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The Journal of Allergy and Clinical... Jul 2022Approximately 400 million individuals are infected with hookworms globally. Protective vaccines are needed to prevent reinfections, which often occur after drug...
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 T 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 (BL), 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
BL and lipid core peptide generated the highest serum anti-Na-APR-1 IgG and fecal anti-APR-1 IgG titers, but only BL generated significant fecal anti-Na-APR-1 IgA titers. Upon challenge, immunization with CpG/alum-adjuvanted p3-P25, BL, 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 R 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.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Epitopes; Hookworm Infections; Immunoglobulin A; Immunoglobulin G; Lipids; Mice; Mice, Inbred BALB C; Necator americanus; Vaccines, Subunit
PubMed: 35278494
DOI: 10.1016/j.jaci.2022.02.020 -
Frontiers in Immunology 2018Soil-transmitted helminths and frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB)... (Observational Study)
Observational Study
Soil-transmitted helminths and 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 ( = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen ( = 0.221; = 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 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.
Topics: Adolescent; Ancylostomatoidea; Animals; Eosinophils; Feces; Gene Expression Profiling; Hookworm Infections; Humans; Latent Tuberculosis; Longitudinal Studies; Male; Mycobacterium tuberculosis; Nepal; Prospective Studies; Risk Factors; Young Adult
PubMed: 30619265
DOI: 10.3389/fimmu.2018.02893 -
PloS One 2022In Malaysia, soil-transmitted helminth (STH) infections still persist among indigenous communities. In the past, local studies have focused mostly on epidemiologic...
In Malaysia, soil-transmitted helminth (STH) infections still persist among indigenous communities. In the past, local studies have focused mostly on epidemiologic aspects of STH infections with a scarcity of information on the efficacy of deworming treatment. The present study consisted of 2 phases: a cross-sectional phase on current epidemiological status and risk factors of STH infections and a longitudinal study over 6 weeks on triple dose albendazole efficacy against STH infections. A total of 253 participants were recruited at baseline and a pre-tested questionnaire was administered to obtain information on socio-demographics, environmental and behavioural risk factors. Stool samples were evaluated using a modified Kato-Katz technique. Cure rate (CR) and egg reduction rate (ERR) were assessed at 3 weeks following a 3-day course of 400mg albendazole treatment and infection status were observed again at 6 weeks. Baseline positivity of trichuriasis, ascariasis and hookworm infections were 56.1%, 11.9% and 20.2%, respectively. Multivariate analysis showed age below 18 years old (P = 0.004), without latrine in house (P = 0.042) and indiscriminate defecation (P = 0.032) were associated with STH infections. In the longitudinal study (N = 89), CR for trichuriasis was 64.6%, while CR of 100% was observed for both ascariasis and hookworm. ERR was above 90% for all three STH species. A rapid increased of Trichuris trichiura egg output was observed at 6 weeks. In conclusion, STH infections are highly prevalent among indigenous communities. Children and teenagers, poor sanitation and hygiene behaviour were determinants for STH infections. Triple dose albendazole is found to be efficacious against Ascaris lumbricoides and hookworm infections but has moderate curative effect with high ERR against T. trichiura. Although triple dose albendazole regimen has logistic challenges and may not be a routine option, consideration of this treatment regime may still be necessary in selective communities to reduce high intensity of T. trichiura infection.
Topics: Adolescent; Albendazole; Animals; Anthelmintics; Ascariasis; Ascaris lumbricoides; Child; Cross-Sectional Studies; Feces; Helminthiasis; Hookworm Infections; Humans; Longitudinal Studies; Soil; Trichuriasis; Trichuris
PubMed: 35960935
DOI: 10.1371/journal.pone.0272821 -
The Journal of Allergy and Clinical... Feb 2015Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment...
BACKGROUND
Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required.
OBJECTIVE
Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects.
METHODS
A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined.
RESULTS
Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g.
PRIMARY OUTCOMES
median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g.
SECONDARY OUTCOMES
quality of life scores improved (46.3-40.6; P = .05); celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4(+) Foxp3(+) regulatory T cells (0.19%-1.12%; P = .001).
CONCLUSIONS
Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
Topics: Adult; Aged; Ancylostomatoidea; Animals; Celiac Disease; Duodenum; Female; Glutens; Hookworm Infections; Humans; Immune Tolerance; Immunophenotyping; Male; Middle Aged; Necator americanus; Patient Outcome Assessment; Surveys and Questionnaires; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory
PubMed: 25248819
DOI: 10.1016/j.jaci.2014.07.022 -
PLoS Neglected Tropical Diseases Sep 2016Even though human hookworm infection is highly endemic in many countries throughout the world, its global economic and health impact is not well known. Without a better...
BACKGROUND
Even though human hookworm infection is highly endemic in many countries throughout the world, its global economic and health impact is not well known. Without a better understanding of hookworm's economic burden worldwide, it is difficult for decision makers such as funders, policy makers, disease control officials, and intervention manufacturers to determine how much time, energy, and resources to invest in hookworm control.
METHODOLOGY/PRINCIPLE FINDINGS
We developed a computational simulation model to estimate the economic and health burden of hookworm infection in every country, WHO region, and globally, in 2016 from the societal perspective. Globally, hookworm infection resulted in a total 2,126,280 DALYs using 2004 disability weight estimates and 4,087,803 DALYs using 2010 disability weight estimates (excluding cognitive impairment outcomes). Including cognitive impairment did not significantly increase DALYs worldwide. Total productivity losses varied with the probability of anemia and calculation method used, ranging from $7.5 billion to $138.9 billion annually using gross national income per capita as a proxy for annual wages and ranging from $2.5 billion to $43.9 billion using minimum wage as a proxy for annual wages.
CONCLUSION
Even though hookworm is classified as a neglected tropical disease, its economic and health burden exceeded published estimates for a number of diseases that have received comparatively more attention than hookworm such as rotavirus. Additionally, certain large countries that are transitioning to higher income countries such as Brazil and China, still face considerable hookworm burden.
Topics: Anemia; Cost of Illness; Global Health; Health Care Costs; Hookworm Infections; Humans; Quality-Adjusted Life Years
PubMed: 27607360
DOI: 10.1371/journal.pntd.0004922 -
The American Journal of the Medical... Apr 2020
Topics: Adult; Albendazole; Animals; Anthelmintics; Female; Hookworm Infections; Humans; India; Iron; Treatment Outcome
PubMed: 31902519
DOI: 10.1016/j.amjms.2019.11.012 -
BMC Infectious Diseases Apr 2021Malaria and helminths diseases are co-endemic in most parts of sub-Saharan Africa. Immune responses from each of these pathogens interact, and these interactions may...
BACKGROUND
Malaria and helminths diseases are co-endemic in most parts of sub-Saharan Africa. Immune responses from each of these pathogens interact, and these interactions may have implications on vaccines. The GMZ2 malaria vaccine candidate is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP R0). GMZ2 has recently showed modest efficacy in a phase IIb multicenter trial. Here, we assessed the effect of hookworm (Necator americanus) infection and anthelmintic treatment on naturally acquired antibody responses against GMZ2 and constituent antigens.
METHODS
This longitudinal cross-sectional study was conducted in the Kintampo North Municipality of Ghana. Blood and stool samples were taken from 158 individuals (4-88 years old) infected with either P. falciparum alone (n = 59) or both hookworm and P. falciparum (n = 63) and uninfected endemic controls (n = 36). Stool hookworm infection was detected by the Kato-Katz method and PCR. Malaria parasitaemia was detected by RDT, light microscopy and P. falciparum-specific 18S rRNA gene PCR. Serum samples were obtained prior to hookworm treatment with a single dose of albendazole (400 mg) and 3 weeks (21 days) after treatment. Levels of IgG1, IgG3 and IgM against GMZ2, MSP3 and GLURP R0 were measured by ELISA and compared among the groups, before and after treatment.
RESULTS
Participants with P. falciparum and hookworm co-infection had significantly higher IgG3 levels to GMZ2 than those with only P. falciparum infection and negative control (p < 0.05) at baseline. Treatment with albendazole led to a significant reduction in IgG3 levels against both GMZ2 and GLURP R0. Similarly, IgM and IgG1 levels against MSP3 also decreased following deworming treatment.
CONCLUSION
Individuals with co-infection had higher antibody responses to GMZ2 antigen. Treatment of hookworm/malaria co-infection resulted in a reduction in antibody responses against GMZ2 and constituent antigens after albendazole treatment. Thus, hookworm infection and treatment could have a potential implication on malaria vaccine efficacy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albendazole; Anthelmintics; Antibodies, Protozoan; Antigens, Protozoan; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Hookworm Infections; Humans; Immunoglobulin G; Longitudinal Studies; Malaria Vaccines; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Protozoan Proteins; Young Adult
PubMed: 33832450
DOI: 10.1186/s12879-021-06027-5 -
Expert Review of Gastroenterology &... Jul 2015Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by exposure to dietary gluten in genetically susceptible individuals.... (Review)
Review
Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by exposure to dietary gluten in genetically susceptible individuals. Currently, lifelong adherence to a gluten-free diet (GFD) is the only available treatment. However, GFD alone is not sufficient to relieve symptoms, control small intestinal inflammation and prevent long-term complications in many patients. The GFD has its challenges including issues related to adherence, lifestyle restrictions and cost. As a result, there is growing interest in and a need for non-dietary therapies to manage this condition. In recent years, different targets in the immune-mediated cascade of CD have been identified in clinical and pre-clinical trials for potential therapies. This review will discuss the latest non-dietary therapies in CD, including endopeptidases, modulators of enterocyte tight junctions and agents involved in gluten tolerization and immunomodulation. We will also discuss the potential implications of approved therapeutics on CD clinical practice.
Topics: Celiac Disease; Combined Modality Therapy; Diet, Gluten-Free; Drug Discovery; Endopeptidases; Enterocytes; GTP-Binding Proteins; Glutens; Hookworm Infections; Humans; Immunomodulation; Molecular Targeted Therapy; Oligopeptides; Probiotics; Protein Glutamine gamma Glutamyltransferase 2; Tight Junctions; Transglutaminases; Vaccines
PubMed: 25864708
DOI: 10.1586/17474124.2015.1033399 -
Wilderness & Environmental Medicine Sep 2018
Topics: Albendazole; Anemia, Iron-Deficiency; Anthelmintics; Diagnosis, Differential; Feces; Female; Hookworm Infections; Humans; Middle Aged; Nails, Malformed; Nepal
PubMed: 29958781
DOI: 10.1016/j.wem.2018.04.005 -
Tropical Doctor Apr 2022Hookworm is one of the soil-transmitted nematodes causing anaemia and low birth weight in pregnant women. This study aimed to assess albendazole efficacy and... (Clinical Trial)
Clinical Trial
Hookworm is one of the soil-transmitted nematodes causing anaemia and low birth weight in pregnant women. This study aimed to assess albendazole efficacy and re-infection rate among pregnant women. A community-based cross-sectional study was conducted from February to September 2021 in Debre Elias District. Albendazole (400mg) was administered to assess efficacy and hookworm re-infection rate. Though the cure rate of single-dose albendazole was 81.7%, with an overall egg reduction rate of 92.5%, the re-infection rate of hookworm 18-24 weeks post-treatment was substantial at 21.4%. More effective intervention measures are thus needed.
Topics: Albendazole; Ancylostomatoidea; Animals; Anthelmintics; Cross-Sectional Studies; Ethiopia; Female; Hookworm Infections; Humans; Pregnancy; Pregnant Women; Reinfection
PubMed: 35156859
DOI: 10.1177/00494755221080593