title: RTS,S vaccination is associated with serologic evidence of decreased exposure to Plasmodium falciparum liver- and blood-stage parasites.
abstract: The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS,S (n = 291) versus comparator vaccine (n = 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual blood-stage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure. Together, these data provide insight into the mechanism by which RTS,S protects from malaria.
authors.affiliation: ‡ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain; §Manhiça Health Research Centre, Manhiça, Mozambique; jcampo@antigendiscovery.com.
authors.forename: Joe J
authors.initials: JJ
authors.lastname: Campo
authors.affiliation: ‡ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain; §Manhiça Health Research Centre, Manhiça, Mozambique;
authors.forename: John J
authors.initials: JJ
authors.lastname: Aponte
authors.affiliation: ¶Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD;
authors.forename: Jeff
authors.initials: J
authors.lastname: Skinner
authors.affiliation: ‡‡Department of Medicine, University of California Irvine, Irvine, CA;
authors.forename: Rie
authors.initials: R
authors.lastname: Nakajima
authors.affiliation: ‖Antigen Discovery Inc., Irvine, CA;
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Molina
authors.affiliation: ‡‡Department of Medicine, University of California Irvine, Irvine, CA;
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.affiliation: §Manhiça Health Research Centre, Manhiça, Mozambique; **Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique.
authors.forename: Jahit
authors.initials: J
authors.lastname: Sacarlal
authors.affiliation: ‡ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain; §Manhiça Health Research Centre, Manhiça, Mozambique;
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Alonso
authors.affiliation: ¶Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD;
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.affiliation: ‡‡Department of Medicine, University of California Irvine, Irvine, CA; ‖Antigen Discovery Inc., Irvine, CA;
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
authors.affiliation: ‡ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain; §Manhiça Health Research Centre, Manhiça, Mozambique;
authors.forename: Carlota
authors.initials: C
authors.lastname: Dobaño
mesh_terms: D000953:Antigens, Protozoan / Q000276:immunology; D016022:Case-Control Studies; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D006801:Humans; D007223:Infant; D008099:Liver / Q000469:parasitology*; D017780:Malaria Vaccines / Q000008:administration & dosage*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D009073:Mozambique; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D040081:Protein Array Analysis; D034101:Sporozoites / Q000187:drug effects / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines