Induction of protective antibodies in Saimiri monkeys by immunization with a multiple antigen construct (MAC) containing the Plasmodium vivax circumsporozoite protein repeat region and a universal T helper epitope of tetanus toxin

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

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Immunogenicity of multiple antigen peptides (MAP) containing T and B cell epitopes of the repeat region of theP. falciparum circumsporozoite protein

European Journal of Immunology ◽

10.1002/eji.1830211217 ◽

1991 ◽

Vol 21 (12) ◽

pp. 3015-3020 ◽

Cited By ~ 44

Author(s):

Dona Yamuna Munesinghe ◽

Pedro Clavijo ◽

Mauricio Calvo Calle ◽

Ruth S. Nussenzweig ◽

Elizabeth Nardin

Keyword(s):

B Cell ◽

Circumsporozoite Protein ◽

Repeat Region ◽

B Cell Epitopes ◽

Multiple Antigen ◽

Multiple Antigen Peptides

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Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

10.1101/2021.08.31.458469 ◽

2021 ◽

Author(s):

Iga Kucharska ◽

Lamia Hossain ◽

Danton Ivanochko ◽

Qiren Yang ◽

John L Rubinstein ◽

...

Keyword(s):

Plasmodium Vivax ◽

Molecular Basis ◽

Parasite Infection ◽

Circumsporozoite Protein ◽

Structural Basis ◽

Structural Studies ◽

Repeat Region ◽

Antibody Recognition ◽

Peptide Conformations ◽

Dynamics Simulations

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

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