title: Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein.
abstract: Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Cate
authors.initials: C
authors.lastname: Speake
authors.affiliation: Department of Cellular Immunology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pichugin
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tejram
authors.initials: T
authors.lastname: Sahu
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Vlad
authors.initials: V
authors.lastname: Malkov
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Morrison
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Cellular Immunology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Laure
authors.initials: L
authors.lastname: Juompan
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Neta
authors.initials: N
authors.lastname: Milman
authors.affiliation: Department of Cellular Immunology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Stasya
authors.initials: S
authors.lastname: Zarling
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wong-Madden
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Wendler
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ishizuka
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: MacMillen
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Valentino
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
authors.affiliation: Department of Cellular Immunology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology* / Q000627:therapeutic use; D000953:Antigens, Protozoan / Q000276:immunology; D005260:Female; D006801:Humans; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity; D010967:Plasmodium yoelii / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D019444:Vaccines, DNA; C041595:circumsporozoite protein, Protozoan