In a matched case-control study of severe P. falciparum malaria in an area of intense seasonal malaria transmission, the production of antibodies to GPI was modestly lower in healthy children compared with children with uncomplicated or severe malaria, and higher in children with cerebral malaria compared with those with other manifestations of severe malaria. Antibody production appeared rapidly with disease onset, peaked during the midseason when malaria transmission was highest, and decreased rapidly with most children becoming seronegative during the subsequent dry season. Furthermore, IgG antibody production increased with age and correlated with parasitemia in the severe malaria cohort.
Longitudinal studies have demonstrated that children rapidly acquire modest level of antibody to GPI after a single malaria infection and incrementally acquire additional antibody with successive infections. In contrast, adults appear to develop high levels of antibody at the time of first infection and are able to sustain antibody levels longitudinally.21
Levels of antibodies to GPI were elevated in both severe and uncomplicated malaria cases compared with healthy controls, suggesting that antibody production increases with disease severity. High-titer antibody levels have been found in West African children and attributed to a rapid boosting effect of antibody production by malaria infection.12
This antibody response appears short-lived, accounting for the low level of antibody detected during the post-transmission follow-up. The high antibody levels noted at the peak of the transmission season may provide further evidence of the close association of infection and antibody development in this young population. Incremental exposure to infection over time may result in age-associated increases in antibody levels. Case-control studies are well suited for studying risk factors for relatively uncommon diseases such as severe malaria, but a prospective, longitudinal cohort study would be ideal to confirm the hypothesis that antibodies to GPI confer protection against the acquisition of disease.
We stratified antibody production by severe disease syndromes, postulating that different manifestations of severe malaria might be associated with defined levels of antibodies to GPI. Contrary to data demonstrating a protective effect of IgG antibodies to GPI with elevated levels noted in adult patients with uncomplicated malaria compared with hospitalized patients with cerebral malaria,13
we found elevated levels of both IgM and IgG antibodies to GPI in children with cerebral malaria compared with healthy controls. Other severe malaria disease sub-classifications did not have different antibodies to GPI compared with cases of uncomplicated malaria or healthy controls. Although it is possible that healthy controls had lower antibody levels because of reduced malaria exposure, the effects of heterogeneous malaria transmission were minimized by matching cases and controls by age and residence. Moreover, nearly all young children in Bandiagara have one or more clinical malaria episodes every season and it is highly unlikely that any are not exposed to malaria infection.17
It is conceivable that this healthy population may have been skewed towards children with other, as yet undetermined factors for malaria resistance, because only aparasitemic healthy controls were enrolled.
Some studies have shown an inverse correlation of antibodies to GPI and parasitemia.22
As malaria immunity is acquired, tolerance to parasitemia increases, leading to asymptomatic malaria infections. Absolute parasitemias decrease with age.22
The WHO recommends the use of hyperparasitemia as a criterion for severe malaria, but the clinical course in children with this manifestation appears to be less acute. At our study site, children whose sole defining criterion for severe malaria is hyperparasitemia appear to fall somewhere between uncomplicated malaria and severe malaria in the spectrum of illness and are generally older than the mean study age of 39.5 months. Given the high number of children enrolled as hyperparasitemic (38%), our findings that levels of antibodies to GPI are directly correlated with parasitemia are likely related to an age-associated correlation in acquisition of antibodies to GPI and not with disease severity. The young age of our study population precludes any determination of age-associated decreases in parasitemia.
In summary, the case-control design of this study allowed us to examine the relationship between levels serum antibodies to GPI in matched cohorts of children distributed among different stages of malarial disease. Our data confirm previous findings suggesting that production of antibodies to GPI is rapid, short-lived, and cumulative in young children in malaria-endemic regions. However, they do not support a role of antibodies to GPI in protection against disease. Prospective, longitudinal cohort studies would be required to determine the role of antibodies to GPI in naturally acquired immunity to malaria.