A multinational Delphi consensus to end the COVID-19 public health threat.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches1, while maintaining proven prevention measures using a vaccines-plus approach2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

Burden of Typhoid and Paratyphoid Fever in India.

BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

Genomic analysis unveils genome degradation events and gene flux in the emergence and persistence of S. Paratyphi A lineages.

Paratyphoid fever caused by S. Paratyphi A is endemic in parts of South Asia and Southeast Asia. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study "Surveillance of Enteric Fever in India (SEFI)." In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis highlights that the genome degradation events and gene acquisitions or losses are key molecular events in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 hypothetically disrupted coding sequences (HDCS) or pseudogenes-forming mutations possibly associated with the emergence of lineages were identified. The pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We have identified six characteristic missense mutations associated with lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A, however, these mutations confer only a low structural impact and possibly have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human-restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and monitoring by means of genomic surveillance would be constantly needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today.

A new twenty-first century science for effective epidemic response.

With rapidly changing ecology, urbanization, climate change, increased travel and fragile public health systems, epidemics will become more frequent, more complex and harder to prevent and contain. Here we argue that our concept of epidemics must evolve from crisis response during discrete outbreaks to an integrated cycle of preparation, response and recovery. This is an opportunity to combine knowledge and skills from all over the world-especially at-risk and affected communities. Many disciplines need to be integrated, including not only epidemiology but also social sciences, research and development, diplomacy, logistics and crisis management. This requires a new approach to training tomorrow's leaders in epidemic prevention and response.

Frequency of bystander exposure to antibiotics for enteropathogenic bacteria among young children in low-resource settings.

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

Environmental Surveillance for Salmonella Typhi and its Association With Typhoid Fever Incidence in India and Malawi.

BACKGROUND: Environmental surveillance (ES) for Salmonella Typhi potentially offers a low-cost tool to identify communities with a high burden of typhoid fever. METHODS: We developed standardized protocols for typhoid ES, including sampling site selection, validation, characterization; grab or trap sample collection, concentration; and quantitative PCR targeting Salmonella genes (ttr, staG, and tviB) and a marker of human fecal contamination (HF183). ES was implemented over 12 months in a historically high typhoid fever incidence setting (Vellore, India) and a lower incidence setting (Blantyre, Malawi) during 2021-2022. RESULTS: S. Typhi prevalence in ES samples was higher in Vellore compared with Blantyre; 39/520 (7.5%; 95% confidence interval [CI], 4.4%-12.4%) vs 11/533 (2.1%; 95% CI, 1.1%-4.0%) in grab and 79/517 (15.3%; 95% CI, 9.8%-23.0%) vs 23/594 (3.9%; 95% CI, 1.9%-7.9%) in trap samples. Detection was clustered by ES site and correlated with site catchment population in Vellore but not Blantyre. Incidence of culture-confirmed typhoid in local hospitals was low during the study and zero some months in Vellore despite S. Typhi detection in ES. CONCLUSIONS: ES describes the prevalence and distribution of S. Typhi even in the absence of typhoid cases and could inform vaccine introduction. Expanded implementation and comparison with clinical and serological surveillance will further establish its public health utility.

Burden of disease attributable to unsafe drinking water, sanitation, and hygiene in domestic settings: a global analysis for selected adverse health outcomes.

BACKGROUND: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels. METHODS: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH. FINDINGS: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH. INTERPRETATION: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns. FUNDING: WHO and Foreign, Commonwealth & Development Office.

Hospital-based norovirus surveillance in children <5 years of age from 2017 to 2019 in India.

After the introduction of the rotavirus vaccine into the Universal Immunization Program in India in 2016, relatively few studies have assessed the prevalence and epidemiological patterns of acute gastroenteritis (AGE) among hospitalized children ≤5 years of age. We used a uniform protocol to recruit children with AGE as well as standardized testing and typing protocols. Stool specimens from children with AGE younger than 5 years of age admitted to six hospitals in three cities in India were collected from January 2017 through December 2019. Norovirus was detected by real-time reverse transcription-polymerase chain reaction (RT-qPCR) followed by typing positive specimens by conventional RT-PCR and Sanger sequencing. Norovirus was detected in 322 (14.8%) of 2182 specimens with the highest rate in 2018 (17.6%, 146/829), followed by 2019 (14.4%, 122/849) and 2017 (10.7%, 54/504). Rotavirus vaccine status was known for 91.6% of the children of which 70.4% were vaccinated and 29.6% not. Norovirus positivity in rotavirus-vaccinated children was 16.3% and 12% in unvaccinated children. GII.4 Sydney[P16] (39.3%), GII.4 Sydney[P31] (18.7%), GII.2[P16] (10%), GI.3[P13] (6.8%), GII.3[P16] (5.9%), and GII.13[P16] (5%) accounted for 85.8% (188/219) of the typed strains. Our data highlight the importance of norovirus in Indian children hospitalized with AGE.

Human challenge trials in vaccine development.

The increasing recent interest in human challenge studies or controlled human infection model studies for accelerating vaccine development has been driven by the recognition of the unique ability of these studies to contribute to the understanding of response to infection and the performance of vaccines. With streamlining of ethical processes, conduct and supervision and the availability of new investigative tools from immunophenotyping to glycobiology, the potential to derive valuable data to inform vaccine testing and development has never been greater. However, issues of availability and standardization of challenge strains, conduct of studies in disease endemic locations and the iteration between clinical and laboratory studies still need to be addressed to gain maximal value for vaccine development.

Association Between Maternal Breastmilk Microbiota Composition and Rotavirus Vaccine Response in African, Asian, and European Infants: A Prospective Cohort Study.

BACKGROUND: Maternal breastmilk is a source of pre- and pro-biotics that impact neonatal gut microbiota colonization. Because oral rotavirus vaccines (ORVs) are administered at a time when infants are often breastfed, breastmilk microbiota composition may have a direct or indirect influence on vaccine take and immunogenicity. METHODS: Using standardized methods across sites, we compared breastmilk microbiota composition in relation to geographic location and ORV response in cohorts prospectively followed from birth to 18 weeks of age in India (n = 307), Malawi (n = 119), and the United Kingdom ([UK] n = 60). RESULTS: Breastmilk microbiota diversity was higher in India and Malawi than the UK across 3 longitudinal samples spanning weeks of life 1 to 13. Dominant taxa such as Streptococcus and Staphylococcus were consistent across cohorts; however, significant geographic differences were observed in the prevalence and abundance of common and rare genera throughout follow up. No consistent associations were identified between breastmilk microbiota composition and ORV outcomes including seroconversion, vaccine shedding after dose 1, and postvaccination rotavirus-specific immunoglobulin A level. CONCLUSIONS: Our findings suggest that breastmilk microbiota composition may not be a key factor in shaping trends in ORV response within or between countries.

Intussusception after Rotavirus Vaccine Introduction in India.

BACKGROUND: A three-dose, oral rotavirus vaccine (Rotavac) was introduced in the universal immunization program in India in 2016. A prelicensure trial involving 6799 infants was not large enough to detect a small increased risk of intussusception. Postmarketing surveillance data would be useful in assessing whether the risk of intussusception would be similar to the risk seen with different rotavirus vaccines used in other countries. METHODS: We conducted a multicenter, hospital-based, active surveillance study at 27 hospitals in India. Infants meeting the Brighton level 1 criteria of radiologic or surgical confirmation of intussusception were enrolled, and rotavirus vaccination was ascertained by means of vaccination records. The relative incidence (incidence during the risk window vs. all other times) of intussusception among infants 28 to 365 days of age within risk windows of 1 to 7 days, 8 to 21 days, and 1 to 21 days after vaccination was evaluated by means of a self-controlled case-series analysis. For a subgroup of patients, a matched case-control analysis was performed, with matching for age, sex, and location. RESULTS: From April 2016 through June 2019, a total of 970 infants with intussusception were enrolled, and 589 infants who were 28 to 365 days of age were included in the self-controlled case-series analysis. The relative incidence of intussusception after the first dose was 0.83 (95% confidence interval [CI], 0.00 to 3.00) in the 1-to-7-day risk window and 0.35 (95% CI, 0.00 to 1.09) in the 8-to-21-day risk window. Similar results were observed after the second dose (relative incidence, 0.86 [95% CI, 0.20 to 2.15] and 1.23 [95% CI, 0.60 to 2.10] in the respective risk windows) and after the third dose (relative incidence, 1.65 [95% CI, 0.82 to 2.64] and 1.08 [95% CI, 0.69 to 1.73], respectively). No increase in intussusception risk was found in the case-control analysis. CONCLUSIONS: The rotavirus vaccine produced in India that we evaluated was not associated with intussusception in Indian infants. (Funded by the Bill and Melinda Gates Foundation and others.).

Increased bacterial taxonomic and functional diversity is associated with impaired rotavirus vaccine immunogenicity in infants from India and Malawi.

The immunogenicity and effectiveness of oral rotavirus vaccines (ORVs) against severe rotavirus-associated gastroenteritis are impaired in low- and middle-income countries (LMICs) where the burden of disease is highest. Determining risk factors for impaired ORV response may help identify strategies to enhance vaccine effectiveness. In this study, we use metagenomic sequencing to provide a high-resolution taxonomic analysis of stool samples collected at 6 weeks of age (coinciding with the first ORV dose) during a prospective study of ORV immunogenicity in India and Malawi. We then analyse the functional capacity of the developing microbiome in these cohorts. Microbiome composition differed significantly between countries, although functional capacity was more similar than taxonomic composition. Our results confirm previously reported findings that the developing microbiome is more diverse in taxonomic composition in ORV non-seroconverters compared with seroconverters, and we additionally demonstrate a similar pattern in functional capacity. Although taxonomic or functional feature abundances are poor predictors of ORV response, we show that skews in the direction of associations within these microbiome data can be used to identify consistent markers of ORV response across LMIC infant cohorts. We also highlight the systemic under-representation of reference genes from LMICs that limit functional annotation in our study (7% and 13% annotation at pathway and enzyme commission level, respectively). Overall, higher microbiome diversity in early life may act as marker for impaired ORV response in India and Malawi, whilst a holistic perspective of functional capacity may be hidden in the "dark matter" of the microbiome.

The Epidemiology of Sapovirus in the Etiology, Risk Factors, and Interactions of Enteric Infection and Malnutrition and the Consequences for Child Health and Development Study: Evidence of Protection Following Natural Infection.

BACKGROUND: Sapovirus is one of the principal agents of acute viral enteritis in children. Because it has not been routinely included in diagnostic evaluations, the epidemiology and natural history remain poorly described. METHODS: A birth cohort of 1715 children from 8 countries contributed surveillance samples (n = 35 620) and diarrheal specimens (n = 6868) from 0 to 24 months of age. Sapovirus was detected by quantitative polymerase chain reaction concurrently to other enteropathogens using multiarray cards. Logistic regression was used to identify risk factors, and longitudinal models were employed to estimate incidence rates and evaluate evidence of protective immunity. RESULTS: Sapovirus was detected in 24.7% (n = 1665) of diarrheal stools and 12.8% (n = 4429) of monthly surveillance samples. More than 90% of children were infected and 60% experienced sapovirus diarrhea in the first 2 years of life. Breastfeeding and higher socioeconomic status were associated with reduced incidence of infection and illness. Specimens with sapovirus detected had an increased odds of coinfection with rotavirus (odds ratio [OR], 1.6 [95% confidence interval {CI}, 1.3-2.0]), astrovirus (OR, 1.5 [95% CI, 1.3-1.7]), adenovirus (OR, 1.3 [95% CI, 1.1-1.5]), and Shigella (OR, 1.4 [95% CI, 1.3-1.6]). Prior infection with sapovirus conferred a risk reduction of 22% for subsequent infection (hazard ratio [HR], 0.78 [95% CI, .74-.85]) and 24% for subsequent diarrhea (95% CI, 11.0%-35.0%; HR, 0.76). CONCLUSIONS: Sapovirus is a common cause of early childhood diarrhea. Further research on coinfections is warranted. Evidence of acquired immunity was observed even in the absence of genotype-specific analysis for this pathogen of known genetic diversity.

Reassessing Reported Deaths and Estimated Infection Attack Rate during the First 6 Months of the COVID-19 Epidemic, Delhi, India.

India reported >10 million coronavirus disease (COVID-19) cases and 149,000 deaths in 2020. To reassess reported deaths and estimate incidence rates during the first 6 months of the epidemic, we used a severe acute respiratory syndrome coronavirus 2 transmission model fit to data from 3 serosurveys in Delhi and time-series documentation of reported deaths. We estimated 48.7% (95% credible interval 22.1%-76.8%) cumulative infection in the population through the end of September 2020. Using an age-adjusted overall infection fatality ratio based on age-specific estimates from mostly high-income countries, we estimated that just 15.0% (95% credible interval 9.3%-34.0%) of COVID-19 deaths had been reported, indicating either substantial underreporting or lower age-specific infection-fatality ratios in India than in high-income countries. Despite the estimated high attack rate, additional epidemic waves occurred in late 2020 and April-May 2021. Future dynamics will depend on the duration of natural and vaccine-induced immunity and their effectiveness against new variants.

Soil-transmitted helminth infections after mass drug administration for lymphatic filariasis in rural southern India.

OBJECTIVES: Targeted deworming is the current strategy for control of morbidity associated with soil-transmitted helminths (STH) among at-risk populations: preschool-aged children, school-aged children and women of childbearing age. We report the prevalence and intensity of STH in a district after lymphatic filariasis (LF) mass drug administration (MDA) in southern India where albendazole was co-administered from 2001. METHODS: Children aged 2 to 15 years and adults (defined as ≥15 years) in a rural administrative block of Tamil Nadu were recruited using a probability proportional to size method. Stool samples were screened and eggs per gram (EPG) determined by Kato-Katz method. Multilevel logistic regression (MLR) and multilevel negative binomial regression (MNBR) analyses were used to identify factors associated with infection and intensity, respectively. RESULTS: Of 862 participants who provided samples, 60 (7.0%; 95% confidence interval (CI): 5.3-8.7) were positive for STH with a predominance of hookworm infections (n = 57, 6.6%; 95% CI: 5.0-8.3). Increasing age (odds ratio (OR): 1.09; 95% CI: 1.04-1.15) and regular usage of the toilet (OR: 0.32; 95% CI: 0.12-0.88) were independently associated with hookworm infection and age was significantly associated with increasing intensity of hookworm infection (infection intensity ratio (IIR): 1.28; 95% CI: 1.19-1.37). A brief review of STH prevalence in endemic settings before and after the stoppage of LF MDA indicated that, in most settings, a substantial reduction in STH prevalence is seen. CONCLUSION: Community-wide MDA in all age groups in these post-LF MDA districts with low prevalence and light intensity infections could result in transmission interruption of STH.

Salmonella Typhi acquires diverse plasmids from other Enterobacteriaceae to develop cephalosporin resistance.

BACKGROUND: Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S. Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S. Typhi isolates from India to predict their potential dissemination. METHODS: Five ceftriaxone resistant S. Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S. Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. RESULTS: Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with blaCTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (blaSHV-12) or IncN (blaTEM-1B + blaDHA-1). CONCLUSION: Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally.

Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India.

BACKGROUND: The case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs. METHODS: We aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017-2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital. RESULTS: A total of 1236 hospitalized patients with blood culture-confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%-1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%-.29%) for all enteric fevers. CONCLUSIONS: Our estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

Salmonella Typhi Shedding and Household Transmission by Children With Blood Culture-Confirmed Typhoid Fever in Vellore, South India.

BACKGROUND: Children suffer the highest burden of the typhoid fever, with a considerable proportion shedding Salmonella Typhi in stool, potentially resulting in transmission of S Typhi. METHODS: We enrolled 70 children with blood culture-confirmed typhoid fever (index cases), from 63 households, during community-based fever surveillance in India. The index cases and their household contacts were followed up with stool samples at multiple time points over 3 weeks and 1 week, respectively. S Typhi was detected using quantitative real-time polymerase chain reaction. RESULTS: Fifteen of 70 (21.4%) children with culture-confirmed typhoid fever shed S Typhi in stool after onset of fever. Ten of 15 children shed S Typhi for a median of 11.5 (range, 3-61) days from the day of completion of antibiotics. Of 172 household contacts from 56 of the 63 index case households, 12 (7%) contacts in 11 (19.6%) households had S Typhi in stool. Five of the 12 contacts who were shedding S Typhi were asymptomatic, whereas 7 reported recent fever. CONCLUSIONS: One in 5 children with typhoid fever shed S Typhi, with shedding persisting even after antibiotics. One in 5 households had at least 1 contact of the child shedding S Typhi, highlighting potential concurrent typhoid infections in households in settings with poor water and sanitation.

Case-Control Study of Household and Environmental Transmission of Typhoid Fever in India.

BACKGROUND: Typhoid fever causes substantial morbidity and mortality in low- and middle-income countries. We conducted a case-control study in Vellore, southern India, to understand risk factors for transmission of typhoid. METHODS: From April 2018 to October 2019, households of blood culture-confirmed typhoid cases that occurred within a fever surveillance cohort aged 6 months-15 years, and controls matched for age, sex, geographic location, and socioeconomic status, were recruited. Information on risk factors was obtained using standard questionnaires. Household and environmental samples were collected for detection of Salmonella Typhi using real-time polymerase chain reaction. Multivariable analysis was used to evaluate associations between risk factors and typhoid. RESULTS: One hundred pairs of cases and controls were recruited. On multivariable regression analysis, mothers eating food from street vendors during the previous week (odds ratio [OR] = 2.04; 95% confidence interval [CI], 1.03-4.12; P = .04) was independently associated with typhoid, whereas treatment of household drinking water (OR = 0.45; 95% CI, 0.25-0.80; P = .007) was protective. There was no significant difference in S Typhi detection between the environmental samples from case and control households. CONCLUSIONS: Street-vended food is a risk factor for typhoid in densely populated urban communities of Vellore. Improved sanitation facilities and awareness about point-of-use water treatment are likely to contribute to typhoid control.

Comparison of Strategies for Typhoid Conjugate Vaccine Introduction in India: A Cost-Effectiveness Modeling Study.

BACKGROUND: Typhoid fever causes substantial global mortality, with almost half occurring in India. New typhoid vaccines are highly effective and recommended by the World Health Organization for high-burden settings. There is a need to determine whether and which typhoid vaccine strategies should be implemented in India. METHODS: We assessed typhoid vaccination using a dynamic compartmental model, parameterized by and calibrated to disease and costing data from a recent multisite surveillance study in India. We modeled routine and 1-time campaign strategies that target different ages and settings. The primary outcome was cost-effectiveness, measured by incremental cost-effectiveness ratios (ICERs) benchmarked against India's gross national income per capita (US$2130). RESULTS: Both routine and campaign vaccination strategies were cost-saving compared to the status quo, due to averted costs of illness. The preferred strategy was a nationwide community-based catchup campaign targeting children aged 1-15 years alongside routine vaccination, with an ICER of $929 per disability-adjusted life-year averted. Over the first 10 years of implementation, vaccination could avert 21-39 million cases and save $1.6-$2.2 billion. These findings were broadly consistent across willingness-to-pay thresholds, epidemiologic settings, and model input distributions. CONCLUSIONS: Despite high initial costs, routine and campaign typhoid vaccination in India could substantially reduce mortality and was highly cost-effective.