Safety and immunogenicity of BK-SE36/CpG malaria vaccine in healthy Burkinabe adults and children: a phase 1b randomised, controlled, double-blinded, age de-escalation trial

Abstract

Background: BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparum serine repeat antigen5 (SE36), adsorbed to aluminium hydroxide gel and reconstituted, prior to administration, with synthetic oligodeoxynucleotides bearing CpG motifs. In healthy Japanese adult males, BK-SE36/CpG was well tolerated. This study assessed its safety and immunogenicity in healthy malaria-exposed African adults and children.

Methods: A double-blind, randomised, controlled, age de-escalating clinical trial was conducted in an urban area of Ouagadougou, Burkina Faso. Healthy participants (n=135) aged 21-45 years (Cohort 1), 5-10 years (Cohort 2) and 12-24 months (Cohort 3) were randomised to receive three vaccine doses (Day 0, 28 and 112) of BK-SE36/CpG or rabies vaccine by intramuscular injection.

Results: One hundred thirty-four of 135 (99.2%) subjects received all three scheduled vaccine doses. Vaccinations were well tolerated with no related Grade 3 (severe) adverse events (AEs). Pain/limitation of limb movement, headache in adults and fever in younger children (all mild to moderate in intensity) were the most frequently observed local and systemic AEs. Eighty-three of BK-SE36/CpG (91%) recipients and 37 of control subjects (84%) had Grade 1/2 events within 28 days post vaccination. Events considered by the investigator to be vaccine related were experienced by 38% and 14% of subjects in BK-SE36/CpG and control arms, respectively. Throughout the trial, six Grade 3 events (in 4 subjects), not related to vaccination, were recorded in the BK-SE36/CpG arm: 5 events (in 3 subjects) within 28 days of vaccination. All serious adverse events (SAEs) (n=5) were due to severe malaria (52-226 days post vaccination) and not related to vaccination. In all cohorts, BK-SE36/CpG arm had higher antibody titres after Dose 3 than after Dose 2. Younger cohorts had stronger immune responses (12-24-month-old > 5-10 years-old > 21-45 years-old). Sera predominantly reacted to peptides that lie in intrinsically unstructured regions of SE36. In the control arm, there were no marked fold changes in antibody titres and participants' sera reacted poorly to all peptides spanning SE36.

Conclusion: BK-SE36/CpG was well-tolerated and immunogenic. These results pave the way for further proof-of-concept studies to demonstrate vaccine efficacy.

Clinical trial registration: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1921, PACTR201701001921166.

Keywords: BK-SE36/CpG; Plasmodium falciparum; SERA5; immunogenicity; malaria vaccine; safety; serine repeat antigen.

Figure 1

Trial profile for 3 age cohorts. The number of subjects screened, excluded, randomised and included in the final analyses is shown. The age de-escalation GO/No GO criteria were based on safety data. For each participant there was a 4-month vaccination period and a one-year follow-up after the first vaccination. (A) Cohort 1, 21-45 years. (B) Cohort 2, 5-10 years. (C) Cohort 3, 12-24-month-old.

Figure 2

Changes in laboratory autoimmune markers. Blue: BK-SE36 arm; pink: control arm. Day 0: prior to first Dose; Day 140: 4 weeks post Dose 3; Day 365: 1 year post Dose 1. Each row corresponds to a cohort indicated on the left. Results were interpreted according to CERBA Criteria: (A) Assessment for ANA: results were categorised based on immunofluorescence testing of the subject’s serum at various dilutions and were reported either as negative (-) or on fluorescent patterns (+: either, speckled, nuclear, homogenous, centromere or NuMa1) observed. (B) Assessment for dsDNA: <10 IU/mL, negative; 10-15 IU/mL, assay limit/threshold; >15 IU/mL, positive. (C, D) ANCA results were first tested by indirect immunofluorescence. Any titre <20 is treated as negative. When titres are ≥20, the specificity of ANCA was investigated by ELISA to help identify the targeted protein in the neutrophils: cANCA (or cytoplasmic ANCA) targets a protein called proteinase 3 (anti-PR3) and pANCA (or perinuclear ANCA) targets a protein called myeloperoxidase (anti-MPO). Teal: BK-SE36 arm; orange: control arm. (C) Assessment for anti-MPO: <3.5 IU/mL, negative; 3.5-5.0 IU/mL, assay limit/threshold; >5.0 IU/mL, positive. (D) Assessment for anti-PR3: < 2.0 IU/mL, negative; 2.0-3.0 IU/mL, assay limit/threshold; >3.0 IU/mL, positive.

Figure 3

Fold change in antibody titres from Day 0. In the 3 age cohorts, fold change in antibody titres from baseline were calculated by dividing the titre at subsequent visits by the titre at Day 0 (prior to Dose 1). The value of 8 was assigned to undetectable titres when calculating the fold change. (A) Cohort 1, 21-45 years. (B) Cohort 2, 5-10 years. (C) Cohort 3, 12-24-month-old. Blue: BK-SE36 arm; pink: control arm.