Antibodies to the N-terminal block 2 of Plasmodium falciparum merozoite surface protein 1 are associated with protection against clinical malaria

Abstract

This longitudinal prospective study shows that antibodies to the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP-1) are associated with protection against clinical malaria in an area of stable but seasonal malaria transmission of Ghana. Antibodies to the block 2 region of MSP-1 were measured in a cohort of 280 children before the beginning of the major malaria transmission season. The cohort was then actively monitored for malaria, clinically and parasitologically, over a period of 17 months. Evidence is presented for an association between antibody responses to block 2 and a significantly reduced risk of subsequent clinical malaria. Furthermore, statistical survival analysis provides new information on the duration of the effect over time. The results support a conclusion that the block 2 region of MSP-1 is a target of protective immunity against P. falciparum and, thus, a promising new candidate for the development of a malaria vaccine.

FIG. 1.

Schematic diagram of MSP-1 block 2 sequences of all recombinant antigens are shown in single amino acid code. Asterisks indicate stop codons.

FIG. 2.

Frequencies and isotype biases of IgG antibodies to different regions of MSP-1. (A) Frequencies of seropositive individuals in the cohort before malaria transmission season (April 1994; n = 280) and after the season (November 1994; n = 266). Percentages of antibody-positive individuals for each full-length Block 2 antigen, Block 1, and MSP-1₁₉ are shown as bars. Asterisks indicate pairs of frequencies that significantly increased between the two samplings (P < 0.05). (B) Comparisons between IgG1 and IgG3 subclasses to Block 2 and MSP-1₁₉. Each point represents levels of antigen-specific subclasses in the April sample from one individual.

FIG. 3.

Kaplan-Meier plots of the cumulative incidence of first malaria episodes between antibody-positive and antibody-negative groups of children over the 17-month follow-up period. Proportions of children who remained malaria free in the antibody-positive and antibody-negative groups are shown as solid lines and dashed lines, respectively. Censored cases in the follow-up are shown by open symbols. The effects of IgG antibodies to different antigens are analyzed in separate panels.

FIG. 4.

Changes in the specificity of Block 2 antibodies. Typical patterns of changes in Block 2 specificity with time are illustrated by antibody reactivities of pairs of serum samples taken from donors 329 and 41. Antibody reactivity is expressed as the OD₄₉₂, comparing preseason (April 1994) and postseason (November 1994) samples from each donor side by side. MSP-1 antigens are shaded by type, as shown in the key. Panel A shows a changeover from a narrow MAD20-type specificity to K1-type specificities. Panel B shows boosts of antibody responses to K1 and MAD20 types and also the acquisition of antibodies against the RO33 type.