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.

Palacpac NM, Ntege E, Yeka A, Balikagala B, Suzuki N, Shirai H, Yagi M, Ito K, Fukushima W, Hirota Y, Nsereko C, Okada T, Kanoi BN, Tetsutani K, Arisue N, Itagaki S, Tougan T, Ishii KJ, Ueda S, Egwang TG, Horii T.

Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.

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.

PMID: 23724021

 

Supplement:

Although our clinical trial was not designed to measure vaccine efficacy, a follow-up study of the subjects yielded data on malaria incidences covering two malaria peak seasons (from 130 to 365 days post-second vaccination). BK-SE36 vaccinees have extended time-to-first high parasitemia (>5000 parasites/μL: hazard ratio, 0.5; 95% CI, 0.28-0.92, p=0.02) and multiple high parasitemia episodes (hazard ratio, 0.57; 95% CI, 0.33-0.99, p=0.05); as well as time-to-first high parasitemia and fever (>5000 parasites/μL + ≥37.5°C: hazard ratio, 0.28; 95% CI, 0.12-0.66, p<0.01) and multiple high parasitemia + fever episodes (hazard ratio, 0.34; 95% CI, 0.15-0.76, p=0.01). This constitutes a first report of an erythrocytic vaccine candidate that is well tolerated, could show substantial difference in time-to-first high parasitemia and multiple malaria episodes in an endemic area covering 2 peak seasons with a study population reporting 84% usage of bednets and minimal practice of indoor insecticide spraying.

Of the known Plasmodium protozoan parasites that infect humans, P. falciparum accounts for greater than 90% of all malaria-attributable deaths and morbidity. Development of malaria vaccines is still ongoing and except for the advanced stages in the clinical trials for the anti-sporozoite vaccine RTS,S/AS01, majority of blood-stage antigens fell short of expectation in field trials (hampered by antigenic variation, extensive polymorphism and conformation-dependency that showed no or poor effectiveness in malaria endemic areas; or in some instances having safety concerns).  There is a strong justification for blood-stage vaccines since protection from anti-sporozoite vaccine is not complete and long lasting; asexual-stage parasites cause symptomatic malaria; blood-stage antigens are targets of acquired immunity; and controlling parasite density may reduce the generation of gametocytes.

A Phase 1b randomized, two-stage, two-dose trial and follow-up study for a blood-stage vaccine candidate known as BK-SE36 was recently completed in Uganda.  BK-SE36 is based from a recombinant protein called SE36 derived from erythrocytic stage serine repeat antigen5 (SERA5) protein of P. falciparum.  In previous studies, SERA5 is neither variant-specificnor conformation-dependent, showing that BK-SE36 is likely to overcome most of the challenges of blood-stage vaccines. In this first report for BK-SE36 in endemic areas, BK-SE36 was demonstrated to be safe and has acceptable immunogenicity.

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