A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria.

José Lozano,Adriana Bermudez,Laura Guasca,Karen Ardila,Yuly Guerrero,Yolanda Silva,Manuel Patarroyo,Martha Forero,Patricia Alba,Yahson Varela,Magnolia Vanegas

doi:10.3390/molecules22111837

Abstract

Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of PfCSP, STARP; MSA1 and Pf155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei-ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

Highlights

Malaria, a devastating disease caused by Plasmodium parasites; is transmitted to humans by the bite of a female Anopheles mosquito
The amino-acid sequences of P. falciparum circumsporozoite (Pf CSP), sporozoite threonine-asparagine-rich protein (STARP), Pf 155/RESA and merozoite surface antigen-1 (MSA1) were downloaded from the GenBank
Bank the Protein Data Bank (PDB, http://www.rcsb.org/pdb) as well as from the Plasmodium genome resource was employed for obtaining protein orthologous proteins present in the Plasmodium berghei and Plasmodium yoelii genomes. As it is well known, Plasmodium circumsporozoite surface antigens constitute important targets for pre-erythrocyte vaccine development, Pf CSP has been extensively regarded as a potential vaccine candidate as elsewhere reported [17]

Summary

Introduction

A devastating disease caused by Plasmodium parasites; is transmitted to humans by the bite of a female Anopheles mosquito. From the five parasites that infect humans, Plasmodium falciparum is the most lethal, being responsibly for 429,000 deaths in 2016 [1]. An effective malaria vaccine remains as a hope for the disease prevention and morbidity/mortality reduction. Pre-erythrocyte and blood parasite stages exhibit important antigens that have been regarded as targets for a malaria vaccine. The RTS,S recombinant vaccine which is composed by antigens from hepatitis B and the P. falciparum circumsporozoite (Pf CSP), has a moderate effectiveness which decreases with vaccination time [2].

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