Safety and immunogenicity of the Na-APR-1 hookworm vaccine in infection-naïve adults.

BACKGROUND: The Necator americanus hemoglobinase, aspartic protease-1 (Na-APR-1), facilitates the ability of adult hookworms to parasitize the intestine of their human hosts. A recombinant version of APR-1 protected laboratory animals against hookworm infection by inducing neutralizing antibodies that block the protein's enzymatic activity and thereby impair blood feeding. A catalytically inactive version of the wild-type hemoglobinase (Na-APR-1(M74)) was expressed by infiltrating Nicotiana benthamiana tobacco plants with an Agrobacterium tumefaciens strain engineered to express the vaccine antigen, which was adjuvanted with aluminum hydroxide adjuvant (Alhydrogel). METHODS: An open-label dose-escalation Phase 1 clinical trial was conducted in 40 healthy, hookworm-naïve adult volunteers in the United States. Participants received 30 or 100 µg of recombinant Na-APR-1(M74) with Alhydrogel or with Alhydrogel co-administered with one of two doses (2.5 or 5.0 µg) of an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF). Intramuscular injections of study vaccine were administered on days 0, 56, and 112. RESULTS: Na-APR-1(M74)/Alhydrogel was well-tolerated; the most frequent adverse events were mild or moderate injection site tenderness and pain, and mild or moderate nausea and headache. No serious adverse events or adverse events of special interest related to vaccination were observed. Significantly higher levels of antigen-specific IgG antibodies were induced in those who received 100 µg Na-APR-1(M74) than those who received 30 µg of antigen. Adding GLA-AF to Na-APR-1(M74)/Alhydrogel resulted in higher levels of IgG against Na-APR-1(M74) in both the 30 and 100 µg Na-APR-1(M74) groups in comparison to the non-GLA formulations at the same antigen dose. CONCLUSIONS: Vaccination of hookworm-naïve adults with recombinant Na-APR-1(M74) was well-tolerated, safe, and induced significant IgG responses against the vaccine antigen Na-APR-1(M74). Given these favorable results, clinical trials of this product were initiated in hookworm-endemic areas of Gabon and Brazil.

Elimination of STH morbidity in Zimbabwe: Results of 6 years of deworming intervention for school-age children.

This paper reports the prevalence and intensity of soil-transmitted helminth (STH) infections measured in Zimbabwe before and after a control intervention based on annual deworming of school-age children (SAC) conducted from 2012 to 2018. In 2010, epidemiological data were collected from 13 195 SAC in 255 randomly selected schools in all districts nationwide using, as diagnostic methods, the Kato-Katz and the formal ether stool concentration technique. At follow up, conducted in 2017, only Kato-Katz was performed; specimens were collected from 13 352 children in 336 schools. The data were evaluated using a geospatial approach. The national prevalence of STH infection in SAC was estimated at 5.8% at baseline, with 0.8% of infections of moderate and heavy intensity. Preventive chemotherapy (PC) targeted all 2.5 million children of school age enrolled in Zimbabwe, with coverage ranging from 49% to 85%. At follow up, national prevalence of STH in SAC was estimated at 0.8%; infections of moderate and heavy intensity almost disappeared (0.1% prevalence). As a result, Zimbabwe can suspend deworming activities in 54 districts and reduce the frequency of PC in the remaining six districts. The total amount of albendazole tablets needed will be approximately 100 000 a year.

Historical epidemiology and global health history / Epidemiologia histórica e história global da saúde

Abstract The subdiscipline of historical epidemiology holds the promise of creating a more robust and more nuanced foundation for global public health decision-making by deepening the empirical record from which we draw lessons about past interventions. This essay draws upon historical epidemiological research on three global public health campaigns to illustrate this promise: the Rockefeller Foundation's efforts to control hookworm disease (1909-c.1930), the World Health Organization's pilot projects for malaria eradication in tropical Africa (1950s-1960s), and the international efforts to shut down the transmission of Ebola virus disease during outbreaks in tropical Africa (1974-2019).

Resumo A subdisciplina epidemiologia histórica se propõe a criar um alicerce robusto e refinado para o processo de tomada de decisões em saúde pública global, aprofundando registros empíricos que nos ensinam sobre intervenções passadas. Este artigo se baseia na pesquisa epidemiológica histórica de três campanhas globais de saúde pública para ilustrar essa proposta: os esforços da Fundação Rockefeller para controle da ancilostomose (1909-c.1930), os projetos-piloto da Organização Mundial da Saúde para erradicação da malária na África tropical (décadas de 1950-1960), e os esforços internacionais de interrupção da transmissão do vírus Ebola durante surtos na África tropical (1974-2019).

Sustained preventive chemotherapy for soil-transmitted helminthiases leads to reduction in prevalence and anthelminthic tablets required.

BACKGROUND: The goal of soil-transmitted helminthiases (STH) control programmes is to eliminate STH-associated morbidity in the target population by reducing the prevalence of moderate- and heavy-intensity infections and the overall STH infection prevalence mainly through preventive chemotherapy (PC) with either albendazole or mebendazole. Endemic countries should measure the success of their control programmes through regular epidemiological assessments. We evaluated changes in STH prevalence in countries that conducted effective PC coverage for STH to guide changes in the frequency of PC rounds and the number of tablets needed. METHODS: We selected countries from World Health Organization (WHO)'s Preventive Chemotherapy and Transmission control (PCT) databank that conducted ≥5 years of PC with effective coverage for school-age children (SAC) and extracted STH baseline and impact assessment data using the WHO Epidemiological Data Reporting Form, Ministry of Health reports and/or peer-reviewed publications. We used pooled and weighted means to plot the prevalence of infection with any STH and with each STH species at baseline and after ≥5 years of PC with effective coverage. Finally, using the WHO STH decision tree, we estimated the reduction in the number of tablets needed. RESULTS: Fifteen countries in four WHO regions conducted annual or semi-annual rounds of PC for STH for 5 years or more and collected data before and after interventions. At baseline, the pooled prevalence was 48.9% (33.1-64.7%) for any STH, 23.2% (13.7-32.7%) for Ascaris lumbricoides, 21.01% (9.7-32.3%) for Trichuris trichiura and 18.2% (10.9-25.5%) for hookworm infections, while after ≥5 years of PC for STH, the prevalence was 14.3% (7.3-21.3%) for any STH, 6.9% (1.3-12.5%) for A. lumbricoides, 5.3% (1.06-9.6%) for T. trichiura and 8.1% (4.0-12.2%) for hookworm infections. CONCLUSIONS: Countries endemic for STH have made tremendous progress in reducing STH-associated morbidity, but very few countries have data to demonstrate that progress. In this study, the data show that nine countries should adapt their PC strategies and the frequency of PC rounds to yield a 36% reduction in drug needs. The study also highlights the importance of impact assessment surveys to adapt control strategies according to STH prevalence.

Sustained effectiveness of weekly iron-folic acid supplementation and regular deworming over 6 years in women in rural Vietnam.

BACKGROUND: Weekly iron-folic acid (IFA) supplementation and regular deworming is effective for the prevention of iron deficiency and anaemia in women of child-bearing age. Between 2006 and 2013, a program of weekly IFA and biannual deworming was implemented in Yen Bai province, Vietnam. In this study we aimed to determine the effectiveness of the program in reducing anaemia and the prevalence of hookworm infection after 72 months (six years). METHODS: This prospective cohort study followed up a cohort of 389 women of child-bearing age from baseline until six years after the introduction of the weekly IFA (one tablet containing 200 mg ferrous sulphate, 0.4mg folic acid) and deworming (one 400mg tablet of albendazole given twice yearly) program (May 2006 to 2012). In each of the six surveys (baseline and five follow-up surveys) we measured haemoglobin and ferritin, and the burden of soil transmitted helminth (STH) infections, and in the 72 month survey we also administered a questionnaire to assess adherence and possible impediments to participating in the program. RESULTS: Two hundred and fifty six (65.8%) of the original 389 women enrolled in the cohort attended the final 72 month survey. Haemoglobin levels were 122 g/L [95% C.I. 120, 124] at baseline and increased to 135g/L [95% C.I. 133, 138] after 72 months. The prevalence of anaemia was 37.8% [95% C.I. 31.0, 44.7] at baseline and reduced to 14.3% [95% C.I. 9.5, 19.1]. Hookworm infection prevalence, 75.9% [95% C.I. 68.1, 83.8] at baseline, reduced to 10.2% [95% C.I. 5.4, 15.0] with no moderate or heavy intensity infections. Seventy-two percent of participants reported still taking at least 75% of the weekly supplements, and 85.0% had taken the most recent deworming treatment. DISCUSSION: Anaemia rates fell significantly during the six-year program, and STH infections were eliminated as a public health risk. Adherence was well maintained but long-term sustainability is challenging in the absence of ongoing external support.

Preventive chemotherapy in one year reduces by over 80% the number of individuals with soil-transmitted helminthiases causing morbidity: results from meta-analysis.

The morbidity due to Ascaris lumbricoides and Trichuris trichiura is caused by infections of moderate and heavy intensity while hookworm infections of all intensities are recognized to cause morbidity. This study aims to evaluate the effect of repeated rounds of preventive chemotherapy on the proportion of soil-transmitted helminth (STH) infections causing morbidity. We identified studies from 17 countries, reporting changes in the proportion of STH infection causing morbidity between baseline and follow-up. In the studies identified, the average proportion of individuals with STH infections of moderate and heavy intensity was of 14% at baseline and was on average reduced to 2% by the intervention (i.e., 85% reduction). There was an average reduction of 73% after the first year of treatment, which reached almost 80% after 5 years and over 95% in 10 years of deworming interventions. The reduction in hookworm prevalence was 57% after 12 months reaching 78% after 5 years. We consider the results presented in this study especially useful for decision makers as it demonstrates the effectiveness of preventive chemotherapy in reducing STH prevalence and morbidity. We encourage the implementation of deworming programs to achieve the goal, set by WHO for 2020, to eliminate STH morbidity in children.

The Use of Microwave-Assisted Solid-Phase Peptide Synthesis and Click Chemistry for the Synthesis of Vaccine Candidates Against Hookworm Infection.

A protein-based vaccine approach against hookworm infection has failed to deliver the expected outcome, due to a problem with an allergic response in the patient or difficulties in the proteins' production. This implication could be overcome by using a chemically synthesized peptide-based vaccine approach. This approach utilizes minimal pathogenic components that are necessary for the stimulation of the immune response without triggering adverse side effects. To boost the peptide's immunogenicity, a lipid core peptide (LCP) system can be utilized as a carrier molecule/immunostimulant. This chapter describes in detail the synthesizing of protected lipoamino acid, the self-adjuvanting moiety (LCP core), the peptide epitope, and the final vaccine candidate. The subunit peptide and the LCP core were synthesized using microwave-assisted solid-phase peptide synthesis (SPPS). Then the final hookworm vaccine construct was assembled using the copper-catalyzed azide-alkyne cycloaddition, or "click," reaction.

Profiling Nonrecipients of Mass Drug Administration for Schistosomiasis and Hookworm Infections: A Comprehensive Analysis of Praziquantel and Albendazole Coverage in Community-Directed Treatment in Uganda.

BACKGROUND: Repeated mass drug administration (MDA) with preventive chemotherapies is the mainstay of morbidity control for schistosomiasis and soil-transmitted helminths, yet the World Health Organization recently reported that less than one-third of individuals who required preventive chemotherapies received treatment. METHODS: Coverage of community-directed treatment with praziquantel (PZQ) and albendazole (ALB) was analyzed in 17 villages of Mayuge District, Uganda. National drug registers, household questionnaires, and parasitological surveys were collected to track 935 individuals before and after MDA. Multilevel logistic regressions, including household and village effects, were specified with a comprehensive set of socioeconomic and parasitological variables. The factors predicting who did not receive PZQ and ALB from community medicine distributors were identified. RESULTS: Drug receipt was correlated among members within a household, and nonrecipients of PZQ or ALB were profiled by household-level socioeconomic factors. Individuals were less likely to receive either PZQ or ALB if they had a Muslim household head or low home quality, belonged to the minority tribe, or had settled for more years in their village. Untreated individuals were also more likely to belong to households that did not purify drinking water, had no home latrine, and had no members who were part of the village government. CONCLUSIONS: The findings demonstrate how to locate and target individuals who are not treated in MDA. Infection risk factors were not informative. In particular, age, gender, and occupation were unable to identify non-recipients, although World Health Organization guidelines rely on these factors. Individuals of low socioeconomic status, minority religions, and minority tribes can be targeted to expand MDA coverage.

Feasibility of controlling hookworm infection through preventive chemotherapy: a simulation study using the individual-based WORMSIM modelling framework.

BACKGROUND: Globally, hookworms infect 440 million people in developing countries. Especially children and women of childbearing age are at risk of developing anaemia as a result of infection. To control hookworm infection and disease (i.e. reduce the prevalence of medium and heavy infection to <1 %), the World Health Organization has set the target to provide annual or semi-annual preventive chemotherapy (PC) with albendazole (ALB) or mebendazole (MEB) to at least 75 % of all children and women of childbearing age in endemic areas by 2020. Here, we predict the feasibility of achieving <1 % prevalence of medium and heavy infection, based on simulations with an individual-based model. METHODS: We developed WORMSIM, a new generalized individual-based modelling framework for transmission and control of helminths, and quantified it for hookworm transmission based on published data. We simulated the impact of standard and more intense PC strategies on trends in hookworm infection, and explored the potential additional impact of interventions that improve access to water, sanitation, and hygiene (WASH). The individual-based framework allowed us to take account of inter-individual heterogeneities in exposure and contribution to transmission of infection, as well as in participation in successive PC rounds. RESULTS: We predict that in low and medium endemic areas, current PC strategies (including targeting of WCBA) will achieve control of hookworm infection (i.e. the parasitological target) within 2 years. In highly endemic areas, control can be achieved with semi-annual PC with ALB at 90 % coverage, combined with interventions that reduce host contributions to the environmental reservoir of infection by 50 %. More intense PC strategies (high frequency and coverage) can help speed up control of hookworm infection, and may be necessary in some extremely highly endemic settings, but are not a panacea against systematic non-participation to PC. CONCLUSIONS: Control of hookworm infection by 2020 is feasible with current PC strategies (including targeting of WCBA). In highly endemic areas, PC should be combined with health education and/or WASH interventions.

Worm Infections in Children.

• On the basis of research evidence, worm infections are important global child health conditions causing chronic disability that lasts from childhood into adulthood (Table 1). (2)(3) Evidence Quality: B • On the basis of research evidence, the major worm infections found in developing countries include ascariasis, trichuriasis, hookworm infection, and schistosomiasis; toxocariasis, enterobiasis, and cysticercosis are also found in poor regions of North America and Europe. (4)(9)(13) Evidence Quality: B • On the basis of expert consensus, children and adolescents are often vulnerable to acquiring large numbers of worms, ie, high-intensity infections (Fig 1)(21)(22)(23) Evidence Quality: D • On the basis of expert consensus and research evidence, moderate and heavy worm burdens cause increased morbidity because of growth and intellectual stunting in children and adolescents. Many of these effects may result from helminth-induced malnutrition. (21)(22)(23) Evidence Quality: C • On the basis of expert consensus and research evidence, worm infections are also commonly associated with eosinophilia. (48) (49) Evidence Quality: B • On the basis of research evidence as well as consensus, helminthes can cause inflammation in the lung (asthma), gastrointestinal tract (enteritis and colitis), liver (hepatitis and fibrosis), and urogenital tract. (7)(21)(22)(23)(27)(28)(40)(41)(43) Evidence Quality: B • On the basis of research evidence, microscopy techniques for diagnosis of worm infections in children often exhibit suboptimal sensitivities and specificities, necessitating new or improved diagnostic modalities such as polymerase chain reaction. (54)(55) Evidence Quality: A • On the basis of research evidence and expert consensus, mass drug administration ("preventive chemotherapy") has becomea standard practice for ministries of health in low- and middle-income countries to control intestinal helminth infections and schistosomiasis. (67)(68) Evidence Quality: B.

New tools for NTD vaccines: A case study of quality control assays for product development of the human hookworm vaccine Na-APR-1M74.

Na-APR-1(M74) is an aspartic protease that is rendered enzymatically inactive by site-directed mutagenesis and is a candidate antigen component in the Human Hookworm Vaccine. The mutant protease exerts vaccine efficacy by inducing antibodies that neutralize the enzymatic activity of wild type enzyme (Na-APR-1wt) in the gut of the hookworm, thereby depriving the worm of its ability to digest its blood meal. Previously, canines immunized with Na-APR-1(M74) and challenged with Ancylostoma caninum were partially protected against hookworm challenge infection, especially from the loss in hemoglobin observed in control canines and canine immunoglobulin (Ig) G raised against Na-APR-1 was shown to inhibit the enzymatic activity of Na-APR-1 wt in vitro, thereby providing proof of concept of Na-APR-1(M74) as a vaccine antigen. The mutated version, Na-APR-1(M74), was then expressed at the cGMP level using a Nicotiana benthamiana expression system (Fraunhofer, CMB, Delaware, MD), formulated with Alhydrogel®, and used to immunize mice in a dose-ranging study to explore the enzyme-neutralizing capacity of the resulting anti- Na-APR-1(M74) IgG. As little as 0.99 µg of recombinant Na-APR-1(M74) could induce anti Na-APR-1(M74) IgG in mice that were capable of inhibiting Na-APR-1w t-mediated digestion of a peptide substrate by 89%. In the absence of enzymatic activity of Na-APR-1(M74) as a surrogate marker of protein functionality, we developed an assay based on the binding of a quenched fluorescence-labeled inhibitor of aspartic proteases, BODIPY-FL pepstatin A (BDP). Binding of BDP in the active site of Na-APR-1 wt was demonstrated by inhibition of enzymatic activity, and competitive binding with unlabelled pepstatin A. BDP also bound to Na-APR-1(M74) which was assessed by fluorescence polarization, but with an ∼ 50-fold reduction in the dissociation constant. Taken together, these assays comprise a "toolbox" that could be useful for the analyses of Na-APR-1(M74) as it proceeds through the clinical development as part of the Human Hookworm Vaccine pipeline.

Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women.

BACKGROUND: Hookworm infections are significant public health issues in South-East Asia. In women of reproductive age, chronic hookworm infections cause iron deficiency anaemia, which, upon pregnancy, can lead to intrauterine growth restriction and low birth weight. Low birth weight is an important risk factor for neonatal and infant mortality and morbidity. METHODOLOGY: We investigated the association between neonatal birth weight and a 4-monthly deworming and weekly iron-folic acid supplementation program given to women of reproductive age in north-west Vietnam. The program was made available to all women of reproductive age (estimated 51,623) in two districts in Yen Bai Province for 20 months prior to commencement of birth weight data collection. Data were obtained for births at the district hospitals of the two intervention districts as well as from two control districts where women did not have access to the intervention, but had similar maternal and child health indicators and socio-economic backgrounds. The primary outcome was low birth weight. PRINCIPAL FINDINGS: The birth weights of 463 infants born in district hospitals in the intervention (168) and control districts (295) were recorded. Twenty-six months after the program was started, the prevalence of low birth weight was 3% in intervention districts compared to 7.4% in control districts (adjusted odds ratio 0.29, 95% confidence interval 0.10 to 0.81, p = 0.017). The mean birth weight was 124 g (CI 68 - 255 g, p<0.001) greater in the intervention districts compared to control districts. CONCLUSIONS/SIGNIFICANCE: The findings of this study suggest that providing women with regular deworming and weekly iron-folic acid supplements before pregnancy is associated with a reduced prevalence of low birth weight in rural Vietnam. The impact of this health system-integrated intervention on birth outcomes should be further evaluated through a more extensive randomised-controlled trial.

Long-term weekly iron-folic acid and de-worming is associated with stabilised haemoglobin and increasing iron stores in non-pregnant women in Vietnam.

BACKGROUND: The prevalence of anaemia and iron deficiency in women remains high worldwide. WHO recommends weekly iron-folic acid supplementation where anaemia rates in non-pregnant women of reproductive age are higher than 20%. In 2006, a demonstration project consisting of weekly iron-folic acid supplementation and regular de-worming was set up in two districts in a northern province in Vietnam where anaemia and hookworm rates were 38% and 76% respectively. In 2008 the project was expanded to all districts in the province, targeting some 250,000 women. The objectives of this study were to: 1) examine changes in haemoglobin, iron stores and soil transmitted helminth infection prevalence over three years and 2) assess women's access to and compliance with the intervention. METHODS AND FINDINGS: The study was a semi-cross-sectional, semi-longitudinal panel design with a baseline survey, three impact surveys at three-, twelve- and thirty months after commencement of the intervention, and three compliance surveys after ten weeks, eighteen and thirty six months. RESULTS: After thirty months, mean haemoglobin stabilised at 130.3 g/L, an increase of 8.2 g/L from baseline, and mean serum ferritin rose from 23.9 µg/L to 52 µg/L. Hookworm prevalence fell from 76% to 22% over the same period. After thirty six months, 81% of the target population were receiving supplements and 87% were taking 75% or more of the supplements they received. CONCLUSIONS: Weekly iron-folic acid supplementation and regular de-worming was effective in significantly and sustainably reducing the prevalence of anaemia and soil transmitted helminth infections and high compliance rates were maintained over three years.

An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.

Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that neutralize enzymatic activity and interrupt blood-feeding. Toward developing a human hookworm vaccine, we expressed both wild-type (Na-APR-1(wt)) and mutant (Na-APR-1(mut)-mutagenesis of the catalytic aspartic acids) forms of Na-APR-1 from the human hookworm, Necator americanus. Refolded Na-APR-1(wt) was catalytically active, and Na-APR-1(mut) was catalytically inactive but still bound substrates. Vaccination of canines with Na-APR-1(mut) and heterologous challenge with A. caninum resulted in significantly reduced parasite egg burdens (P=0.034) and weight loss (P=0.022). Vaccinated dogs also had less gut pathology, fewer adult worms, and reduced blood loss compared to controls but these did not reach statistical significance. Vaccination with Na-APR-1(mut) induced antibodies that bound the native enzyme in the parasite gut and neutralized enzymatic activity of Na-APR-1(wt) and APR-1 orthologues from three other hookworm species that infect humans. IgG1 against Na-APR-1(mut) was the most prominently detected antibody in sera from people resident in high-transmission areas for N. americanus, indicating that natural boosting may occur in exposed humans. Na-APR-1(mut) is now a lead antigen for the development of an antihematophagy vaccine for human hookworm disease.

The effect of iron fortification and de-worming on anaemia and iron status of Vietnamese schoolchildren.

Previous data from Vietnam show that anaemia is highly prevalent among schoolchildren, who are considered not to be iron deficient. Trichuris infection doubled the risk of anaemia. The present study aimed to evaluate the hypothesis that de-worming is more effective than iron fortification in an anaemic, infection-prone population. In a trial with a 2 x 2 factorial design, 425 anaemic children aged 6-8 years were randomly assigned to receive either iron-fortified noodles or placebo, and mebendazole or placebo. Outcomes considered were change in haematological indicators of iron status (Hb, serum ferritin (SF), serum transferrin receptor (TfR) and haemoglobinopathies analysis); inflammations (C-reactive protein (CRP)); parasite infection status (hookworm, Trichuris and Ascaris infection); and IgE. ANOVA and logistic regression were used to assess the effects of iron fortification and de-worming on Hb, SF, TfR, body iron and anaemia. Hb improved in all groups after 6 months of intervention. Iron fortification significantly improved Hb, SF and body iron (2.6 g/l, 16.3 microg/l and 1 mg/kg, respectively). Prevalence of elevated IgE was very high at baseline (99%) and significantly reduced to about 75% in all groups after intervention. De-worming unexpectedly showed no effect on Hb, iron status and IgE level. It is concluded that iron fortification slightly improved anaemia and iron status in anaemic schoolchildren in rural Vietnam that were not considered iron deficient. Chronic infection or other unidentified factors may play an important role in the seasonal reduction of anaemia seen in all treatment groups.

Impact of a national helminth control programme on infection and morbidity in Ugandan schoolchildren.

OBJECTIVE: We aimed to assess the health impact of a national control programme targeting schistosomiasis and intestinal nematodes in Uganda, which has provided population-based anthelmintic chemotherapy since 2003. METHODS: We conducted longitudinal surveys on infection status, haemoglobin concentration and clinical morbidity in 1871 randomly selected schoolchildren from 37 schools in eight districts across Uganda at three time points - before chemotherapy and after one year and two years of annual mass chemotherapy. FINDINGS: Mass treatment with praziquantel and albendazole led to a significant decrease in the intensity of Schistosoma mansoni - 70% (95% confidence interval (CI): 66-73%) after one year and 82% (95% CI: 80-85%) after two years of treatment. Intensity of hookworm infection also decreased (75% and 93%; unadjusted). There was a significant increase in haemoglobin concentration after one (0.135 g/dL (95% CI: 0.126-0.144)) and two years (0.303 g/dL (95% CI: 0.293-0.312)) of treatment, and a significant decrease in signs of early clinical morbidity. The impact of intervention on S. mansoni prevalence and intensity was similar to that predicted by mathematical models of the impact of chemotherapy on human schistosomiasis. Improvements in haemoglobin concentration were greatest among children who were anaemic or harbouring heavy S. mansoni infection at baseline. CONCLUSION: Anthelmintic treatment delivered as part of a national helminth control programme can decrease infection and morbidity among schoolchildren and improve haemoglobin concentration.

Common intestinal parasites.

Intestinal parasites cause significant morbidity and mortality. Diseases caused by Enterobius vermicularis, Giardia lamblia, Ancylostoma duodenale, Necator americanus, and Entamoeba histolytica occur in the United States. E. vermicularis, or pinworm, causes irritation and sleep disturbances. Diagnosis can be made using the "cellophane tape test." Treatment includes mebendazole and household sanitation. Giardia causes nausea, vomiting, malabsorption, diarrhea, and weight loss. Stool ova and parasite studies are diagnostic. Treatment includes metronidazole. Sewage treatment, proper handwashing, and consumption of bottled water can be preventive. A. duodenale and N. americanus are hookworms that cause blood loss, anemia, pica, and wasting. Finding eggs in the feces is diagnostic. Treatments include albendazole, mebendazole, pyrantel pamoate, iron supplementation, and blood transfusion. Preventive measures include wearing shoes and treating sewage. E. histolytica can cause intestinal ulcerations, bloody diarrhea, weight loss, fever, gastrointestinal obstruction, and peritonitis. Amebas can cause abscesses in the liver that may rupture into the pleural space, peritoneum, or pericardium. Stool and serologic assays, biopsy, barium studies, and liver imaging have diagnostic merit. Therapy includes luminal and tissue amebicides to attack both life-cycle stages. Metronidazole, chloroquine, and aspiration are treatments for liver abscess. Careful sanitation and use of peeled foods and bottled water are preventive.

Experimental approaches to the development of a recombinant hookworm vaccine.

Hookworm infection is a major parasitic cause of morbidity in the developing nations of the tropics. Development of a genetically engineered vaccine would be a useful tool in the control of this infection in highly endemic areas. Recombinant polypeptides belonging to the Ancylostoma secreted protein (ASP)-1 family have shown promise for reducing hookworm burdens after larval challenge infections in mice. Typically, these polypeptides are expressed in Escherichia coli and administered as an alum precipitate. Vaccine protection is antibody dependent. It is anticipated that a cocktail of different recombinant hookworm antigens may be required in order to effectively prevent heavy hookworm infections and disease. The progress of this work has been hampered by the absence of both a convenient laboratory animal with which to study hookworm infections resembling human infection, as well as the lack of easy availability of native hookworm antigens. In addition, useful human serologic correlates of antihookworm immunity are still poorly defined.

Conforming strategies of public health campaigns to disease specificity and national contexts: Rockefeller Foundation's early campaigns against hookworm and malaria in Brazil.

The early experience of Rockefeller Foundation in Brazil, starting in 1915, reflected the idea of extending learned experience in Southern US to a wide international context. Health education and the creation of permanent local health services were expressed as main guidelines for cooperation with State and federal Brazilian agencies. Translating to the shaping of public health models the terms of scientific hygiene associated with the pastorian revolution, RF pictured different actions as part of a three step rationale of survey, experiment and demonstrations. In this paper we focus on Lewis Hackett's campaign, designed as a demonstration campaign of the "intensive method" of hookworm control, with the final purpose of enlisting local agencies in long-term action (1919-1924) and the malaria campaign in Rio de Janeiro State Lowlands (1922-1928) led initially by Mark Boyd as an "experimental control work" of field observation, campaign, control and maintenance to set guidelines to malaria control in tropical areas. The course and ultimate results of these experiences showed the need to adapt formal models to complex national and State-building context and to disease specificity, leading to pragmatic adaptations in the issue of control and eradication and on the shaping of vertical and horizontal health services. The failure of these two experiences in terms of disease control helped to strengthen the move, predominant in the next two decades, to vertical campaigns with least dependency on local social and political dynamics, as in the exemplar case of Frederick Soper's Anopheles gambiae eradication campaign (1938-1942).