Abstract
The malaria vaccine candidate antigen, SE36, is based on the N-terminal 47 kDa domain of Plasmodium falciparum serine repeat antigen 5 (SERA5). In epidemiological studies, we have previously shown the inhibitory effects of SE36 specific antibodies on in vitro parasite growth and the negative correlation between antibody level and malaria symptoms. A phase 1 b trial of the BK-SE36 vaccine in Uganda elicited 72% protective efficacy against symptomatic malaria in children aged 6–20 years during the follow-up period 130–365 days post–second vaccination. Here, we performed epitope mapping with synthetic peptides covering the whole sequence of SE36 to identify and map dominant epitopes in Ugandan adult serum presumed to have clinical immunity to P. falciparum malaria. High titer sera from the Ugandan adults predominantly reacted with peptides corresponding to two successive N-terminal regions of SERA5 containing octamer repeats and serine rich sequences, regions of SERA5 that were previously reported to have limited polymorphism. Affinity purified antibodies specifically recognizing the octamer repeats and serine rich sequences exhibited a high antibody-dependent cellular inhibition (ADCI) activity that inhibited parasite growth. Furthermore, protein structure predictions and structural analysis of SE36 using spectroscopic methods indicated that N-terminal regions possessing inhibitory epitopes are intrinsically unstructured. Collectively, these results suggest that strict tertiary structure of SE36 epitopes is not required to elicit protective antibodies in naturally immune Ugandan adults.
Highlights
Despite the vast malaria burden no effective malaria vaccine exists [1,2]
We have demonstrated previously that antibodies raised against N-terminal region of PfSERA5 strongly inhibit in vitro parasite growth by antibody-dependent cellular inhibition (ADCI) at concentrations which do not show any detectable direct inhibition of growth [16], we used this assay as a screen for functional inhibition activity of anti-SE36 IgG
The study utilizes residual samples from a cross-sectional study of 40 (37 sera are available for this study) healthy Ugandan adults living in Atopi Parish, a malaria holoendemic area, located 5 km west of Apac Town, 300 km north of Kampala
Summary
The development of malaria vaccines has mainly focused on Plasmodium falciparum, the most deadly of five Plasmodium species that infect humans. Malaria vaccine development strategies vary depending on the target stages of the parasite life cycle, i.e. sporozoite, intra-hepatocytic stage, asexual erythrocyte stages, gametocyte, and mosquito midgut stages. Sequence polymorphism of many antigens, as observed in several vaccine candidates such as merozoite surface protein (MSP)-1, MSP-2 [3] and apical membrane antigen-1 (AMA-1) [4], hamper the systematic vaccine development strategy based on host immune responses against malaria parasites. P. falciparum serine repeat antigen 5 (PfSERA5) is one of the candidate vaccines in human trial [5,6,7]. PfSERA5 was the first physiological substrate identified for P. falciparum subtilisinlike serine protease (PfSUB1) [10]
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