title: Plasmodium vivaxCell-Traversal Protein for Ookinetes and Sporozoites: Naturally Acquired Humoral Immune Response and B-Cell Epitope Mapping in Brazilian Amazon Inhabitants.
abstract: The cell-traversal protein for ookinetes and sporozoites (CelTOS), a highly conserved antigen involved in sporozoite motility, plays an important role in the traversal of host cells during the preerythrocytic stage ofPlasmodiumspecies. Recently, it has been considered an alternative target when designing novel antimalarial vaccines againstPlasmodium falciparum. However, the potential ofPlasmodium vivaxCelTOS as a vaccine target is yet to be explored. This study evaluated the naturally acquired immune response against a recombinantP. vivaxCelTOS (PvCelTOS) (IgG and IgG subclass) in 528 individuals from Brazilian Amazon, as well as the screening of B-cell epitopesin silicoand peptide assays to associate the breadth of antibody responses of those individuals with exposition and/or protection correlates. We show that PvCelTOS is naturally immunogenic in Amazon inhabitants with 94 individuals (17.8%) showing specific IgG antibodies against the recombinant protein. Among responders, the IgG reactivity indexes (RIs) presented a direct correlation with the number of previous malaria episodes (p= 0.003;r= 0.315) and inverse correlation with the time elapsed from the last malaria episode (p= 0.031;r= -0.258). Interestingly, high responders to PvCelTOS (RI > 2) presented higher number of previous malaria episodes, frequency of recent malaria episodes, and ratio of cytophilic/non-cytophilic antibodies than low responders (RI < 2) and non-responders (RI < 1). Moreover, a high prevalence of the cytophilic antibody IgG1 over all other IgG subclasses (p< 0.0001) was observed. B-cell epitope mapping revealed five immunogenic regions in PvCelTOS, but no associations between the specific IgG response to peptides and exposure/protection parameters were found. However, the epitope (PvCelTOSI136-E143) was validated as a main linear B-cell epitope, as 92% of IgG responders to PvCelTOS were also responders to this peptide sequence. This study describes for the first time the natural immunogenicity of PvCelTOS in Amazon individuals and identifies immunogenic regions in a full-length protein. The IgG magnitude was mainly composed of cytophilic antibodies (IgG1) and associated with recent malaria episodes. The data presented in this paper add further evidence to consider PvCelTOS as a vaccine candidate.
authors.affiliation: Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Rodrigo Nunes
authors.initials: RN
authors.lastname: Rodrigues-da-Silva
authors.affiliation: Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Isabela Ferreira
authors.initials: IF
authors.lastname: Soares
authors.affiliation: Nuffield Department of Medicine, The Jenner Institute, The Henry Wellcome Building for Molecular Physiology, University of Oxford , Oxford , UK.
authors.forename: Cesar
authors.initials: C
authors.lastname: Lopez-Camacho
authors.affiliation: Computational Modeling Group, Fiocruz , Fortaleza , Brazil.
authors.forename: João Hermínio
authors.initials: JH
authors.lastname: Martins da Silva
authors.affiliation: Laboratory of Clinical Immunology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Daiana de Souza
authors.initials: DS
authors.lastname: Perce-da-Silva
authors.affiliation: Laboratory of Immunodiagnostics, Department of Biological Sciences, National School of Public Health, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Antônio
authors.initials: A
authors.lastname: Têva
authors.affiliation: Laboratory of Leishmaniasis and Chagas Disease, National Institute of Amazonian Research , Manaus , Brazil.
authors.forename: Antônia Maria
authors.initials: AM
authors.lastname: Ramos Franco
authors.affiliation: Laboratory of Leishmaniasis and Chagas Disease, National Institute of Amazonian Research , Manaus , Brazil.
authors.forename: Francimeire Gomes
authors.initials: FG
authors.lastname: Pinheiro
authors.affiliation: Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Lana Bitencourt
authors.initials: LB
authors.lastname: Chaves
authors.affiliation: Laboratory of Malaria Research, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Lilian Rose
authors.initials: LR
authors.lastname: Pratt-Riccio
authors.affiliation: Nuffield Department of Medicine, The Jenner Institute, The Henry Wellcome Building for Molecular Physiology, University of Oxford , Oxford , UK.
authors.forename: Arturo
authors.initials: A
authors.lastname: Reyes-Sandoval
authors.affiliation: Laboratory of Clinical Immunology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Dalma Maria
authors.initials: DM
authors.lastname: Banic
authors.affiliation: Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.
authors.forename: Josué da Costa
authors.initials: JD
authors.lastname: Lima-Junior
keywords: P. vivax; PvCelTOS; epitope mapping; epitope prediction; malaria; malaria vaccines; vaccines