Geographical and temporal conservation of antibody recognition of Plasmodium falciparum variant surface antigens

Abstract

The slow acquisition of protection against Plasmodium falciparum malaria probably reflects the extensive diversity of important antigens. The variant surface antigens (VSA) that mediate parasite adhesion to a range of host molecules are regarded as important targets of acquired protective immunity, but their diversity makes them questionable vaccine candidates. We determined levels of VSA-specific immunoglobulin G (IgG) in human plasma collected at four geographically distant and epidemiologically distinct localities with specificity for VSA expressed by P. falciparum isolates from three African countries. Plasma levels of VSA-specific IgG recognizing individual parasite isolates depended on the transmission intensity at the site of plasma collection but were largely independent of the geographical origin of the parasites. The total repertoire of immunologically distinct VSA thus appears to be finite and geographically conserved, most likely due to functional constraints. Furthermore, plasma samples frequently had high IgG reactivity to VSA expressed by parasites isolated more than 10 years later, showing that the repertoire is also temporally stable. Parasites from patients with severe malaria expressed VSA (VSASM) that were better recognized by plasma IgG than VSA expressed by other parasites, but importantly, VSASM-type antigens also appeared to show substantial antigenic homogeneity. Our finding that the repertoire of immunologically distinct VSA in general, and in particular that of VSASM, is geographically and temporally conserved raises hopes for the feasibility of developing VSA-based vaccines specifically designed to accelerate naturally acquired immunity, thereby enhancing protection against severe and life-threatening P. falciparum malaria.

FIG. 1.

VSA-specific plasma IgG levels in relation to the geographical origins of the plasma sample and of the VSA-expressing parasite isolate. Each data point (Table 1) represents the mean of MFI values obtained with an individual plasma sample (IO, Indonesia; GH, Ghana; TZ, Tanzania; SD, Sudan) tested against P. falciparum isolates from Ghana (left), Tanzania (center), and Sudan (right). Centerlines indicate medians, boxes indicate the central 50% of data points, and bars indicate the central 80% of data points.

FIG. 2.

Geographical conservation of VSA. Data points represent the geometric mean of MFI values obtained for each of 76 individual P. falciparum isolates from Ghana, Tanzania, and Sudan tested against plasma samples from Ghana (n = 96) and Sudan (n = 57). The linear regression line and the 95% confidence interval for the regression line are indicated.

FIG. 3.

Antigenic similarity of VSA in relation to serologically defined VSA type (VSA_SM [n = 5] or VSA_UM [n = 5]; see the text for details). Each data point represents the correlation coefficient (R value) obtained from the comparison of a pair-wise permutation of the five most recognized (H1 to H5) and the five least recognized (L1 to L5) parasite isolates tested with a panel of 96 Ghanaian plasma samples (see the text for details). Permutations among well-recognized parasites only (H versus H), among poorly recognized parasites only (L versus L), and mixed permutations (pairs of one well-recognized and one poorly recognized isolate; H versus L) are shown separately. Centerlines indicate medians, boxes indicate the central 50% of data points, bars indicate the central 80% of data points, and circles indicate individual outliers.