Early life predictors of antibody response to vaccination in Bangladeshi children
Lead Research Organisation:
Medical Research Council
Department Name: Medical Research Council
Abstract
It is now established that factors in early life (such as prenatal nutrition and post-natal feeding practices) can influence long-term health. For example, evidence exists to suggest that small size at birth can increase an individual?s later susceptibility to chronic degenerative diseases such as heart disease and diabetes. Evidence is also emerging to suggest that immune function may also be ?programmed? early in life, increasing risk of morbidity and mortality from infectious diseases. As a research group we are currently investigating the early life predictors of immune function in population groups considered to be at greatest risk from the combined effects of high rates of low birth weight infants and high levels of exposure to infectious disease.
In rural Bangladesh, the nutritional status of much of the population is poor and this can be seen through the high prevalence of intrauterine growth retardation observed. A large-scale study of combined interventions to improve maternal and infant health (the ?MINIMat study?) is looking at both pre- and post-natal interventions to address the issues of maternal, fetal, and infant malnutrition in rural Bangladesh. Within the study design, all women are randomised to receive a combination of protein energy and micronutrient supplements during pregnancy. The main study is now complete, with a total of 3,282 infants born. These infants are now being followed up to look at the long-term consequences of prenatal nutrition interventions. The proposed study is designed as an add on to the main study to specifically explore the direct relationship between early-life nutritional status and immune function in young Bangladeshi children.
In the current study, we plan to give a typhoid and pneumococcal vaccine to a sub-group of 1000 children selected from the main cohort, and then measure response to vaccination, by measuring antibody levels in blood samples collected before and after the children received the vaccine. We also plan to measure cell mediated immunity using a delayed-type hypersensitivity skin test. We will then compare response rates in children according to their pre-natal nutritional status. If we are able find a relationship between early life nutrition and later immune function, then this will help us to understand some of the mechanisms involved in programming of disease, and further measures can then be taken to health improve birth outcomes and infant growth in Bangladesh and in other at risk population groups.
In rural Bangladesh, the nutritional status of much of the population is poor and this can be seen through the high prevalence of intrauterine growth retardation observed. A large-scale study of combined interventions to improve maternal and infant health (the ?MINIMat study?) is looking at both pre- and post-natal interventions to address the issues of maternal, fetal, and infant malnutrition in rural Bangladesh. Within the study design, all women are randomised to receive a combination of protein energy and micronutrient supplements during pregnancy. The main study is now complete, with a total of 3,282 infants born. These infants are now being followed up to look at the long-term consequences of prenatal nutrition interventions. The proposed study is designed as an add on to the main study to specifically explore the direct relationship between early-life nutritional status and immune function in young Bangladeshi children.
In the current study, we plan to give a typhoid and pneumococcal vaccine to a sub-group of 1000 children selected from the main cohort, and then measure response to vaccination, by measuring antibody levels in blood samples collected before and after the children received the vaccine. We also plan to measure cell mediated immunity using a delayed-type hypersensitivity skin test. We will then compare response rates in children according to their pre-natal nutritional status. If we are able find a relationship between early life nutrition and later immune function, then this will help us to understand some of the mechanisms involved in programming of disease, and further measures can then be taken to health improve birth outcomes and infant growth in Bangladesh and in other at risk population groups.
Technical Summary
Research in The Gambia has demonstrated a strong correlation between adult mortality from infectious disease and season of birth, suggesting an early-life programming effect on immune function. We are currently investigating the biological mechanisms underpinning this observation through a series of studies in a number of research locations. In The Gambia, a prospective birth-cohort study has demonstrated seasonal effects on both reduced thymic size (measured by ultrasonography) and function (measured by lymphocyte profiles and frequency of T-cell receptor excision circles) in infants when measured in the hungry season. In addition, we have demonstrated seasonal differences in breast milk levels of the trophic cytokine IL-7, suggesting a possible post-natal influence on thymic and immune development. Recent preliminary analysis of data from a large maternal supplementation study in Bangladesh supports these observations from The Gambia of an early-life programming effect on thymic size. In a cohort of adults from Lahore, Pakistan we have observed a relationship between small size at birth and an impaired antibody response to a polysaccharide vaccine. This deficit remains apparent even after a second booster dose of the same vaccine. Further studies with more detailed information on specific early-life exposures are required to fully understand these observations.
A major birth cohort originating from a randomised pre-natal dietary supplementation study in Bangladesh (the ?MINIMat study?) offers the opportunity to explore early-life predictors of immune function in more detail. The MINIMat study is looking at the effects of two combined pre-natal nutritional interventions among a group of approximately 3,000 undernourished women; (i) a food supplementation programme and (ii) a micronutrient supplement (three combinations of iron, folic acid and multiple micronutrients). A second intervention further randomised all subjects to receive either (i) counselling for exclusive breastfeeding or (ii) a different health message of equivalent intensity. Outcomes from this study include detailed measures of fetal growth by serial ultrasonography, birth size, infant growth and morbidity, and thymic development by ultrasonography. The proposed study will recruit 1000 infants born within the MINIMat study to test the primary hypothesis that season of birth affects later immune function, assessed by antibody response to vaccination and delayed-type hypersensitivity skin reactions. Subsidiary analyses will test for differential effects of birth weight, gestational age, pre-natal supplementation groups in addition to investigating influences of fetal growth, infant-feeding patterns, thymic growth during infancy and infant growth and morbidity.
A major birth cohort originating from a randomised pre-natal dietary supplementation study in Bangladesh (the ?MINIMat study?) offers the opportunity to explore early-life predictors of immune function in more detail. The MINIMat study is looking at the effects of two combined pre-natal nutritional interventions among a group of approximately 3,000 undernourished women; (i) a food supplementation programme and (ii) a micronutrient supplement (three combinations of iron, folic acid and multiple micronutrients). A second intervention further randomised all subjects to receive either (i) counselling for exclusive breastfeeding or (ii) a different health message of equivalent intensity. Outcomes from this study include detailed measures of fetal growth by serial ultrasonography, birth size, infant growth and morbidity, and thymic development by ultrasonography. The proposed study will recruit 1000 infants born within the MINIMat study to test the primary hypothesis that season of birth affects later immune function, assessed by antibody response to vaccination and delayed-type hypersensitivity skin reactions. Subsidiary analyses will test for differential effects of birth weight, gestational age, pre-natal supplementation groups in addition to investigating influences of fetal growth, infant-feeding patterns, thymic growth during infancy and infant growth and morbidity.