Development of prediction models to identify hotspots of schistosomiasis in endemic regions to guide mass drug administration.

Schistosomiasis is a neglected tropical disease affecting over 150 million people. Hotspots of Schistosoma transmission-communities where infection prevalence does not decline adequately with mass drug administration-present a key challenge in eliminating schistosomiasis. Current approaches to identify hotspots require evaluation 2-5 y after a baseline survey and subsequent mass drug administration. Here, we develop statistical models to predict hotspots at baseline prior to treatment comparing three common hotspot definitions, using epidemiologic, survey-based, and remote sensing data. In a reanalysis of randomized trials in 589 communities in five endemic countries, a regression model predicts whether Schistosoma mansoni infection prevalence will exceed the WHO threshold of 10% in year 5 ("prevalence hotspot") with 86% sensitivity, 74% specificity, and 93% negative predictive value (NPV; assuming 30% hotspot prevalence), and a regression model for Schistosoma haematobium achieves 90% sensitivity, 90% specificity, and 96% NPV. A random forest model predicts whether S. mansoni moderate and heavy infection prevalence will exceed a public health goal of 1% in year 5 ("intensity hotspot") with 92% sensitivity, 79% specificity, and 96% NPV, and a boosted trees model for S. haematobium achieves 77% sensitivity, 95% specificity, and 91% NPV. Baseline prevalence is a top predictor in all models. Prediction is less accurate in countries not represented in training data and for a third hotspot definition based on relative prevalence reduction over time ("persistent hotspot"). These models may be a tool to prioritize high-risk communities for more frequent surveillance or intervention against schistosomiasis, but prediction of hotspots remains a challenge.

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.).

Childhood vaccines and antibiotic use in low- and middle-income countries.

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics1-4. However, the effects of vaccination on antibiotic consumption remain poorly understood-especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest5. Here we show that vaccines that have recently been implemented in the World Health Organization's Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4-43.4%) and 11.4% (4.0-18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens6,7. Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance8.

Dating in the Dark: Elevated Substitution Rates in Cave Cockroaches (Blattodea: Nocticolidae) Have Negative Impacts on Molecular Date Estimates.

Rates of nucleotide substitution vary substantially across the Tree of Life, with potentially confounding effects on phylogenetic and evolutionary analyses. A large acceleration in mitochondrial substitution rate occurs in the cockroach family Nocticolidae, which predominantly inhabit subterranean environments. To evaluate the impacts of this among-lineage rate heterogeneity on estimates of phylogenetic relationships and evolutionary timescales, we analysed nuclear ultraconserved elements (UCEs) and mitochondrial genomes from nocticolids and other cockroaches. Substitution rates were substantially elevated in nocticolid lineages compared with other cockroaches, especially in mitochondrial protein-coding genes. This disparity in evolutionary rates is likely to have led to different evolutionary relationships being supported by phylogenetic analyses of mitochondrial genomes and UCE loci. Furthermore, Bayesian dating analyses using relaxed-clock models inferred much deeper divergence times compared with a flexible local clock. Our phylogenetic analysis of UCEs, which is the first genome-scale study to include all thirteen major cockroach families, unites Corydiidae and Nocticolidae and places Anaplectidae as the sister lineage to the rest of Blattoidea. We uncover an extraordinary level of genetic divergence in Nocticolidae, including two highly distinct clades that separated ~115 million years ago despite both containing representatives of the genus Nocticola. The results of our study highlight the potential impacts of high among-lineage rate variation on estimates of phylogenetic relationships and evolutionary timescales.

Determining Herd Immunity Thresholds for Hepatitis A Virus Transmission to Inform Vaccination Strategies Among People Who Inject Drugs in 16†US States.

BACKGROUND: Widespread outbreaks of person-to-person transmitted hepatitis A virus (HAV), particularly among people who inject drugs (PWID), continue across the United States and globally. However, the herd immunity threshold and vaccination coverage required to prevent outbreaks are unknown. We used surveillance data and dynamic modeling to estimate herd immunity thresholds among PWID in 16 US states. METHODS: We used a previously published dynamic model of HAV transmission calibrated to surveillance data from outbreaks involving PWID in 16 states. Using state-level calibrated models, we estimated the basic reproduction number (R0) and herd immunity threshold for PWID in each state. We performed a meta-analysis of herd immunity thresholds to determine the critical vaccination coverage required to prevent most HAV outbreaks among PWID. RESULTS: Estimates of R0 for HAV infection ranged from 2.2 (95% confidence interval [CI], 1.9-2.5) for North Carolina to 5.0 (95% CI, 4.5-5.6) for West Virginia. Corresponding herd immunity thresholds ranged from 55% (95% CI, 47%-61%) for North Carolina to 80% (95% CI, 78%-82%) for West Virginia. Based on the meta-analysis, we estimated a pooled herd immunity threshold of 64% (95% CI, 61%-68%; 90% prediction interval, 52%-76%) among PWID. Using the prediction interval upper bound (76%) and assuming 95% vaccine efficacy, we estimated that vaccination coverage of 80% could prevent most HAV outbreaks. CONCLUSIONS: Hepatitis A vaccination programs in the United States may need to achieve vaccination coverage of at least 80% among PWID in order to prevent most HAV outbreaks among this population.

Pervasive relaxed selection in termite genomes.

Genetic changes that enabled the evolution of eusociality have long captivated biologists. More recently, attention has focussed on the consequences of eusociality on genome evolution. Studies have reported higher molecular evolutionary rates in eusocial hymenopteran insects compared with their solitary relatives. To investigate the genomic consequences of eusociality in termites, we analysed nine genomes, including newly sequenced genomes from three non-eusocial cockroaches. Using a phylogenomic approach, we found that termite genomes have experienced lower rates of synonymous substitutions than those of cockroaches, possibly as a result of longer generation times. We identified higher rates of non-synonymous substitutions in termite genomes than in cockroach genomes, and identified pervasive relaxed selection in the former (24-31% of the genes analysed) compared with the latter (2-4%). We infer that this is due to reductions in effective population size, rather than gene-specific effects (e.g. indirect selection of caste-biased genes). We found no obvious signature of increased genetic load in termites, and postulate efficient purging of deleterious alleles at the colony level. Additionally, we identified genomic adaptations that may underpin caste differentiation, such as genes involved in post-translational modifications. Our results provide insights into the evolution of termites and the genomic consequences of eusociality more broadly.

Enhanced heterozygosity from male meiotic chromosome chains is superseded by hybrid female asexuality in termites.

Although males are a ubiquitous feature of animals, they have been lost repeatedly in diverse lineages. The tendency for obligate asexuality to evolve is thought to be reduced in animals whose males play a critical role beyond the contribution of gametes, for example, via care of offspring or provision of nuptial gifts. To our knowledge, the evolution of obligate asexuality in such species is unknown. In some species that undergo frequent inbreeding, males are hypothesized to play a key role in maintaining genetic heterozygosity through the possession of neo-sex chromosomes, although empirical evidence for this is lacking. Because inbreeding is a key feature of the life cycle of termites, we investigated the potential role of males in promoting heterozygosity within populations through karyotyping and genome-wide single-nucleotide polymorphism analyses of the drywood termite Glyptotermes nakajimai We showed that males possess up to 15 out of 17 of their chromosomes as sex-linked (sex and neo-sex) chromosomes and that they maintain significantly higher levels of heterozygosity than do females. Furthermore, we showed that two obligately asexual lineages of this species-representing the only known all-female termite populations-arose independently via intraspecific hybridization between sexual lineages with differing diploid chromosome numbers. Importantly, these asexual females have markedly higher heterozygosity than their conspecific males and appear to have replaced the sexual lineages in some populations. Our results indicate that asexuality has enabled females to supplant a key role of males.

The genome and sex-dependent responses to temperature in the common yellow butterfly, Eurema hecabe.

BACKGROUND: Lepidoptera (butterflies and moths) is one of the most geographically widespread insect orders in the world, and its species play important and diverse ecological and applied roles. Climate change is one of the biggest challenges to biodiversity this century, and lepidopterans are vulnerable to climate change. Temperature-dependent gene expression differences are of relevance under the ongoing climate crisis. However, little is known about how climate affects gene expression in lepidopterans and the ecological consequences of this, particularly with respect to genes with biased expression in one of the sexes. The common yellow butterfly, Eurema hecabe (Family Pieridae), is one of the most geographically widespread lepidopterans that can be found in Asia, Africa, and Australia. Nevertheless, what temperature-dependent effects there may be and whether the effects differ between the sexes remain largely unexplored. RESULTS: Here, we generated high-quality genomic resources for E. hecabe along with transcriptomes from eight developmental stages. Male and female butterflies were subjected to varying temperatures to assess sex-specific gene expression responses through mRNA and microRNA transcriptomics. We find that there are more temperature-dependent sex-biased genes in females than males, including genes that are involved in a range of biologically important functions, highlighting potential ecological impacts of increased temperatures. Further, by considering available butterfly data on sex-biased gene expression in a comparative genomic framework, we find that the pattern of sex-biased gene expression identified in E. hecabe is highly species-specific, rather than conserved across butterfly species, suggesting that sex-biased gene expression responses to climate change are complex in butterflies. CONCLUSIONS: Our study lays the foundation for further understanding of differential responses to environmental stress in a widespread lepidopteran model and demonstrates the potential complexity of sex-specific responses of lepidopterans to climate change.

Evaluation of the US Definitions for Coronavirus Disease 2019 Community Risk Levels.

The US Centers for Disease Control and Prevention (CDC) defines a county metric of coronavirus disease 2019 (COVID-19) community levels to inform public health measures. We find that the COVID-19 community levels vary frequently over time, which may not be optimal for decision making. Alternative metric formulations that do not compromise predictive ability are shown to reduce variability.

Public Health Impact and Cost-Effectiveness of Screening for Active Tuberculosis Disease or Infection Among Children in South Africa.

BACKGROUND: Although tuberculosis disease is a leading cause of global childhood mortality, there remain major gaps in diagnosis, treatment, and prevention in children because tuberculosis control programs rely predominantly on presentation of symptomatic children or contact tracing. We assessed the public health impact and cost-effectiveness of age-based routine screening and contact tracing in children in South Africa. METHODS: We used a deterministic mathematical model to evaluate age-based routine screening in 1-year increments from ages 0 to 5 years, with and without contact tracing and preventive treatment. Screening incorporated symptom history and tuberculin skin testing, with chest x-ray and GeneXpert Ultra for confirmatory testing. We projected tuberculosis cases, deaths, disability-adjusted life years (DALYs), and costs (in 2021 U.S. dollars) and evaluated the incremental cost-effectiveness ratios comparing each intervention. RESULTS: Routine screening at age 2 years with contact tracing and preventive treatment averted 11 900 tuberculosis cases (95% confidence interval [CI]: 6160-15 730), 1360 deaths (95% CI: 260-3800), and 40 000 DALYs (95% CI: 13 000-100 000) in the South Africa pediatric population over 1 year compared with the status quo. This combined strategy was cost-effective (incremental cost-effectiveness ratio $9050 per DALY; 95% CI: 2890-22 920) and remained cost-effective above an annual risk of infection of 1.6%. For annual risk of infection between 0.8% and 1.6%, routine screening at age 2 years was the dominant strategy. CONCLUSIONS: Routine screening for tuberculosis among young children combined with contact tracing and preventive treatment would have a large public health impact and be cost-effective in preventing pediatric tuberculosis deaths in high-incidence settings such as South Africa.

The evolution of intramitochondriality in Midichloria bacteria.

Midichloria spp. are intracellular bacterial symbionts of ticks. Representatives of this genus colonise mitochondria in the cells of their hosts. To shed light on this unique interaction we evaluated the presence of an intramitochondrial localization for three Midichloria in the respective tick host species and generated eight high-quality draft genomes and one closed genome, showing that this trait is non-monophyletic, either due to losses or multiple acquisitions. Comparative genomics supports the first hypothesis, as the genomes of non-mitochondrial symbionts are reduced subsets of those capable of colonising the organelles. We detect genomic signatures of mitochondrial tropism, including the differential presence of type IV secretion system and flagellum, which could allow the secretion of unique effectors and/or direct interaction with mitochondria. Other genes, including adhesion molecules, proteins involved in actin polymerisation, cell wall and outer membrane proteins, are only present in mitochondrial symbionts. The bacteria could use these to manipulate host structures, including mitochondrial membranes, to fuse with the organelles or manipulate the mitochondrial network.

Genomic analysis reveals strong population structure in the Giant Sydney Crayfish (Euastacus spinifer (Heller, 1865)).

Australia is home to over 140 species of freshwater crayfish (Decapoda: Parastacidae), representing a centre of diversity for this group in the Southern Hemisphere. Species delimitation in freshwater crayfish is difficult because many species show significant variation in colouration and morphology. This is particularly evident in the genus Euastacus, which exhibits large variations in colour and spination throughout its putative range. To understand this variation, we investigated the genetic diversity, population structure, phylogeny, and evolutionary timescale of the Giant Sydney Crayfish (Euastacus spinifer (Heller, 1865)). Our data set is sampled from over 70 individuals from across the ∼600 km range of the species, and includes a combination of two mitochondrial markers and more than 7000 single-nucleotide polymorphisms (SNPs) from the nuclear genome. Data were also obtained for representatives of the close relative, Euastacus vesper McCormack and Ahyong, 2017. Genomic SNP analyses revealed strong population structure, with multiple distinct populations showing little evidence of gene flow or migration. Phylogenetic analyses of mitochondrial data revealed similar structure between populations. Taken together, our analyses suggest that E. spinifer, as currently understood, represents a species complex, of which E. vesper is a member. Molecular clock estimates place the divergences within this group during the Pleistocene. The isolated and highly fragmented populations identified in our analyses probably represent relict populations of a previously widespread ancestral species. Periodic flooding events during the Pleistocene are likely to have facilitated the movement of these otherwise restricted freshwater crayfish within and between drainage basins, including the Murray-Darling and South East Coast Drainages. We present evidence supporting the recognition of populations in the southern parts of the range of E. spinifer as one or two separate species, which would raise the number of species within the E. spinifer complex to at least three. Our results add to the growing body of evidence that many freshwater crayfish exhibit highly fragmented, range-restricted distributions. In combination with the life-history traits of these species, the restricted distributions exacerbate the threats already placed on freshwater crayfish, which are among the five most endangered animal groups globally.

Phylogenetic analysis of Blaberoidea reveals non-monophyly of taxa and supports the creation of multiple new subfamilies.

The superfamily Blaberoidea is a highly species-rich group of cockroaches. High-level blaberoidean phylogenetics are still under debate owing to variable taxon sampling and incongruence between mitochondrial and nuclear evolution, as well as different methods used in various phylogenetic studies. We here present a phylogenetic analysis of Blaberoidea based on a dataset combining the mitochondrial genome with two nuclear markers from representatives of all recognized families within the superfamily. Our results support the monophyly of Blaberiodea, which includes Ectobiidae s.s. (=Ectobiinae), Pseudophyllodromiidae, Nyctiboridae, Blattellidae s.s. (=Blattellinae) and Blaberidae. Ectobiidae s.s. was recovered as sister to the remaining Blaberoidea in all inferences. Pseudophyllodromiidae was paraphyletic with respect to Anaplectoidea + Malaccina. Blattellidae s.s. excluding Anaplectoidea + Malaccina formed a monophyletic group that was sister to Blaberidae. Based on our results, we propose a revised classification for Blaberoidea: Anaplectoidinae subfam.nov. and Episorineuchora gen.nov., and two new combinations at species level within Pseudophyllodromiidae; Rhabdoblattellinae subfam.nov., Calolamprodinae subfam.nov., Acutirhabdoblatta gen.nov., as well as new combinations for three species within Blaberidae. Ancestral state reconstructions based on four morphological characters allow us to infer that the common ancestor of blaberoid cockroaches is likely to be a species with characteristics similar to those found in Ectobiidae, that is, front femur Type B, arolium present, abdomen with a visible gland and male genital hook on the left side.

Molecular phylogeny of Spirotrichonymphea (Parabasalia) with emphasis on Spironympha, Spirotrichonympha, and three new genera Pseudospironympha, Nanospironympha, and Brugerollina.

Spirotrichonymphea, one of the six classes of phylum Parabasalia, are characterized by bearing many flagella in spiral rows, and they occur exclusively in the guts of termites. Phylogenetic relationships among the 13 described genera are not well understood due to complex morphological evolution and a paucity of molecular data. One such understudied genus is Spironympha. It has been variously considered a valid genus, a subgenus of Spirotrichonympha, or an "immature" life cycle stage of Spirotrichonympha. To clarify this, we sequenced the small subunit rRNA gene sequences of Spironympha and Spirotrichonympha cells isolated from the hindguts of Reticulitermes species and Hodotermopsis sjostedti and confirmed the molecular identity of H. sjostedti symbionts using fluorescence in situ hybridization. Spironympha as currently circumscribed is polyphyletic, with both H. sjostedti symbiont species branching separately from the "true" Spironympha from Reticulitermes. Similarly, the Spirotrichonympha symbiont of H. sjostedti branches separately from the "true" Spirotrichonympha found in Reticulitermes. Our data support Spironympha from Reticulitermes as a valid genus most closely related to Spirotrichonympha, though its monophyly and interspecific relationships are not resolved in our molecular phylogenetic analysis. We propose three new genera to accommodate the H. sjostedti symbionts and two new species of Spirotrichonympha from Reticulitermes.

Enhanced Mutation Rate, Relaxed Selection, and the "Domino Effect" are associated with Gene Loss in Blattabacterium, A Cockroach Endosymbiont.

Intracellular endosymbionts have reduced genomes that progressively lose genes at a timescale of tens of million years. We previously reported that gene loss rate is linked to mutation rate in Blattabacterium, however, the mechanisms causing gene loss are not yet fully understood. Here, we carried out comparative genomic analyses on the complete genome sequences of a representative set of 67 Blattabacterium strains, with sizes ranging between 511 and 645 kb. We found that 200 of the 566 analyzed protein-coding genes were lost in at least one lineage of Blattabacterium, with the most extreme case being one gene that was lost independently in 24 lineages. We found evidence for three mechanisms influencing gene loss in Blattabacterium. First, gene loss rates were found to increase exponentially with the accumulation of substitutions. Second, genes involved in vitamin and amino acid metabolism experienced relaxed selection in Cryptocercus and Mastotermes, possibly triggered by their vertically inherited gut symbionts. Third, we found evidence of epistatic interactions among genes leading to a "domino effect" of gene loss within pathways. Our results highlight the complexity of the process of genome erosion in an endosymbiont.

Vicariance and dispersal events inferred from mitochondrial genomes and nuclear genes (18S, 28S) shaped global Cryptocercus distributions.

Cryptocercus Scudder, a genus of wingless, subsocial cockroaches, has low vagility but exhibits a disjunct distribution in eastern and western North America, and in China, South Korea and the Russian Far East. This distribution provides an ideal model for testing hypotheses of vicariance through plate tectonics or other natural barriers versus dispersal across oceans or other natural barriers. We sequenced 45 samples of Cryptocercus to resolve phylogenetic relationships among members of the genus worldwide. We identified four types of tRNA rearrangements among samples from the Qin-Daba Mountains. Our maximum-likelihood and Bayesian phylogenetic trees, based on mitochondrial genomes and nuclear genes (18S, 28S), strongly supported six major lineages of Cryptocercus, which displayed a clear geographical distribution pattern. We used Bayesian molecular dating to estimate the evolutionary timescale of the genus, and reconstructed Cryptocercus ancestral ranges using statistical dispersal-vicariance analysis (S-DIVA) in RASP. Two dispersal events and six vicariance events for Cryptocercus were inferred with high support. The initial vicariance event occurred between American and Asian lineages at 80.5 Ma (95% credibility interval: 60.0-104.7 Ma), followed by one vicariance event within the American lineage 43.8 Ma (95% CI: 32.0-57.5 Ma), and two dispersal 31.9 Ma (95% CI: 25.8-39.5 Ma), 21.7 Ma (95% CI: 17.3-27.1 Ma) plus four vicariance events c. 29.3 Ma, 27.2 Ma, 24.8 Ma and 16.7 Ma within the Asian lineage. Our analyses provide evidence that both vicariance and dispersal have played important roles in shaping the distribution and diversity of these woodroaches.

Phylogenomic Analysis of Concatenated Ultraconserved Elements Reveals the Recent Evolutionary Radiation of the Fairy Wrasses (Teleostei: Labridae: Cirrhilabrus).

The fairy wrasses (genus Cirrhilabrus) are among the most successful of the extant wrasse lineages (Teleostei: Labridae), with their 61 species accounting for nearly 10$\%$ of the family. Although species complexes within the genus have been diagnosed on the basis of coloration patterns and synapomorphies, attempts to resolve evolutionary relationships among these groups using molecular and morphological data have largely been unsuccessful. Here, we use a phylogenomic approach with a data set comprising 991 ultraconserved elements (UCEs) and mitochondrial COI to uncover the evolutionary history and patterns of temporal and spatial diversification of the fairy wrasses. Our analyses of phylogenetic signal suggest that most gene-tree incongruence is caused by estimation error, leading to poor resolution in a summary-coalescent analysis of the data. In contrast, analyses of concatenated sequences are able to resolve the major relationships of Cirrhilabrus. We determine the placements of species that were previously regarded as incertae sedis and find evidence for the nesting of Conniella, an unusual, monotypic genus, within Cirrhilabrus. Our relaxed-clock dating analysis indicates that the major divergences within the genus occurred around the Miocene-Pliocene boundary, followed by extensive cladogenesis of species complexes in the Pliocene-Pleistocene. Biogeographic reconstruction suggests that the fairy wrasses emerged within the Coral Triangle, with episodic fluctuations of sea levels during glacial cycles coinciding with shallow divergence events but providing few opportunities for more widespread dispersal. Our study demonstrates both the resolving power and limitations of UCEs across shallow timescales where there is substantial estimation error in individual gene trees.[Biogeography; concatenation; gene genealogy interrogation; gene trees; molecular dating; summary coalescent; UCEs.].

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.

Geographic Pattern of Typhoid Fever in India: A Model-Based Estimate of Cohort and Surveillance Data.

BACKGROUND: Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India. METHODS: We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence. RESULTS: We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north. CONCLUSIONS: There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.