Structural Modifications Enable Conserved Peptides to Fit into MHC Molecules thus Inducing Protection against Malaria

Abstract

Developing a rational methodology for obtaining vaccines against P. falciparum malaria (the disease's most lethal form, afflicting more than 250 million people around the world per year and killing about 2 million of them) [1] has become one of the main objectives of public health authorities around the world. [2] A multiantigenic vaccine, containing molecules from the parasite's different developmental stages, is required due to the parasite's remarkable complexity and adaptability. [3] The first such approach (the SPf66 synthetic vaccine), [4,5] which used peptides from molecules from different parasite stages, conferred limited protective efficacy in Aotus monkey studies and in field trials carried out on human volunteers around the world. [6] [a] Prof.

Recent advances in the development of a chemically synthesised anti-malarial vaccine

“…Remarkably, it was found that both Mrz-and Spz-derived mHABPs bound to different HLA-DRb1* molecules while most unmodified cHABPs did not do so or were highly promiscuous, confirming what had been postulated: the changes allowed a better fit of mHABPs into the HLA-DRb1* peptide binding region (PBR) groove and improved MHC II--mHABP interaction specificity which, in turn, was correlated with protective immunity in Aotus monkeys [76,84,89,90].…”

“…These highly defined and specific structural interactions between MHC II molecules and mHABPs explain why certain modifications rendered mHABPs immunogenic and protection-inducing while other changes only induced immunogenicity, short-lived protection and/or cellular immune response, but not protection [67,68,76,83,89]. On the other hand, we found that mHABPs (Spz-and Mrz-derived) having PPII L structures achieved a perfect fit into MHC II molecules having 7 --11 H-bonds and thus stable and suitable mHABP--MHC II complex formation for appropriate presentation to the TCR, thereby inducing an effective immune response [11,85,86,103].…”

“…Much of the recent body of our work has dealt with the immunogenicity (IFA and WB assays) of individual Mrz-and Spz-derived mHABPs and their protection-inducing ability by the most stringent test available (intravenous inoculation of a highly virulent Aotus-adapted P. falciparum strain), showing that mHABPs from Mrz and Spz parasite stages cover most MHC II genetic variants and face the parasite regarding two lines of defence: Spz and Mrz invasion [11,67,68,74,76,78,84,89,90].…”

Identification of the Plasmodium falciparum rhoptry neck protein 5 (PfRON5)

“…Our group has been working for more than three decades in figuring out a rational methodology for vaccine development which includes functional assays to determine those peptide regions involved in target cell binding and then performing specific modifications to them to allow a better fit into immune system molecules. This approach has allowed us to turn nonimmunogenic conserved binding regions to target cells into immunogenic and protection-inducing ones, when they are tested in the Aotus monkey model (Patarroyo et al, 2004Cifuentes et al, 2008;.…”

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…41,44,[50][51][52][53][54][55][56][57][58] This distance was 6.5 ( 0.5 Å and 4.5 ( 1.5 Å shorter in short-lived and long-lasting antibody-inducing but non-protection-inducing modified HABPs, respectively, than in immunogenic, protection-inducing ones; residue orientation was also different. 42,43 In essence, immunogenic protection-inducing modified conserved HABPs have been modified so that they can fit perfectly into the MHC II-peptide-TCR complex for triggering an appropriate immune response, providing tremendous support for using chemically synthesized, specifically modified conserved HABPs in vaccine development.…”