Safety and immunogenicity of BK-SE36 in a blinded, randomized, controlled, age de-escalating phase Ib clinical trial in Burkinabe children

Abstract

BackgroundA blood-stage vaccine targeting the erythrocytic-stages of the malaria parasite Plasmodium falciparum could play a role to protect against clinical disease. Antibodies against the P. falciparum serine repeat antigen 5 (SE47 and SE36 domains) correlate well with the absence of clinical symptoms in sero-epidemiological studies. A previous phase Ib trial of the recombinant SE36 antigen formulated with aluminum hydroxyl gel (BK-SE36) was promising. This is the first time the vaccine candidate was evaluated in young children below 5 years using two vaccination routes.MethodsSafety and immunogenicity of BK-SE36 was assessed in a double-blind, randomized, controlled, age de-escalating phase Ib trial. Fifty-four Burkinabe children in each age cohort, 25–60 or 12–24 months, were randomized in a 1:1:1 ratio to receive three doses of BK-SE36 either by intramuscular (BK IM) or subcutaneous (BK SC) route on Day 0, Week 4, and 26; or the control vaccine, Synflorix®via IM route on Day 0, Week 26 (and physiological saline on Week 4). Safety data and samples for immunogenicity analyses were collected at various time-points.ResultsOf 108 subjects, 104 subjects (96.3%) (Cohort 1: 94.4%; Cohort 2: 98.1%) received all three scheduled vaccine doses. Local reactions, mostly mild or of moderate severity, occurred in 99 subjects (91.7%). The proportion of subjects that received three doses without experiencing Grade 3 adverse events was similar across BK-SE36 vaccines and control arms (Cohort 1: 100%, 89%, and 89%; and Cohort 2: 83%, 82%, and 83% for BK IM, BK SC, and control, respectively). BK-SE36 vaccine was immunogenic, inducing more than 2-fold change in antibody titers from pre-vaccination, with no difference between the two vaccination routes. Titers waned before the third dose but in both cohorts titers were boosted 6 months after the first vaccination. The younger cohort had 2-fold and 4-fold higher geometric mean titers compared to the 25- to 60-month-old cohort after 2 and 3 doses of BK-SE36, respectively.ConclusionBK-SE36 was well tolerated and immunogenic using either intramuscular or subcutaneous routes, with higher immune response in the younger cohort.Clinical Trial Registrationhttps://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=934, identifier PACTR201411000934120.

African-specific polymorphisms in Plasmodium falciparum serine repeat antigen 5 in Uganda and Burkina Faso clinical samples do not interfere with antibody response to BK-SE36 vaccination

“…The epitope mapping data suggest that (i) intrinsically unstructured regions allow some flexibility for the epitopes to interact with other molecules/proteins; (ii) the regions adjacent to the repeats are not strictly disordered as they showed a tendency to form a secondary structure; (iii) the protective epitopes of BK-SE36 are located in the N-terminal region where the repeat number of octamer units varied among alleles; and (iv) serum from mice and squirrel monkeys vaccinated with BK-SE36 also showed a broad range of reactivity against peptides covering the SR region (Yagi et al, 2014). Indeed, serum samples from clinical trial participants that received BK-SE36 preferentially recognized epitopes corresponding to the SR and flanking regions (including 13mer insertion/deletion, polyserine residue and 17-mer dimorphic region) (Ezoe et al, 2020;Bougouma et al, 2022). Thus, these indicate that the antibodies induced by BK-SE36 vaccination bound, with reproducibility, to epitopes located in the disordered regions of the protein.…”

“…If this interpretation is true, young children or individuals with limited malaria infection history would respond better to BK-SE36 vaccination similar to malaria naïve Japanese adults. Indeed, the seroconversion rate was higher in the 24-60-month-old and 12-24-month-old Burkinabe children (79-83% after two-and 89-97% after three-vaccinations) (Bougouma et al, 2022). This immune tolerance could also explain why SERA5 is less likely to be under substantial immune selection pressure compared to other blood-stage malaria vaccine antigens such as AMA1 and CSP.…”

“…The Burkina Faso trial was a double-blind, randomized, controlled, age de-escalation safety and immunogenicity trial and follow-up study conducted in Banfora, south western Burkina Faso (Pan African Clinical Trials Registry: PACTR201411000934120; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=934 ) (Bougouma et al, 2022). The trial site, Unitéde Recherche Clinique de Banfora, is in a region where transmission occurs throughout the year with a peak for clinical malaria occurring within the 4 months (June-September) of the rainy season of May-November (Tiono et al, 2014).…”

“…The phase 1b randomized trial and follow-up study in Uganda, conducted in 2010-2012, showed that the vaccine was safe and immunogenic; and the 6-20-year-olds that received the vaccine had a reduced risk of time-to-first episodes and all episodes of high parasitemia (>5000 parasites/µL) and fever at 130-365 days post-second vaccination (Palacpac et al, 2013). A clinical trial in Burkina Faso with 12-60-month-old children was also completed (Bougouma et al, 2022).…”

Plasmodium falciparum infection coinciding with the malaria vaccine candidate BK-SE36 administration interferes with the immune responses in Burkinabe children

“…Phase I safety and immunogenicity trials of BK-SE36 were conducted in healthy, malaria-naïve Japanese adults ( 10 ), in malaria-exposed Ugandan volunteers aged 6- to 32-year-old ( 21 ), and in healthy 12- to 60-month-old Burkinabe children ( 22 ). These trials have demonstrated the safety and immunogenicity of BK-SE36.…”