Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1

Abstract

Naturally acquired antibodies to Plasmodium falciparum schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from Plasmodium berghei (PbSEA-1A) decreases parasitemia and prolongs survival following P. berghei ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes.

Keywords: B-cell epitopes; PfSEA-1; malaria.

FIG 1

Aotus monkeys vaccinated with rPFSEA-1A predominantly recognize 5 epitopes within PfSEA-1A. (A) Sera from six of the rPfSEA-1A-vaccinated primates (M13F, M7F, M3F, M8F, M4, and M1F) were tested and bound discrete peptide regions on an overlapping PfSEA-1A peptide (n = 273) microarray. Serum from primate M9F, which was vaccinated with adjuvant only, did not bind any of the peptides on the microarray (data not shown). (B) Epitope-conjugated beads were challenged with sera from rPfSEA-1A-vaccinated (n = 7) and adjuvant-only-vaccinated monkeys (n = 7). Fluorescence levels for each epitope were normalized by subtracting responses to BSA-conjugated beads.

FIG 2

Antibody levels to PfSEA-1A epitopes 1, 4, and 5 predict resistance to parasitemia. Least-squares mean parasitemia for individuals with antibody levels greater than the median (n = 134) were compared to those with antibody levels less than or equal to the median (n = 134) throughout the entire follow-up period by a generalized estimating equation. *, P <0.05; **, P, <0.01. (A) Epitopes 1 to 5 considered individually. (B) Epitopes 1, 4, and 5 considered in combinations.