The hybrid protein BTH2 suppresses allergic airway inflammation in a murine model of HDM-specific immunotherapy.

BACKGROUND: Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment approach to change disease-causing allergens. Hypoallergenic derivatives show promise as potential therapeutics, amongst which BTH2 was designed to induce tolerance against Blomia tropicalis allergy. Our aim was to investigate the hypoallergenicity and immunoregulatory activity of BTH2 in vitro and its therapeutic potential in a mouse model of AIT. METHODS: Recombinant Blo t 5 and Blo t 21 allergens and their hybrid derivatives (BTH1 and BTH2) were expressed and purified. IgE binding capacity was tested by ELISA using sera from Brazilian, Colombian, and Ecuadorian subjects. Secretion of cytokines in supernatants from human cell cultures was measured following stimulation with the four recombinants and controls. The capacity of BTH2 to ameliorate allergic airway inflammation induced by B. tropicalis extract was evaluated in a murine model of AIT. RESULTS: rBlo t 5 and rBlo t 21 were identified as major allergens in Latin American patients, and BTH2 had the lowest IgE binding. In vitro stimulation of human cells induced greater levels of IL-10 and IFN-γ and reduced the secretion of Th2 cytokines. BTH2 ameliorated allergic airway inflammation in B. tropicalis-challenged A/J mice, as evidenced by the histopathological and humoral biomarkers: decreased Th2 cytokines and cellular infiltration (especially eosinophils), lower activity of eosinophil peroxidase, an increase in IgG blocking antibodies and strong reduction of mucus production by goblet cells. CONCLUSIONS: Our study shows that BTH2 represents a promising candidate for the treatment of B. tropicalis allergy with hypoallergenic, immune regulatory and therapeutic properties. Further pre-clinical studies are required in murine models of chronic asthma to further address the efficacy and safety of BTH2 as a vaccine against B. tropicalis-induced allergy.

Helminth infections and allergic diseases: Systematic review and meta-analysis of the global literature.

BACKGROUND: There is considerable research interest in the role of helminth infections in the development of allergic diseases. However, findings from previous studies are mixed. Existing systematic reviews of these studies are outdated. We performed a systematic review of the global literature on the association between helminth infections and development and clinical outcomes of allergic diseases. METHODS: We searched Cochrane Library, MEDLINE, EMBASE, ISI Web of Science, PubMed, Global Index Medicus, Scielo, KoreaMed, Google Scholar, and Lilacs for studies published up to January 2020. We included observational epidemiological studies (cohort, case-control, and cross-sectional studies) of children and adults reporting associations between helminth infections and asthma, allergic rhinitis, eczema, and atopy. We performed random-effects meta-analysis to summarize the effect estimates. RESULTS: We included 80 studies with 99,967 participants. In the meta-analyses, we did not observe an overall association between helminth infections and allergic diseases. There was, however, evidence that Ascaris lumbricoides infections were associated with an increased risk of bronchial hyperreactivity in children (risk ratio, 1.41; 95% CI, 1.17-1.70; I2 = 50; P for I2 = .09), and were associated with an increased risk of atopy among helminth-infected adults (risk ratio, 1.37; 95% CI, 1.18-1.61; I2 = 52; P for I2 = .02). We found no study that addressed the association between helminth infection and clinical outcomes of allergic diseases. The overall strength of the underlying evidence was low to moderate. CONCLUSIONS: Helminth infections may increase the risk of bronchial hyperreactivity in children and atopy in adults. Well-designed longitudinal cohorts may help clarify potential causal associations between chronic helminth infections and allergic diseases.

Zoonotic Ancylostoma ceylanicum Hookworm Infections, Ecuador.

Ancylostoma ceylanicum hookworms are zoonotic parasites that can infect humans. To detect autochthonous transmission, we analyzed human fecal samples collected in 2000. Multiparallel quantitative PCR detected infection in persons who had never traveled outside Ecuador. These data indicate human transmission of A. ceylanicum in the Americas, although endemicity remains unknown.

α-Gal specific-IgE prevalence and levels in Ecuador and Kenya: Relation to diet, parasites, and IgG4.

BACKGROUND: IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated. OBJECTIVE: We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya. METHODS: IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG4 to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children. RESULTS: In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG4 were not high in Ecuador, but were greater than in children from the United States. CONCLUSIONS: These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.

Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years.

BACKGROUND: Early-life exposures to geohelminths may protect against development of wheeze/asthma and atopy. OBJECTIVE: To study the effect of maternal geohelminths and infections in children during the first 5 years on atopy, wheeze/asthma and airways reactivity/inflammation at 8 years. METHODS: Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. RESULTS: 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children. CONCLUSIONS: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).

Urbanisation and asthma in low-income and middle-income countries: a systematic review of the urban-rural differences in asthma prevalence.

BACKGROUND: Urbanisation has been associated with temporal and geographical differences in asthma prevalence in low-income and middle-income countries (LMICs). However, little is known of the mechanisms by which urbanisation and asthma are associated, perhaps explained by the methodological approaches used to assess the urbanisation-asthma relationship. OBJECTIVE: This review evaluated how epidemiological studies have assessed the relationship between asthma and urbanisation in LMICs, and explored urban/rural differences in asthma prevalence. METHODS: Asthma studies comparing urban/rural areas, comparing cities and examining intraurban variation were assessed for eligibility. Included publications were evaluated for methodological quality and pooled OR were calculated to indicate the risk of asthma in urban over rural areas. RESULTS: Seventy articles were included in our analysis. Sixty-three compared asthma prevalence between urban and rural areas, five compared asthma prevalence between cities and two examined intraurban variation in asthma prevalence. Urban residence was associated with a higher prevalence of asthma, regardless of asthma definition: current-wheeze OR:1.46 (95% CI:1.22 to 1.74), doctor diagnosis OR:1.89 (95% CI:1.47 to 2.41), wheeze-ever OR:1.44 (95% CI:1.15 to 1.81), self-reported asthma OR:1.77 (95% CI:1.33 to 2.35), asthma questionnaire OR:1.52 (95% CI:1.06 to 2.16) and exercise challenge OR:1.96 (95% CI:1.32 to 2.91). CONCLUSIONS: Most evidence for the relationship between urbanisation and asthma in LMICs comes from studies comparing urban and rural areas. These studies tend to show a greater prevalence of asthma in urban compared to rural populations. However, these studies have been unable to identify which specific characteristics of the urbanisation process may be responsible. An approach to understand how different dimensions of urbanisation, using contextual household and individual indicators, is needed for a better understanding of how urbanisation affects asthma. PROSPERO REGISTRATION NUMBER: CRD42017064470.

Predictors of severe asthma attack re-attendance in Ecuadorian children: a cohort study.

Asthma is a common cause of emergency care attendance in low- and middle-income countries (LMICs). While few prospective studies of predictors for emergency care attendance have been undertaken in high-income countries, none have been performed in a LMIC.We followed a cohort of 5-15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months' follow-up.We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79-0.96 per year), previous asthma diagnosis (2.2, 1.2-3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1-1.5), food triggers (2.0, 1.1-3.6) and eczema diagnosis (4.2, 1.02-17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50-0.95). Laboratory and lung function tests did not predict recurrence.Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused.

Soil-transmitted helminth parasites and allergy: Observations from Ecuador.

There is considerable interest as to potential protective effects of soil-transmitted helminths (STH) against allergy and allergic diseases. Here, we discuss findings of studies done of the effects of STH parasites on atopy and allergic diseases in Ecuador. While cross-sectional studies have consistently shown a reduced prevalence of allergen skin prick test (SPT) reactivity among infected schoolchildren, the removal of these infections by repeated deworming did not affect SPT prevalence over the short-term (ie, 12 months) but may have increased SPT prevalence over the long-term (ie, 15-17 years). In the case of allergic symptoms, cross-sectional studies have generally not shown associations with STH and intervention studies showed no impact on prevalence. However, a birth cohort suggested that early STH infections might reduce wheeze by 5 years. Allergic sensitization to Ascaris, however, explained a significant proportion of wheezing among rural schoolchildren. Studies of the effects of STH on immune and inflammatory responses indicated a potential role of STH in contributing to more robust regulation. The effects of STH on allergy are likely to be determined by history of exposure over the life-course and by interactions with a wide variety of other infectious and non-infectious factors.

Parasites and allergy: Observations from Brazil.

Brazil is a middle-income country undergoing the epidemiological transition. Effects of changes in daily life habits and access to clean water, sanitation and urban services on a growing urban population have contributed to a double burden of both infectious and noncommunicable chronic diseases. Studies have indicated that parasite infections may modulate the human immune system and influence the development of allergic conditions such as asthma. However, there is no consensus in the published literature on the effects of parasitic infections on allergy, perhaps as a consequence of factors determining the epidemiology of these infections that vary between populations such as age of first infection, duration and chronicity of infections, parasite burden and species, and host genetic susceptibility. In this review, we discuss the observations from Brazil concerning the relationship between parasite infections and allergy.

Effect of Early-Life Geohelminth Infections on the Development of Wheezing at 5 Years of Age.

RATIONALE: Exposures to geohelminths during gestation or early childhood may reduce risk of wheezing illness/asthma and atopy during childhood in tropical regions. OBJECTIVES: To investigate the effect of maternal and early childhood geohelminths on development of wheeze/asthma and atopy during the first 5 years of life. METHODS: A cohort of 2,404 neonates was followed to 5 years of age in a rural district in coastal Ecuador. Data on wheeze were collected by questionnaire and atopy was measured by allergen skin prick test reactivity to 10 allergens at 5 years. Stool samples from mothers and children were examined for geohelminths by microscopy. MEASUREMENTS AND MAIN RESULTS: A total of 2,090 (86.9%) children were evaluated at 5 years. Geohelminths were observed in 45.5% of mothers and in 34.1% of children by 3 years. Wheeze and asthma were reported for 12.6% and 5.7% of children, respectively, whereas 14.0% had skin test reactivity at 5 years. Maternal geohelminths were associated with an increased risk of wheeze (adjusted odds ratio, 1.41; 95% confidence interval, 1.06-1.88), whereas childhood geohelminths over the first 3 years of life were associated with reduced risk of wheeze (adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.96) and asthma (adjusted odds ratio, 0.60; 95% confidence interval, 0.38-0.94) but not skin prick test reactivity. The effects on wheeze/asthma were greatest with later age of first infection, were observed only in skin test-negative children, but were not associated with parasite burden or specific geohelminths. CONCLUSIONS: Although maternal exposures to geohelminths may increase childhood wheeze, childhood geohelminths during the first 3 years may provide protection through a nonallergic mechanism. Registered as an observational study (ISRCTN41239086).

Abnormal sensory eye dominance in stereoanomalous subjects.

Stereoanomalous (SA) subjects have normal visual acuity but reduced stereopsis and may have a prevalence of up to 30%. It has been suggested that, in SA subjects, an imbalance in interocular inhibition might underlie an asymmetry in sensory eye dominance (SED). Our study expands upon previous findings by examining binocular rivalry (BR) mean dominance durations, dichoptic masking (DM) thresholds and SED for a group of SA subjects compared to naïve controls. We examined BR dominance durations and DM thresholds for 15 stereonormal (SN) subjects and 10 SA subjects with normal or corrected-to-normal visual acuity. All subjects had visual acuity of 20/40 or better and less than or equal to two lines difference between eyes. Individuals who scored ≥6/9 on the Randot stereo test and <100 arcmin on the PacMan Stereo Acuity test were considered SN. We compared near-vertical and near-horizontal oriented sine-wave gratings for BR and DM in order to dissociate stereo-related mechanisms that rely on horizontal disparities from other eye-based integration mechanisms. Mean randot scores for SN subjects were 8.5/9 with a PacMan stereoacuity of 33 arcmin, and SA subjects scored 2.5/9 and 3,380 arcmin, respectively. The mean difference in SED was 0.19 for SN and 0.48 for SA when measured with a neutral density filter bar. The SA group showed a large interocular difference in BR durations that was significantly greater than normal (p = 0.004) and correlated with loss of stereoacuity. Moreover, the interocular difference for DM was similarly greater for SA subjects (p = 0.04) although a proportional difference in monocular sensitivity could partially account for this. We also found that both SN and SA subjects presented higher DM thresholds and, to some extent, sensitivity for vertical than horizontal orientations. SA subjects show an abnormal bias toward their dominant eye for both BR and DM. These data suggest that common mechanisms of monocular sensitivity and interocular inhibition may limit multiple binocular measures and provides a practical link to better understand the heterogeneity of stereopsis in amblyopia.

Associations between infant fungal and bacterial dysbiosis and childhood atopic wheeze in a nonindustrialized setting.

BACKGROUND: Asthma is the most prevalent chronic disease of childhood. Recently, we identified a critical window early in the life of both mice and Canadian infants during which gut microbial changes (dysbiosis) affect asthma development. Given geographic differences in human gut microbiota worldwide, we studied the effects of gut microbial dysbiosis on atopic wheeze in a population living in a distinct developing world environment. OBJECTIVE: We sought to determine whether microbial alterations in early infancy are associated with the development of atopic wheeze in a nonindustrialized setting. METHODS: We conducted a case-control study nested within a birth cohort from rural Ecuador in which we identified 27 children with atopic wheeze and 70 healthy control subjects at 5 years of age. We analyzed bacterial and eukaryotic gut microbiota in stool samples collected at 3 months of age using 16S and 18S sequencing. Bacterial metagenomes were predicted from 16S rRNA data by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and categorized by function with Kyoto Encyclopedia of Genes and Genomes ontology. Concentrations of fecal short-chain fatty acids were determined by using gas chromatography. RESULTS: As previously observed in Canadian infants, microbial dysbiosis at 3 months of age was associated with later development of atopic wheeze. However, the dysbiosis in Ecuadorian babies involved different bacterial taxa, was more pronounced, and also involved several fungal taxa. Predicted metagenomic analysis emphasized significant dysbiosis-associated differences in genes involved in carbohydrate and taurine metabolism. Levels of the fecal short-chain fatty acids acetate and caproate were reduced and increased, respectively, in the 3-month stool samples of children who went on to have atopic wheeze. CONCLUSIONS: Our findings support the importance of fungal and bacterial microbiota during the first 100 days of life on the development of atopic wheeze and provide additional support for considering modulation of the gut microbiome as a primary asthma prevention strategy.

Sporulation capability and amylosome conservation among diverse human colonic and rumen isolates of the keystone starch-degrader Ruminococcus bromii.

Ruminococcus bromii is a dominant member of the human colonic microbiota that plays a 'keystone' role in degrading dietary resistant starch. Recent evidence from one strain has uncovered a unique cell surface 'amylosome' complex that organizes starch-degrading enzymes. New genome analysis presented here reveals further features of this complex and shows remarkable conservation of amylosome components between human colonic strains from three different continents and a R. bromii strain from the rumen of Australian cattle. These R. bromii strains encode a narrow spectrum of carbohydrate active enzymes (CAZymes) that reflect extreme specialization in starch utilization. Starch hydrolysis products are taken up mainly as oligosaccharides, with only one strain able to grow on glucose. The human strains, but not the rumen strain, also possess transporters that allow growth on galactose and fructose. R. bromii strains possess a full complement of sporulation and spore germination genes and we demonstrate the ability to form spores that survive exposure to air. Spore formation is likely to be a critical factor in the ecology of this nutritionally highly specialized bacterium, which was previously regarded as 'non-sporing', helping to explain its widespread occurrence in the gut microbiota through the ability to transmit between hosts.

Global issues in allergy and immunology: Parasitic infections and allergy.

Allergic diseases are on the increase globally in parallel with a decrease in parasitic infection. The inverse association between parasitic infections and allergy at an ecological level suggests a causal association. Studies in human subjects have generated a large knowledge base on the complexity of the interrelationship between parasitic infection and allergy. There is evidence for causal links, but the data from animal models are the most compelling: despite the strong type 2 immune responses they induce, helminth infections can suppress allergy through regulatory pathways. Conversely, many helminths can cause allergic-type inflammation, including symptoms of "classical" allergic disease. From an evolutionary perspective, subjects with an effective immune response against helminths can be more susceptible to allergy. This narrative review aims to inform readers of the most relevant up-to-date evidence on the relationship between parasites and allergy. Experiments in animal models have demonstrated the potential benefits of helminth infection or administration of helminth-derived molecules on chronic inflammatory diseases, but thus far, clinical trials in human subjects have not demonstrated unequivocal clinical benefits. Nevertheless, there is sufficiently strong evidence to support continued investigation of the potential benefits of helminth-derived therapies for the prevention or treatment of allergic and other inflammatory diseases.

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.

All-printed diode operating at 1.6 GHz.

Printed electronics are considered for wireless electronic tags and sensors within the future Internet-of-things (IoT) concept. As a consequence of the low charge carrier mobility of present printable organic and inorganic semiconductors, the operational frequency of printed rectifiers is not high enough to enable direct communication and powering between mobile phones and printed e-tags. Here, we report an all-printed diode operating up to 1.6 GHz. The device, based on two stacked layers of Si and NbSi2 particles, is manufactured on a flexible substrate at low temperature and in ambient atmosphere. The high charge carrier mobility of the Si microparticles allows device operation to occur in the charge injection-limited regime. The asymmetry of the oxide layers in the resulting device stack leads to rectification of tunneling current. Printed diodes were combined with antennas and electrochromic displays to form an all-printed e-tag. The harvested signal from a Global System for Mobile Communications mobile phone was used to update the display. Our findings demonstrate a new communication pathway for printed electronics within IoT applications.

Effects of maternal geohelminth infections on allergy in early childhood.

BACKGROUND: Maternal geohelminth infections during pregnancy may protect against allergy development in childhood. OBJECTIVE: We sought to investigate the effect of maternal geohelminths on the development of eczema, wheeze, and atopy during the first 3 years of life. METHODS: A cohort of 2404 neonates was followed to 3 years of age in a rural district in coastal Ecuador. Data on wheeze and eczema were collected by means of questionnaire and physical examination at 13, 24, and 36 months of age. Atopy was measured based on skin prick test (SPT) reactivity to 9 allergens at 36 months. Maternal stool samples were examined for geohelminths by microscopy. Data on potential confounders was collected after birth by questionnaire. RESULTS: Geohelminths were observed in 45.9% of mothers. Eczema and wheeze were reported for 17.7% and 25.9%, respectively, of 2069 (86.1%) children with complete follow-up to 3 years, and allergen SPT reactivity to any allergen was present in 17.2% and to house dust mite in 8.7%. Maternal geohelminth infections were not significantly associated with eczema (adjusted odds ratio [OR], 1.26; 95% CI, 0.98-1.61), wheeze (adjusted OR, 1.02; 95% CI, 0.82-1.27), and SPT reactivity to any allergen (adjusted OR, 0.79; 95% CI, 0.61-1.01). In subgroup analyses maternal geohelminths were associated with a significantly reduced risk of SPT reactivity to mite and other perennial allergens, and maternal ascariasis was associated with an increased risk of eczema and reduced risk of SPT reactivity to all allergens. CONCLUSION: Our data do not support a protective effect of maternal infections with geohelminth parasites during pregnancy against the development of eczema and wheeze in early childhood, although there was evidence in subgroup analyses for a reduction in SPT reactivity to house dust mites and perennial allergens.

Maternal Helminth Infection Is Associated With Higher Infant Immunoglobulin A Titers to Antigen in Orally Administered Vaccines.

BACKGROUND: Many studies have documented lower vaccine efficacy among children in low-income countries, compared with their counterparts in high-income countries. This disparity is especially apparent with respect to oral vaccines such as rotavirus and oral polio vaccines. One potential contributing factor is the presence of maternal antenatal helminth infections, which can modulate the infant's developing immune system. METHODS: Using a multiplex immunoassay, we tested plasma immunoglobulin A (IgA) or immunoglobulin G (IgG) levels specific for antigens in 9 routinely administered childhood vaccines among 1639 children aged approximately 13 months enrolled in the ECUAVIDA (Ecuador Life) birth cohort study in Ecuador. We compared vaccine responses in 712 children of mothers who tested positive for helminth infections in the last trimester of pregnancy to responses in 927 children of mothers without helminth infection. RESULTS: Plasma IgA levels specific for antigens in rotavirus vaccine and oral polio vaccine containing poliovirus serotypes 1 and 3 were all significantly higher in children of helminth-infected mothers, compared with children of uninfected mothers. Plasma IgG levels specific for diphtheria, tetanus, pertussis, measles, rubella, and Haemophilus influenzae type b vaccine antigens were comparable between the 2 groups. CONCLUSIONS: Antenatal maternal helminth infections were not associated with reduced antibody responses to infant vaccines, but rather with modestly increased IgA responses to oral vaccines.

Applied immuno-epidemiological research: an approach for integrating existing knowledge into the statistical analysis of multiple immune markers.

BACKGROUND: Immunologists often measure several correlated immunological markers, such as concentrations of different cytokines produced by different immune cells and/or measured under different conditions, to draw insights from complex immunological mechanisms. Although there have been recent methodological efforts to improve the statistical analysis of immunological data, a framework is still needed for the simultaneous analysis of multiple, often correlated, immune markers. This framework would allow the immunologists' hypotheses about the underlying biological mechanisms to be integrated. RESULTS: We present an analytical approach for statistical analysis of correlated immune markers, such as those commonly collected in modern immuno-epidemiological studies. We demonstrate i) how to deal with interdependencies among multiple measurements of the same immune marker, ii) how to analyse association patterns among different markers, iii) how to aggregate different measures and/or markers to immunological summary scores, iv) how to model the inter-relationships among these scores, and v) how to use these scores in epidemiological association analyses. We illustrate the application of our approach to multiple cytokine measurements from 818 children enrolled in a large immuno-epidemiological study (SCAALA Salvador), which aimed to quantify the major immunological mechanisms underlying atopic diseases or asthma. We demonstrate how to aggregate systematically the information captured in multiple cytokine measurements to immunological summary scores aimed at reflecting the presumed underlying immunological mechanisms (Th1/Th2 balance and immune regulatory network). We show how these aggregated immune scores can be used as predictors in regression models with outcomes of immunological studies (e.g. specific IgE) and compare the results to those obtained by a traditional multivariate regression approach. CONCLUSION: The proposed analytical approach may be especially useful to quantify complex immune responses in immuno-epidemiological studies, where investigators examine the relationship among epidemiological patterns, immune response, and disease outcomes.

Single-cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents.

Innate immunity instructs adaptive immunity, and suppression of innate immunity is associated with an increased risk for infection. We showed previously that whole-blood cellular components from a cohort of South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors compared with whole blood from cohorts of Ecuadorian, Belgian, or Canadian children. To begin dissecting the responsible molecular mechanisms, we set out to identify the relevant cellular source of these differences. Across the four cohorts represented in our study, we identified significant variation in the cellular composition of whole blood; however, a significant reduction in the intracellular cytokine production on the single-cell level was only detected in South African children's monocytes, conventional dendritic cells, and plasmacytoid dendritic cells. We also uncovered a marked reduction in polyfunctionality for each of these cellular compartments in South African children compared with children from the other continents. Together, our data identify differences in cell composition, as well as profoundly lower functional responses of innate cells, in our cohort of South African children. A possible link between altered innate immunity and increased risk for infection or lower response to vaccines in South African infants needs to be explored.