title: An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses.
abstract: Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated T* was previously identified by screening T cells from volunteers immunized with irradiated P. falciparum sporozoites. The T* sequence spans twenty amino acids that contains multiple T cell epitopes restricted by various HLA alleles. Subunit malaria vaccines including T* are highly immunogenic in rodents, non-human primates and humans. In this study we characterized a highly conserved HLA-DRβ1*04:01 (DR4) restricted T cell epitope (QNT-5) located at the C-terminus of T*. We found that a peptide containing QNT-5 was able to elicit long-term anti-CS Ab responses and prime CD4 T cells in HLA-DR4 transgenic mice despite forming relatively unstable MHC-peptide complexes highly susceptible to HLA-DM editing. We attempted to improve the immunogenicity of QNT-5 by replacing the P1 anchor position with an optimal tyrosine residue. The modified peptide QNT-Y formed stable MHC-peptide complexes highly resistant to HLA-DM editing. Contrary to expectations, a linear peptide containing QNT-Y elicited almost 10-fold lower long-term antibody and IFN-γ responses compared to the linear peptide containing the wild type QNT-5 sequence. Some possibilities regarding why QNT-5 is more effective than QNT-Y in inducing long-term T cell and anti-CS Ab when used as vaccine are discussed.
authors.affiliation: Department of Microbiology, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia; Graduate School in Biomedical Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parra-López
authors.affiliation: Department of Microbiology, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia; Graduate School in Biomedical Sciences, Universidad Nacional de Colombia, Bogotá, Colombia; Fundación Salud de los Andes, Research Group of Immunology and Clinical Oncology - GIIOC, Bogotá, Colombia.
authors.forename: David
authors.initials: D
authors.lastname: Bernal-Estévez
authors.forename: Liusong
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Microbiology, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Luis Eduardo
authors.initials: LE
authors.lastname: Vargas
authors.affiliation: Department of Microbiology, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pulido-Calixto
authors.affiliation: Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Luz Mary
authors.initials: LM
authors.lastname: Salazar
authors.affiliation: University of Massachusetts Medical School, Department of Pathology and Biochemistry and the Department of Molecular Pharmacology, Worcester, Massachusetts, United States of America.
authors.forename: J Mauricio
authors.initials: JM
authors.lastname: Calvo-Calle
authors.affiliation: University of Massachusetts Medical School, Department of Pathology and Biochemistry and the Department of Molecular Pharmacology, Worcester, Massachusetts, United States of America.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010963:Plasmodium falciparum / Q000276:immunology*; D055550:Protein Stability; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan