Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera

• Type of Material: Article
• Authors: Monica Cabrera-Mora, Emory University; Jairo Andres Fonseca, Emory University; Balwan Singh, Emory University; Joseli Oliveira-Ferreira, Oswaldo Cruz Foundation (FIOCRUZ); Josué da Costa Lima-Junior, Oswaldo Cruz Foundation (FIOCRUZ); J. Mauricio Calvo-Calle, University of Massachusetts; Alberto Moreno, Emory University
• Language: English
• Date: 2015-09-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2015, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/IAI.00480-15
• Title of Journal or Parent Work: Infection and Immunity
• ISSN: 0019-9567
• Volume: 83
• Issue: 9
• Start Page: 3749
• End Page: 3761
• Grant/Funding Information: This research was supported by National Institutes of Health, NIAID grants R56-AI103382-01A1, R21-AI094402-01, and R21-AI095718-01 and the Yerkes National Primate Research Center Base grant RR00165 awarded by the National Center for Research Resources of the National Institutes of Health.; J.M.C.-C.'s involvement was supported by NIH-U19-AI109858.
• Keywords: Immunology; Infectious Diseases; HLA-DR; IRRADIATED SPOROZOITES; MALARIA VACCINE; Science & Technology; DQ MOLECULES; STAGE MALARIA; INHIBITORY-ACTIVITY; PROTECTIVE IMMUNITY; Life Sciences & Biomedicine; PEPTIDE BINDING; HEPARAN-SULFATE; SYNTHETIC VACCINE
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Immunology

Abstract

Plasmodium vivax is the most widespread species of Plasmodium, causing up to 50% of the malaria cases occurring outside sub-Saharan Africa. An effective vaccine is essential for successful control and potential eradication. A well-characterized vaccine candidate is the circumsporozoite protein (CSP). Preclinical and clinical trials have shown that both antibodies and cellular immune responses have been correlated with protection induced by immunization with CSP. On the basis of our reported approach of developing chimeric Plasmodium yoelii proteins to enhance protective efficacy, we designed PvRMC-CSP, a recombinant chimeric protein based on the P. vivax CSP (PvCSP). In this engineered protein, regions of the PvCSP predicted to contain human T cell epitopes were genetically fused to an immunodominant B cell epitope derived from the N-terminal region I and to repeat sequences representing the two types of PvCSP repeats. The chimeric protein was expressed in soluble form with high yield. As the immune response to PvCSP has been reported to be genetically restricted in the murine model, we tested the immunogenicity of PvRMC-CSP in groups of six inbred strains of mice. PvRMC-CSP was able to induce robust antibody responses in all the mouse strains tested. Synthetic peptides representing the allelic forms of the P. vivax CSP were also recognized to a similar extent regardless of the mouse strain. Furthermore, the immunization regimen induced high frequencies of multifunctional CD4(+) and CD8(+) PvRMC-CSP-specific T cells. The depth and breadth of the immune responses elicited suggest that immunization with PvRMC-CSP can circumvent the genetic restriction of the immune response to P. vivax CSP. Interestingly, PvRMC-CSP was also recognized by naturally acquired antibodies from individuals living in areas where malaria is endemic. These features make PvRMC-CSP a promising vaccine candidate for further development.