Burden Of Typhoid Fever Research Articles

Clinical Features and Socio – Demographic Factors Affecting the Prevalence of Enteric Fever: A Prospective Observational Study

Background: Enteric fever otherwise called Typhoid fever is a systemic disease caused by Salmonella typhi and Salmonella paratyphi, having reservoir in contaminated water and food. It affects considerable number of populations of the world but regions of South Asia are most commonly affected.
 Aims and Objective: The objective of this study to find the prevalence of Typhoid fever with respect to age, gender, marital status, occupation, seasonal variation, treatment of drinking domestic water source, and clinical features.
 Methodology: This is a cross- sectional observational study conducted at Bangladesh Medical College Hospital (BMCH), Dhanmondi, Dhaka from January to December 2019. Those presenting both outpatient departments or admitted to the inpatient units with complains of fever and abdominal pain underwent blood culture for the diagnosis of Typhoid fever. Patients with informed consent and positive blood culture report (including both Salmonella typhi and Salmonella paratyphi) were included in the study.
 Results: Total 1375 tests were performed, out of which 407 came out to be positive blood culture report (including both Salmonella typhi and Salmonella paratyphi). Out of these tests 31.65% were males and 27.35% were females. Highest occurrence of typhoid fever was observed among males of age group 18 – 45 years and least with patients between age group above 75 years. As for the influence of occupation, male civil servants recorded the highest occurrence in the hospitals while artisans recorded the least. The influence of marital status revealed the highest occurrence in the single males with the married females had the least. In relation to months the prevalence was the highest in the month of July - September (11.42%). Water quality, vaccination and season have great impact on the burden of typhoid fever in population. Fever, diarrhea and abdominal pain are the major symptoms associated with typhoid fever.
 Conclusion: Socio-demographic factors such as age, gender, marital status, and seasonal variation, treatment of drinking water supply, occupation and presenting complaints influenced the distribution pattern of typhoid fever among the population in BMCH, Dhanmondi, Dhaka.
 Bangladesh Crit Care J September 2020; 8(2): 86-90

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

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. 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. 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. 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.

A Review on Recent Developments for the Cure of Salmonella Enterica Serovar Typhi, the Causative Agent for Typhoid Fever

Salmonella enterica typhi is typhoid or enteric fever agent which is a serious water-borne disease and is a human host restricted organism. So, an important cause of death in underdeveloped countries, typhoid fever is a public health concern. Worldwide, 15-30 million people suffer from this disease every year, causing more than 200,000 deaths. However, several lines of evidence suggest that the advent of multidrug-resistant non-typhoidal strains of Salmonella has an important impact on the effectiveness of current strategies, including reductions in the effectiveness of early empirical treatment for controlling and managing foodborne diseases. Recent studies show more than 2000 strains of salmonella bacteria with around 100 strains connected to human infection - with myriad common strains from Salmonella Heidelberg to Typhimurium to Salmonella infantis. The multi-medicinal strain S. Typhi H58 has developed into the main circulating strain in many parts of the world, and an extensively drug-resistant (XDR) subclade has been recently found. Most of the people agree that the most effective way to control infection is to vaccinate susceptible populations. The commercially available live attenuated (Ty21a) vaccine, on the other hand, is not recommendable for children under the age of six, whereas the poor long-term efficacy of Vi-polysaccharide-based vaccine against typhoid fever. Furthermore, there are no vaccines available to protect against S. para typhi infection. Subsequently, a new formulation is urgently needed that can provide long-term protection against both pathogens while healthy for all age groups. Pakistan is the first country in the world to incorporate the WHO-recommended conjugate vaccine into its routine typhoid immunization program (2019). As a result, the purpose of this review is to describe the various diagnostic procedures for typhoid fever diagnosis and cure development. This article addressed some of the elements and components required for the implementation of typhoid vaccine.
 With an analysis of past and current enteric fever vaccines in progress as well as the ethical issues relevant to CHIM in typhoid vaccine efficacy research, we have combined the new methods to predict typhoid burden and vaccines impact.

Intestinal Perforations Associated With a High Mortality and Frequent Complications During an Epidemic of Multidrug-resistant Typhoid Fever in Blantyre, Malawi.

BackgroundTyphoid fever remains a major source of morbidity and mortality in low-income settings. Its most feared complication is intestinal perforation. However, due to the paucity of diagnostic facilities in typhoid-endemic settings, including microbiology, histopathology, and radiology, the etiology of intestinal perforation is frequently assumed but rarely confirmed. This poses a challenge for accurately estimating burden of disease.MethodsWe recruited a prospective cohort of patients with confirmed intestinal perforation in 2016 and performed enhanced microbiological investigations (blood and tissue culture, plus tissue polymerase chain reaction [PCR] for Salmonella Typhi). In addition, we used a Poisson generalized linear model to estimate excess perforations attributed to the typhoid epidemic, using temporal trends in S. Typhi bloodstream infection and perforated abdominal viscus at Queen Elizabeth Central Hospital from 2008–2017.ResultsWe recruited 23 patients with intraoperative findings consistent with intestinal perforation. 50% (11/22) of patients recruited were culture or PCR positive for S. Typhi. Case fatality rate from typhoid-associated intestinal perforation was substantial at 18% (2/11). Our statistical model estimates that culture-confirmed cases of typhoid fever lead to an excess of 0.046 perforations per clinical typhoid fever case (95% CI, .03–.06). We therefore estimate that typhoid fever accounts for 43% of all bowel perforation during the period of enhanced surveillance.ConclusionsThe morbidity and mortality associated with typhoid abdominal perforations are high. By placing clinical outcome data from a cohort in the context of longitudinal surgical registers and bacteremia data, we describe a valuable approach to adjusting estimates of the burden of typhoid fever.

Environmental Surveillance as a Tool for Identifying High-risk Settings for Typhoid Transmission.

Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever.

Gavi Support for Typhoid Conjugate Vaccines: Moving From Global Investments to Country Introduction

Nine years elapsed between Gavi’s investment decision to support typhoid conjugate vaccines (TCVs) in 2008 and Gavi support becoming available for countries to introduce TCV. The protracted path toward Gavi support for TCV highlights the challenges of vaccine development for lower-income countries and the importance of Gavi engagement as early as possible in product development processes to support the alignment of manufacturing, global policy, and program implementation. Early engagement would provide inputs to inform strategic vaccine investment decisions that transition more efficiently toward country implementation. Several countries have been approved for Gavi support to introduce TCV in 2019–2020. The paucity of generalizable typhoid epidemiological data in early introducing countries has reinforced the need for continued evidence generation regarding typhoid epidemiology and TCV impact. This has led to the development of guidance and tools to support country decision making for TCV introduction based on enhanced understanding of local typhoid burden and risk.

Prevalence and Associated Risk Factors of Typhoid Fever in Children Attending 'Deo Gratias' Hospital in Douala, Littoral Region of Cameroon

Typhoid fever is a communicable disease transmitted by the bacteria Salmonella typhi, related to serotype paratyphi A, B and C. The disease is of a significant health concern in most developing countries especially Cameroon. Objectives: The study aimed at determining the prevalence and associated risk factors of typhoid fever in children ( 0-18 years) attending the “Deo Gratias” hospital in Douala. Method: A hospital base cross sectional study from August to September 2018 was carried out in patients’ age 0-18 years suffering from typhoid fever at the Deo gratias Catholic hospital. Widal slide agglutination test was the diagnostic test used. Positive tested patients were administered questionnaires to evaluate the level of knowledge, attitude and practice toward the disease, as well as their self-management abilities. Data obtained from respondents was analysed by descriptive statistics. One-way ANOVA and means comparison using Tukey’s test (α = 0.05) was performed to check whether the population of respondents differed significantly across risk factor practices. Results were finally presented on bar charts, tables and pie chart. Results: Typhoid fever was more prevalent in females (52.3%) than in males (47.7%), with a high proportion in the ages 5-9 years (38.6%). A significant difference was observed in population of respondents across risk factor practices. Conclusion: Water quality have a great impact on the burden of typhoid fever among children. The identification of risk factors associated to the disease is of great importance in the development of rational control strategies of the disease.

Changes in historical typhoid transmission across 16 U.S. cities, 1889-1931: Quantifying the impact of investments in water and sewer infrastructures.

Investments in water and sanitation systems are believed to have led to the decline in typhoid fever in developed countries, such that most cases now occur in regions lacking adequate clean water and sanitation. Exploring seasonal and long-term patterns in historical typhoid mortality in the United States can offer deeper understanding of disease drivers. We fit modified Time-series Susceptible-Infectious-Recovered models to city-level weekly mortality counts to estimate seasonal and long-term typhoid transmission. We examined seasonal transmission separately by city and aggregated by water source. Typhoid transmission peaked in late summer/early fall. Seasonality varied by water source, with the greatest variation occurring in cities with reservoirs. We then fit hierarchical regression models to measure associations between long-term transmission and annual financial investments in water and sewer systems. Overall historical $1 per capita ($16.13 in 2017) investments in the water supply were associated with approximately 5% (95% confidence interval: 3-6%) decreases in typhoid transmission, while $1 increases in the overall sewer system investments were associated with estimated 6% (95% confidence interval: 4-9%) decreases. Our findings aid in the understanding of typhoid transmission dynamics and potential impacts of water and sanitation improvements, and can inform cost-effectiveness analyses of interventions to reduce the typhoid burden.

Simulating the transmission dynamics and control of typhoid fever in Ibadan, Nigeria

This study aims to assess transmission dynamics of typhoid and simulate effects of treatment, isolation and vaccination in reducing the burden of typhoid fever in Ibadan metropolis, Nigeria. Secondary data of the Integrated Disease Surveillance Response on reported typhoid fever cases for 2010 to 2017 period in Ibadan South-East Local Government Area, Oyo State, Nigeria were used to achieve the set-out objectives. The study adapted the Susceptible-Infected-Carrier-Recovered (SIIcR) model to simulate effects of the three preventive and control strategies on typhoid fever transmission. Typhoid fever cases were most rampant among the age groups 20 to 40 years (29.0% infected) and > 40 years (35% asymptomatic carriers and 45.0% death) and the least in age group 0 to 28 days (0.22% infected and no death case). A decreasing trend in typhoid fever cases (56 cases per year) was observed which was attributed to improved functional health facilities and their effective utilization. Significant seasonal variation in typhoid infections was found with the highest reported cases at the start of wet (April) and dry (November) seasons. The SIIcR model simulations suggested likelihood of typhoid fever epidemic within two weeks in the community if no prevention and intervention measures were put in place. Major reduction in the carriers’ population significantly reduced the number of infected class and suggested disease-free population within a season of typhoid epidemic (100 days). Model simulations suggested that vaccination and isolation significantly reduced the effect of infected and asymptomatic carrier populations at p<0.05 on the transmission dynamics of typhoid fever.

The need & the issues related to new-generation typhoid conjugate vaccines in India

The low- and middle-income countries bear the highest burden of typhoid fever in the world. India, along with other South Asian countries, has a significant incidence of typhoid fever among young children though there is a paucity of published data on community burden. In spite of the availability of Vi-polysaccharide (Vi-PS) and conjugated Vi-PS vaccines, these are not adequately utilized in India and in the neighbouring countries. To address many shortcomings of the unconjugated Vi-PS vaccines, typhoid conjugate vaccines (TCVs) are developed by conjugating Vi-PS with different carrier proteins. Three such vaccines using tetanus toxoid as a carrier protein are already licensed in India. Several other Vi-PS conjugates are currently in various stages of development. The current review provides an update on the existing and upcoming new TCVs along with a detailed discussion on the various issues involved with their clinical use and limitations.

Typhoid Fever: Recent Advances in Understanding, Diagnosis, and Management Strategies for Endemic Regions

Typhoid fever, caused by Salmonella enterica serotype Typhi, remains a significant public health challenge in developing countries despite major declines in incidence in the Western world. Historically, typhoid fever was a major cause of morbidity and mortality in Europe and the United States, primarily due to poor sanitation and inadequate water supply. Advances in public health infrastructure have markedly reduced its prevalence in developed regions, but it continues to affect millions annually in parts of Asia, including Bangladesh. The disease disproportionately impacts children and persists in areas with suboptimal sanitation and overcrowded living conditions. In Bangladesh, inadequate data on typhoid fever burden complicates effective management and control. Challenges include the prevalence of outpatients, insufficient diagnostic facilities, unreliable record-keeping, and limitations of the Widal test, which has moderate sensitivity and specificity. This review aims to consolidate recent advancements in understanding typhoid fever, particularly within the Indian context, by examining its epidemiology, pathogenesis, symptomatology, diagnostic methods, and treatment strategies. Notable epidemiological trends reveal high incidence rates in South Asia, with significant seasonal variation. Improved diagnostic tools, such as PCR and newer serological tests, are emerging, but blood culture remains the gold standard. Treatment has evolved with concerns over drug resistance, and prevention strategies emphasize the importance of improved sanitation and water safety. This review highlights the need for enhanced public health efforts and research to address the persistent challenges of typhoid fever in endemic regions.

An Epidemiological study of Enteric Fever among children attending OPD of a tertiary Medical Institute situated in rural area

Introduction: Typhoid fever is a commonly encountered systemic disease caused by the gram negative bacteria Salmonella entericaser over typhi. It is considered as one of the most serious infectious disease threats to public health on a global scale because of its rapid and widespread emergence of resistance to multiple antibiotics. Looking at the serious consequences of Enteric fever among children, it is important to know the burden of the problem with its correlates. This will help in formulating interventions for prevention and control. Methods: Primary caregivers (mother/father/ guardians) of 100 ill children aged 2–12 years who came to seek medical care in out-patient department (OPD) for their children were interviewed. Study subjects fulfilling the inclusion criteria were selected by simple random sampling method. The study was conducted over a period of 7 months .Detailed Clinical Examination was done of all 100 children. Diagnosis was made on the basis of Suggestive clinical features & Serology by Widal test with titre of TO > 1:160 was taken as diagnostic. Results: Total of 100 cases of enteric fever case were Examined / seen in OPD / admitted during the study period. The leading clinical feature were fever , headache , followed by coated tongue & anorexia. Total 78 out of 100 suspected cases were Widal Positive. Positive and significant relationship was found between the source of drinking water, level of housing , Education of Parent & levels of earning with typhoid. Conclusion: This study presents important insight into the burden of Enteric fever in rural children. These findings can be used to plan future strategies for health education interventions in the community. There is a need to take immediate measures for prevention and control of Enteric fever in children. Awareness campaigns about the common causes & complications related to Typhoid are recommended

Molecular mechanism of azithromycin resistance among typhoidal Salmonella strains in Bangladesh identified through passive pediatric surveillance.

BackgroundWith the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism.Methods and findingsWe conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009–2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32–64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance.ConclusionsThis report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever.

The Invisible Burden: Diagnosing and Combatting Typhoid Fever in Asia and Africa.

Measuring the burden of typhoid fever and developing effective strategies to reduce it require a surveillance infrastructure that is currently lacking in many endemic countries. Recent efforts and partnerships between local and international researchers have helped to provide new data on the incidence and control of typhoid in parts of Asia and Africa. Here, we highlight examples from India, Nepal, Vietnam, Fiji, Sierra Leone, and Malawi that summarize past and present experiences with the diagnosis, treatment, and prevention of typhoid fever in different locations with endemic disease. While there is no validated road map for the elimination of typhoid, the lessons learned in studying the epidemiology and control of typhoid in these settings can provide insights to guide future disease control efforts.

Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi.

Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0–4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62–94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.

Estimating the burden of enteric fever in Chhattisgarh: A single-center study on culture-positive cases from a newly built tertiary care hospital.

BACKGROUND:Enteric fever is the most common cause of community acquired blood stream infections in under developed and developing countries. The enteric fever is exclusive to humans and transmitted through the faeco-oral route. Though India is an endemic zone for enteric fever, the data is very scarce from Central India. The present study was undertaken to determine the prevalence of enteric fever in this region and to know the antimicrobial susceptibility pattern of the isolated typhoidal Salmonellae.MATERIAL AND METHOD:We conducted a retrospective analysis of blood culture positive cases of enteric fever over a period of two years (December 2015 to December 2017). All blood cultures submitted for suspected enteric fever and associated symptoms were included in the study. Relevant demographic, clinical and laboratory data were analyzed.RESULT:A total of 51 cases (3.56%) were of typhoidal Salmonella from a total of 1430 blood culture submission. Salmonella Typhi were 70.5% while Salmonella Paratyphi A were 29.5% of the total isolated Salmonellae. The most vulnerable age group was 10-19years (41.2%). The mean minimum inhibitory concentration of ciprofloxacin for Salmonella Typhi and Salmonella Paratyphi A are 1.20 and 1.97 μg/ml respectively. All the isolates were susceptible to ceftriaxone. Highest isolation was in the July – September quarter (35.3%).CONCLUSION:There is a high prevalence of the disease which needs urgent focus on safe water, sanitation services and also to establish guidelines for empiric therapy for enteric fever.

Anti-microbial Resistance surveillance in typhoidal Salmonella in Ahmedabad Objective

Anti-microbial Resistance surveillance in typhoidal Salmonella in Ahmedabad Objective

Cost-effectiveness of routine and campaign use of typhoid Vi-conjugate vaccine in Gavi-eligible countries: a modelling study

SummaryBackgroundTyphoid fever is a major cause of morbidity and mortality in low-income and middle-income countries. In 2017, WHO recommended the programmatic use of typhoid Vi-conjugate vaccine (TCV) in endemic settings, and Gavi, The Vaccine Alliance, has pledged support for vaccine introduction in these countries. Country-level health economic evaluations are now needed to inform decision-making.MethodsIn this modelling study, we compared four strategies: no vaccination, routine immunisation at 9 months, and routine immunisation at 9 months with catch-up campaigns to either age 5 years or 15 years. For each of the 54 countries eligible for Gavi support, output from an age-structured transmission-dynamic model was combined with country-specific treatment and vaccine-related costs, treatment outcomes, and disability weights to estimate the reduction in typhoid burden, identify the strategy that maximised average net benefit (ie, the optimal strategy) across a range of country-specific willingness-to-pay (WTP) values, estimate and investigate the uncertainties surrounding our findings, and identify the epidemiological conditions under which vaccination is optimal.FindingsThe optimal strategy was either no vaccination or TCV immunisation including a catch-up campaign. Routine vaccination with a catch-up campaign to 15 years of age was optimal in 38 countries, assuming a WTP value of at least US$200 per disability-adjusted life-year (DALY) averted, or assuming a WTP value of at least 25% of each country's gross domestic product (GDP) per capita per DALY averted, at a vaccine price of $1·50 per dose (but excluding Gavi's contribution according to each country's transition phase). This vaccination strategy was also optimal in 48 countries assuming a WTP of at least $500 per DALY averted, in 51 with assumed WTP values of at least $1000, in 47 countries assuming a WTP value of at least 50% of GDP per capita per DALY averted, and in 49 assuming a minimum of 100%. Vaccination was likely to be cost-effective in countries with 300 or more typhoid cases per 100 000 person-years. Uncertainty about the probability of hospital admission (and typhoid incidence and mortality) had the greatest influence on the optimal strategy.InterpretationCountries should establish their own WTP threshold and consider routine TCV introduction, including a catch-up campaign when vaccination is optimal on the basis of this threshold. Obtaining improved estimates of the probability of hospital admission would be valuable whenever the optimal strategy is uncertain.FundingBill & Melinda Gates Foundation, Research Foundation–Flanders, and the Belgian–American Education Foundation.

Assessing the Impact of a Vi-polysaccharide Conjugate Vaccine in Preventing Typhoid Infections Among Nepalese Children: A Protocol for a Phase III, Randomized Control Trial

BackgroundEnteric fever is estimated to affect 11–20 million people worldwide each year. Morbidity and mortality from enteric fever primarily occur in lower-income countries, with children under 5 years of age experiencing a significant portion of the burden. Over the last few decades, the control of enteric fever has focused primarily on improved water and sanitation, with the available vaccines unsuitable for children and primarily used by travelers. A new typhoid conjugate vaccine (Vi-TCV), prequalified by the World Health Organization (WHO) and highly immunogenic in children under 5, has the potential to reduce the typhoid burden in endemic countries.MethodsThis study is a double-blinded, randomized, controlled trial with a 2-year follow-up to assess the protective impact of the Vi-TCV vaccine, compared with a control vaccine, in children from 9 months to 16 years of age. The primary outcome of interest is the reduction in the number of culture-confirmed typhoid cases attributable to Vi-TCV. Approximately 20 000 children living in the Lalitpur district, within the Kathmandu valley, will be enrolled in the study and followed to measure both safety and efficacy data, which will include adverse events, hospitalizations, antibiotic use, and fever frequency.ResultsBoth the intervention and control vaccines are WHO prequalified vaccines, which provide a health benefit to all participants. Children have been chosen to participate because they bear a substantial burden of both typhoid morbidity and mortality in this population. The results of this study will be disseminated through a series of published articles. The findings will also be made available to the participants and the broader community, as well as local stakeholders, within Nepal.ConclusionsThis is the first large-scale, individually randomized, controlled trial of Vi-TCV in children in an endemic setting, and will provide new data on Vi-TCV field efficacy. With Vi-TCV introduction being considered in high-burden countries, this study will support important policy decisions.Clinical Trials RegistrationThe trial is registered on the ISRCTN registry (for details, see https://doi.org/10.1186/ISRCTN43385161; registry number: ISRCTN 43385161).

Age-Associated Heterogeneity of Ty21a-Induced T Cell Responses to HLA-E Restricted Salmonella Typhi Antigen Presentation.

Human-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever—a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases.