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Since 2015, India has coordinated the largest school-based deworming program globally, targeting soil-transmitted helminths (STH) in ~250 million children aged 1 to 19 years twice yearly. Despite substantial progress in reduction of morbidity associated with STH, reinfection rates in endemic communities remain high. We conducted a community based parasitological survey in Tamil Nadu as part of the DeWorm3 Project—a cluster-randomised trial evaluating the feasibility of interrupting STH transmission at three geographically distinct sites in Africa and Asia—allowing the estimation of STH prevalence and analysis of associated factors. In India, following a comprehensive census, enumerating 140,932 individuals in 36,536 households along with geospatial mapping of households, an age-stratified sample of individuals was recruited into a longitudinal monitoring cohort (December 2017-February 2018) to be followed for five years. At enrolment, a total of 6089 consenting individuals across 40 study clusters provided a single adequate stool sample for analysis using the Kato-Katz method, as well as answering a questionnaire covering individual and household level factors. The unweighted STH prevalence was 17.0% (95% confidence interval [95%CI]: 16.0–17.9%), increasing to 21.4% when weighted by age and cluster size. Hookworm was the predominant species, with a weighted infection prevalence of 21.0%, the majority of which (92.9%) were light intensity infections. Factors associated with hookworm infection were modelled using mixed-effects multilevel logistic regression for presence of infection and mixed-effects negative binomial regression for intensity. The prevalence of both Ascaris lumbricoides and Trichuris trichiura infections were rare ( < 1%) and risk factors were therefore not assessed. Increasing age (multivariable odds ratio [mOR] 21.4, 95%CI: 12.3–37.2, p<0.001 for adult age-groups versus pre-school children) and higher vegetation were associated with an increased odds of hookworm infection, whereas recent deworming (mOR 0.3, 95%CI: 0.2–0.5, p<0.001) and belonging to households with higher socioeconomic status (mOR 0.3, 95%CI: 0.2–0.5, p<0.001) and higher education level of the household head (mOR 0.4, 95%CI: 0.3–0.6, p<0.001) were associated with lower odds of hookworm infection in the multilevel model. The same factors were associated with intensity of infection, with the use of improved sanitation facilities also correlated to lower infection intensities (multivariable infection intensity ratio [mIIR] 0.6, 95%CI: 0.4–0.9, p<0.016). Our findings suggest that a community-based approach is required to address the high hookworm burden in adults in this setting. Socioeconomic, education and sanitation improvements alongside mass drug administration would likely accelerate the drive to elimination in these communities. Trial Registration: NCT03014167 .

School-based deworming programmes can reduce morbidity attributable to soil-transmitted helminths in children but do not interrupt transmission in the wider community. We assessed the effects of alternative mass treatment strategies on community soil-transmitted helminth infection. In this cluster-randomised controlled trial, 120 community units (clusters) serving 150 000 households in Kenya were randomly assigned (1:1:1) to receive albendazole through annual school-based treatment targeting 2–14 year olds or annual or biannual community-wide treatment targeting all ages. The primary outcome was community hookworm prevalence, assessed at 12 and 24 months through repeat cross-sectional surveys. Secondary outcomes were Ascaris lumbricoides and Trichuris trichiura prevalence, infection intensity of each soil-transmitted helminth species, and treatment coverage and costs. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02397772. After 24 months, prevalence of hookworm changed from 18·6% (95% CI 13·9–23·2) to 13·8% (10·5–17·0) in the annual school-based treatment group, 17·9% (13·7–22·1) to 8·0% (6·0–10·1) in the annual community-wide treatment group, and 20·6% (15·8–25·5) to 6·2% (4·9–7·5) in the biannual community-wide treatment group. Relative to annual school-based treatment, the risk ratio for annual community-wide treatment was 0·59 (95% CI 0·42–0·83; p<0·001) and for biannual community-wide treatment was 0·46 (0·33–0·63; p<0·001). More modest reductions in risk were observed after 12 months. Risk ratios were similar across demographic and socioeconomic subgroups after 24 months. No adverse events related to albendazole were reported. Community-wide treatment was more effective in reducing hookworm prevalence and intensity than school-based treatment, with little additional benefit of treating every 6 months, and was shown to be remarkably equitable in coverage and effects. Bill & Melinda Gates Foundation, the Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, the Wellcome Trust, and the Children's Investment Fund Foundation.

The reduced prevalence of insulin resistance and type 2 diabetes in countries with endemic parasitic worm infections suggests a protective role for worms against metabolic disorders, however clinical evidence has been non-existent. This 2-year randomised, double-blinded clinical trial in Australia of hookworm infection in 40 male and female adults at risk of type 2 diabetes assessed the safety and potential metabolic benefits of treatment with either 20 ( n  = 14) or 40 ( n  = 13) Necator americanus larvae (L3) or Placebo ( n  = 13) (Registration ACTRN12617000818336). Primary outcome was safety defined by adverse events and completion rate. Homoeostatic model assessment of insulin resistance, fasting blood glucose and body mass were key secondary outcomes. Adverse events were more frequent in hookworm-treated participants, where 44% experienced expected gastrointestinal symptoms, but completion rates were comparable to Placebo. Fasting glucose and insulin resistance were lowered in both hookworm-treated groups at 1 year, and body mass was reduced after L3-20 treatment at 2 years. This study suggests hookworm infection is safe in people at risk of type 2 diabetes and associated with improved insulin resistance, warranting further exploration of the benefits of hookworms on metabolic health. A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.

The association between hygiene and prevalence of autoimmune disease has been attributed in part to enteric helminth infection. A pilot study of experimental infection with the hookworm Necator americanus was undertaken among a group of otherwise healthy people with celiac disease to test the potential of the helminth to suppress the immunopathology induced by gluten. In a 21-week, double-blinded, placebo-controlled study, we explored the effects of N. americanus infection in 20 healthy, helminth-naïve adults with celiac disease well controlled by diet. Staged cutaneous inoculations with 10 and 5 infective 3(rd) stage hookworm larvae or placebo were performed at week-0 and -12 respectively. At week-20, a five day oral wheat challenge equivalent to 16 grams of gluten per day was undertaken. Primary outcomes included duodenal Marsh score and quantification of the immunodominant α-gliadin peptide (QE65)-specific systemic interferon-γ-producing cells by ELISpot pre- and post-wheat challenge. Enteric colonisation with hookworm established in all 10 cases, resulting in transiently painful enteritis in 5. Chronic infection was asymptomatic, with no effect on hemoglobin levels. Although some duodenal eosinophilia was apparent, hookworm-infected mucosa retained a healthy appearance. In both groups, wheat challenge caused deterioration in both primary and several secondary outcomes. Experimental N. americanus infection proved to be safe and enabled testing its effect on a range of measures of the human autoimmune response. Infection imposed no obvious benefit on pathology. ClinicalTrials.gov NCT00671138.

Two hookworm vaccine candidates, Na-GST-1 and Na-APR-1, formulated with Glucopyranosyl Lipid A (GLA-AF) adjuvant, have been shown to be safe, well tolerated, and to induce antibody responses in a Phase 1 clinical trial (Clinicaltrials.gov NCT02126462) conducted in Gabon. Here, we characterized T cell responses in 24 Gabonese volunteers randomized to get vaccinated three times with Na-GST-1 and Na-APR-1 at doses of 30μg (n = 8) or 100μg (n = 10) and as control Hepatitis B (n = 6). Blood was collected pre- and post-vaccination on days 0, 28, and 180 as well as 2-weeks after each vaccine dose on days 14, 42, and 194 for PBMCs isolation. PBMCs were stimulated with recombinant Na-GST-1 or Na-APR-1, before (days 0, 28 and 180) and two weeks after (days 14, 42 and 194) each vaccination and used to characterize T cell responses by flow and mass cytometry. A significant increase in Na-GST-1 -specific CD4 + T cells producing IL-2 and TNF, correlated with specific IgG antibody levels, after the third vaccination (day 194) was observed. In contrast, no increase in Na-APR-1 specific T cell responses were induced by the vaccine. Mass cytometry revealed that, Na-GST-1 cytokine producing CD4 + T cells were CD161 + memory cells expressing CTLA-4 and CD40-L. Blocking CTLA-4 enhanced the cytokine response to Na-GST-1. In Gabonese volunteers, hookworm vaccine candidate, Na-GST-1, induces detectable CD4 + T cell responses that correlate with specific antibody levels. As these CD4 + T cells express CTLA-4, and blocking this inhibitory molecules resulted in enhanced cytokine production, the question arises whether this pathway can be targeted to enhance vaccine immunogenicity.

Background A method is outlined for the use of an individual-based stochastic model of parasite transmission dynamics to assess different designs for a cluster randomized trial in which mass drug administration (MDA) is employed in attempts to eliminate the transmission of soil-transmitted helminths (STH) in defined geographic locations. The hypothesis to be tested is: Can MDA alone interrupt the transmission of STH species in defined settings? Clustering is at a village level and the choice of clusters of villages is stratified by transmission intensity (low, medium and high) and parasite species mix (either Ascaris , Trichuris or hookworm dominant). Results The methodological approach first uses an age-structured deterministic model to predict the MDA coverage required for treating pre-school aged children (Pre-SAC), school aged children (SAC) and adults (Adults) to eliminate transmission (crossing the breakpoint in transmission created by sexual mating in dioecious helminths) with 3 rounds of annual MDA. Stochastic individual-based models are then used to calculate the positive and negative predictive values (PPV and NPV, respectively, for observing elimination or the bounce back of infection) for a defined prevalence of infection 2 years post the cessation of MDA. For the arm only involving the treatment of Pre-SAC and SAC, the failure rate is predicted to be very high (particularly for hookworm-infected villages) unless transmission intensity is very low (R 0 , or the effective reproductive number R, just above unity in value). Conclusions The calculations are designed to consider various trial arms and stratifications; namely, community-based treatment and Pre-SAC and SAC only treatment (the two arms of the trial), different STH transmission settings of low, medium and high, and different STH species mixes. Results are considered in the light of the complications introduced by the choice of statistic to define success or failure, varying adherence to treatment, migration and parameter uncertainty.

Malawi has successfully leveraged multiple delivery platforms to scale-up and sustain the implementation of preventive chemotherapy (PCT) for the control of morbidity caused by soil-transmitted helminths (STH). Sentinel monitoring demonstrates this strategy has been successful in reducing STH infection in school-age children, although our understanding of the contemporary epidemiological profile of STH across the broader community remains limited. As part of a multi-site trial evaluating the feasibility of interrupting STH transmission across three countries, this study aimed to describe the baseline demographics and the prevalence, intensity and associated risk factors of STH infection in Mangochi district, southern Malawi. Between October-December 2017, a community census was conducted across the catchment area of seven primary healthcare facilities, enumerating 131,074 individuals across 124 villages. A cross-sectional parasitological survey was then conducted between March-May 2018 in the censused area as a baseline for a cluster randomised trial. An age-stratified random sample of 6,102 individuals were assessed for helminthiasis by Kato-Katz and completed a detailed risk-factor questionnaire. The age-cluster weighted prevalence of any STH infection was 7.8% (95% C.I. 7.0%-8.6%) comprised predominantly of hookworm species and of entirely low-intensity infections. The presence and intensity of infection was significantly higher in men and in adults. Infection was negatively associated with risk factors that included increasing levels of relative household wealth, higher education levels of any adult household member, current school attendance, or recent deworming. In this setting of relatively high coverage of sanitation facilities, there was no association between hookworm and reported access to sanitation, handwashing facilities, or water facilities. These results describe a setting that has reduced the prevalence of STH to a very low level, and confirms many previously recognised risk-factors for infection. Expanding the delivery of anthelmintics to groups where STH infection persist could enable Malawi to move past the objective of elimination of morbidity, and towards the elimination of STH. Trial registration: NCT03014167 .

Recombinant Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) formulated on Alhydrogel (Na-GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na-GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na-GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy. A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 were randomized to receive 100 µg of Na-GST-1/Alhydrogel and 8 to receive 30 µg or 100 µg of Na-GST-1/Alhydrogel plus the Cytosine-phospho-Guanine (CpG) oligodeoxynucleotide Toll-like receptor-9 agonist, CpG 10104, in the first and second cohorts, respectively. Progression to the second cohort was dependent upon evaluation of 7-day safety data after all participants in the first cohort had received the first dose of vaccine. Three intramuscular injections of study product were administered on days 0, 56, and 112, after which participants were followed for 6 months. IgG and IgG subclass antibody responses to Na-GST-1 were measured by qualified indirect ELISAs at pre- and post-vaccination time points. Na-GST-1/Alhydrogel administered with or without CpG 10104 was well-tolerated. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. There were no vaccine-related serious adverse events or adverse events of special interest. Both dose concentrations of Na-GST-1/Alhydrogel plus CpG 10104 had significantly higher post-vaccination levels of antigen-specific IgG antibody compared to Na-GST-1/Alhydrogel without CpG, starting after the second injection. Peak anti-Na-GST-1 IgG levels were observed between 2 and 4 weeks following the third dose, regardless of Na-GST-1 formulation. IgG levels decreased but remained significantly above baseline in all groups by day 290, at which point all participants (20 of 20 evaluable participants) still had detectable IgG. Longitudinal antigen-specific IgG1 and IgG3 subclass responses mirrored those of total IgG, whereas IgG4 responses were lower in the groups that received the vaccine with the CpG adjuvant compared to the non-CpG group. Vaccination of hookworm-naïve adults with Na-GST-1/Alhydrogel plus CpG 10104 was safe and minimally reactogenic. Addition of CpG 10104 to Na-GST-1/Alhydrogel resulted in significant improvement in IgG responses against the vaccine antigen. These promising results have led to inclusion of the CpG 10104 formulation of Na-GST-1/Alhydrogel in a Phase 2 proof-of-concept controlled human infection trial.

Persons with lymphatic filariasis (LF) are often co-infected with soil-transmitted helminths. A single co-administered dose of ivermectin/diethylcarbamazine/albendazole (IDA) is recommended by WHO for mass drug administration (MDA) for LF instead of diethylcarbamazine/albendazole (DA) in Papua New Guinea (PNG). We compared the effectiveness of a single round of MDA with IDA or DA on hookworm and strongyloidiasis in PNG. This study was conducted as part of a cluster randomized trial of MDA with IDA versus DA for LF in individuals willing to provide stool and blood samples at baseline and 12 months after MDA. Participants from 23 villages were included in the clinical trial. Primary outcomes were changes in hookworm prevalence and infection intensity assessed by Kato Katz and Strongyloides prevalence by serology. Hookworm prevalence at baseline was 78% (91/117) and 80% (119/149) in villages assigned to DA and IDA treatment, respectively. Twelve months post-MDA, hookworm prevalence decreased to 56.5% in DA- and 34.4% in IDA-treated villages, respectively (p<0.001, both comparisons). The proportion of individuals with moderate to heavy infection (>2000 egg per gram (EPG)) similarly decreased from 8.7% to 1.5% after DA (p = 0.001) and from 5.7% to 1.0% after IDA (p = 0.002). Using a logistic regression model adjusting for age, gender, baseline hookworm prevalence, and village drug coverage, IDA resulted in a 45% greater reduction in hookworm prevalence than DA (Odds ratio 0.55, 95% CI [0.31,0.99], p = 0.049). MDA also reduced hookworm transmission. Strongyloides seroprevalence at baseline was 68% (192/283) and 62% (180/290) in IDA and DA villages, respectively, with 49% becoming seronegative in the IDA versus 23% in DA villages at 12 months (p = 0.0001). MDA with IDA was more effective than DA for reducing hookworm and Strongyloides infections in PNG, extending the benefit of MDA with IDA beyond its effect on LF.

Background Hookworms, specifically Ancylostoma caninum and Uncinaria stenocephala , have a clinical impact on the health of dogs, with A. caninum posing a zoonotic risk worldwide. The studies presented here were conducted to evaluate the efficacy of a novel, oral chewable tablet (Credelio Quattro) containing lotilaner, moxidectin, praziquantel, and pyrantel (as pamoate salt) against fourth-stage larvae (L 4 ), immature adult, and adult A. caninum , as well as adult U. stenocephala , infections in dogs. Methods Nine negatively controlled, masked, randomized laboratory studies evaluated the efficacy and non-interference of the drugs against various stages of A. caninum and U. stenocephala . In addition to one pilot study conducted against L 4 A .  caninum and one study that assessed efficacy in dogs with naturally acquired U. stenocephala , two experimental studies were conducted against each of the target hookworm species and stages. A total of 16–31 dogs comprised each study. With the exception of the study in dogs with naturally acquired U. stenocephala , dogs were experimentally infected with the target parasite and dosed on Day 0 or 4 with placebo tablets, Credelio Quattro tablets (or components of Credelio Quattro formulation for the pilot study), or individual actives, moxidectin or pyrantel, in the specific studies designed to assess interference. Efficacy was evaluated by comparing the number of worms recovered at necropsy 5–10 days post-treatment between the treated and control groups. Results All dogs tolerated Credelio Quattro well. Efficacy of Credelio Quattro was ≥ 99.0% against L 4 A. caninum , ≥ 99.8% against immature adult A. caninum , ≥ 99.9% against adult A. caninum , and ≥ 99.6% against adult U. stenocephala. Additionally, treatment with Credelio Quattro provided a ≥ 99.9% reduction in fecal egg counts 10 days post-treatment. Conclusions Credelio Quattro, a novel oral chewable tablet administered at the minimum effective dosages of 20 mg/kg lotilaner, 0.02 mg/kg moxidectin, 5.0 mg/kg praziquantel, and 5.0 mg/kg pyrantel (as pamoate salt), was safe and effective for the treatment and control of L 4 , immature adult, and adult stages of A. caninum and adult U. stenocephala in dogs. Graphical Abstract