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).

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.

Figure 1. Enrollment and outcomes for Stage1.

The number of subjects screened, those excluded (due to various medical conditions), those randomized to each treatment, events leading to changes in subject number and the final number of subjects contributing to analyses are indicated. All subjects were included in the full analysis set. Subjects with protocol deviations were excluded from the immunogenicity per-protocol set. Exclusive use of the whole third floor at LMC, facilitated transport and LMC being a primary health provider in Lira and neighboring districts favored high subject compliance rates to clinic visits.

Figure 2. Enrollment and outcomes for Stage2.

Trial schedule was similar to Stage1. Ethical clearance for a longitudinal study with additional age-match control group (no intervention) was approved after the trial. In the follow-up study, scheduled four weekly visits continued for up to 1-year post-second vaccination.

Figure 3. Kaplan-Meier curves of falciparum malaria episodes in 6 to 20-year old, 130–365 days post-second vaccination.

Incidence of first (or only) high parasitemia (≥5000 parasites/µL) episodes. The control group consisted of both placebo (vaccinated with saline) and subjects with no intervention. (A) According to vaccine group. Log rank test detected significant difference between control vs. BKSE1.0 (Chi square 4.92, p = 0.03) but not vs. BKSE0.5 (Chi square 1.59, p = 0.21). (B) Pooled analysis of all subjects vaccinated with BK-SE36 (BKSE1.0, BKSE0.5) compared to control with at least one episode of high parasitemia (Chi square 5.27, p = 0.02) or (C) high parasitemia+fever (axillary temperature ≥37.5°C) (Chi square 9.10, p = 0.003).