title: A synthetic TLR4 agonist formulated in an emulsion enhances humoral and Type 1 cellular immune responses against GMZ2--a GLURP-MSP3 fusion protein malaria vaccine candidate.
abstract: GMZ2 adjuvanted by aluminum hydroxide is a candidate malaria vaccine that has successfully passed phase 1 clinical testing in adult German and Gabonese volunteers and Gabonese children under five. Here we report a preclinical study screening a series of adjuvant vehicles and Toll-like receptor (TLR) agonists in CB6F1 mice to identify an improved formulation of GMZ2 suitable for further human clinical studies. GMZ2 formulated in an oil-in-water emulsion plus the synthetic TLR4 agonist GLA elicits the highest (a) vaccine-specific IgG2a and total IgG titers, (b) parasite-specific IFA titers, (c) levels of Type 1 cytokine responses (IFN-γ), and (d) number of long-lived-plasma cells (LLPC) secreting antibodies against both the GMZ2 fusion and its two components. Thus, GLA helps to elicit a vaccine-specific Type 1 antibody profile together with high levels of LLPC, both of which are thought to be essential for the development of long-term protective immunity against clinical malaria.
authors.affiliation: Department of Clinical Biochemistry and Immunology, State Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.
authors.forename: Susana
authors.initials: S
authors.lastname: Lousada-Dietrich
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Jogdand
authors.forename: Søren
authors.initials: S
authors.lastname: Jepsen
authors.forename: Vera V
authors.initials: VV
authors.lastname: Pinto
authors.forename: Sisse B
authors.initials: SB
authors.lastname: Ditlev
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Severin Olesen
authors.initials: SO
authors.lastname: Larsen
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.forename: Vanitha S
authors.initials: VS
authors.lastname: Raman
authors.forename: Randall F
authors.initials: RF
authors.lastname: Howard
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Vedvick
authors.forename: Gregory
authors.initials: G
authors.lastname: Ireton
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Theisen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood*; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008050:Lipid A / Q000008:administration & dosage*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D007074:Immunoglobulin G; D008050:Lipid A; D017780:Malaria Vaccines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4