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The pan-reactivity of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) validated by Reverse Vaccinology, reveals a promising malaria vaccine candidate

Pedro Cravo 1 ; Renato Beilner Machado 2 ; Juliana Almeida Leite 3 ; Taizy Leda 2 ; Rossarin Suwanarusk 4 ; Najara Carneiro Bittencourt 3 ; Letusa Albrecht 5 ; Carla Judice 3 ; Stefanie Costa Pinto Lopes 6 ; Marcus Vinícius Guimarães de Lacerda 7 ; Marcelo Ferreira 8 ; Irene Soares 9 ; Yun Shan Goh 4 ; Daniel Youssef Bargieri 8 ; François Nosten 10 ; Bruce Russell 11 ; Laurent Renia 12 ; Fabio Costa 3
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Background Malaria remains a world threatening disease largely due to the lack of a long-lasting and fully effective vaccine. The P. vivax unique biology and severe technical limitations for culturing have impaired the discovery of novel vaccine candidates. Reverse vaccinology has emerged as a powerful strategy to predict or to analyze the potential of novel vaccine candidates. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of DBL-EBP and AMA1 antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, the ectodomains M1 and M2, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. We have previously demonstrated the immunogenicity of the M2 domain MAEBL antigen cloned from the P. yoelii murine strain. Methods we used a genome-wide reverse vaccinology approach consisting of computational approaches to select the most appropriate vaccine candidate and algorithms to predict T- and B-cell immune epitopes. We analyzed the results which identified MAEBL. Then, a detailed epitope mapping of MAEBL through immunoinformatics was performed. Also, we investigated the pan-reactivity of the P. yoelii M2-MAEBL antisera against P. falciparum and P. vivax. Results We analyzed the results in the light of reverse vaccinology and MAEBL appeared one of twenty putative malaria vaccine candidates. Epitope mapping of MAEBL identified several MHCI, MHCII and B-cell epitopes throughout the peptide, with several of these lying in the M2 domain and being conserved between P. vivax, P. yoelii and P. falciparum, hinting that the M2-MAEBL is pan-reactive. This hypothesis was tested through functional assays, showing that P. yoelii M2-MAEBL antisera were able to recognize and inhibit erythrocyte invasion from both P. falciparum and P. vivax parasites isolated from Thai patients, in ex vivo assays. Moreover, the sequence of the M2-MAEBL is shown to be highly conserved between P. vivax isolates from the Amazon and Thailand. Conclusion In light of these observations our findings reinforce the potential of MAEBL antigen as a promising interspecies malaria vaccine candidate.