Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36

PLoS One. 2013 May 28;8(5):e64073. doi: 10.1371/journal.pone.0064073. Print 2013.

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).

Conclusion: 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.

Trial registration: Controlled-Trials.com ISRCTN71619711.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Protozoan / immunology
  • Antigens, Protozoan / immunology*
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Life Cycle Stages*
  • Malaria Vaccines / adverse effects
  • Malaria Vaccines / immunology*
  • Malaria, Falciparum / immunology*
  • Malaria, Falciparum / prevention & control*
  • Plasmodium falciparum / growth & development*
  • Plasmodium falciparum / immunology*
  • Treatment Outcome
  • Uganda
  • Vaccination
  • Young Adult

Substances

  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Malaria Vaccines
  • serine repeat antigen 5, Plasmodium falciparum

Associated data

  • ISRCTN/ISRCTN71619711

Grants and funding

BIKEN is the vaccine manufacturer, clinical trial sponsor for Phase 1b and provided funding support for the follow-up study. BIKEN was involved in the design and conduct of the study and provided logistical support during the trial. The confidentiality agreement between the sponsor and the investigators permit publication. BIKEN permitted authors access and independent analysis of the data for publication. TH received the following grants in Japan as additional support for trial-related travels and activities: (2006–2010) Grant-in-Aids for Scientific Research (18073013) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); (2007–2009) Regional Innovation Cluster Program, MEXT; (2010–2011) Regional Innovation Strategy Support Program, MEXT; (2009–2011) Bridge Program to Promote Technological Development from Basic Research to Clinical Research, New Energy and Industrial Technology Development Organization (NEDO). MEXT had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Quintiles, a contract research organization, was contracted by BIKEN for the clinical trial. Quintiles provided on-site training on GCP, randomization, monitoring, data management and analysis. The individuals and their roles are detailed in the Acknowledgments.