An analysis of natural immunity to invasive pneumococcal disease among infants and young children in Kilifi, Kenya. (360G-Wellcome-061089_Z_00_C)

Invasive pneumococcal disease (IPD) causes approximately 1 million deaths in infants and young children in the developing world each year. Although protein conjugated pneumococcal vaccines are highly efficacious against IPD they are unlikely to be made widely available in Africa for reasons of cost. Vaccination exploits natural mechanisms of immunity in humans and yet the basis of immunity to pneumococcal disease among infants is not known. African infants have low or undetectable concentrations of serotype-specific antibody, the major defence mechanism of adults, but most infants still do not develop disease despite frequent exposure to the pathogen. The rise in anti-capsular antibody concentrations towards adults levels takes place months or years after the sharp decline in the risk of IPD during the second year of life suggesting that protection at this point is independent of anti-capsular responses. Alternative explanations of immunity in infants are the functional quality, rather than quantity, of anti-capsular antibody, the kinetics of the anti-capsular response, or mucosal responses to capsular antigens which mature more rapidly then systemic responses. Alternatively, immunity may be determined by antibodies to non-capsular targets such as C-polysaccharide or common pneumococcal proteins, pneumolysin, PspA and PsaA. Some susceptibility to disease is clearly attributable to genetic variables such as sickle cell disease, deficiency of mannose binding protein and variations in the receptor for IgG2, Fc gamma RIIa. So far it has not been possible to examine the correlation between serological factors and protection from IPD in humans because of the difficulty of obtaining serum samples before the onset of disease. The original feature of this study is that it overcomes this limitation by nesting a case-control study of immunological variables within a cohort of 5,000 infants who are followed up with 3 monthly serum and saliva samples throughout the first 21 months of life. The study will be conducted in a population with a high incidence of IPD, which will be detected by a combination of sensitive and specific diagnostic techniques to yield approximately 100 cases. Studies of additional value will be incorporated into the design to examine epidemiological risk factors for IPD, and to describe the morbidity experience of the cohort. Finally, the design offers considerable scope for immunological case-control studies of other major infectious diseases of children.