Strategies for developing multi‐epitope, subunit‐based, chemically synthesized anti‐malarial vaccines

Abstract

An anti-malarial vaccine against the extremely lethal Plasmodium falciparum is desperately needed. Peptides from this parasite's proteins involved in invasion and having high red blood cell-binding ability were identified; these conserved peptides were not immun genic or protection-inducing when used for immunizing Aotus monkeys. Modifying some critical binding residues in these high-activi binding peptides' (HABPs') attachment to red blood cells (RBC) allowed them to induce immunogenicity and protection against expermental challenge and acquire the ability to bind to specific HLA-DRp1* alleles. These modified HABPs adopted certain characterist structural configurations as determined by circular dichroism (CD) and 1H nuclear magnetic resonance (NMR) associated with certain HLA-DRβ1* haplotype binding activities and characteristics, such as a 2-Å-distance difference between amino acids fitting into HLA-DRp1 Pockets 1 to 9, residues participating in binding to HLA-DR pockets and residues making contact with the TCR, suggesting haplotyp and allele-conscious TCR. This has been demonstrated in HLA-DR-like genotyped monkeys and provides the basis for designing high effective, subunit-based, multi-antigen, multi-stage, synthetic vaccines, for immediate human use, malaria being one of them.

Binding activity, structure, and immunogenicity of synthetic peptides derived from Plasmodium falciparum CelTOS and TRSP proteins

“…3a). Such results are relevant since previous studies have shown that specific structural modifications made on a-helical HABPs have been able to induce protective immune responses in Aotus monkeys when immunized with these modified merozoite HABPs Patarroyo et al 2008a).…”

“…to produce a protective immune response against P. falciparum challenge in the Aotus model (Cifuentes et al 2009;Patarroyo et al 2008a;Patarroyo and Patarroyo 2008). Complete CelTOS and TRSP sequences have been finely mapped using HeLa and (Fig.…”

Functional, Immunological and Three-Dimensional Analysis of Chemically Synthesised Sporozoite Peptides as Components of a Fully-Effective Antimalarial Vaccine

“…Our institute has thus adopted a functional approach towards resolving this problem by only working with molecules which have been shown to fulfil highly relevant roles in parasite invasion and by only including attractive candidates as potential components of a new, fully-protective, antimalarial vaccine (as suggested by the title of this manuscript). Such vaccine's activity must be directed against Furthermore, chemically-synthesised peptides' amino acid sequences can be easily modified to produce analogues able to modulate an immune response, leading to much more potent vaccines being obtained, as has been thoroughly shown by us at the merozoite stage where a large number of structurally-modified, biologically-relevant peptides have been able to induce fully-protective immunity in some monkeys against the most stringent challenge (the intravenous inoculation of a 100% infective strain) [5,14,16,71]. Additionally, 15-20 amino acid-long peptides are able to mimic the three-dimensional (3D) structure of the native protein from which they have been derived [16], and 3D structure of modified peptides correlates with the major histocompatibility class IIpeptide complex formation.…”

“…This has led to the following specific in-house rules having been honed over more than twelve years intensive work: F R; W Y; L H; I N; P D; M K; C T or V; Q E; A S [5,14,84,85].…”

“…The severity of the global situation regarding malaria has fostered thousands of studies aimed at developing new and more effective control mechanisms for tackling this scourge. Most of these efforts have been based on the chemical, physical or biological elimination of anopheline mosquito vectors, producing more effective antimalarial drugs and treatment and using different approaches for developing antimalarial vaccines [5][6][7][8].…”