It is proposed to examine the non-specific effects of BCG vaccination through three randomised trials with possible implications for immunisation policies in developing countries. It will be examined whether revaccination with BCG reduces mortality, whether BCG vaccination at the birth of low birthweight children is associated with better BCG coverage and lower mortality, and whether vitamin A supplementation simultaneously with BCG vaccination is associated with a reduction in infant mortality. None of these measures are standard in the current immunisation programmes in developing countries; however, observational studies suggest that BCG vaccination may have non-specific beneficial effects. The impact on severe morbidity and hospitalisations, in particular from malaria, will also be examined through surveillance at the paediatric department. The possible immunological basis for non-specific effects will be examined. If these studies are successful, they may have direct implications for current immunisation policies in developing countries.
The major goal of this proposal is to examine the non-specific effects of BCG vaccination on childhood morbidity and mortality through intervention trials. Novel approaches will be used to examine the immunological basis for non-specific effects. The specific objectives are to examine in randomised intervention trials as to whether revaccination with BCG reduces childhood mortality after 19 months of age by 30%, BCG vaccination of low birthweight children reduces infant mortality by 25%, and simultaneous administration of BCG vaccination and vitamin A reduces infant mortality by 30%.
The project consists of three randomised trials of the effect of revaccination with BCG, of vaccinating low birthweight (LBW) children at birth, and of providing vitamin A supplementation simultaneously with BCG vaccination. The trials are based on following all children born in several districts of the capital in Guinea-Bissau with a total population of 70 000. Children for the study of vitamin A supplementation will be recruited at maternity and health centres in the study area, and for the study of revaccination with BCG, the children will be recruited through the demographic surveillance system, which has been in place in the study area for more than 20 years. For the study of LBW children, it will be necessary to follow all LBW children born at the main hospital in the city. Subgroups of the study cohorts will be followed intensively to assess impact on morbidity and possible adverse events. The risk of severe morbidity and hospitalisation for children enrolled in the three trials will be assessed through maintaining a registration system at the only paediatric department in the country. It will be examined specifically as to whether the quality of response to BCG vaccination and revaccination has an effect on malaria morbidity. The effect of vaccination on immunological responses will be examined through the assessment of crude immunological markers including tuberculin reaction, scar formation, thymus growth, eosinophil numbers and antibody levels. The multiplexed particle-based flow cytometric assay will be optimised for use with small amounts of blood to allow the assessment of cytokine profiles after vaccination on large numbers of children. The project involves the collaboration of epidemiological centres and laboratories with a long experience and strong track record in field studies, vaccine trials and basic immunological research in Africa. Research training will be an integral part of the project.
The project will produce definitive results on the impact of BCG vaccination and possible modifications of the current BCG vaccination policy. The results are important for vaccine development; if vaccines have non-specific effects these need to be considered in the assessment of new vaccines. Furthermore, modifying the disease-specific perspective on vaccines will have many consequences for our understanding of health and disease prevention.
Statens Serum Institut
Department of Epidemiology Research
Tel: +45 32 683950
Fax: +45 32 683165