RESUMEN
BACKGROUND: The World Health Organization emphasizes the importance of integrated monitoring and evaluation in neglected tropical disease (NTD) control programs. Serological assays offer a potential solution for integrated diagnosis of NTDs, particularly for those requiring mass drug administration (MDA) as primary control and elimination strategy. This scoping review aims (i) to provide an overview of assays using serum or plasma to detect infections with soil-transmitted helminths (STHs) in both humans and animals, (ii) to examine the methodologies used in this research field and (iii) to discuss advancements in serological diagnosis of STHs to guide prevention and control programs in veterinary and human medicine. METHODOLOGY: We conducted a systematic search in the Ovid MEDLINE, Embase and Cochrane Library databases, supplemented by a Google search using predefined keywords to identify commercially available serological assays. Additionally, we performed a patent search through Espacenet. PRINCIPAL FINDINGS: We identified 85 relevant literature records spanning over 50 years, with a notable increased interest in serological assay development in recent years. Most of the research efforts concentrated on diagnosing Ascaris infections in both humans and pigs, primarily using ELISA and western blot technologies. Almost all records targeted antibodies as analytes, employing proteins and peptides as analyte detection agents. Approximately 60% of sample sets described pertained to human samples. No commercially available tests for Trichuris or hookworms were identified, while for Ascaris, there are at least seven different ELISAs on the market. CONCLUSIONS: While a substantial number of assays are employed in epidemiological research, the current state of serological diagnosis for guiding STH prevention and control programs is limited. Only two assays designed for pigs are used to inform efficient deworming practices in pig populations. Regarding human diagnosis, none of the existing assays has undergone extensive large-scale validation or integration into routine diagnostics for MDA programs.
Asunto(s)
Pruebas Serológicas , Suelo , Trichuris , Humanos , Animales , Suelo/parasitología , Pruebas Serológicas/métodos , Trichuris/inmunología , Trichuris/aislamiento & purificación , Tricuriasis/diagnóstico , Tricuriasis/epidemiología , Tricuriasis/inmunología , Ancylostomatoidea/inmunología , Ancylostomatoidea/aislamiento & purificación , Infecciones por Uncinaria/diagnóstico , Infecciones por Uncinaria/epidemiología , Ascariasis/diagnóstico , Ascariasis/epidemiología , Ascariasis/inmunología , Helmintiasis/diagnóstico , Helmintiasis/epidemiología , Helmintiasis/transmisión , Helmintiasis/inmunología , Ascaris/inmunología , Ascaris/aislamiento & purificación , Anticuerpos Antihelmínticos/sangreRESUMEN
Hookworms are hematophagous nematode parasites that have infected a billion people worldwide. Anthelmintic drugs have limited efficacy and do not prevent reinfection. Therefore, prophylactic vaccines are in high demand. Whole parasite vaccines are allergic and unsafe; thus, research into subunit vaccines has been warranted. A comprehensive overview of protein or peptide subunit vaccines' safety, protective efficacy, and associated immune responses is provided herein. The differences between the immune responses against hookworm infection by patients from epidemic versus nonepidemic areas are discussed in detail. Moreover, the different immunologic mechanisms of protection are discussed, including those that rely on allergic and nonallergic humoral and antibody-dependent cellular responses. The allergic and autoimmune potential of hookworm antigens is also explored, as are the immunoregulatory responses induced by the hookworm secretome. The potential of oral mucosal immunizations has been overlooked. Oral immunity against hookworms is a long-lived and safer immune response that is associated with elimination of infection and protective against reinfections. However, the harsh conditions of the gastrointestinal environment necessitates special oral delivery systems to unlock vaccines' protective potential. The potential for development of safer and more effective peptide- and protein-based anthelmintic vaccines is explored herein.
Asunto(s)
Antígenos Helmínticos/inmunología , Infecciones por Uncinaria/inmunología , Intestinos/inmunología , Necatoriasis/inmunología , Vacunas/inmunología , Ancylostomatoidea/inmunología , Animales , Humanos , Inmunidad Mucosa , Vacunas de SubunidadRESUMEN
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.
Asunto(s)
Ancylostomatoidea/inmunología , Antígenos Helmínticos/administración & dosificación , Infecciones por Uncinaria/inmunología , Infecciones por Uncinaria/prevención & control , Linfocitos T/inmunología , Vacunas/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Ancylostomatoidea/genética , Animales , Anticuerpos Antihelmínticos/inmunología , Formación de Anticuerpos , Antígenos Helmínticos/genética , Antígenos Helmínticos/inmunología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Femenino , Gabón , Infecciones por Uncinaria/parasitología , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Vacunación , Vacunas/genética , Vacunas/inmunología , Adulto JovenRESUMEN
BACKGROUND: IgE characterizes the humoral response of allergic sensitization but less is known about what modulates its function and why some patients present clinical symptoms for a given IgE level and others do not. An IgE response also occurs during helminth diseases, independently of allergic symptoms. This response could be a model of non-functional IgE. OBJECTIVE: To study the IgE response against environmental allergens induced during natural helminth infection. METHODS: In 28 non allergic subjects from the periphery of Ho Chi Minh city with (H+, n = 18) and without helminth infection (H-, n = 10), we measured IgE and IgG4 against several components of Dermatophagoïdes pteronyssinus (Dpt) and Ascaris (a marker of immunization against nematodes), and determined the IgE component sensitization profile using microarray ISAC biochips. The functional ability of IgE to induce degranulation of cultured mast cells was evaluated in the presence of Dpt. RESULTS: Non allergic H+ subjects exhibited higher levels of IgE against Dpt compared to H- subjects. Dpt IgE were not functional in vitro and did not recognize usual Dpt major allergens. IgE recognized other component allergens that belong to different protein families, and most were glycosylated. Depletion of IgE recognizing carbohydrate cross-reactive determinant (CCD) did not induce a reduction in Dpt IgE. The Dpt IgG4 were not significantly different. CONCLUSION: Helminth infections induced IgE against allergens such as Dpt and molecular components that belong to different sources as well as against CCD (such as ß-1,2-xylose and/or âº-1,3-fucose substituted N-glycans). Dpt IgE were not able to induce degranulation of mast cells and were not explained by sensitization to usual major allergens or N-glycans.
Asunto(s)
Alérgenos/inmunología , Dermatophagoides pteronyssinus/inmunología , Inmunoglobulina E/inmunología , Infecciones por Nematodos/inmunología , Adolescente , Adulto , Anciano , Ancylostomatoidea/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Ascaris/inmunología , Estudios de Casos y Controles , Células Cultivadas , Reacciones Cruzadas , Femenino , Voluntarios Sanos , Humanos , Inmunoglobulina E/sangre , Masculino , Mastocitos , Persona de Mediana Edad , Infecciones por Nematodos/sangre , Infecciones por Nematodos/parasitología , Cultivo Primario de Células , Vietnam , Adulto JovenRESUMEN
BACKGROUND: Like other helminths, hookworms (HW) induce a regulatory immune response able to modulate and dampen reactivity of the host to antigens. No data about the evolution of the immune response after treatment are available. We aim to phenotype the regulatory immune response during natural HW infection and its evolution after treatment. METHODOLOGY: Twenty hookworm infected (HW+) and 14 non-infected subjects HW-from endemic area in the periphery of Ho Chi Minh City were included. Blood and feces samples were obtained before, 2 and 4 weeks after treatment with Albendazole 400mg. Additional samples were obtained at 3 and 12 months in the HW+ group. Hematological parameters, Treg (CD4+CD25hiFoxP3hi) and surface molecules (CD39, CD62L, ICOS, PD-1, CD45RA) were measured as well as inflammatory and lymphocytes differentiation cytokines such as IL-1ß, IL-6, IFNγ, IL-4, IL-17, IL-10, IL-2 and TGFß. RESULTS: HW+ subjects showed higher Treg, TregICOS+, Treg PD1-, TregCD62L+ and CD45RA+FoxP3lo resting Treg (rTreg). CD45RA-FoxP3lo non-suppressive Treg cells were also increased. No preferential Th1/Th2 orientation was observed, nor difference for IL-10 between two groups. After treatment, Treg, TregICOS+, TregCD62L+, Treg PD1- and rTreg decreased while IL-4 and IL-6 cytokines increased. CONCLUSION: During HW infection, Treg are increased and characterized by a heterogeneous population: a highly suppressive as well as a non-suppressive T cells phenotype. After treatment, Treg with immune-suppressive phenotype exhibited a decrease parallel to an inflammatory Th2 response.
Asunto(s)
Albendazol/administración & dosificación , Ancylostomatoidea/inmunología , Antihelmínticos/administración & dosificación , Infecciones por Uncinaria/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Adulto , Albendazol/farmacología , Animales , Antihelmínticos/farmacología , Sangre/parasitología , Estudios de Casos y Controles , Citocinas/metabolismo , Heces/parasitología , Regulación de la Expresión Génica/efectos de los fármacos , Infecciones por Uncinaria/inmunología , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Hookworm infection is a major public health problem that threatens about 500 million people throughout tropical areas of the world. Adult hookworms survive for many years in the host intestine, where they suck blood, causing iron deficiency anemia and malnutrition. Numerous molecules, named excretory/secretory (ES) products, are secreted by hookworm adults and/or larvae to aid in parasite survival and pathobiology. Although the molecular cloning and characterization of hookworm ES products began 25 years ago, the biological role and molecular nature of many of them are still unclear. Hookworm ES products, with distinct structures and functions, have been linked to many essential events in the disease pathogenesis. These events include host invasion and tissue migration, parasite nourishment and reproduction, and immune modulation. Several of these products represent promising vaccine targets for controlling hookworm disease and therapeutic targets for many inflammatory diseases. This review aims to summarize our present knowledge about hookworm ES products, including their role in parasite biology, host-parasite interactions, and as vaccine and pharmaceutical targets and to identify research gaps and future research directions in this field.
Asunto(s)
Ancylostomatoidea/inmunología , Líquidos Corporales/inmunología , Infecciones por Uncinaria/inmunología , Infecciones por Uncinaria/parasitología , Interacciones Huésped-Parásitos/inmunología , Ancylostoma , Ancylostomatoidea/metabolismo , Animales , Antioxidantes , Líquidos Corporales/química , Clonación Molecular , Femenino , Proteínas del Helminto/inmunología , Infecciones por Uncinaria/prevención & control , Infecciones por Uncinaria/terapia , Humanos , Factores Inmunológicos , Masculino , Péptido Hidrolasas , Inhibidores de Proteasas , Vacunas/inmunologíaRESUMEN
Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.
Asunto(s)
Ancylostomatoidea/inmunología , Endodesoxirribonucleasas/biosíntesis , Trampas Extracelulares/metabolismo , Evasión Inmune , Animales , Interacciones Huésped-Parásitos , Ratones , Neutrófilos/metabolismo , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunologíaRESUMEN
As laws change around the United States, wildlife that were once kept as companion animals are now often confiscated by local authorities. They are then euthanized unless a home is found for them at a sanctuary. Wolf sanctuaries are, therefore, becoming increasingly important for their conservation and management. However, little data is available on best practices for the health management of captive wolves, including data on parasitic diseases. Our objective was to assess the prevalence of parasites of captive wolves combining classical coprological techniques and immunoassays based on the detection of coproantigen of selected canid parasites. Fecal samples of 39 animals were collected upon observation of individual animals defecating. All samples were processed using the Fecal Dx® tests, a suite of coproantigen ELISAs for detection of ascarid, hookworm, whipworm, and Giardia (IDEXX Laboratories Inc.). Out of the 39 samples, 38 were processed using the double-centrifugation sugar flotation (DCSF) and 34 using a modification of the Baermann technique. Twenty-eight samples (71.8%) were positive for hookworm, and none positive for the other parasites tested using coproantigen ELISA. Ancylostoma sp. (26, 68.4%), Eucoleus boehmi (13, 34.2%), and Trichuris sp. (2; 5.3%), and Sarcocystis sp. (13, 34.2%) were detected using DCSF. No metastrongyloid lungworm larvae were found. The Cohen's kappa index (0.97) showed excellent agreement between the hookworm coproantigen ELISA and the DCSF using feces preserved in ethanol for a short period of time. This study provides a baseline on the parasites of captive wolves, and shows that recent innovative diagnostics in veterinary parasitology, developed and optimized for dogs, may be used for assessing the health of wolves.
Asunto(s)
Heces/parasitología , Helmintiasis Animal/diagnóstico , Infecciones Protozoarias en Animales/diagnóstico , Lobos/parasitología , Ancylostoma/inmunología , Ancylostoma/aislamiento & purificación , Ancylostomatoidea/inmunología , Ancylostomatoidea/aislamiento & purificación , Animales , Antígenos Helmínticos/análisis , Antígenos Helmínticos/aislamiento & purificación , Antígenos de Protozoos/análisis , Antígenos de Protozoos/aislamiento & purificación , Centrifugación/métodos , Centrifugación/veterinaria , Ensayo de Inmunoadsorción Enzimática/veterinaria , Helmintiasis Animal/epidemiología , Helmintiasis Animal/parasitología , Nematodos/inmunología , Nematodos/aislamiento & purificación , Pennsylvania , Infecciones Protozoarias en Animales/epidemiología , Infecciones Protozoarias en Animales/parasitología , Sarcocystis/inmunología , Sarcocystis/aislamiento & purificación , Sensibilidad y Especificidad , Trichuris/inmunología , Trichuris/aislamiento & purificación , Estados UnidosRESUMEN
Increases in ocean temperature are associated with changes in the distribution of fish stocks, and the foraging regimes and maternal attendance patterns of marine mammals. However, it is not well understood how these changes affect offspring health and survival. The maternal attendance patterns and immunity of South American fur seals were assessed in a rookery where hookworm disease is the main cause of pup mortality. Pups receiving higher levels of maternal attendance had a positive energy balance and a more reactive immune system. These pups were able to expel hookworms through a specific immune mediated mechanism and survived the infection. Maternal attendance was higher in years with low sea surface temperature, therefore, the mean hookworm burden and mortality increased with sea surface temperature over a 10-year period. We provide a mechanistic explanation regarding how changes in ocean temperature and maternal care affect infectious diseases dynamics in a marine mammal.
Asunto(s)
Ancylostomatoidea/inmunología , Enfermedades de los Animales/inmunología , Enfermedades de los Animales/mortalidad , Organismos Acuáticos , Lobos Marinos , Infecciones por Uncinaria/veterinaria , Animales , Calentamiento Global , Infecciones por Uncinaria/inmunología , Infecciones por Uncinaria/mortalidad , Conducta Materna , Océanos y Mares , Análisis de Supervivencia , TemperaturaRESUMEN
BACKGROUND: In many rural areas of tropical countries such as Indonesia, the prevalence of soil-transmitted helminths (STH) infections remains high. At the same time, the burden of allergic disorders in such rural areas is reported to be low and inversely associated with helminth infections. To reduce the morbidity and transmission of helminth infections, the world health organization recommends preventive treatment of school children by providing mass drug administration (MDA) with albendazole. Here, we had an opportunity to evaluate the prevalence of skin reactivity to allergens before and after albendazole treatment to get an indication of the possible impact of MDA on allergic sensitization. METHODS: A study was conducted among 150 school children living in an area endemic for STH infections. Before and 1 year after anthelminthic treatment with albendazole, stool samples were examined for the presence of STH eggs, skin prick tests (SPT) for cockroach and house dust mites were performed, blood eosinophilia was assessed, and total immunoglobulin E (IgE) and C-reactive protein (CRP) were measured in plasma. RESULTS: Anthelminthic treatment significantly reduced the prevalence of STH from 19.6 before treatment to 6% after treatment (p < 0.001). Levels of total IgE (estimate: 0.30; 95% CI 0.22-0.42, p < 0.0001), CRP (estimate: 0.60; 95% CI 0.42-0.86, p = 0.006), and eosinophil counts (estimate: 0.70; 95% CI 0.61-0.80, p < 0.001) decreased significantly. The prevalence of SPT positivity increased from 18.7 to 32.7%. Multivariate analysis adjusted for confounding factors showed an increased risk of being SPT positive to any allergen (OR 3.04; 95% CI 1.338-6.919, p = 0.008). CONCLUSIONS: This study indicates that 1 year of MDA with albendazole was associated with a reduced prevalence of STH infections. This study shows that the prevalence of allergic sensitization increases after 1 year of albendazole treatment. Placebo-controlled and larger studies are needed to further substantiate a role of deworming treatment in an increased risk of allergic sensitization.
Asunto(s)
Ancylostomatoidea/inmunología , Anticuerpos Antihelmínticos/sangre , Ascaris lumbricoides/inmunología , Helmintiasis/epidemiología , Hipersensibilidad Inmediata/epidemiología , Inmunoglobulina E/sangre , Trichuris/inmunología , Albendazol/administración & dosificación , Albendazol/uso terapéutico , Alérgenos/inmunología , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/uso terapéutico , Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/inmunología , Proteína C-Reactiva/análisis , Niño , Cucarachas/inmunología , Femenino , Helmintiasis/tratamiento farmacológico , Helmintiasis/parasitología , Humanos , Hipersensibilidad Inmediata/sangre , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/inmunología , Indonesia/epidemiología , Masculino , Administración Masiva de Medicamentos , Pyroglyphidae/inmunologíaRESUMEN
Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. However, few studies have focused on latent TB infection (LTBI), which predominates globally. We performed a large observational study of healthy adults migrating from Nepal to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to control virulent mycobacterial growth in vitro than from those without, which was lost following hookworm treatment. There was a significant negative relationship between mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene expression characterized the whole blood transcriptome of hookworm infection and correlated with improved mycobacterial control. These data provide a potential alternative explanation for the reduced prevalence of LTBI among individuals with hookworm infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils.
Asunto(s)
Ancylostomatoidea/inmunología , Infecciones por Uncinaria/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/inmunología , Adolescente , Ancylostomatoidea/fisiología , Animales , Eosinófilos/inmunología , Eosinófilos/metabolismo , Heces/microbiología , Heces/parasitología , Perfilación de la Expresión Génica/métodos , Infecciones por Uncinaria/genética , Infecciones por Uncinaria/parasitología , Humanos , Tuberculosis Latente/genética , Tuberculosis Latente/microbiología , Estudios Longitudinales , Masculino , Mycobacterium tuberculosis/fisiología , Nepal , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Hookworm is a major public health concern, yet still relatively little is known about the immunological responses involved in human infection. Animal studies are mainly confined to using the natural rodent helminth Nippostrongylus brasiliensis as this has been proposed as the most accurate model of hookworm infection in the mouse, with both its life cycle and the immune responses it invokes having been extremely well characterized. In this review, we examine the roles that type 2 innate lymphoid cells (ILC2s) play in immunity and host tolerance to hookworm infection, particularly N. brasiliensis. This includes their role in the initiation and regulation of immune responses, as well as in the resolution and limitation of tissue damage required after an infection with a large organism, such as a helminth.
Asunto(s)
Ancylostomatoidea/inmunología , Citocinas/inmunología , Infecciones por Uncinaria/inmunología , Inmunidad Innata/inmunología , Nippostrongylus/inmunología , Células Th2/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Infecciones por Uncinaria/parasitología , Humanos , Masculino , Ratones , Enfermedades Desatendidas/inmunología , Enfermedades Desatendidas/parasitologíaRESUMEN
Approximately one billion people are currently infected with hookworm. Despite its high prevalence and the concomitant immune suppression seen in infected individuals, little research has been performed on the mechanism of immunosuppression by hookworm. Our study focused on characterizing mechanisms utilized by hookworm to suppress the host immune response. Splenocytes and draining lymph node cells from mice injected with hookworm excretory/secretory (ES) proteins showed decreased proliferation in response to both heterologous and species-specific antigens while also having increased nitric oxide secretion. Analysis by fluorescence-activated cell sorting revealed that mice injected with ES had reduced percentages of CD4+ T cells indicating potential effects of ES proteins on lymphocyte homeostasis. Antibody and cytokine response analyses demonstrated that immunization with ES proteins decreased IgG and IgG1 levels, also decreased interleukin (IL-)-4 and increased IL-12 and interferon-gamma (IFN-γ) cytokine production suggesting impairment of B-cell activation and a shift towards a nonhealing IL-12 directed T helper-1 immune response. Together, these data demonstrate for the first time that host immunosuppression by hookworms is orchestrated by ES proteins and provide mechanisms underlying the shift towards a nonhealing Th-1 profile as seen in humans suffering from hookworm infection.
Asunto(s)
Ancylostomatoidea/inmunología , Antígenos Helmínticos/inmunología , Proteínas del Helminto/inmunología , Infecciones por Uncinaria/inmunología , Evasión Inmune/inmunología , Tolerancia Inmunológica/inmunología , Células TH1/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Linfocitos B/inmunología , Cricetinae , Citocinas/metabolismo , Femenino , Citometría de Flujo , Infecciones por Uncinaria/parasitología , Humanos , Inmunoglobulina G/inmunología , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Células Th2/inmunologíaRESUMEN
Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 µg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).
Asunto(s)
Ancylostomatoidea/inmunología , Antígenos Helmínticos/inmunología , Glutatión Transferasa/inmunología , Infecciones por Uncinaria/prevención & control , Vacunas Sintéticas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Hidróxido de Aluminio/administración & dosificación , Animales , Anticuerpos Antihelmínticos/sangre , Brasil , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Glucósidos/administración & dosificación , Voluntarios Sanos , Vacunas contra Hepatitis B/administración & dosificación , Infecciones por Uncinaria/inmunología , Humanos , Inmunoglobulina G/sangre , Inyecciones Intramusculares , Lípido A/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados Unidos , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Adulto JovenRESUMEN
Informed consent is one of the principal ethical requirements of conducting clinical research, regardless of the study setting. Breaches in the quality of the informed consent process are frequently described in reference to clinical trials conducted in developing countries, due to low levels of formal education, a lack of familiarity with biomedical research, and limited access to health services in these countries. However, few studies have directly compared the quality of the informed consent process in developed and developing countries using the same tool and in similar clinical trials. This study was conducted to compare the quality of the informed consent process of a series of clinical trials of an investigational hookworm vaccine that were performed in Brazil and the United States. A standardized questionnaire was used to assess the ethical quality of the informed consent process in a series of Phase 1 clinical trials of the Na-GST-1/Alhydrogel hookworm vaccine that were conducted in healthy adults in Brazil and the United States. In Brazil, the trial was conducted at two sites, one in the hookworm non-endemic urban area of Belo Horizonte, Minas, and one in the rural, resource-limited town of Americaninhas, both in the state of Minas Gerais; the American trial was conducted in Washington, DC. A 32-question survey was administered after the informed consent document was signed at each of the three trial sites; it assessed participants' understanding of information about the study presented in the document as well as the voluntariness of their decision to participate. 105 participants completed the questionnaire: 63 in Americaninhas, 18 in Belo Horizonte, and 24 in Washington, DC. Overall knowledge about the trial was suboptimal: the mean number of correct answers to questions about study objectives, methods, duration, rights, and potential risks and benefits, was 45.6% in Americaninhas, 65.2% in Belo Horizonte, and 59.1% in Washington, DC. Although there was no difference in the rate of correct answers between participants in Belo Horizonte and Washington, DC, there was a significant gap between participants at these two locations compared to Americaninhas (p = 0.0002 and p = 0.0001, respectively), which had a lower percentage of correct answers. Attitudes towards participating in the clinical trial also differed by site: while approximately 40% had doubts about participating in Washington, DC and Belo Horizonte, only 1.5% had concerns in Americaninhas. Finally, in Belo Horizonte and Washington, high percentages cited a desire to help others as motivation for participating, whereas in Americaninhas, the most common reason for participating was personal interest (p = 0.001). Understanding of information about a Phase 1 clinical trial of an experimental hookworm vaccine following informed consent was suboptimal, regardless of study site. Although overall there were no differences in knowledge between Brazil and the US, a lower level of understanding about the trial was seen in participants at the rural, resource-limited Brazilian site. These findings demonstrate the need for educational interventions directed at potential clinical trial participants, both in developing and developed countries, in order to improve understanding of the informed consent document.
Asunto(s)
Ancylostomatoidea/inmunología , Infecciones por Uncinaria/prevención & control , Consentimiento Informado/normas , Adolescente , Adulto , Ancylostomatoidea/fisiología , Animales , Brasil , Estudios Transversales , Países en Desarrollo/estadística & datos numéricos , Estudios de Evaluación como Asunto , Femenino , Infecciones por Uncinaria/parasitología , Infecciones por Uncinaria/psicología , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Estados Unidos , Vacunas/administración & dosificación , Vacunas/inmunología , Adulto JovenRESUMEN
Hookworms are soil-transmitted nematode parasites that can reside for many years in the small intestine of their human hosts; Necator americanus is the predominant infecting species. Adult worms feed on the blood of a host and can cause iron deficiency anaemia, especially in high-risk populations (children and women of childbearing age). Almost 500 million people in developing tropical countries are infected, and simulation models estimate that hookworm infection is responsible for >4 million disability-adjusted life years lost annually. Humans mount an immune response to hookworms, but it is mostly unsuccessful at removing adult worms from the bowel. Accordingly, the host switches to an immune-tolerant state that enables hookworms to reside in the gut for many years. Although anthelmintic drugs are available and widely used, their efficacy varies and the drugs do not prevent reinfection. Thus, other control strategies aimed at improving water quality, sanitation and hygiene are needed. In addition, efforts are underway to develop a human hookworm vaccine through public-private partnerships. However, hookworms could also be a resource; as hookworms have the capability to regulate the host's inflammation, researchers are experimentally infecting patients to treat some inflammatory diseases as an approach to discover new anti-inflammatory molecules. This area of endeavour might well yield new biotherapeutics for autoimmune and allergic diseases.
Asunto(s)
Infecciones por Uncinaria/complicaciones , Infecciones por Uncinaria/fisiopatología , Albendazol/farmacología , Albendazol/uso terapéutico , Ancylostomatoidea/inmunología , Ancylostomatoidea/patogenicidad , Anemia/complicaciones , Anemia/etiología , Animales , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Factor VIIa/efectos adversos , Factor XIa/efectos adversos , Factor Xa/efectos adversos , Heces/parasitología , Hemorragia/etiología , Hemorragia/parasitología , Infecciones por Uncinaria/epidemiología , Humanos , Intestino Delgado/parasitología , Intestino Delgado/fisiopatología , Larva Migrans/etiología , Mebendazol/farmacología , Mebendazol/uso terapéutico , Necator americanus/inmunología , Necator americanus/patogenicidad , Prevalencia , Factores de Riesgo , Suelo/parasitologíaRESUMEN
Intestinal worms are well known for their potent immuno-modulatory capacity. In a recent study, Navarro et al. (2016) identify a secreted hookworm protein that can suppress allergic responses in both mice and humans. This represents an exciting strategy for treating chronic inflammatory disorders such as allergy.
Asunto(s)
Ancylostomatoidea/inmunología , Infecciones por Uncinaria/inmunología , Infecciones por Uncinaria/terapia , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Ancylostomatoidea/patogenicidad , Animales , Antígenos CD , Asma/terapia , Autoinmunidad/inmunología , Enfermedad Crónica , Células Dendríticas/inmunología , Helmintiasis/inmunología , Infecciones por Uncinaria/parasitología , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunidad Humoral , Inmunidad Innata , Inmunomodulación/inmunología , Cadenas alfa de Integrinas , Parasitosis Intestinales/inmunología , Pulmón/inmunología , Ganglios Linfáticos/inmunología , Ratones , Proteínas/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
A reduced diversity of the gastrointestinal commensal microbiota is associated with the development of several inflammatory diseases. Recent reports in humans and animal models have demonstrated the beneficial therapeutic effects of infections by parasitic worms (helminths) in some inflammatory disorders, such as inflammatory bowel disease (IBD) and coeliac disease (CeD). Interestingly, these studies have described how helminths may alter the intestinal microbiota, potentially representing a mechanism by which they regulate inflammation. However, for practical reasons, these reports have primarily analysed the faecal microbiota. In the present investigation, we have assessed, for the first time, the changes in the microbiota at the site of infection by a parasitic helminth (hookworm) and gluten-dependent inflammation in humans with CeD using biopsy tissue from the duodenum. Hookworm infection and gluten exposure were associated with an increased abundance of species within the Bacteroides phylum, as well as increases in the richness and diversity of the tissue-resident microbiota within the intestine, results that are consistent with previous reports using other helminth species in humans and animal models. Hence, this may represent a mechanism by which parasitic helminths may restore intestinal immune homeostasis and exert a therapeutic benefit in CeD, and potentially other inflammatory disorders.
Asunto(s)
Ancylostomatoidea/fisiología , Bacterias/clasificación , Enfermedad Celíaca/microbiología , Duodeno/microbiología , Ancylostomatoidea/inmunología , Animales , Bacterias/genética , Bacterias/aislamiento & purificación , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/parasitología , Duodeno/inmunología , Duodeno/parasitología , Heces/microbiología , Humanos , Microbiota , Análisis de Secuencia de ADNRESUMEN
A case control, multicenter, prospective randomized two arm parallel group clinical trials was conducted on 190 patients. The main objective of this study is to provide comparative efficacy results of both trialed medicines. The comparison was done in between herbal medicine D-Worm and Mebandazole allopathic drug for the treatment of helminthiasis. All the rules of GCP (Good Clinical Practices) were followed including clinical history, clinical presentation, examination findings and stool tests. Stool D/R and Parasite antigen tests were performed before and after treatment. The comparison of symptoms were also done including the improvement in abdominal pain, worms in stool, anal itching, nausea and vomiting, loss of appetite, and fatigue etc. The data on clinical proforma was gathered and subjected to statistical analysis. Parasite specific antigen test and stool D/R is considered as gold standard test for the diagnosis and confirmation of helminthes infection. Different parameter i.e. age, sex, and other clinical sign and symptoms were studied and compared between two treatment groups (Control and Test groups) at baseline and end of therapeutic application. Consent of patient was taken at first before the start of examination. Majority of the patients (90%) included in this study group get cured after herbal treatment. The statistical analysis used for the assessment of the effect of the treatment also showed significant improvement after treatment.