Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36

<div><p>Background</p><p>Up to now a malaria vaccine remains elusive. The <i>Plasmodium falciparum</i> 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.</p><p>Methods</p><p>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 (<i>BKSE1.0</i>) (<i>n</i> = 36) or saline (<i>n</i> = 20) and in Stage2 (6–20 year-olds) to <i>BKSE1.0</i> (<i>n</i> = 33), 0.5-mL BK-SE36 (<i>BKSE0.5</i>) (<i>n</i> = 33), or saline (<i>n</i> = 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.</p><p>Results</p><p>Nearly all subjects who received BK-SE36 had induration (Stage1, <i>n</i> = 33, 92%; Stage2, <i>n</i> = 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], <i>p</i> = 0.004) and 6–10 year-olds (5.71-fold [95% CI, 2.38–13.72], <i>p</i> = 0.002) vaccinated with <i>BKSE1.0.</i> Immunogenicity response to <i>BKSE0.5</i> was low and not significant (1.55-fold [95% CI, 1.24–1.94], <i>p</i> = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in <i>BKSE1.0</i> and 10 cases/33 subjects in <i>BKSE0.5 vs.</i> 29 cases/66 subjects in the control group. Risk ratio for <i>BKSE1.0</i> was 0.48 (95% CI, 0.24–0.98; <i>p</i> = 0.04).</p><p>Conclusion</p><p>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.</p><p>Trial Registration</p><p>Controlled-Trials.com ISRCTN71619711 <a href="http://www.controlled-trials.com/ISRCTN71619711" target="_blank">ISRCTN71619711</a></p></div