Antibody responses to a novel Plasmodium falciparum merozoite surface protein vaccine correlate with protection against experimental malaria infection in Aotus monkeys.

David R Cavanagh,Clemens H M Kocken,Kay Samuel,Annemarie Voorberg-Van Der Wel,Jana S Mcbride,Graeme J M Cowan,John H White,Alan W Thomas,Martin A Dubbeld,David E Arnot,Lars Hviid

doi:10.1371/journal.pone.0083704

Abstract

The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals.

Highlights

The only malaria vaccine to reach Phase 3 clinical trials (RTS,S) was recently shown to have,50% protective efficacy against clinical malaria episodes in 5–17 month old children [1], protective efficacy waned rapidly and was lost within 3 years [2]
Recombinant antigen production Since the malaria parasite challenge strain used at Biomedical Primate Research Centre (BPRC) is falciparum Vietnam Oak Knoll (FVO), recombinant antigens based on the exact merozoite surface protein 1 (MSP-1) Block 2 sequence of the FVO strain were used to produce a homologous immunizing antigen
DNA sequencing confirmed that the challenge strain used at BPRC was identical at the Block 2 locus to the published FVO msp-1 sequence [38], and to the Block 2 sequence of the Wellcome isolate [39]

Summary

Introduction

The only malaria vaccine to reach Phase 3 clinical trials (RTS,S) was recently shown to have ,50% protective efficacy against clinical malaria episodes in 5–17 month old children [1], protective efficacy waned rapidly and was lost within 3 years [2]. The most abundant protein on the surface of the merozoite is the ,190 kDa merozoite surface protein 1 (MSP-1) This protein is proteolytically cleaved into a number of fragments during merozoite development and invasion, and antibodies specific for the C-terminal region of MSP-1 have been shown to inhibit this processing [5]. These MSP-1 fragments (p83, p31, p38 and p42) remain as a non-covalent complex on the surface of the merozoite [6] until the p42 component is further cleaved at or just before merozoite invasion [7]. The RO33 Block 2 type contains similar hydrophilic amino acid residues to the other Block 2 types, but is relatively conserved and non-repetitive [20,22]

Methods

Results

Conclusion