title: Protective epitopes of the Plasmodium falciparum SERA5 malaria vaccine reside in intrinsically unstructured N-terminal repetitive sequences.
abstract: The malaria vaccine candidate antigen, SE36, is based on the N-terminal 47 kDa domain of Plasmodium falciparum serine repeat antigen 5 (SERA5). In epidemiological studies, we have previously shown the inhibitory effects of SE36 specific antibodies on in vitro parasite growth and the negative correlation between antibody level and malaria symptoms. A phase 1 b trial of the BK-SE36 vaccine in Uganda elicited 72% protective efficacy against symptomatic malaria in children aged 6-20 years during the follow-up period 130-365 days post-second vaccination. Here, we performed epitope mapping with synthetic peptides covering the whole sequence of SE36 to identify and map dominant epitopes in Ugandan adult serum presumed to have clinical immunity to P. falciparum malaria. High titer sera from the Ugandan adults predominantly reacted with peptides corresponding to two successive N-terminal regions of SERA5 containing octamer repeats and serine rich sequences, regions of SERA5 that were previously reported to have limited polymorphism. Affinity purified antibodies specifically recognizing the octamer repeats and serine rich sequences exhibited a high antibody-dependent cellular inhibition (ADCI) activity that inhibited parasite growth. Furthermore, protein structure predictions and structural analysis of SE36 using spectroscopic methods indicated that N-terminal regions possessing inhibitory epitopes are intrinsically unstructured. Collectively, these results suggest that strict tertiary structure of SE36 epitopes is not required to elicit protective antibodies in naturally immune Ugandan adults.
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Bang
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tougan
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Nirianne M Q
authors.initials: NM
authors.lastname: Palacpac
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Arisue
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Laboratory of Molecular Immunology, School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Med Biotech Laboratories, Kampala, Uganda.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Egwang
authors.affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Druilhe
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Horii
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000276:immunology*; D012453:Saimiri; D055815:Young Adult
chemical_list: D000939:Epitopes; D017780:Malaria Vaccines