title: A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens.
abstract: BACKGROUND
  The polymorphic nature of many malaria vaccine candidates presents major challenges to achieving highly efficacious vaccines. Presently, there is very little knowledge on the prevalence and patterns of functional immune responses to polymorphic vaccine candidates in populations to guide vaccine design. A leading polymorphic vaccine candidate against blood-stage Plasmodium falciparum is apical membrane antigen 1 (AMA1), which is essential for erythrocyte invasion. The importance of AMA1 as a target of acquired human inhibitory antibodies, their allele specificity and prevalence in populations is unknown, but crucial for vaccine design.
  
  
  METHODS
  P. falciparum lines expressing different AMA1 alleles were genetically engineered and used to quantify functional antibodies from two malaria-exposed populations of adults and children. The acquisition of AMA1 antibodies was also detected using enzyme-linked immunosorbent assay (ELISA) and competition ELISA (using different AMA1 alleles) from the same populations.
  
  
  RESULTS
  We found that AMA1 was a major target of naturally acquired invasion-inhibitory antibodies that were highly prevalent in malaria-endemic populations and showed a high degree of allele specificity. Significantly, the prevalence of inhibitory antibodies to different alleles varied substantially within populations and between geographic locations. Inhibitory antibodies to three specific alleles were highly prevalent (FVO and W2mef in Papua New Guinea; FVO and XIE in Kenya), identifying them for potential vaccine inclusion. Measurement of antibodies by standard or competition ELISA was not strongly predictive of allele-specific inhibitory antibodies. The patterns of allele-specific functional antibody responses detected with our novel assays may indicate that acquired immunity is elicited towards serotypes that are prevalent in each geographic location.
  
  
  CONCLUSIONS
  These findings provide new insights into the nature and acquisition of functional immunity to a polymorphic vaccine candidate and strategies to quantify functional immunity in populations to guide rational vaccine design.
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia.
authors.forename: Damien R
authors.initials: DR
authors.lastname: Drew
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia.|Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Danny W
authors.initials: DW
authors.lastname: Wilson
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia.
authors.forename: Salenna R
authors.initials: SR
authors.lastname: Elliott
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Cross
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia.|Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Terheggen
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hodder
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: Kenya Medical Research Institute, Kisian, Kenya.
authors.forename: Kiprotich
authors.initials: K
authors.lastname: Chelimo
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Arlene E
authors.initials: AE
authors.lastname: Dent
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Kazura
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, 3004, Australia. beeson@burnet.edu.au.|Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. beeson@burnet.edu.au.|Department of Microbiology, Monash University, Clayton, Victoria, Australia. beeson@burnet.edu.au.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
keywords: Antibodies; Apical membrane antigen 1; Immunity; Malaria; Plasmodium falciparum; Vaccines