste directly outside the house (AOR 4.0, 95% CI: 2.7–5.9) were more likely to present with diarrhea during the epidemic. During the epidemic, patients were more likely to present with severe dehydration (odds ratio [OR] 1.6, 95% CI: 1.3–2.0) and require inpatient admission (OR 2.5, 95% CI: 1.9–3.3), intravenous rehydration (OR 1.7, 95% CI: 1.4–2.1), and antibiotics (OR 2.2, 95% CI: 1.8–2.7). The in-hospital case fatality rate was low (13 patients; 0.04%), and the hospital averted between 12,523 and 17,265 deaths during the epidemic. Conclusions/Significance Vibrio cholerae played the primary role in the 2018 diarrhea epidemic in Dhaka. Campylobacter, enterotoxigenic Escherichia coli, and rotavirus had a secondary role. Adolescents and adults, residents of the metropolitan area, and those who were relatively poor and lacked safe water, sanitation, and hygiene (WASH) practices comprised the most vulnerable groups. Despite the increased disease severity during the epidemic, the case fatality rate was less than 0.1%. icddr,b Dhaka Hospital saved as many as 17,265 lives during the epidemic., Author summary We analyzed records of patients presenting during a diarrhea epidemic in 2018 to the world’s largest diarrhea treatment hospital in Dhaka, Bangladesh. Patients presenting during the epidemic and the non-epidemic periods were compared at multiple levels. We found that Vibrio cholerae played a crucial role in the diarrhea epidemic. Campylobacter, enterotoxigenic Escherichia coli, and rotavirus had a secondary role. Adolescents and adults, residents of the Dhaka metropolitan area, and those who were relatively poor and lacked safe water, sanitation, and hygiene (WASH) practices were more vulnerable to the epidemic. Patients had increased disease severity during the epidemic, but the death rate was extremely low in the hospital. icddr,b Dhaka Hospital saved several thousand lives by taking care of diarrhea patients during the epidemic.

The burden of Salmonella enterica serotype Typhi (S. Typhi) shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic patient with typhoid, although none persisted at 1-year follow-up. Anti–virulence capsule (Vi)–immunoglobulin (Ig) G titers were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti–Vi-IgG titers identified 1 asymptomatic carrier with shedding. These findings suggest that ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases, although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.

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 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

Safe and effective rotavirus vaccines (RVs) are needed to reduce the enormous public health burden of rotavirus illness in developing countries. Vaccination is critical for effective control of rotavirus infection since it cannot be prevented with improvements in water and sanitation. The International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) has completed several groundbreaking RV trials (Phase I–Phase IV). The safety, immunogenicity, efficacy, and effectiveness of different RVs were evaluated among both urban and rural populations. In this study, we present the results, policy implications, and lessons learned for successful implementation of these trials as well as future directions for rotavirus vaccination in Bangladesh.

Background:Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control.Methods:In a 3-year case-control study, we investigated typhoid among children aged Results:148 S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1 %. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype 58), with the majority of each (76% and 88%) being multidrug-resistant strains in three sublineages of the H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled.Conclusions:The high rate of multidrug-resistant H58 S. Typhi, and the close phylogenetic relationships between cases and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting.Funding:National Institutes of Health (R01AI099525); Wellcome Trust (106158/Z/14/Z); European Commission (TyphiNET No 845681); National Institute for Health Research (NIHR); Bill and Melinda Gates Foundation (OPP1175797).

Background Rotavirus is one of the causes of severe diarrhea and death in young children. To control the disease, safe and effective vaccines are being used in several countries. We assessed the impact of vaccination on the risk factors for acute rotavirus diarrhea (ARD) in Bangladesh. Methods We used the data of a cluster-randomized trial. The clusters were 142 villages, 71 in each of the two arms of study. The infants were offered human rotavirus vaccine (HRV), Rotarix, over three-year period. We divided the time period into two equal periods (T1 and T2). A generalized estimating equation with logit-link function was used to evaluate the risk factors by arm and by period. Results Among 10,917 children, 5,759 (53%) were in the HRV villages. We had 359 cases; 44% in the HRV villages. Mean age of attack was similar between the arms of study in T1, but significantly higher in HRV villages than that in the non-HRV villages in T2. In HRV villages, males were at a higher risk of having ARD than females in T1, but not in T2. In contrast, males were at a higher risk of having ARD in both the time periods in non-HRV villages. In HRV-villages, children having literate mother were at significantly higher risk of having ARD in T1 but not in T2; whereas children in the non-HRV villages had a higher risk of having ARD in T2. Children living in an area with higher phone users had more cases than their counterpart in non-HRV villages, but not in HRV villages. Conclusion Our study illustrates that several risk factors for ARD varied between the two arms of study as well as between the two periods of study. Assessing post-vaccination risk factors is, therefore, important for understanding the impact of vaccination and undertaking post-vaccination control measures.

We have earlier reported that a single dose of oral cholera vaccine (OCV) is protective in adults and children ≥5 years of age and sustained for 2 years. We enrolled participants (n = 240) from this study, between March-September 2017, over 3 years after receiving a primary single dose. Immune responses were measured in placebo group (Primary Immunization group: PI) and compared with those who received a single dose (Booster Immunization group: BI). The children were 4 to 18 years. Blood was collected at day 0 (before vaccination) and after receiving 1st and 2nd doses of OCV. Overall, the BI and PI groups showed vibriocidal antibody response after 1st and 2nd dose of vaccination in all age groups to V. cholerae O1 and O139. Young children in the BI group showed significantly higher vibriocidal antibody response two weeks after receiving the first dose as compared to PI group to LPS. Elevated plasma IgA responses to LPS after the first dose were observed among the BI group compared to the PI group among the young children. Mucosal antibody responses measured in fecal extracts showed similar increases as that of vibriocidal and LPS responses in the BI group. These results suggest a single boosting dose of OCV generated immune response in primed population >5 years of age who had earlier received OCV. However, young children who had received OCV earlier, boosting after a single dose, resulted in increased immune responses compared to the PI group. Further studies are needed to assess protection obtained from different strategies, especially for young children and to determine the numbers of primary and booster doses needed. In addition, more information is needed regarding the optimum interval between primary and booster doses to plan future interventions for cholera control. ClinicalTrials.gov Identifier: NCT 02027207.

Objectives: To assess the safety and reactogenicity of single oral dose of heat-stable rotavirus vaccine (HSRV) in healthy adults aged 18–45 years followed by assessment of safety, reactogenicity, and immunogenicity of three doses of HSRV in healthy infants aged 6–8 weeks at enrollment. Trial Design: Single-center randomized controlled, sequential, blinded (adults) and open-label (infants). Setting: Single site at International Center for Diarrheal Disease Research, Bangladesh (icddr,b). Participants: Fifty eligible adults randomized in 1:1 ratio (HSRV: Placebo) followed by 50 eligible infants randomized in 1:1 ratio (HSRV: Comparator (RotaTeq®, pentavalent human-bovine (WC3) reassortant live-attenuated, rotavirus vaccine)). Intervention: Adults received either a single dose of HSRV or placebo and followed for 14 days. Infants received three doses of either HSRV or comparator with a follow-up for 28 days after each dose. Main Outcome Measures: Solicited and unsolicited adverse events (AEs) along with any serious adverse events (SAEs) were part of the safety and reactogenicity assessment in adults and infants whereas serum anti-rotavirus IgA response rates were part of immunogenicity assessment in infants only. Post-vaccination fecal shedding of vaccine-virus rotavirus strains was also determined in adults and infants. Results: In this study, HSRV, when compared with placebo, did not result in increase in solicited adverse events (solicited AEs) in adults. In infants, HSRV had a safety profile similar to comparator vis-à-vis solicited AEs. In infants, fecal shedding of vaccine-virus strains was not detected in HSRV recipients but was observed in two comparator recipients. Percentage of infants exhibiting threefold rise in serum anti-rotavirus IgA titers from baseline to 1-month post-dose 3 in HSRV group was 88% (22/25) and 84% (21/25) in comparator group. Conclusion: HSRV was found to be generally well-tolerated in both adults and infants and immunogenic in infants.

Background The World Health Organization now recommends the use of typhoid conjugate vaccines (TCVs) in typhoid-endemic countries, and Gavi, the Vaccine Alliance, added TCVs into the portfolio of subsidized vaccines. Data from the Severe Typhoid Fever in Africa (SETA) program were used to contribute to TCV introduction decision-making processes, exemplified for Ghana and Madagascar. Methods Data collected from both countries were evaluated, and barriers to and benefits of introduction scenarios are discussed. No standardized methodological framework was applied. Results The Ghanaian healthcare system differs from its Malagasy counterpart: Ghana features a functioning insurance system, antimicrobials are available nationwide, and several sites in Ghana deploy blood culture–based typhoid diagnosis. A higher incidence of antimicrobial-resistant Salmonella Typhi is reported in Ghana, which has not been identified as an issue in Madagascar. The Malagasy people have a low expectation of provided healthcare and experience frequent unavailability of medicines, resulting in limited healthcare-seeking behavior and extended consequences of untreated disease. Conclusions For Ghana, high typhoid fever incidence coupled with spatiotemporal heterogeneity was observed. A phased TCV introduction through an initial mass campaign in high-risk areas followed by inclusion into routine national immunizations prior to expansion to other areas of the country can be considered. For Madagascar, a national mass campaign followed by routine introduction would be the introduction scenario of choice as it would protect the population, reduce transmission, and prevent an often-deadly disease in a setting characterized by lack of access to healthcare infrastructure. New, easy-to-use diagnostic tools, potentially including environmental surveillance, should be explored and improved to facilitate identification of high-risk areas.

Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age-specific population-level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility-based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under-detection of cases. We developed a Bayesian approach that adjusts the count of reported blood-culture-positive cases for blood culture detection, blood culture collection, and healthcare seeking—and how these factors vary by age—while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision-making for typhoid prevention and control.

Vaccine herd protection is the extension of the defense conferred by immunization beyond the vaccinated to unvaccinated persons in a population, as well as the enhancement of the protection among the vaccinated, due to vaccination of the surrounding population. Vaccine herd protection has traditionally been inferred from observations of disease trends after inclusion of a vaccine in national immunization schedules. Rather than awaiting outcomes of widescale vaccine deployment, earlier-stage evaluation of vaccine herd protection during trials or mass vaccination projects could help inform policy decisions about potential vaccine introduction. We describe the components, influencing factors, and implications of vaccine herd protection and discuss various methods for assessing herd protection, using examples from cholera and typhoid vaccine studies.

Highlights • The “fried-egg” analytic approach was applied to a cluster randomized trial (CRT). • Overall analysis failed to reveal rotavirus vaccine (RV) herd protection. • Same approach unmasked herd protection of other enteric vaccines failed for RV., Background Vaccine herd protection assessed in a cluster-randomized trial (CRT) may be masked by disease transmission into the cluster from outside. However, herd effects can be unmasked using a ‘fried-egg’ approach whereby the analysis, restricted to the innermost households of clusters, ‘yolk’, creates an insulating ‘egg-white’ periphery. This approach has been demonstrated to unmask vaccine herd protection in reanalyses of cholera and typhoid vaccine CRTs. We applied this approach to an earlier CRT in Bangladesh of rotavirus vaccine (RV) whose overall analysis had failed to detect herd protection. Herein we present the results of this analysis. Methods In the study area, infants in 142 villages were randomized to receive two doses of RV with routine EPI vaccines (RV villages) or only EPI vaccines (non-RV villages). We analyzed RV protection against acute rotavirus diarrhoea for the entire cluster (P100) and P75, P50, P25 clusters, representing 75%, 50% and 25% of the innermost households for each cluster, respectively. Results During 2 years of follow-up, there was evidence of 27% overall (95 %CI: 7, 43) and 42% total protection (95 %CI: 23, 56) in the P100 cluster, but it did not increase when moved in smaller yolks. There was no evidence of indirect vaccine protection in the yolks at any cluster size. Conclusion Our reanalysis of the CRT using the fried- egg approach did not detect RV herd protection. Whether these findings reflect a true inability of the RV to confer herd protection in this setting, or are due to limitations of the approach, requires further study.

Estimating population-level effects of a vaccine is challenging because there may be interference, i.e., the outcome of one individual may depend on the vaccination status of another individual. Partial interference occurs when individuals can be partitioned into groups such that interference occurs only within groups. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to draw inference about causal effects of an exposure or treatment. Tchetgen Tchetgen and VanderWeele (2012) proposed a modified IPW estimator for causal effects in the presence of partial interference. Motivated by a cholera vaccine study in Bangladesh, this paper considers an extension of the Tchetgen Tchetgen and VanderWeele IPW estimator to the setting where the outcome is subject to right censoring using inverse probability of censoring weights (IPCW). Censoring weights are estimated using proportional hazards frailty models. The large sample properties of the IPCW estimators are derived, and simulation studies are presented demonstrating the estimators’ performance in finite samples. The methods are then used to analyze data from the cholera vaccine study.

Highlights • Ivermectin, an FDA-approved anti-parasitic agent, was found to be an inhibitor of SARS-CoV-2 replication in the laboratory. • Ivermectin may be effective for the treatment of early-onset mild Covid-19 in adult patients. Early viral clearance of SARS-CoV-2 was observed in treated patients. • Remission of fever, cough and sore throat did not differ between those treated with or without ivermectin. No severe adverse event observed with the longer duration of ivermectin use. • Larger trials will be needed to confirm these preliminary findings., Ivermectin, an FDA-approved anti-parasitic agent, was found in vitro to inhibit SARS-CoV-2 replication. To determine the rapidity of viral clearance and safety of ivermectin among adult SARS-CoV-2 patients we conducted a randomized, double-blind, placebo-controlled trial of oral ivermectin alone (12 mg once daily for 5 days) or in combination with doxycycline (12 mg ivermectin single dose and 200 mg stat doxycycline day-1 followed by 100 mg 12hrly for next 4 days) compared with placebo among 72 hospitalized patients in Dhaka, Bangladesh. Clinical symptoms of fever, cough and sore throat were comparable among the three treatment arms. Virological clearance was earlier in the 5-day ivermectin treatment arm versus the placebo group (9.7 days vs. 12.7 days; P = 0.02); but not with the ivermectin + doxycycline arm (11.5 days; P = 0.27). There were no severe adverse drug events recorded in the study. A 5-day course of ivermectin was found to be safe and effective in treating mild COVID-19 adult patients. Larger trials will be needed to confirm these preliminary findings.

After the recent announcement of COVID-19 vaccine efficacy in clinical trials by several manufacturers for protection against severe disease, a comprehensive post-efficacy strategy for the next steps to ensure vaccination of the global population is now required. These considerations should include how to manufacture billions of doses of high-quality vaccines, support for vaccine purchase, coordination of supply, the equitable distribution of vaccines and the logistics of global vaccine delivery, all of which are a prelude to a massive vaccination campaign targeting people of all ages. Furthermore, additional scientific questions about the vaccines remain that should be answered to improve vaccine efficacy, including questions regarding the optimization of vaccination regimens, booster doses, the correlates of protection, vaccine effectiveness, safety and enhanced surveillance. The timely and coordinated execution of these post-efficacy tasks will bring the pandemic to an effective, and efficient, close.

Background In Bangladesh, about 80% of healthcare is provided by the private sector. Although free diagnosis and care is offered in the public sector, only half of the estimated number of people with tuberculosis are diagnosed, treated, and notified to the national program. Private sector engagement strategies often have been small scale and time limited. We evaluated a Social Enterprise Model combining external funding and income generation at three tuberculosis screening centres across the Dhaka Metropolitan Area for diagnosing and treating tuberculosis. Methods and findings The model established three tuberculosis screening centres across Dhaka Metropolitan Area that carried the icddr,b brand and offered free Xpert MTB/RIF tests to patients visiting the screening centres for subsidized, digital chest radiographs from April 2014 to December 2017. A network of private and public health care providers, and community recommendation was formed for patient referral. No financial incentives were offered to physicians for referrals. Revenues from radiography were used to support screening centres’ operation. Tuberculosis patients could choose to receive treatment from the private or public sector. Between 2014 and 2017, 1,032 private facilities networked with 8,466 private providers were mapped within the Dhaka Metropolitan Area. 64, 031 patients with TB symptoms were referred by the private providers, public sector and community residents to the three screening centres with 80% coming from private providers. 4,270 private providers made at least one referral. Overall, 10,288 pulmonary and extra-pulmonary tuberculosis cases were detected and 7,695 were bacteriologically positive by Xpert, corresponding to 28% of the total notifications in Dhaka Metropolitan Area. Conclusion The model established a network of private providers who referred individuals with presumptive tuberculosis without financial incentives to icddr,b’s screening centres, facilitating a quarter of total tuberculosis notifications in Dhaka Metropolitan Area. Scaling up this approach may enhance national and international tuberculosis response.

Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to microbiologically safe water and improved sanitation. These differences in part reflect the heterogeneity of the epidemiology of invasive salmonellosis globally, and thus enable generation of data that are useful to policymakers in decision-making for the introduction of typhoid conjugate vaccines (TCVs). Moreover, each study is evaluating the large-scale deployment of TCVs, and may ultimately be used to assess post-introduction vaccine impact. The data generated by these studies will also be used to refine global disease burden estimates. It is important to ensure that lessons learned from these studies not only inform vaccination policy, but also are incorporated into sustainable, low-cost, integrated vaccine-preventable disease surveillance systems. ispartof: CLINICAL INFECTIOUS DISEASES vol:71 issue:Suppl 2 pages:S102-S110 ispartof: location:United States status: published

Background In Kenya, typhoid fever and invasive non-typhoidal salmonellosis present a huge burden of disease, especially in poor-resource settings where clean water supply and sanitation conditions are inadequate. The epidemiology of both diseases is poorly understood in terms of severity and risk factors. The aim of the study was to determine the disease burden and spatial distribution of salmonellosis, as well as socioeconomic and environmental risk factors for these infections, in a large informal settlement near the city of Nairobi, from 2013 to 2017. Methods Initially, a house-to-house baseline census of 150,000 population in Mukuru informal settlement was carried out and relevant socioeconomic, demographic, and healthcare utilization information was collected using structured questionnaires. Salmonella bacteria were cultured from the blood and faeces of children Salmonella serotypes and risk factors were conducted using Pearson Chi-Square (χ2) test. Results A total of 16,236 children were recruited into the study. The prevalence of bloodstream infections by Non-Typhoidal Salmonella (NTS), consisting of Salmonella Typhimurium/ Enteriditis, was 1.3%; Salmonella Typhi was 1.4%, and this was highest among children Salmonella Typhimurium/ Enteriditis was not significantly associated with rearing any domestic animals. Rearing chicken was significantly associated with high prevalence of S. Typhi (2.1%; p = 0.011). The proportion of children infected with Salmonella Typhimurium/ Enteriditis was significantly higher in households that used water pots as water storage containers compared to using water directly from the tap (0.6%). Use of pit latrines and open defecation were significant risk factors for S. Typhi infection (1.6%; p = 0.048). The proportion of Salmonella Typhimurium/ Enteriditis among children eating street food 4 or more times per week was higher compared to 1 to 2 times/week on average (1.1%; p = 0.032). Conclusion Typhoidal and NTS are important causes of illness in children in Mukuru informal settlement, especially among children less than 16 years of age. Improving Water, Sanitation and Hygiene (WASH) including boiling water, breastfeeding, hand washing practices, and avoiding animal contact in domestic settings could contribute to reducing the risk of transmission of Salmonella disease from contaminated environments.

We evaluated the protection conferred by a first documented visit for clinical care of typhoid fever against recurrent typhoid fever prompting a visit. This study takes advantage of multi-year follow-up of a population with endemic typhoid participating in a cluster-randomized control trial of Vi capsular polysaccharide typhoid vaccine in Kolkata, India. A population of 70,566 individuals, of whom 37,673 were vaccinated with one dose of either Vi vaccine or a control (Hepatitis A) vaccine, were observed for four years. Surveillance detected 315 first typhoid visits, among whom 4 developed subsequent typhoid, 3 due to reinfection, defined using genomic criteria and corresponding to -124% (95% CI: -599, 28) protection by the initial illness. Point estimates of protection conferred by an initial illness were negative or negligible in both vaccinated and non-vaccinated subjects, though confidence intervals around the point estimates were wide. These data provide little support for a protective immunizing effect of clinically treated typhoid illness, though modest levels of protection cannot be excluded., Author summary Recurrent episodes of typhoid fever can occur in individuals, particularly those living in typhoid endemic regions. Natural typhoid infection should, in theory, offer a degree of protection against future typhoid, however, this protection has only been assessed in a limited number of studies, none of which were conducted recently nor in the context of a carefully controlled clinical trial. The findings from our study, which were based on data from a cluster-randomized trial of Vi polysaccharide vaccine in Kolkata, India, suggest that previous typhoid fever does not provide an appreciable level of protection against future typhoid disease. This finding is important for informing mathematical modelers who predict transmission dynamics within a population and influence the design of effective vaccine intervention strategies.

Invasive Non-typhoidal Salmonella (iNTS) disease is a major public health challenge, especially in Sub-Saharan Africa (SSA). In Kenya, mortality rates are high (20–25%) unless prompt treatment is instituted. The most common serotypes are Salmonella enterica serotype Typhimurium (S. Typhimurium) and Salmonella enterica serotype Enteritidis (S. Enteritidis). In a 5 year case-control study in children residing in the Mukuru informal settlement in Nairobi, Kenya, a total of 4201 blood cultures from suspected iNTS cases and 6326 fecal samples from age-matched controls were studied. From the laboratory cultures we obtained a total of 133 S. Typhimurium isolates of which 83(62.4%) came from cases (53 blood and 30 fecal) and 50(37.6%) from controls (fecal). A total of 120 S. Enteritidis consisted of 70(58.3%) from cases (43 blood and 27 fecal) and 50(41.7%) from controls (fecal). The S. Typhimurium population fell into two distinct ST19 lineages constituting 36.1%, as well as ST313 lineage I (27.8%) and ST313 lineage II (36.1%) isolates. The S. Enteritidis isolates fell into the global epidemic lineage (46.6%), the Central/Eastern African lineage (30.5%), a novel Kenyan-specific lineage (12.2%) and a phylogenetically outlier lineage (10.7%). Detailed phylogenetic analysis revealed a high level of relatedness between NTS from blood and stool originating from cases and controls, indicating a common source pool. Multidrug resistance was common throughout, with 8.5% of such isolates resistant to extended spectrum beta lactams. The high rate of asymptomatic carriage in the population is a concern for transmission to vulnerable individuals and this group could be targeted for vaccination if an iNTS vaccine becomes available., Author summary Blood-stream infections in young children in Sub-Saharan Africa cause high levels of morbidity and mortality. Non-typhoidal Salmonella (NTS) serovars Typhimurium and Enteritidis are especially important in causing blood-stream infections in Kenya. In this case-control study we examined a total of 4201 children with potential blood-stream infections and compared their NTS genotypes with those found in fecal samples of 6326 asymptomatic age-matched controls. From a phylogenetic analysis, we observed a high rate of carriage in cases and controls of multidrug resistant Salmonella genotypes with similarity to those causing invasive disease. We hypothesize that the high carriage rates in asymptomatic population may be contributing to maintenance and transmission of NTS disease among vulnerable population of children.

Clinical trials of typhoid conjugate vaccine (TCV) are ongoing in 4 countries. Early data confirm safety, tolerability, and immunogenicity of typhoid conjugate vaccine, and early efficacy results are promising. These data support World Health Organization recommendations and planned country introductions. Forthcoming trial data will continue to inform programmatic use of typhoid conjugate vaccine.

Background Antimicrobial resistance (AMR) is a major global health concern, yet, there are noticeable gaps in AMR surveillance data in regions such as sub-Saharan Africa. We aimed to measure the prevalence of extended-spectrum β-lactamase (ESBL) producing Gram-negative bacteria in bloodstream infections from 12 sentinel sites in sub-Saharan Africa. Methods Data were generated during the Typhoid Fever Surveillance in Africa Program (TSAP), in which standardized blood cultures were performed on febrile patients attending 12 health facilities in 9 sub-Saharan African countries between 2010 and 2014. Pathogenic bloodstream isolates were identified at the sites and then subsequently confirmed at a central reference laboratory. Antimicrobial susceptibility testing, detection of ESBL production, and conventional multiplex polymerase chain reaction (PCR) testing for genes encoding for β-lactamase were performed on all pathogens. Results Five hundred and five pathogenic Gram-negative bloodstream isolates were isolated during the study period and available for further characterization. This included 423 Enterobacteriaceae. Phenotypically, 61 (12.1%) isolates exhibited ESBL activity, and genotypically, 47 (9.3%) yielded a PCR amplicon for at least one of the screened ESBL genes. Among specific Gram-negative isolates, 40 (45.5%) of 88 Klebsiella spp., 7 (5.7%) of 122 Escherichia coli, 6 (16.2%) of 37 Acinetobacter spp., and 2 (1.3%) of 159 of nontyphoidal Salmonella (NTS) showed phenotypic ESBL activity. Conclusions Our findings confirm the presence of ESBL production among pathogens causing bloodstream infections in sub-Saharan Africa. With few alternatives for managing ESBL-producing pathogens in the African setting, measures to control the development and proliferation of AMR organisms are urgently needed.

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

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.

Paratyphoid fever is one of the major causes of morbidity of febrile illnesses in endemic regions. We report a case of high-grade fever in an infant who was positive for Salmonella enterica serovar Paratyphi B (S. Paratyphi B) both in blood and stool cultures. The baby was enrolled in the passive surveillance of multicenter, multicomponent epidemiological study of enteric fever (Strategic Typhoid alliance across Africa and Asia; STRATAA) conducted in a population of 110,000 residents over 2 years in an urban slum, Dhaka, Bangladesh. This is the only patient who was positive for S. Paratyphi B in blood and stool among more than 6,000 febrile ill patients enrolled in the passive surveillance. The report shows the significance of surveillance to identify changes in the epidemiology of enteric fever.

Introduction: Cholera is a highly infectious disease and remains a serious public health burden in Bangladesh. The objective of the study was to measure the private demand for oral cholera vaccines (OCV) in Bangladesh and to investigate the key determinants of this demand, reflected in the household’s willingness to pay (WTP) for oral cholera vaccine. \ud Methods: A contingent valuation method was employed in an urban setting of Bangladesh during December 2015 to January 2016. All respondents (N= 1051) received a description of World Health Organization (WHO) prequalified OCV, Shanchol™. Interviews were conducted with either the head of households or their spouse or a major economic contributor of the households. Respondents were asked about how much at maximum they were willing to pay for OCV for their own and their household members’ protection. Results are presented as the average and median of the reported maximum WTP of the respondents with standard deviations and 95% confidence interval. Natural log-linear regression model was employed to examine the factors influencing participants’ WTP for OCV.\ud Results: About 99% of the respondents expressed WTP for OCV with a maximum mean and median WTP per vaccination (2 doses) of US$ 2.23 and US$ 1.92 respectively. On the household level with an average number of 4.62 members, the estimated mean WTP was US$ 10 (median: US$ 7.69) which represents the perceived demand for OCV of a household to vaccinate against cholera.\ud Conclusions: The demand of vaccination further indicates that there is a potential scope for recovering a certain portion of the expenditure of immunization program by introducing direct user fees for future cholera vaccination in Bangladesh. Findings from this study will be useful for the policy-makers to make decision on cost-recovery in future oral cholera vaccination programs in Bangladesh and in similar countries.

After the large influx of Rohingya nationals (termed Forcibly Displaced Myanmar National; FDMN) from Rakhine State of Myanmar to Cox’s Bazar in Bangladesh, it was apparent that outbreaks of cholera was very likely in this setting where people were living under adverse water and sanitation conditions. Large campaigns of oral cholera vaccine (OCV) were carried out as a preemptive measure to control cholera epidemics. The aim of the study was to evaluate the immune responses of healthy adults and children after administration of two doses of OCV at 14 days interval in FDMN population and compare with the response observed in Bangladeshi’s vaccinated earlier. A cross-sectional immunogenicity study was conducted among FDMNs of three age cohort; in adults (18+years; n = 83), in older children (6–17 years; n = 63) and in younger children (1–5 years; n = 80). Capillary blood was collected at three time points to measure vibriocidal antibodies using either plasma or dried blood spot (DBS) specimens. There was a significant increase of responder frequency of vibriocidal antibody titer at day 14 in all groups for Vibrio cholerae O1 (Ogawa/Inaba: adults-64%/64%, older children-70%/89% and younger children-51%/75%). There was no overall difference of vibriocidal antibody titer between FDMN and Bangladeshi population at baseline (p = 0.07–0.08) and at day 14, day 28 in all age groups for both serotypes. The seroconversion rate and geometric mean titer (GMT) of either serotype were comparable using both plasma and DBS specimens. These results showed that OCV is capable of inducing robust immune responses in adults and children among the FDMN population which is comparable to that seen in Bangladeshi participants in different age groups or that reported from other cholera endemic countries. Our results also suggest that the displaced population were exposed to V. cholerae prior to seeking shelter in Bangladesh., Author summary Oral cholera vaccines (OCV) are now on the WHO stockpile and targeted for use for countries with outbreaks and epidemics but also for control of endemic cholera. In Bangladesh many studies have been carried out to assess the safety, immunogenicity as well as feasibility of vaccination in the endemic settings of the country. However, with the large recent influx of displaced Rohingya nationals from Myanmar (termed Forcibly Displace Myanmar National; FDMN), mass campaigns with OCV were conducted between October 2017-December 2018. However, no data is available of the previous exposure to cholera of this population, prior to their arrival in Bangladesh. An assessment of immunogenicity status of FDMN is needed to find out if OCV is able to elicit comparable immune response and whether the same dose regimen of OCV was immunogenic among the FDMNs. In this study, we have measured the immune responses to the OCV, Shanchol, in adults (18 years and above), older children (6–17 years), and younger children (1–5 years). The results of this study shows that the oral cholera vaccine capable of inducing an immune response in adults and children among this FDMN population and the responses were comparable to that seen in Bangladeshi participants in earlier studies.

Background Cholera is known to be transmitted from person to person, and inactivated oral cholera vaccines (OCVs) have been shown to confer herd protection via interruption of this transmission. However, the geographic dimensions of chains of person-to-person transmission of cholera are uncertain. The ability of OCVs to confer herd protection was used to define these dimensions in two cholera-endemic settings, one in rural Bangladesh and the other in urban India. Methods Two large randomized, placebo-controlled trials of inactivated OCVs, one in rural Matlab, Bangladesh and the other in urban Kolkata, India, were reanalyzed. Vaccine herd protection was evaluated by relating the risk of cholera in placebo recipients to vaccine coverage of surrounding residents residing within concentric rings. In Matlab, concentric rings in 100-m increments up to 700m were evaluated; in Kolkata, 50-m increments up to 350m were evaluated. Results One hundred and eight cholera cases among 24667 placebo recipients were detected during 1year of post-vaccination follow-up at Matlab; 128 cholera cases among 34968 placebo recipients were detected during 3 years of follow-up in Kolkata. Consistent inverse relationships were observed between vaccine coverage of the ring and the risk of cholera in the central placebo recipient for rings with radii up to 500m in Matlab and up to 150m in Kolkata. Conclusions These results suggest that the dimensions of chains of person-to-person transmission in endemic settings can be quite large and may differ substantially from setting to setting. Using OCVs as ‘probes' to define these dimensions can inform geographical targeting strategies for the deployment of these vaccines in endemic settings.

Background After a multi-country Asian outbreak of cholera due to Vibrio cholerae serogroup O139 which started in 1992, it is rarely detected from any country in Asia and has not been detected from patients in Africa. Methodology/Principal findings We extracted surveillance data from the Dhaka and Matlab Hospitals of International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) to review trends in isolation of Vibrio cholerae O139 in Bangladesh. Data from the Dhaka Hospital is a 2% sample of > 100,000 diarrhoeal patients treated annually. Data from the Matlab Hospital includes all diarrhoeal patients who hail from the villages included in the Matlab Health and Demographic Surveillance System. Vibrio cholerae O139 was first isolated in Dhaka in 1993 and had been isolated every year since then except for a gap between 2005 and 2008. An average of thirteen isolates was detected annually from the Dhaka Hospital during the last ten years, yielding an estimated 650 cases annually at this hospital. During the last ten years, cases due to serogroup O139 represented 0.47% of all cholera cases; the others being due to serogroup O1. No cases with serogroup O139 were identified at Matlab since 2006. Clinical signs and symptoms of cholera due to serogroup O139 were similar to cases due to serogroup O1 though more of the O139 cases were not dehydrated. Most isolates of O139 remained sensitive to tetracycline, ciprofloxacin, and azithromycin, but they became resistant to erythromycin starting in 2009. Conclusions/Significance Cholera due to Vibrio cholerae serogroup O139 continues to cause typical cholera in Dhaka, Bangladesh., Author summary Vibrio cholerae O139 isolates were reported for the first time in Dhaka in 1993, but then declined and seemed to disappear as a threat. It was never isolated from patients in Africa. Data from the diarrhoeal diseases surveillance systems of hospitals in Dhaka and Matlab, Bangladesh were reviewed to observe the trends in isolation of Vibrio cholerae O139. Based on a representative 2% sample of patients at the Dhaka hospital, about 650 cholera patients were infected with V. cholerae O139 in recent years except during a gap period between 2005 and 2008 when no isolates were identified. The illnesses due to serotype O139 represent less than 1% of all cholera patients seen at the Dhaka hospital. The last patient with cholera due to V cholerae O139 in Matlab was detected in 2005. Clinical signs and symptoms of cholera due to serogroup O139 and serogroup O1 were similar though more of the O139 cases were not dehydrated. Most isolates of O139 remained susceptible to tetracycline, azithromycin, and ciprofloxacin; however, sensitivity to erythromycin changed following the gap years. Prior to 2005, they were sensitive, but they were resistant when they returned in 2009. We conclude that cholera caused by Vibrio cholerae O139 has not disappeared but continues at a low level in Dhaka, Bangladesh and surveillance needs to continue for this serogroup in Bangladesh.

Background: With a prevalence of 3.1%, approximately, 450 000 children in Bangladesh are having severe acute malnutrition (SAM). There is currently no national community-based program run by government to take care of these children, one of the reasons being lack of access to ready-to-use therapeutic food (RUTF). Objective: To develop RUTF using locally available food ingredients and test its acceptability. Methods: A checklist was prepared for all food ingredients available and commonly consumed in Bangladesh that have the potential of being used for developing a RUTF. Linear programming was used to identify the combinations of nutrients that would result in an ideal RUTF. To test the acceptability of 2 local RUTFs compared to the prototype RUTF, Plumpy’Nut, a clinical trial with a crossover design was conducted among 30 children in the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh. The acceptability was determined by using the mean proportion of offered food consumed by the children themselves. Results: Two RUTFs were developed, one based on chickpea and the other on rice–lentils. The total energy content of 100 g of chickpea and rice–lentil-based RUTF were 537.4 and 534.5 kcal, protein 12.9 and 13.5 g, and fat 31.8 and 31.1 g, respectively, without any significant difference among the group. On an average, 85.7% of the offered RUTF amount was consumed by the children in 3 different RUTF groups which implies that all types of RUTF were well accepted by the children. Conclusion: Ready-to-use therapeutic foods were developed using locally available food ingredients—rice, lentil, and chickpeas. Chickpea-based and rice–lentil-based RUTF were well accepted by children with SAM.

Faecal contamination of groundwater from pit latrines is widely perceived as a major threat to the safety of drinking water for several billion people in rural and peri-urban areas worldwide. On the floodplains of the Ganges-Brahmaputra-Meghna delta in Bangladesh, we constructed latrines and monitored piezometer nests monthly for two years. We detected faecal coliforms (FC) in 3.3-23.3% of samples at four sites. We differentiate a near-field, characterised by high concentrations and frequent, persistent and contiguous contamination in all directions, and a far-field characterised by rare, impersistent, discontinuous low-level detections in variable directions. Far-field FC concentrations at four sites exceeded 0 and 10 cfu/100 ml in 2.4-9.6% and 0.2-2.3% of sampling events respectively. The lesser contamination of in-situ groundwater compared to water at the point-of-collection from domestic wells, which itself is less contaminated than at the point-of-consumption, demonstrates the importance of recontamination in the well-pump system. We present a conceptual model comprising four sub-pathways: the latrine-aquifer interface (near-field); groundwater flowing from latrine to well (far-field); the well-pump system; and post-collection handling and storage. Applying a hypothetical dose-response model suggests that 1-2% of the diarrhoeal disease burden from drinking water is derived from the aquifer, 29% from the well-pump system, and 70% from post-collection handling. The important implications are (i) that leakage from pit latrines is a minor contributor to faecal contamination of drinking water in alluvial-deltaic terrains; (ii) fears of increased groundwater pollution should not constrain expanding latrine coverage, and (iii) that more attention should be given to reducing contamination around the well-head.

© 2017 Background Cholera remains a threat globally, and socioeconomic factors play an important role in transmission of the disease. We assessed socioeconomic risk factors for cholera in vaccinated and non-vaccinated communities to understand whether the socioeconomic risk factors differ by transmission patterns for cholera. Methods We used data from a cluster randomized control trial conducted in Dhaka, Bangladesh. There were 90 geographic clusters; 30 in each of the three arms of the study: vaccine (VAC), vaccine plus behavioural change (VBC), and non-intervention. The data were analysed for the three populations: (1) vaccinees in the vaccinated communities (VAC and VBC arms), (2) non-vaccinated individuals in the vaccinated communities and (3) all individuals in the non-vaccinated communities (non-intervention arm). A generalized estimating equation with logit link function was used to evaluate the risk factors for cholera among these different populations adjusting for household level correlation in the data. Results A total of 528 cholera and 226 cholera with severe dehydration (CSD) in 268,896 persons were observed during the two-year follow-up. For population 1, the cholera risk was not associated with any socioeconomic factors; however CSD was less likely to occur among individuals living in a household having ≤4 members (aOR = 0.55, 95% CI = 0.32–0.96). Among population 2, younger participants and individuals reporting diarrhoea during registration were more likely to have cholera. Females and individuals reporting diarrhoea during registration were at increased risk of CSD. Among population 3, individuals living in a household without a concrete floor, in an area with high population density, closer to the study hospital, or not treating drinking water were at significantly higher risk for both cholera and CSD. Conclusion The profile of socioeconomic factors associated with cholera varies by individuals’ vaccination status as well as the transmission setting. In a vaccinated community where transmission would be expected to be lower, socioeconomic factors may not increase the risk of the disease.

The switching of serotype from Ogawa to Inaba and back to Ogawa has been observed temporally in Vibrio cholerae O1, which is responsible for endemic cholera in Bangladesh. The serospecificity is key for effective intervention and for preventing cholera, a deadly disease that continues to cause significant morbidity and mortality worldwide. In the present study, WGS of V. cholerae allowed us to better understand the factors associated with the serotype switching events observed during 2015 to 2018. Genomic data analysis of strains isolated during this interval highlighted variations in the genes ctxB, tcpA, and rtxA and also identified significant differences in the genetic content of the mobilome, which included key elements such as SXT ICE, VSP-II, and PLE. Our results indicate that selective forces such as antibiotic resistance and phage resistance might contribute to the clonal expansion and predominance of a particular V. cholerae serotype responsible for an outbreak., The temporal switching of serotypes from serotype Ogawa to Inaba and back to Ogawa was identified in Vibrio cholerae O1, which was responsible for seasonal outbreaks of cholera in Dhaka during the period 2015 to 2018. In order to delineate the factors responsible for this serotype transition, we performed whole-genome sequencing (WGS) of V. cholerae O1 multidrug-resistant strains belonging to both the serotypes that were isolated during this interval where the emergence and subsequent reduction of the Inaba serotype occurred. The whole-genome-based phylogenetic analysis revealed clonal expansion of the Inaba isolates mainly responsible for the peaks of infection during 2016 to 2017 and that they might have evolved from the prevailing Ogawa strains in 2015 which coclustered with them. Furthermore, the wbeT gene in these Inaba serotype isolates was inactivated due to insertion of a transposable element at the same position signifying the clonal expansion. Also, V. cholerae isolates in the Inaba serotype dominant clade mainly contained classical ctxB allele and revealed differences in the genetic composition of Vibrio seventh pandemic island II (VSP-II) and the SXT integrative and conjugative element (SXT-ICE) compared to those of Ogawa serotype strains which remerged in 2018. The variable presence of phage-inducible chromosomal island-like element 1 (PLE1) was also noted in the isolates of the Inaba serotype dominant clade. The detailed genomic characterization of the sequenced isolates has shed light on the forces which could be responsible for the periodic changes in serotypes of V. cholerae and has also highlighted the need to analyze the mobilome in greater detail to obtain insights into the mechanisms behind serotype switching.

Background In a cluster randomized trial (CRT) of a Vi polysaccharide vaccine against typhoid in the slums of Kolkata we found evidence of vaccine herd protection. However, transmission of typhoid into clusters from the outside likely occurred in this densely populated setting, which could have diminished our estimates of vaccine herd protection. Methods Eighty clusters (40 in each arm) were randomised to receive a single dose of either Vi or inactivated hepatitis A vaccine. We analysed protection for the entire cluster and for subclusters consisting of residents of the innermost households. Results During 2 y of follow-up, total protection was 61% (95% CI 41 to 75), overall protection was 57% (95% CI 37 to 71) and indirect protection was 44% (95% CI 2 to 69). Analyses of the innermost 75% and 50% of households of the clusters showed similar findings. However, in the innermost 25% of households of the clusters, total protection was 82% (95% CI 48 to 94) and overall protection was 66% (95% CI 27 to 84). There was not a sufficient sample size to demonstrate such a trend for indirect protection in these innermost households. Conclusions The findings suggest that analyses of the entire cluster may have led to underestimation of herd protection against typhoid by Vi vaccine and that restriction of the analyses to the inner subclusters may have led to a more accurate estimation of vaccine herd effects.