Helminths may protect against cardiometabolic risk through effects on inflammation and metabolism; their treatment may be detrimental to metabolic outcomes.
In a cluster-randomized trial in 26 ...Ugandan fishing communities we investigated effects of community-wide intensive (quarterly single-dose praziquantel, triple-dose albendazole) vs standard (annual single-dose praziquantel, biannual single-dose albendazole) anthelminthic treatment on metabolic outcomes, and observational associations between helminths and metabolic outcomes. The primary outcome, homeostatic model assessment of insulin resistance (HOMA-IR), and secondary outcomes (including blood pressure, fasting blood glucose, lipids) were assessed after 4 years' intervention among individuals aged ≥10 years.
We analyzed 1898 participants. Intensive treatment had no effect on HOMA-IR (adjusted geometric mean ratio, 0.96 95% confidence interval {CI}, .86-1.07; P = .42) but resulted in higher mean low-density lipoprotein cholesterol (LDL-c) (2.86 vs 2.60 mmol/L; adjusted mean difference, 0.26 95% CI, -.03 to .56; P = .08). Lower LDL-c levels were associated with Schistosoma mansoni (2.37 vs 2.80 mmol/L; -0.25 95% CI, -.49 to -.02; P = .04) or Strongyloides (2.34 vs 2.69 mmol/L; -0.32 95% CI, -.53 to -.12; P = .003) infection. Schistosoma mansoni was associated with lower total cholesterol (4.24 vs 4.64 mmol/L; -0.25 95% CI, -.44 to -.07; P = .01) and moderate to heavy S. mansoni infection with lower triglycerides, LDL-c, and diastolic blood pressure.
Helminth infections improve lipid profiles and may lower blood pressure. Studies to confirm causality and investigate mechanisms may contribute to understanding the epidemiological transition and suggest new approaches to prevent cardiometabolic disease.
ISRCTN47196031.
Vaccination has potential to eliminate infectious diseases. However, parasitic infections such as helminths may hinder vaccines from providing optimal protection. We reviewed existing literature on ...the effects of helminth infections and their treatment on vaccine responses in humans and animals. We searched literature until 31 January 2022 in Medline, EMBASE, Global health, Scopus, and Web of science; search terms included WHO licensed vaccines and human helminth types. Standardized mean differences (SMD) in vaccine responses between helminth infected and uninfected or anthelminthic treated and untreated individuals were obtained from each study with suitable data for meta‐analysis, and combined using a random effects model. Analysis was stratified by whether helminth exposure was direct or prenatal and by vaccine type. This study is registered with PROSPERO (CRD42019123074). Of the 4402 articles identified, 37 were included in the review of human studies and 24 for animal experiments. For human studies, regardless of vaccine type, overall SMD for helminth uninfected/treated, compared to infected/untreated, was 0.56 (95% CI 0.04–1.07 and I2 = 93.5%) for direct helminth exposure and 0.01 (95% CI −0.04 to 0.07 and I2 = 85.9%) for prenatal helminth exposure. Effects of anthelminthic treatment were inconsistent, with no overall benefit shown. Results differed by vaccine type, with responses to live vaccines most affected by helminth exposure. For animal studies, the most affected vaccine was BCG. This result indicates that helminth‐associated impairment of vaccine responses is more severe for direct, than for prenatal, helminth exposure. Further research is needed to ascertain whether deworming of individuals before vaccination may help improve responses.
Graphical Abstract
Reactivity to crude allergen extracts and classical CCD epitope (core β-1,2-xylose, α-1,3-fucose)-modified N-glycans is positively associated with the rural,
Schistosoma ...mansoni-endemic
environment. However, a higher proportion of urban, compared to rural participants, recognise recombinant established major allergenic components. There are inverse associations between reactivity to a subset of core α-1,3-fucosesubstituted N-glycans and asthma, but not for CCD-specific IgE in general.
Summary
Background
Serum inhibition of allergen‐specific IgE has been associated with competing IgG4 and non‐specific polyclonal IgE. In allergen immunotherapy, beneficial responses have been ...associated with high IgG4/IgE ratios. Helminths potentiate antibody class switching to IgG4 and stimulate polyclonal IgE synthesis; therefore, we hypothesized a role for helminth‐associated IgG4 and total IgE in protection against atopic sensitization and clinical allergy (asthma) in tropical low‐income countries.
Methods
Among community residents of Ugandan rural Schistosoma mansoni (Sm)–endemic islands and a mainland urban setting with lower helminth exposure, and among urban asthmatic schoolchildren and non‐asthmatic controls, we measured total, Schistosoma adult worm antigen (SWA)–specific, Schistosoma egg antigen (SEA)–specific and allergen (house dust mite HDM and German cockroach)–specific IgE and IgG4 by ImmunoCAP® and/or ELISA. We assessed associations between these antibody profiles and current Sm infection, the rural‐urban environment, HDM and cockroach skin prick test (SPT) reactivity, and asthma.
Results
Total IgE, total IgG4 and SWA‐, SEA‐ and allergen‐specific IgE and IgG4 levels were significantly higher in the rural, compared to the urban setting. In both community settings, both Sm infection and SPT reactivity were positively associated with allergen‐specific and total IgE responses. SPT reactivity was inversely associated with Schistosoma‐specific IgG4, allergen‐specific IgG4/IgE ratios and total IgE/allergen‐specific IgE ratios. Asthmatic schoolchildren, compared with non‐asthmatic controls, had significantly higher levels of total and allergen‐specific IgE, but lower ratios of allergen‐specific IgG4/IgE and total IgE/allergen‐specific IgE.
Conclusions and clinical relevance
Our immuno‐epidemiological data support the hypothesis that the IgG4–IgE balance and the total IgE–allergen‐specific IgE balance are more important than absolute total, helminth‐ or allergen‐specific antibody levels in inhibition of allergies in the tropics.
The scar prevalence at recruitment to our trial aligns with our data on scarring with this strain in this cohort.6 It has been shown that neonatal BCG vaccine efficacy wanes between ages 10 and 15 ...years.7 The median age of our adolescent participants at recruitment to the randomised phase 2a trial was 15 years (IQR 14–16),2 which is the optimal age to administer and to test the immunogenicity and efficacy of tuberculosis vaccine regimens designed to boost neonatal BCG vaccine responses. ...most of the participants who converted their ESAT-6/CFP-10 ELISpot response reverted by their next clinic visit. Only four participants remained IGRA positive throughout the study.2 None of our participants who converted developed signs or symptoms of active tuberculosis.2 Given that false positive conversions with IGRAs have been observed among 563 health-care workers undergoing occupational tuberculosis screening at four health-care institutions in the USA and a low tuberculosis incidence area with an average tuberculosis case rate that ranged from 4 to 9 per 100 000 persons,8 it is not certain that our participants acquired LTBI during the study.
Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved ...hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1–17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-γ and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-γ, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response.
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•Vaccine (BCG, tetanus)-specific immune responses differ by urban/rural setting.•Associations between helminths and vaccine-specific response also differ by setting.•Urban-rural differences are not fully explained by helminth infection prevalence.•Helminths likely work in concert with other factors to influence vaccine response.
BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A–MVA85A ...compared with BCG revaccination among Ugandan adolescents.
After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12–17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 geometric mean and days 0–224 area under the curve; AUC).
Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A–MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A–MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A–MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A–MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 95% CI 17·46–53·59, p<0·0001, day 63; AUC mean difference 57 091 95% CI 40 524–73 658, p<0·0001, days 0–224).
The ChAdOx1 85A–MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines.
UK Research and Innovations and Medical Research Council.
For the Swahili and Luganda translations of the abstract see Supplementary Materials section.
Summary
Background
It is proposed that helminth exposure protects against allergy‐related disease, by mechanisms that include disconnecting risk factors (such as atopy) from effector responses.
...Objective
We aimed to assess how helminth exposure influences rural‐urban differences in risk factors for allergy‐related outcomes in tropical low‐ and middle‐income countries.
Methods
In cross‐sectional surveys in Ugandan rural Schistosoma mansoni (Sm)‐endemic islands, and in nearby mainland urban communities with lower helminth exposure, we assessed risk factors for atopy (allergen‐specific skin prick test SPT reactivity and IgE asIgE sensitization) and clinical allergy‐related outcomes (wheeze, urticaria, rhinitis and visible flexural dermatitis), and effect modification by Sm exposure.
Results
Dermatitis and SPT reactivity were more prevalent among urban participants, urticaria and asIgE sensitization among rural participants. Pairwise associations between clinical outcomes, and between atopy and clinical outcomes, were stronger in the urban survey. In the rural survey, SPT positivity was inversely associated with bathing in lakewater, Schistosoma‐specific IgG4 and Sm infection. In the urban survey, SPT positivity was positively associated with age, non‐Ugandan maternal tribe, being born in a city/town, BCG scar and light Sm infection. Setting (rural vs urban) was an effect modifier for risk factors including Sm‐ and Schistosoma‐specific IgG4. In both surveys, the dominant risk factors for asIgE sensitization were Schistosoma‐specific antibody levels and helminth infections. Handwashing and recent malaria treatment reduced odds of asIgE sensitization among rural but not urban participants. Risk factors for clinical outcomes also differed by setting. Despite suggestive trends, we did not find sufficient evidence to conclude that helminth (Sm) exposure explained rural‐urban differences in risk factors.
Conclusions and clinical relevance
Risk factors for allergy‐related outcomes differ between rural and urban communities in Uganda but helminth exposure is unlikely to be the sole mechanism of the observed effect modification between the two settings. Other environmental exposures may contribute significantly.
Background
In high‐income, temperate countries, IgE to allergen extracts is a risk factor for, and mediator of, allergy‐related diseases (ARDs). In the tropics, positive IgE tests are also prevalent, ...but rarely associated with ARD. Instead, IgE responses to ubiquitous cross‐reactive carbohydrate determinants (CCDs) on plant, insect and parasite glycoproteins, rather than to established major allergens, are dominant. Because anti‐CCD IgE has limited clinical relevance, it may impact ARD phenotyping and assessment of contribution of atopy to ARD.
Methods
Using an allergen extract‐based test, a glycan and an allergen (glyco)protein microarray, we mapped IgE fine specificity among Ugandan rural Schistosoma mansoni (Sm)‐endemic communities, proximate urban communities, and importantly in asthmatic and nonasthmatic schoolchildren.
Results
Overall, IgE sensitization to extracts was highly prevalent (43%‐73%) but allergen arrays indicated that this was not attributable to established major allergenic components of the extracts (0%‐36%); instead, over 40% of all participants recognized CCD‐bearing components. Using glycan arrays, we dissected IgE responses to specific glycan moieties and found that reactivity to classical CCD epitopes (core β‐1,2‐xylose, α‐1,3‐fucose) was positively associated with sensitization to extracts, rural environment and Sm infection, but not with skin reactivity to extracts or sensitization to their major allergenic components. Interestingly, we discovered that reactivity to only a subset of core α‐1,3‐fucose‐carrying N‐glycans was inversely associated with asthma.
Conclusions
CCD reactivity is not just an epiphenomenon of parasite exposure hampering specificity of allergy diagnostics; mechanistic studies should investigate whether specific CCD moieties identified here are implicated in the protective effect of certain environmental exposures against asthma.
Reactivity to crude allergen extracts and classical CCD epitope (core β‐1,2‐xylose, α‐1,3‐fucose)‐modified N‐glycans is positively associated with the rural, Schistosoma mansoni‐endemic environment. However, a higher proportion of urban, compared to rural participants, recognise recombinant established major allergenic components. There are inverse associations between reactivity to a subset of core α‐1,3‐fucose‐substituted N‐glycans and asthma, but not for CCD‐specific IgE in general. Abbreviation: CCD, cross‐reactive carbohydrate determinant.
Abstract
Background
The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, ...community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity.
Methods
In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly.
Results
The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio RR 1.11, 95% confidence interval CI 0.64–1.93), SPT (RR 1.10, 95% CI 0.85–1.42), or asIgE (RR 0.96, 95% CI 0.82–1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55–0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31–1.00). There were no differences in anemia or hepatospenomegaly between trial arms.
Conclusions
Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions.
Clinical Trials Registration
ISRCTN47196031.
In a cluster-randomized trial of intensive versus standard anthelminthic treatment, intensive treatment reduced Schistosoma mansoni intensity and hookworm prevalence, but did not effect atopy, allergy-related diseases, or helminth-related pathology. Additional interventions are required to reduce transmission in schistosomiasis hot spots.
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