title: The effect of immunization schedule with the malaria vaccine candidate RTS,S/AS01E on protective efficacy and anti-circumsporozoite protein antibody avidity in African infants.
abstract: BACKGROUND
  The malaria vaccine RTS,S induces antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and the concentration of Immunoglobulin G (IgG) against the repeat region of CSP following vaccination is associated with protection from P. falciparum malaria. So far, only the quantity of anti-CSP IgG has been measured and used to predict vaccination success, although quality (measured as avidity) of the antigen-antibody interaction shall be important since only a few sporozoites circulate for a short time after an infectious mosquito bite, likely requiring fast and strong binding.
  
  
  METHODS
  Quantity and avidity of anti-CSP IgG in African infants who received RTS,S/AS01E in a 0-1-2-month or a 0-1-7-month schedule in a phase 2 clinical trial were measured by enzyme-linked immunosorbent assay. Antibody avidity was defined as the proportion of IgG able to bind in the presence of a chaotropic agent (avidity index). The effect of CSP-specific IgG concentration and avidity on protective efficacy was modelled using Cox proportional hazards.
  
  
  RESULTS
  After the third dose, quantity and avidity were similar between the two vaccination schedules. IgG avidity after the last vaccine injection was not associated with protection, whereas the change in avidity following second and third RTS,S/AS01E injection was associated with a 54% risk reduction of getting malaria (hazard ratio: 0.46; 95% confidence interval (CI): 0.22-0.99) in those participants with a change in avidity above the median. The change in anti-CSP IgG concentration following second and third injection was associated with a 77% risk reduction of getting malaria (hazard ratio: 0.23, 95% CI: 0.11-0.51).
  
  
  CONCLUSIONS
  Change in IgG response between vaccine doses merits further evaluation as a surrogate marker for RTS,S efficacy.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier NCT00436007 .
authors.affiliation: Eberhard Karls Universität Tübingen, Institut für Tropenmedizin, Wilhelmstraße 27, 72074, Tübingen, Germany. ajua.anthony@gmail.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ajua
authors.affiliation: Eberhard Karls Universität Tübingen, Institut für Tropenmedizin, Wilhelmstraße 27, 72074, Tübingen, Germany. bertrand.lell@lambarene.org.|Centre de Recherches Médicales de Lambaréné (CERMEL), BP118, Lambaréné, Gabon. bertrand.lell@lambarene.org.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), BP118, Lambaréné, Gabon. agnandjis@lambarene.org.
authors.forename: Selidji Todagbe
authors.initials: ST
authors.lastname: Agnandji
authors.affiliation: Kintampo Health Research Centre, PO Box 200, Kintampo, Ghana. kwakupoku.asante@kintampo-hrc.org.
authors.forename: Kwaku Poku
authors.initials: KP
authors.lastname: Asante
authors.affiliation: Kintampo Health Research Centre, PO Box 200, Kintampo, Ghana. seth.owusu-agyei@lshtm.ac.uk.|Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. seth.owusu-agyei@lshtm.ac.uk.
authors.forename: Seth
authors.initials: S
authors.lastname: Owusu-Agyei
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Bagamoyo, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania. gmwangoka@ihi.or.tz.
authors.forename: Grace
authors.initials: G
authors.lastname: Mwangoka
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Bagamoyo, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania. mmpina@ihi.or.tz.
authors.forename: Maxmilliam
authors.initials: M
authors.lastname: Mpina
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Bagamoyo, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania. nsalim@ihi.or.tz.
authors.forename: Nahya
authors.initials: N
authors.lastname: Salim
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Bagamoyo, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania. marcel.tanner@unibas.ch.|Swiss Tropical and Public Health Institute, Basel, Switzerland. marcel.tanner@unibas.ch.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
authors.affiliation: Bagamoyo Research and Training Centre of Ifakara Health Institute, Bagamoyo, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania. sabdulla@ihi.or.tz.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. johan.vekemans@gsk.com.
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. erik.x.jongert@gsk.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. marc.lievens@gsk.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Lievens
authors.affiliation: GlaxoSmithKline Biologicals, Rixensart, Belgium. pierre.cambron@gsk.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cambron
authors.affiliation: PATH Malaria Vaccine Initiative, 455 Massachusetts Avenue NW, Suite 1000, Washington, DC, 20001, USA. cockenhouse@path.org.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: Eberhard Karls Universität Tübingen, Institut für Tropenmedizin, Wilhelmstraße 27, 72074, Tübingen, Germany. peter.kremsner@uni-tuebingen.de.|Centre de Recherches Médicales de Lambaréné (CERMEL), BP118, Lambaréné, Gabon. peter.kremsner@uni-tuebingen.de.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Eberhard Karls Universität Tübingen, Institut für Tropenmedizin, Wilhelmstraße 27, 72074, Tübingen, Germany. benjamin.mordmueller@uni-tuebingen.de.|Centre de Recherches Médicales de Lambaréné (CERMEL), BP118, Lambaréné, Gabon. benjamin.mordmueller@uni-tuebingen.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
mesh_terms: D000915:Antibody Affinity / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007115:Immunization Schedule; D053208:Kaplan-Meier Estimate; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology*
chemical_list: D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan