Strain-specific humoral response to a polymorphic malaria vaccine

Abstract

The 3D7 form of the merozoite surface protein 2 (MSP2) of Plasmodium falciparum was one of three subunits of the malaria vaccine Combination B that were tested in a phase I/IIb double-blind randomized placebo-controlled trial, which was undertaken with 120 Papua New Guinean children of 5 to 9 years of age. Because only one variant of the highly polymorphic MSP2 was used for vaccination, we examined whether the elicited response was directed against conserved or strain-specific epitopes. Postvaccination (week 12) titers of antibody against recombinantly expressed individual domains of MSP2 were measured by enzyme-linked immunosorbent assay and compared to baseline values. We found that vaccination with the 3D7 form of MSP2 induced a significant strain-specific humoral response directed against the repetitive and semiconserved family-specific part. The conserved N- and C-terminal domains were not immunogenic. Titers of antibody against the alternate FC27 family-specific domain showed a tendency to increase in vaccinated children, but there was no increase in antibodies against FC27-type 32-mer repeats. These results indicate that vaccination with one MSP2 variant mainly induced a strain-specific response, which can explain the selective effect of vaccination with combination B on the genotypes of breakthrough parasites. These findings support the inclusion of both family-specific domains (3D7 and FC27) in an improved vaccine formulation.

FIG. 1.

Schematic diagram of recombinant and synthetic MSP2 antigens used for ELISA. The constructs are aligned with full-length MSP2 alleles representing the two allelic families of MSP2. The 3D7 vaccine molecule included in Combination B is also shown.

FIG. 2.

IgG responses of different treatment groups to recombinant and synthetic MSP2 constructs. Geometric means of titers are shown for each treatment group to all tested antigens: conserved N terminus, conserved C terminus, 3D7 family-specific domain, 3D7 4-mer repeat, FC27 family-specific domain, and FC27 32-mer repeat. White columns represent titers at baseline; gray columns represent titers at week 12 postvaccination with combination B. Standard errors are indicated. The numbers of tested sera at baseline and week 12, respectively, for the different groups were as follows: placebo, 56 and 57; vaccine, 56 and 58; placebo with no SP, 29 and 29; vaccine with no SP, 29 and 30; placebo with SP, 27 and 28; and vaccine with SP, 27 and 28.