title: Identification and prioritization of merozoite antigens as targets of protective human immunity to Plasmodium falciparum malaria for vaccine and biomarker development.
abstract: The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control.
authors.affiliation: Department of Immunology, Burnet Institute, Melbourne 3001, Victoria, Australia.
authors.forename: Jack S
authors.initials: JS
authors.lastname: Richards
authors.forename: Thangavelu U
authors.initials: TU
authors.lastname: Arumugam
authors.forename: Linda
authors.initials: L
authors.lastname: Reiling
authors.forename: Julie
authors.initials: J
authors.lastname: Healer
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hodder
authors.forename: Freya J I
authors.initials: FJ
authors.lastname: Fowkes
authors.forename: Nadia
authors.initials: N
authors.lastname: Cross
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.forename: Satoru
authors.initials: S
authors.lastname: Takeo
authors.forename: Alex D
authors.initials: AD
authors.lastname: Uboldi
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Thompson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
authors.forename: Motomi
authors.initials: M
authors.lastname: Torii
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tsuboi
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000953:Antigens, Protozoan / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control*; D008297:Male; D052940:Merozoites / Q000276:immunology*; D018512:Parasitemia / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D015415:Biomarkers; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C077028:merozoite major surface antigen, Plasmodium