title: Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36.
abstract: BACKGROUND
  Up to now a malaria vaccine remains elusive. The Plasmodium falciparum serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda.
  
  
  METHODS
  We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21-40 year-olds) to 1-mL BK-SE36 (BKSE1.0) (n = 36) or saline (n = 20) and in Stage2 (6-20 year-olds) to BKSE1.0 (n = 33), 0.5-mL BK-SE36 (BKSE0.5) (n = 33), or saline (n = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130-365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals.
  
  
  RESULTS
  Nearly all subjects who received BK-SE36 had induration (Stage1, n = 33, 92%; Stage2, n = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56-2.43], p = 0.004) and 6-10 year-olds (5.71-fold [95% CI, 2.38-13.72], p = 0.002) vaccinated with BKSE1.0. Immunogenicity response to BKSE0.5 was low and not significant (1.55-fold [95% CI, 1.24-1.94], p = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in BKSE1.0 and 10 cases/33 subjects in BKSE0.5 vs. 29 cases/66 subjects in the control group. Risk ratio for BKSE1.0 was 0.48 (95% CI, 0.24-0.98; p = 0.04).
  
  
  CONCLUSIONS
  BK-SE36 is safe and immunogenic. The promising potential of BK-SE36, observed in the follow-up study, warrants a double-blind phase 1/2b trial in children under 5 years.
  
  
  BACKGROUND
  Controlled-Trials.com ISRCTN71619711.
authors.affiliation: Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Nirianne Marie Q
authors.initials: NM
authors.lastname: Palacpac
authors.forename: Edward
authors.initials: E
authors.lastname: Ntege
authors.forename: Adoke
authors.initials: A
authors.lastname: Yeka
authors.forename: Betty
authors.initials: B
authors.lastname: Balikagala
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shirai
authors.forename: Masanori
authors.initials: M
authors.lastname: Yagi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ito
authors.forename: Wakaba
authors.initials: W
authors.lastname: Fukushima
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirota
authors.forename: Christopher
authors.initials: C
authors.lastname: Nsereko
authors.forename: Takuya
authors.initials: T
authors.lastname: Okada
authors.forename: Bernard N
authors.initials: BN
authors.lastname: Kanoi
authors.forename: Kohhei
authors.initials: K
authors.lastname: Tetsutani
authors.forename: Nobuko
authors.initials: N
authors.lastname: Arisue
authors.forename: Sawako
authors.initials: S
authors.lastname: Itagaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tougan
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Ueda
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Egwang
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Horii
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008018:Life Cycle Stages; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000254:growth & development* / Q000276:immunology*; D016896:Treatment Outcome; D014454:Uganda; D014611:Vaccination; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; C480167:serine repeat antigen 5, Plasmodium falciparum