title: Synthetic TLR4 agonists enhance functional antibodies and CD4+ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen.
abstract: A subunit vaccine targeting both transmission and pathogenic asexual blood stages of Plasmodium falciparum, i.e., a multi-stage vaccine, could be a powerful tool to combat malaria. Here, we report production and characterization of the recombinant protein GMZ2.6C, which contains a fragment of the sexual-stage protein Pfs48/45-6C genetically fused to GMZ2, an asexual vaccine antigen in advanced clinical development. To select the most suitable vaccine formulation for downstream clinical studies, GMZ2.6C was tested with various immune modulators in different adjuvant formulations (stable emulsions, liposomes, and alum) in C57BL/6 mice. Some, but not all, formulations containing either the synthetic TLR4 agonist GLA or SLA elicited the highest parasite-specific antibody titers, the greatest IFN-γ responses in CD4+ TH1 cells, and the highest percentage of multifunctional CD4+ T cells expressing IFN-γ and TNF in response to GMZ2.6C. Both of these agonists have good safety records in humans.
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Baldwin
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Will
authors.initials: W
authors.lastname: Roeffen
authors.affiliation: Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark; Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Susheel K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark; Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark.
authors.forename: Regis W
authors.initials: RW
authors.lastname: Tiendrebeogo
authors.affiliation: Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Elyse
authors.initials: E
authors.lastname: Beebe
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Randall F
authors.initials: RF
authors.lastname: Howard
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave. E., Suite 400, Seattle, WA 98102, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.affiliation: Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark; Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark. Electronic address: mth@ssi.dk.
authors.forename: Michael
authors.initials: M
authors.lastname: Theisen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007371:Interferon-gamma / Q000276:immunology; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000276:immunology; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum; D015800:Protozoan Proteins / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C000599052:GMZ2 vaccine; D017780:Malaria Vaccines; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D051197:Toll-Like Receptor 4; C084847:pfs48-45 protein, Plasmodium falciparum; D007371:Interferon-gamma
keywords: CD4 T-helper cells; GLA; GMZ2; Pfs48/45; Plasmodium falciparum; SLA; Transmission blocking