The Search of a Malaria Vaccine: The Time for Modified Immuno-Potentiating Probes

Abstract

Malaria is a deadly disease that takes the lives of more than 420,000 people a year and is responsible for more than 229 million clinical cases globally. In 2019, 95% of malaria morbidity occurred in African countries. The development of a highly protective vaccine is an urgent task that remains to be solved. Many vaccine candidates have been developed, from the use of the entire attenuated and irradiated pre-erythrocytic parasite forms (or recombinantly expressed antigens thereof) to synthetic candidates formulated in a variety of adjuvants and delivery systems, however these have unfortunately proven a limited efficacy. At present, some vaccine candidates are finishing safety and protective efficacy trials, such as the PfSPZ and the RTS,S/AS01 which are being introduced in Africa. We propose a strategy for introducing non-natural elements into target antigens representing key epitopes of Plasmodium spp. Accordingly, chemical strategies and knowledge of host immunity to Plasmodium spp. have served as the basis. Evidence is obtained after being tested in experimental rodent models for malaria infection and recognized for human sera from malaria-endemic regions. This encourages us to propose such an immune-potentiating strategy to be further considered in the search for new vaccine candidates.

Keywords: Plasmodium spp.; malaria vaccine; non-natural elements; structurally modified antigen.

Figure 1

(A) Malaria incidence 2019 [1]. Selected villages and provinces of malaria endemic areas in Colombia are 1. San Juan de Nepomuceno (Bolívar), 2. Tierralta (Córdoba),3. Quibdó (Chocó), 4. Tumaco (Nariño) and 5. Bogotá DC (non-endemic for malaria) (B) Plasmodium spp. life cycle and antigen targets for vaccine development are numbered from 1 to 3.

Figure 2

Progress in developing vaccine candidates for malaria.

Figure 3

(A) P. falciparum blood-stages protein targets, amino-acid sequences, and modified analogs. (B) Localization of the AMA1 antigen-epitope highlighted in yellow ribbons and its key modified peptide-bond. (C) N-terminus MSP1 3D structure modelized from a predicted model generated by I-Tasser. C-terminal MSP1 fragment pdb file 1ob1 code was employed. Structure recreation shows all peptides sequences. (D) Localization of one EBA175 antigen-epitope highlighted in red ribbons and its two key modified peptide-bonds are denoted with arrows. Protein and epitope modeling and personalization were performed with the VMD 1.9.3 version software, from the NIH Biomedical Research Center for Macromolecular Modeling and Bioinformatics, University of Illinois [158]. Protein databank PDB coordinate files used were 4r1c for AMA-1, 1zro for EBA175, and 1ob1 for C-term MSP1.

Figure 4

(A) Reactivity of serum-antibodies of BALB/c mice immunized with selected blood-stage modified epitopes from P. falciparum, versus the 3D7 strain by Western blot. (B) Human sera reactivity of samples collected from Colombian malaria endemic areas versus P. falciparum 3D7 and FCB-2 strains.

Figure 5

Selected human sera recognizes designed modified-epitope antigens of Plasmodium spp. by ELISA tests. (A) Samples from San Juan de Nepomuceno village (Bolivar) (B) Samples from Tierralta (Cordoba). (C) Samples from Quibdó (Chocó) and (D) Samples from Tumaco (Nariño). Human sera from a malaria non-endemic areas were obtained from Bogotá DC and used as negative controls. The CLIP endogenous peptide was employed as a non-relevant antigen.

Figure 5

Selected human sera recognizes designed modified-epitope antigens of Plasmodium spp. by ELISA tests. (A) Samples from San Juan de Nepomuceno village (Bolivar) (B) Samples from Tierralta (Cordoba). (C) Samples from Quibdó (Chocó) and (D) Samples from Tumaco (Nariño). Human sera from a malaria non-endemic areas were obtained from Bogotá DC and used as negative controls. The CLIP endogenous peptide was employed as a non-relevant antigen.