Public engagement for the conduct of a controlled human infection study testing vaccines against Necator americanus (hookworm) in areas of active hookworm transmission in Brazil.

Controlled Human Infection Models (CHIS) involve administering human pathogens to healthy participants in controlled medical settings, which can elicit complex bioethical issues. Understanding how the community perceives such studies can significantly increase the participant's sense of cooperation and increases the researcher's and the participant's transparency. The current study describes the development of an educational intervention to achieve these ends as it aims to (1) analyze perceptions of the Controlled Human Infection Studies (CHIS), and (2) evaluate the participants' comprehension of the CHIS. METHODS: This is a qualitative action research that includes the development of an educational intervention with residents of a rural area in Minas Gerais, Brazil, where there is continuous natural transmission of the human pathogen Necator americanus ("hookworm"). In this area, it is intended to carry out a proposed phase 3 vaccine clinical trial in the future to test the efficacy of hookworm vaccines using controlled human infection. Two data collection strategies were used: an educational intervention and a focus group. RESULTS: The participants' perceptions showed distinct perspectives on CHIS. On one side, they recognized that the investigation is essential for the community, but on the other side, they thought that there would be resistance to its conduct by fear of infection. The idea that the study would generate a benefit for the greater good, contributing to the prevention of hookworm infection, was clearly stated. The participants perceived that the study offered concrete risks that could be reduced by constant monitoring by the researchers. They also mentioned the importance of access to information and the positive influence those who express interest in participating in the study can exert in the community. In relation to comprehension the participants memorized the information, mobilized it to explain everyday situations and created strategies to disseminate the study and engage the community in its development. By repeating and making sense of the information, the participant not only assimilates the knowledge transmitted, but also creates new knowledge. CONCLUSION: We concluded that an educational process of discussion and dialogue around participants' perceptions about the CHIS, promotes understanding and allows ways to disseminate information about the research to be collectively created.

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial.

BACKGROUND: A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. METHODS: This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 µg, 30 µg, and 100 µg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed. FINDINGS: Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 µg of the co-administered antigens (n=8 for each injection schedule), 30 µg (n=8 for each schedule), 100 µg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively). INTERPRETATION: Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. FUNDING: European Union Seventh Framework Programme.

A Journey in Science: Molecular vaccines for global child health in troubled times of anti-science.

My scientific life in translational medicine runs in two parallel, yet often converging paths. The first, is four-decade-long commitment to develop new vaccines for parasitic and neglected tropical diseases, as well as pandemic threats. This includes a vaccine for human hookworm infection that I began as an MD-PhD student in New York City in the 1980s, and a new low-cost COVID vaccine that reached almost 100 million people in low- and middle-income countries. Alongside this life in scientific research, is one in public engagement for vaccine and neglected disease diplomacy to ensure that people who live in extreme poverty can benefit from access to biomedical innovations. A troubling element has been the daunting task of countering rising antivaccine activism, which threatens to undermine our global vaccine ecosystem. Yet, this activity may turn out to become just as important for saving lives as developing new vaccines.

Protective efficacy of short-term infection with Necator americanus hookworm larvae in healthy volunteers in the Netherlands: a single-centre, placebo-controlled, randomised, controlled, phase 1 trial.

BACKGROUND: Vaccine development against hookworm is hampered by the absence of the development of protective immunity in populations repeatedly exposed to hookworm, limiting identification of mechanisms of protective immunity and new vaccine targets. Immunisation with attenuated larvae has proven effective in dogs and partial immunity has been achieved using an irradiated larvae model in healthy volunteers. We aimed to investigate the protective efficacy of immunisation with short-term larval infection against hookworm challenge. METHODS: We did a single-centre, placebo-controlled, randomised, controlled, phase 1 trial at Leiden University Medical Center (Leiden, Netherlands). Healthy volunteers (aged 18-45 years) were recruited using advertisements on social media and in publicly accessible areas. Volunteers were randomly assigned (2:1) to receive three short-term infections with 50 infectious Necator americanus third-stage filariform larvae (50L3) or placebo. Infection was abrogated with a 3-day course of albendazole 400 mg, 2 weeks after each exposure. Subsequently all volunteers were challenged with two doses of 50L3 at a 2-week interval. The primary endpoint was egg load (geometric mean per g faeces) measured weekly between weeks 12 and 16 after first challenge, assessed in the per-protocol population, which included all randomly assigned volunteers with available data on egg counts at week 12-16 after challenge. This study is registered with ClinicalTrials.gov, NCT03702530. FINDINGS: Between Nov 8 and Dec 14, 2018, 26 volunteers were screened, of whom 23 enrolled in the trial. The first immunisation was conducted on Dec 18, 2018. 23 volunteers were randomly assigned (15 to the intervention group and eight to the placebo group). Egg load after challenge was lower in the intervention group than the placebo group (geometric mean 571 eggs per g [range 372-992] vs 873 eggs per g [268-1484]); however, this difference was not statistically significant (p=0·10). Five volunteers in the intervention group developed a severe skin rash, which was associated with 40% reduction in egg counts after challenge (geometric mean 742 eggs per g [range 268-1484] vs 441 eggs per g [range 380-520] after challenge; p=0·0025) and associated with higher peak IgG1 titres. INTERPRETATION: To our knowledge, this is the first study to describe a protective effect of short-term exposure to hookworm larvae and show an association with skin response, eosinophilic response, and IgG1. These findings could inform future hookworm vaccine development. FUNDING: Dioraphte Foundation.

How do disease control measures impact spatial predictions of schistosomiasis and hookworm? The example of predicting school-based prevalence before and after preventive chemotherapy in Ghana.

BACKGROUND: Schistosomiasis and soil-transmitted helminth infections are among the neglected tropical diseases (NTDs) affecting primarily marginalized communities in low- and middle-income countries. Surveillance data for NTDs are typically sparse, and hence, geospatial predictive modeling based on remotely sensed (RS) environmental data is widely used to characterize disease transmission and treatment needs. However, as large-scale preventive chemotherapy has become a widespread practice, resulting in reduced prevalence and intensity of infection, the validity and relevance of these models should be re-assessed. METHODOLOGY: We employed two nationally representative school-based prevalence surveys of Schistosoma haematobium and hookworm infections from Ghana conducted before (2008) and after (2015) the introduction of large-scale preventive chemotherapy. We derived environmental variables from fine-resolution RS data (Landsat 8) and examined a variable distance radius (1-5 km) for aggregating these variables around point-prevalence locations in a non-parametric random forest modeling approach. We used partial dependence and individual conditional expectation plots to improve interpretability of results. PRINCIPAL FINDINGS: The average school-level S. haematobium prevalence decreased from 23.8% to 3.6% and that of hookworm from 8.6% to 3.1% between 2008 and 2015. However, hotspots of high-prevalence locations persisted for both infections. The models with environmental data extracted from a buffer radius of 2-3 km around the school location where prevalence was measured had the best performance. Model performance (according to the R2 value) was already low and declined further from approximately 0.4 in 2008 to 0.1 in 2015 for S. haematobium and from approximately 0.3 to 0.2 for hookworm. According to the 2008 models, land surface temperature (LST), modified normalized difference water index, elevation, slope, and streams variables were associated with S. haematobium prevalence. LST, slope, and improved water coverage were associated with hookworm prevalence. Associations with the environment in 2015 could not be evaluated due to low model performance. CONCLUSIONS/SIGNIFICANCE: Our study showed that in the era of preventive chemotherapy, associations between S. haematobium and hookworm infections and the environment weakened, and thus predictive power of environmental models declined. In light of these observations, it is timely to develop new cost-effective passive surveillance methods for NTDs as an alternative to costly surveys, and to focus on persisting hotspots of infection with additional interventions to reduce reinfection. We further question the broad application of RS-based modeling for environmental diseases for which large-scale pharmaceutical interventions are in place.

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.

Development of a peptide vaccine against hookworm infection: Immunogenicity, efficacy, and immune correlates of protection.

BACKGROUND: Approximately 400 million individuals are infected with hookworms globally. Protective vaccines are needed to prevent reinfections, which often occur after drug treatment in endemic areas. Ideal vaccines are highly efficacious and well tolerated, and do not present risks to patient safety. Peptide vaccines can generate specific, highly protective responses because they focus on minimal antigenic target(s) with a specific immunoprotective mechanism. Necator americanus aspartyl protease 1 (Na-APR-1) is one of the most promising hookworm vaccine antigens. The neutralizing epitope p3 (TSLIAGPKAQVEAIQKYIGAEL), together with universal the TH epitope P25 (KLIPNASLIENCTKAEL), has been used previously to produce peptide vaccines and was found to protect BALB/c mice against rodent hookworm infections, resulting in worm burden reductions of up to 98%. However, because of extensive digestion in the gastrointestinal tract, large oral vaccination doses were necessary to achieve this level of efficacy. OBJECTIVE: We sought to overcome the limitations of oral vaccine delivery and to investigate protective efficacy and immune correlates of protection. Herein, we examined 5 different peptide vaccines following intraperitoneal injection, to compare their efficacy with that of the clinical protein antigen APR-1. METHODS: BALB/c mice were immunized with p3-P25-based antigen that was adjuvanted with (1) lipid core peptide, (2) polymethyl methacrylate, (3) linear polyleucine, and (4) branched polyleucine (BL10), or with (5) CpG/aluminum hydroxide adjuvant (alum)-adjuvanted control and protein-based (6) CpG/alum-adjuvanted Na-APR-1. The mice sera, saliva, and feces were sampled for immune response evaluation. The immunized mice were further challenged via hookworm larvae infection, and protection was evaluated by conducting intestinal hookworm counts. RESULTS: BL10 and lipid core peptide generated the highest serum anti-Na-APR-1 IgG and fecal anti-APR-1 IgG titers, but only BL10 generated significant fecal anti-Na-APR-1 IgA titers. Upon challenge, immunization with CpG/alum-adjuvanted p3-P25, BL10, and lipid core peptide provided the highest worm burden reductions of 75%, 77%, and 59%, respectively, whereas the group immunized with Na-APR-1 had only modest worm reduction of 26%. The relationships between serum anti-Na-APR-1 IgG, fecal anti-Na-APR-1 IgA and IgG, and worm burden reduction were established with R2 values greater than or equal to 0.9, and the crucial role of both anti-Na-APR-1 IgG and IgA responses was identified. CONCLUSIONS: We demonstrated for the first time that p3-based vaccine candidates are safer and can deliver higher protection against hookworm infection compared with the clinical vaccine candidate, Na-APR-1.

Inactivating Effects of Common Laboratory Disinfectants, Fixatives, and Temperatures on the Eggs of Soil Transmitted Helminths.

Soil-transmitted helminths (STH) are important and widespread intestinal pathogens of humans and animals. It is presently unknown which inactivating procedures may be universally effective for safe transport, preservation, and disinfection of STH-contaminated specimens, and this lack of knowledge may expose laboratory staff to higher risk of laboratory-acquired infections (LAI's). There are limited data on the efficacy of commonly used disinfectants and fecal fixatives for inactivating the eggs of STH. This work tested five disinfectants for surface cleanup, four storage temperature conditions, and six transport/storage fixatives, to inactivate eggs of three species of STH of animal origin (Ascaris suum "roundworm," Trichuris vulpis "whipworm" and Ancylostoma caninum "hookworm") as surrogates for human STH. Among disinfectants, exposure to 10% povidone-iodine for ≥5 min inactivated 100% of the three species tested, while 5 min exposure to 95% ethanol inactivated T. vulpis and A. caninum eggs. All of the fixatives tested had inactivation effects on A. caninum hookworm eggs within 24 h of exposure, except potassium dichromate, which required 48 h. 95% ethanol for ≥48 h inactivated eggs from all three STH species. Freezing at ≤-20°C for ≥24 h inactivated eggs of T. vulpis and A. caninum, but only freezing at -80°C for ≥24 h inactivated >99% eggs, including A. suum. This work provides an evidence base for health and safety guidelines and mitigation strategies for the handling, storage, and disposal of stool samples containing STH eggs in laboratory, health care, childcare, or veterinary settings. IMPORTANCE This study systematically evaluates common laboratory disinfectants and storage conditions for their effectiveness in inactivating the infective stages of soil-transmitted helminths (STH). Animal-infecting proxy species were chosen to represent three major groups of STH that infect humans: roundworms, whipworms, and hookworms. Previously published work in this area typically focuses on a particular inactivation method, either for a single STH species, or on a subset of closely related species. Because prediagnostic fecal specimens must be regarded as potentially infectious with a mix of species, such information may be of limited utility in a working laboratory. We provide a straightforward summary of storage and disinfection methods that can achieve complete inactivation across a range of STH species, which represents a significant advance for clinical, veterinary and research laboratory biosafety.

The yin and yang of human soil-transmitted helminth infections.

The major soil-transmitted helminths that infect humans are the roundworms, whipworms and hookworms. Soil-transmitted helminth infections rank among the most important neglected tropical diseases in terms of morbidity, and almost one billion people are still infected with at least one species. While anthelmintic drugs are available, they do not offer long term protection against reinfection, precipitating the need for vaccines that provide long-term immunologic defense. Vaccine discovery and development is in advanced clinical development for hookworm infection, with a bivalent human hookworm vaccine in clinical trials in Brazil and Africa, but is in its infancy for both roundworm (ascariasis) and whipworm (trichuriasis) infections. One of the greatest hurdles to developing soil-transmitted helminth vaccines is the potent immunoregulatory properties of these helminths, creating a barrier to the induction of meaningful long-term protective immunity. While challenging for vaccinologists, this phenomenon presents unique opportunities to develop an entirely new class of anti-inflammatory drugs that capitalise on these immunomodulatory strategies. Epidemiologic studies and clinical trials employing experimental soil-transmitted helminth challenge models, when coupled with findings from animal models, show that at least some soil-transmitted helminth-derived molecules can protect against the onset of autoimmune, allergic and metabolic disorders, and several natural products with the desired bioactivity have been isolated and tested in pre-clinical settings. The yin and yang of soil-transmitted helminth infections reflect both the urgency for effective vaccines and the potential for new immunoregulatory molecules from parasite products.

Characterization of T cell responses to co-administered hookworm vaccine candidates Na-GST-1 and Na-APR-1 in healthy adults in Gabon.

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.

Epidemiology of soil-transmitted helminths following sustained implementation of routine preventive chemotherapy: Demographics and baseline results of a cluster randomised trial in southern Malawi.

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.

Safety and immunogenicity of co-administered hookworm vaccine candidates Na-GST-1 and Na-APR-1 in Gabonese adults: a randomised, controlled, double-blind, phase 1 dose-escalation trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: European Union Seventh Framework Programme.

Serious limitations of the current strategy to control Soil-Transmitted Helminths and added value of Ivermectin/Albendazole mass administration: A population-based observational study in Cameroon.

BACKGROUND: Soil-transmitted helminth (STH) infections remain a public health concern in sub-Saharan Africa. School-based mass drug administration (MDA) using the anthelminthic drug Mebendazole/Albendazole have succeeded in controlling morbidity associated to these diseases but failed to interrupt their transmission. In areas were filarial diseases are co-endemic, another anthelminthic drug (Ivermectin) is distributed to almost the entire population, following the community-directed treatment with ivermectin (CDTI) strategy. Since Ivermectin is a broad spectrum anthelmintic known to be effective against STH, we conducted cross-sectional surveys in two health districts with very contrasting histories of Ivermectin/Albendazole-based PC in order to investigate whether CDTI might have contributed in STH transmission interruption. METHODOLOGY: Cross-sectional surveys were conducted in two health districts with similar socio-environmental patterns but with very contrasting CDTI histories (Akonolinga health district where CDTI was yet to be implemented vs. Yabassi health district where CDTI has been ongoing for two decades). Stool samples were collected from all volunteers aged >2 years old and analyzed using the Kato-Katz technique. Infections by different STH species were compared between Akonolinga and Yabassi health districts to decipher the impact of Ivermectin/Albendazole-based MDA on STH transmission. PRINCIPAL FINDINGS: A total of 610 and 584 participants aged 2-90 years old were enrolled in Akonolinga and Yabassi health districts, respectively. Two STH species (Ascaris lumbricoides and Trichuris trichiura) were found, with prevalence significantly higher in Akonolinga health district (43.3%; 95% CI: 38.1-46.6) compared to Yabassi health district (2.5%; 95% CI: 1.1-5.1) (chi-square: 90.8; df: 1; p < 0.001). CONCLUSION/SIGNIFICANCE: These findings (i) suggest that Mebendazole- or Albendazole-based MDA alone distributed only to at-risk populations might not be enough to eliminate STH, (ii) support the collateral impact of Ivermectin/Albendazole MDA on A. lumbricoides and T. trichiura infections, and (iii) suggest that Ivermectin/Albendazole-based PC could accelerate STH transmission interruption.

Community-based survey on helminth infections in Kwilu province, the Democratic Republic of the Congo, and implications for local control strategies.

To adequately plan mass drug administration campaigns, the Democratic Republic of the Congo (DRC) needs further support for the mapping and monitoring of schistosomiasis (SCH) and soil-transmitted helminths (STH). We conducted a community-based survey in the health districts of Mosango and Yasa Bonga of the Kwilu province, DRC. A stratified two-stage cluster random sampling method was used to include participants into three different strata: Preschool-aged children (PSAC), school-aged children (SAC), and adults who were further subdivided into women of reproductive age (WRA) and other adults. In total, surveyors visited 30 villages, and 1 206 individuals participated in the study. Stool samples were collected to perform duplicate Kato-Katz smears for the detection of SCH and STH infection. Hookworm was the most prevalent infection in both districts, 34.1% (95%CI: 32.0-38.4), followed by A. lumbricoides (2.7%; 95%CI: 1.3-2.9) and T. trichiura (1.9%; 95%CI: 1.1-2.7). We did not find any SCH infection. The prevalence of each STH infection was similar across all risk groups, and the majority of the infected individuals was carrying light intensity infection. Compared to SAC, other adults were equally infected with hookworm. The prevalence of STH infection in SAC guides the MDA implementation because schoolchildren are most at risk and easily accessible program targets if school attendance is high. The current treatment strategy targets PSAC, SAC and WRA. However, this study shows that adults in general could also benefit from deworming. Therefore, community-wide preventive chemotherapy would be the most appropriate choice to control the hookworm burden rapidly.

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.

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).

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).

Soil-transmitted helminthiasis in four districts in Bangladesh: household cluster surveys of prevalence and intervention status.

BACKGROUND: In 2016, after 8 years of twice-annual nationwide preventive chemotherapy (PC) administration to school-age children (SAC), the Bangladesh Ministry of Health & Family Welfare (MOHFW) sought improved impact and intervention monitoring data to assess progress toward the newly adopted goal of eliminating soil-transmitted helminthiasis (STH) as a public health problem. METHODS: We surveyed four Bangladeshi districts between August and October 2017. We conducted a multi-stage, cluster-sample, household survey which produced equal-probability samples for preschool-age children (PSAC; 1-4 years), SAC (5-14 years), and adults (≥ 15 years). Standardized questionnaires were administered, using Android-based smart phones running an Open Data Kit application. Stool samples were collected and testing for STH prevalence and infection intensity used the Kato-Katz technique. RESULTS: In all, 4318 stool samples were collected from 7164 participants. Estimates of STH prevalence by risk group in three of the four surveyed districts ranged from 3.4 to 5.0%, all with upper, 1-sided 95% confidence limits < 10%. However, STH prevalence estimates in Sirajganj District ranged from 23.4 to 29.1%. Infections in that district were spatially focal; four of the 30 survey clusters had > 50% prevalence in at least one risk group. Among all tested specimens, Ascaris lumbricoides was the most common STH parasite [8.2% (n = 352)], followed by Trichuris trichiura [0.9% (n = 37)], and hookworm [0.6% (n = 27)]. In each district, PC coverage among SAC was above the 75% program target but did not exceed 45% among PSAC in any district. Improved sanitation at home, school, or work was over 90% in all districts. CONCLUSIONS: In the three low-prevalence districts, the MOHFW is considering decreasing the frequency of mass drug administration, per World Health Organization (WHO) guidelines. Also, the MOHFW will focus programmatic resources and supervisory efforts on Sirajganj District. Despite considering WHO guidance, the MOHFW will not expand PC administration to women of reproductive age partly due to the low prevalence of hookworm and T. trichiura, the STH parasites that contribute most to morbidity in that risk group. Data collected from surveys such as ours would help effectively guide future STH control efforts in Bangladesh and elsewhere.