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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.

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 .

Hookworms cause substantial morbidity in children and women of reproductive age. The control strategy of mass drug administration is suboptimal, hence the need for a vaccine. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are involved in the digestion and detoxification of haemoglobin in the hookworm digestive tract. In animal models, vaccination against these antigens resulted in protection from challenge infection. Both vaccine candidates were shown to be safe and well tolerated when administered separately to healthy adults. We assessed the safety and immunogenicity of co-administered Na-GST-1 and Na-APR-1 (M74) vaccines in healthy Gabonese adults. This randomised, controlled, double-blind, phase 1, dose-escalation trial was done at the Centre de Recherches Médicales de Lambaréné, in a region of Gabon where N americanus and other helminths are prevalent. Healthy adults aged 18–50 years and living in Lambaréné or the surrounding areas were recruited to the study. Participants were enrolled consecutively into two dose cohorts (30 μg or 100 μg of the experimental vaccines) and randomly assigned in blocks (block size four) to receive three doses of either co-administered Na-GST-1 plus Na-APR-1 (M74; 30 μg or 100 μg of each), adjuvanted with Alhydrogel (aluminium hydroxide gel suspension) together with an aqueous formulation of glucopyranosyl lipid A, or hepatitis B vaccine plus saline (control group). Vaccines were administered intramuscularly on days 0, 28, and 180. The primary endpoint was safety, with immunogenicity a secondary endpoint. The intention-to-treat population was used for safety analyses, whereas for immunogenicity analyses, the per-protocol population was used (participants who received all scheduled vaccinations). Control vaccine recipients for both dose cohorts were combined for the analyses. The trial is registered with ClinicalTrials.gov, NCT02126462. Between Oct 27, 2014, and Jan 31, 2015, 56 individuals were screened for eligibility, of whom 32 were enrolled and randomly assigned to one of the three study groups (12 each in the 30 μg and 100 μg experimental vaccine groups and eight in the control group). Both study vaccines were well tolerated in both dose groups. The most common adverse events were mild-to-moderate injection-site pain, headache, myalgia, and nausea. No severe or serious adverse events related to the vaccines were recorded. 52 unsolicited vaccine-related adverse events occurred during the study, but there was no difference in frequency between vaccine groups. IgG antibodies were induced to each of the vaccine antigens, with mean IgG levels increasing after each vaccination. Vaccination with 100 μg of each vaccine antigen consistently induced IgG seroconversion (IgG levels above the reactivity threshold). Peak IgG responses were observed 2 weeks after the third vaccine dose for both antigens, with all participants who received the 100 μg doses seroconverting at that timepoint. IgG levels steadily declined until the final study visit 6 months after the third vaccination, although they remained significantly higher than baseline in the 100 μg dose group. Vaccination with recombinant Na-GST-1 and Na-APR-1 (M74) in healthy adults living in N americanus-endemic areas of Gabon was safe and induced IgG to each antigen. To our knowledge, this study is the first to report results of Na-APR-1 (M74) co-administered with Alhydrogel in participants from an N americanus-endemic area. Further clinical development of these vaccines should involve efficacy studies. European Union Seventh Framework Programme.

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.

Abstract Background The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. Methods In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. Results The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64–1.93), SPT (RR 1.10, 95% CI 0.85–1.42), or asIgE (RR 0.96, 95% CI 0.82–1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55–0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31–1.00). There were no differences in anemia or hepatospenomegaly between trial arms. Conclusions Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions. Clinical Trials Registration ISRCTN47196031. In a cluster-randomized trial of intensive versus standard anthelminthic treatment, intensive treatment reduced Schistosoma mansoni intensity and hookworm prevalence, but did not effect atopy, allergy-related diseases, or helminth-related pathology. Additional interventions are required to reduce transmission in schistosomiasis hot spots.

Variations in vaccine responses have been observed between populations. A role for helminth infections has been proposed due to their immunomodulatory properties. In a secondary analysis of data from a randomised trial assessing effects of anthelminthic treatment on vaccine responses, we examined associations between helminth infections at baseline prior to vaccine administration, and vaccine responses among adolescents (9-17 years) in Koome Islands, Lake Victoria, Uganda. Participants received BCG [week 0], yellow fever (YF-17D), oral typhoid (Ty21a), HPV-prime [week 4], and HPV-boost, tetanus/diphtheria [week 28]. Outcomes were BCG-specific interferon-γ ELISpot responses and antibody responses to yellow-fever-, typhoid-, HPV-, tetanus- and diphtheria-specific antigens measured at two time points post vaccination. infection was determined as positive if either the plasma Circulating Anodic Antigen (CAA) assay or stool PCR were positive. Hookworm and were determined by stool PCR. Linear mixed effects regression was used to assess associations. Among 478 adolescents, 70% were (Sm) infected and 23% hookworm infected at baseline. was associated with lower Typhi O:LPS-specific IgG responses (adjusted geometric mean ratio (aGMR) 0.69 (0.57-0.83)), and hookworm with higher diphtheria-specific IgG (aGMR 1.16 (1.02, 1.31)) and lower HPV-16-specific IgG (aGMR 0.70 (0.55, 0.90)) post-vaccination. High intensity was associated with lower BCG-specific interferon-γ and Typhi O:LPS-specific IgG. We found inverse associations between and responses to two live vaccines, whereas hookworm was positively associated with diphtheria-specific IgG. These findings support the hypothesis that helminth infections can modulate vaccine responses, while also highlighting potential heterogeneity in the direction of these effects.

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 .

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.

Hookworms (Necator americanus and Ancylostoma duodenale) remain a major public health problem worldwide. Infections with hookworms (e.g., A. caninum, A. ceylanicum and A. braziliense) are also prevalent in dogs, but the role of dogs as a reservoir for zoonotic hookworm infections in humans needs to be further explored. As part of an open-label community based cluster-randomized trial in a tribal area in Tamil Nadu (India; 2013-2015), a total of 143 isolates of hookworm eggs from human stool were speciated based on a previously described PCR-RFLP methodology. The presence of hookworm DNA was confirmed in 119 of 143 human samples. N. americanus (100%) was the most prevalent species, followed by A. caninum (16.8%) and A. duodenale (8.4%). Because of the high prevalence of A. caninum in humans, dog samples were also collected to assess the prevalence of A. caninum in dogs. In 68 out of 77 canine stool samples the presence of hookworms was confirmed using PCR-RFLP. In dogs, both A. caninum (76.4%) and A. ceylanicum (27.9%) were identified. Additionally, to determine the contamination of soil with zoonotic hookworm larvae, topsoil was collected from defecating areas. Hookworm DNA was detected in 72 out of 78 soil samples that revealed presence of hookworm-like nematode larvae. In soil, different hookworm species were identified, with animal hookworms being more prevalent (A. ceylanicum: 60.2%, A. caninum: 29.4%, A. duodenale: 16.6%, N. americanus: 1.4%, A. braziliense: 1.4%). In our study we regularly detected the presence of A. caninum DNA in the stool of humans. Whether this is the result of infection is currently unknown but it does warrant a closer look at dogs as a potential reservoir.