Abstract
BackgroundUp 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.MethodsWe 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.ResultsNearly 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).ConclusionBK-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 RegistrationControlled-Trials.com ISRCTN71619711 ISRCTN71619711
Highlights
A malaria vaccine is crucial in the face of continued high malaria transmission, increasing drug and insecticide resistance, and inadequate coverage of current control interventions [1,2,3,4]
serine repeat antigen-5 (SERA5) was selected for clinical development on the basis of the following: (i) epidemiological studies showing high antibody titers that inversely correlate with malaria symptoms and severe disease; (ii) in vitro studies demonstrating induction of antibodies that are inhibitors of parasite growth, exert antibody-dependent complement-mediated lysis of schizonts, or antibody-dependent monocyte-mediated parasite growth inhibition; and (iii) animal studies demonstrating protection against P. falciparum challenge in non-human primates [14,15]
A blood-stage vaccine either alone or as a component of a multistage vaccine would be useful to protect against severe or epidemic malaria. This is the first comprehensive safety and immunogenicity study of BK-SE36, a malaria vaccine candidate based on P. falciparum SERA5, in a malaria endemic population
Summary
A malaria vaccine is crucial in the face of continued high malaria transmission, increasing drug and insecticide resistance, and inadequate coverage of current control interventions [1,2,3,4]. SERA5 was selected for clinical development on the basis of the following: (i) epidemiological studies showing high antibody titers that inversely correlate with malaria symptoms and severe disease; (ii) in vitro studies demonstrating induction of antibodies that are inhibitors of parasite growth, exert antibody-dependent complement-mediated lysis of schizonts, or antibody-dependent monocyte-mediated parasite growth inhibition; and (iii) animal studies demonstrating protection against P. falciparum challenge in non-human primates [14,15]. The safety and immunogenicity of BK-SE36 was demonstrated in a phase1a trial in malaria naıve Japanese adults [14]. 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 assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda
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