A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria VaccineReportar como inadecuado




A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal Title:

PLoS ONE

Volume:

Volume 11, Number 4

Publisher:

Public Library of Science | 2016-04-29, Pages e0154819-e0154819

Type of Work:

Article | Final Publisher PDF

Abstract: A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multi-stage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions HVR of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity and protective efficacy of adenoviral based malaria vaccines.

Subjects: Health Sciences, General - Health Sciences, Immunology - Health Sciences, Pharmacology - Research Funding: This work was supported by the National Institute of Allergy and Infectious Diseases: R56- AI103382-01A1, R21-AI094402-01 and R21-AI095718-01. It was also supported by the National Center for Research Resources: Yerkes National Primate Research Center Base Grant No RR00165.

Keywords: Science and Technology - Multidisciplinary Sciences - FALCIPARUM CIRCUMSPOROZOITE PROTEIN - ADENOVIRUS TYPE 5 - PHASE 2A TRIAL - IMMUNE-RESPONSES - PREEXISTING IMMUNITY - DENDRITIC CELLS - NEUTRALIZING ANTIBODIES - HYPERVARIABLE REGIONS - CAPSID DISPLAY - GENE-TRANSFER - T cells - Antibodies - Cytotoxic T cells - Adenoviruses - Plasmodium yoelii - Recombinant proteins - Malaria - Viral packaging -



Autor: Jairo Andres Fonseca, Monica Cabrera-Mora, Elena A. Kashentseva, John Paul Villegas, Alejandra Fernandez, Amelia Van Pelt, Igor P

Fuente: https://open.library.emory.edu/



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