title: Protective humoral immunity elicited by a needle-free malaria vaccine comprised of a chimeric Plasmodium falciparum circumsporozoite protein and a Toll-like receptor 5 agonist, flagellin.
abstract: Immunization with Plasmodium sporozoites can elicit high levels of sterile immunity, and neutralizing antibodies from protected hosts are known to target the repeat region of the circumsporozoite (CS) protein on the parasite surface. CS-based subunit vaccines have been hampered by suboptimal immunogenicity and the requirement for strong adjuvants to elicit effective humoral immunity. Pathogen-associated molecular patterns (PAMPs) that signal through Toll-like receptors (TLRs) can function as potent adjuvants for innate and adaptive immunity. We examined the immunogenicity of recombinant proteins containing a TLR5 agonist, flagellin, and either full-length or selected epitopes of the Plasmodium falciparum CS protein. Mice immunized with either of the flagellin-modified CS constructs, administered intranasally (i.n.) or subcutaneously (s.c.), developed similar levels of malaria-specific IgG1 antibody and interleukin-5 (IL-5)-producing T cells. Importantly, immunization via the i.n. but not the s.c. route elicited sporozoite neutralizing antibodies capable of inhibiting >90% of sporozoite invasion in vitro and in vivo, as measured using a transgenic rodent parasite expressing P. falciparum CS repeats. These findings demonstrate that functional sporozoite neutralizing antibody can be elicited by i.n. immunization with a flagellin-modified P. falciparum CS protein and raise the potential of a scalable, safe, needle-free vaccine for the 40% of the world's population at risk of malaria.
authors.affiliation: Department of Microbiology, Division of Medical Parasitology, New York University School of Medicine, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carapau
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchell
authors.forename: Adéla
authors.initials: A
authors.lastname: Nacer
authors.forename: Alan
authors.initials: A
authors.lastname: Shaw
authors.forename: Caroline
authors.initials: C
authors.lastname: Othoro
authors.forename: Ute
authors.initials: U
authors.lastname: Frevert
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nardin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005408:Flagellin / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D015848:Interleukin-5 / Q000096:biosynthesis; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D034101:Sporozoites / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000819:agonists; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D015848:Interleukin-5; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D022223:Vaccines, Subunit; C041595:circumsporozoite protein, Protozoan; D005408:Flagellin
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