Impact of early life exposures to geohelminth infections on the development of vaccine immunity, allergic sensitization, and allergic inflammatory diseases in children living in tropical Ecuador: the ECUAVIDA birth cohort study

Abstract

Background: Geohelminth infections are highly prevalent infectious diseases of childhood in many regions of the Tropics, and are associated with significant morbidity especially among pre-school and school-age children. There is growing concern that geohelminth infections, particularly exposures occurring during early life in utero through maternal infections or during infancy, may affect vaccine immunogenicity in populations among whom these infections are endemic. Further, the low prevalence of allergic disease in the rural Tropics has been attributed to the immune modulatory effects of these infections and there is concern that widespread use of anthelmintic treatment in high-risk groups may be associated with an increase in the prevalence of allergic diseases. Because the most widely used vaccines are administered during the first year of life and the antecedents of allergic disease are considered to occur in early childhood, the present study has been designed to investigate the impact of early exposures to geohelminths on the development of protective immunity to vaccines, allergic sensitization, and allergic disease.

Methods/design: A cohort of 2,403 neonates followed up to 8 years of age. Primary exposures are infections with geohelminth parasites during the last trimester of pregnancy and the first 2 years of life. Primary study outcomes are the development of protective immunity to common childhood vaccines (i.e. rotavirus, Haemophilus influenzae type B, Hepatitis B, tetanus toxoid, and oral poliovirus type 3) during the first 5 years of life, the development of eczema by 3 years of age, the development of allergen skin test reactivity at 5 years of age, and the development of asthma at 5 and 8 years of age. Potential immunological mechanisms by which geohelminth infections may affect the study outcomes will be investigated also.

Discussion: The study will provide information on the potential effects of early exposures to geohelminths (during pregnancy and the first 2 years of life) on the development of vaccine immunity and allergy. The data will inform an ongoing debate of potential effects of geohelminths on child health and will contribute to policy decisions on new interventions designed to improve vaccine immunogenicity and protect against the development of allergic diseases.

Trial registration: Current Controlled Trials ISRCTN41239086.

Figure 1

Study site. A. Map of Ecuador showing location of District of Quinindé, Esmeraldas Province (black oval) (Courtesy of The General Libraries, The University of Texas at Austin). The recruitment area for the cohort was defined by the geographic boundaries of this district. B. Map showing parishes the District of Quinindé including La Concordia. H-Hospital Padre Alberto Buffoni. C. Geographic location of households of cohort infants.

Figure 2

Conceptual model for effects of maternal and infant geohelminth infections on vaccine immune responses measured at 7 months, 2 years or 5 years. Maternal infections would be expected to mediate effects on vaccine responses at 7 months and 2 years, although infant infections, generally acquired during the second year of life, may contribute to effects at 2 years. The suppressive effects of infant infections would be expected to be most important at 5 years. Potential immunological mechanisms that may mediate the suppressive effects of geohelminth exposures are shown in dashed boxes.

Figure 3

Conceptual model of effects of maternal and infant geohelminth infections on allergen skin test reactivity. The effects of both exposures are presumed to occur via the development of a modified Th2 (mTh2) response during chronic geohelminth infection. A modified Th2 response may affect allergen skin test reactivity through 2 distinct mechanisms: 1) a direct effect on mast cell function independent of aeroallergen-specific IgE resulting in an increased threshold for activation through enhanced production of spontaneous or geohelminth-induced IL-10. Such effects would be predicted to effect wheal sizes non-specifically including the histamine positive control. 2) An indirect effect on mast cell function by attenuation of the association between specific IgE and skin test reactivity. This effect would be predicted to be aeroallergen-specific, affect only those wheals for which an individual has significant levels of specific IgE (at > 0.35 kU/L) but not the positive control, and be mediated by aeroallergen-induced IL-10. The effect could also be mediated by geohelminth-induced IL-10 for aeroallergens where the IL-10-stimulating allergens share significant immunological cross-reactivity with helminth allergens.

Figure 4

Conceptual model for the effects of maternal and infant geohelminth infections on asthma in children. The effects of these exposures on asthma are considered to occur via effects on bronchial hyperreactivity. The protective effects of chronic helminth exposures (maternal and infant infections within the first 2 years of life) are presumed to occur via the development of a modified Th2 (mTh2) response that may affect bronchial hyperreactivity through: 1) Immune regulation/suppression-suppression of airways inflammation via enhanced production of geohelminth or aeroallergen-induced IL-10. 2) Homeostasis-enhanced production of spontaneous IL-10 will suppress airways inflammation non-specifically. Alternatively children without early geohelminth exposures and that are first exposed to infection after 2 years of age (> 24 m) may respond to A. lumbricoides infection with strong inflammatory responses in the airways that up-regulate pro-inflammatory pathways including Th1, Th2, and Th17. The modified Th2 response will be defined by the presence of specific IgG4 antibodies to geohelminths. RTIs- respiratory tract infections. ETS-environmental tobacco smoke.

Figure 5

Conceptual model for the effects of maternal geohelminth infections on eczema. Effects of maternal geohelminth exposures on eczema are considered to occur through the capacity of the immune system to regulate inflammation of the skin caused by external insults. Factors that may determine the ability of the immune system to do this include: 1) Immune maturation-the speed of maturation of the immune response in early life is likely to effect the ability of the immune response to respond to infections and other insults with appropriate but measured inflammatory responses. 2). Immune regulation/suppression-the development of robust and specific immune regulatory mechanisms are important for the development of an appropriate inflammatory response to specific insults. 3) Immune homeostasis-robust mechanisms to limit responses to pro-inflammatory stimuli may be an importance mechanism for the control of inflammation.