title: A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine.
abstract: A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage 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.
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.|Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jairo Andres
authors.initials: JA
authors.lastname: Fonseca
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Cabrera-Mora
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kashentseva
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Villegas
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Amelia
authors.initials: A
authors.lastname: Van Pelt
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.|Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D036022:Capsid Proteins; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C018315:hexon capsid protein, Adenovirus