Determinants of the semi-immune state in an area with seasonal malaria transmission: Bancoumana, Mali
Description
This study examined the hypothesis that immunity to P. falciparum glycosylphophatidylinositol (GPI) could be the basis of the semi-immune state. The hypothesis is based on the fact that GPI, a candidate for the 'malaria toxin' may be responsible for the paroxysmal release of tumor necrosis factor alpha (TNF-alpha), which is associated with severe malaria. We examined the age-specific sero-prevalence of antibodies to GPI among 233 children and 66 adults of the village of Bancoumana, Mali, in March 2001. We also tested in-vitro the ability of these natural antibodies (from 9 subjects) to block the TNF-alpha release by murine macrophages stimulated with GPI. Antibodies to GPI were uncommon among children less than 5 years of age (∼20%) who are at risk of severe disease, but frequent among children ≥6 years of age and adults who are protected from severe disease (80% and 86%, respectively), p < 0.001. Plasma samples with high antibodies titers to GPI inhibited TNF-alpha release by macrophages in vitro, which is consistent with the hypothesis that antibodies to GPI protect against disease by inhibiting TNF-alpha release. To support our hypothesis, we assessed factors associated with anti-parasite immunity including the prevalence, incidence and recovery rates for asymptomatic P. falciparum infection. Data from a village wide-cohort (2000--2500 children 0--14 years old followed from 1996--2001) show a peak of severe malaria in children 2--5 years of age. In contrast, the incidence of infection (estimated from the reversible catalytic method and by person-month of observation) and the prevalence peak among children 6--9 years old, decrease only after the age of 15 years These findings are consistent with the idea that there are two epidemiologically distinct immune responses to the malaria parasite. Anti-disease (antitoxic) immunity, which is based on antibodies that neutralize the parasite GPI, is acquired within the first 5--6 years of life in malaria-endemic areas. In contrast, anti-parasite immunity develops more slowly in older children and becomes effective only after 15 years of age, resulting in lower parasite densities. Vaccine development should not be focused merely on anti-parasite immunity. It should strive to create the semi-immune state in order to prevent disease and death and produce anti-parasite immunity in order to reduce simultaneously the prevalence and the magnitude of infection