Vitamin A and zinc supplementation have contrasting or inconsistent effects on diarrheal disease morbidity. These two micronutrients also have contrasting effects on the T helper type 1 (Th1) and type 2 (Th2) responses: vitamin A supplementation up-regulates a Th2 response while zinc supplementation upregulates a Th1 response. This differential impact may be responsible for the contrasting efficacies of vitamin A and zinc since a protective immune response against specific diarrheal disease pathogens can involve distinct combinations of the Th1-Th2 response. The goal of our proposal is to characterize the differential impact of vitamin A and zinc on health outcomes associated with specific pathogen infections and determine if the regulation of the Th1-Th2 response is the biological mechanism mediating this impact. This study is a double blind, randomized, placebo-controlled trial in which children between the ages of 6-15 months are assigned to one of four groups: a group receiving 200,000 IU of retinol every two months (100,000 IU for children aged less than one year), a group receiving a daily doses 20 mg of zinc methionin, a group receiving a combined vitamin A-zinc supplement and a placebo group. The 788 children enrolled in the study are being followed for up to 15 months with project personnel visiting household twice a week to monitor morbidity episodes in the child. Stool samples, collected once a month and following a diarrheal disease episode, are being screened for the presence of enteric pathogens. Basal and final blood samples are being collected to determine levels of retinol and zinc and the production of Th1 and Th2 cytokines by T lymphocytes. The evaluation of the impact of the vitamin A and zinc supplements on infections by diarrheal disease pathogens will be carried out through the use of multi-state, competing risks hazards models. The same analytical method will be used to validate each of the Th1-Th2 cytokines for use in predicting the impact of supplementation on infections. A meta-analysis of the pooled effect of vitamin A and zinc on growth will also be carried out to confirm the findings from the community micronutrient trial regarding the efficacy of supplementation in improving growth. Information generated from this research project will significantly enhance the current understanding of the role of the Th1-Th2 response in mediating the differential impact of vitamin A and zinc on health outcomes. In the Iong term, this work will allow the development of new micronutrient supplementation strategies that more effectively reduce childhood mortality and morbidity in developing countries. These studies will provide the necessary training in epidemiology and immunology that will further prepare the applicant for a career as an independent investigator in the biomedical sciences.
