Safety and Immunogenicity of the ID93 + GLA-SE Tuberculosis Vaccine in BCG-Vaccinated Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

Abstract

Introduction: This randomized, double-blind, placebo-controlled, phase 2a trial was conducted to evaluate the safety and immunogenicity of the ID93 + glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) vaccine in human immunodeficiency virus (HIV)-negative, previously Bacillus Calmette-Guérin (BCG)-vaccinated, and QuantiFERON-TB-negative healthy adults in South Korea.

Methods: Adults (n = 107) with no signs or symptoms of tuberculosis were randomly assigned to receive three intramuscular injections of 2 μg ID93 + 5 μg GLA-SE, 10 μg ID93 + 5 μg GLA-SE, or 0.9% normal saline placebo on days 0, 28, and 56. For safety assessment, data on solicited adverse events (AEs), unsolicited AEs, serious AEs (SAEs), and special interest AEs were collected. Antigen-specific antibody responses were measured using serum enzyme-linked immunosorbent assay. T-cell immune responses were measured using enzyme-linked immunospot and intracellular cytokine staining.

Results: No SAEs, deaths, or AEs leading to treatment discontinuation were found. The solicited local and systemic AEs observed were consistent with those previously reported. Compared with adults administered with the placebo, those administered with three intramuscular vaccine injections exhibited significantly higher antigen-specific antibody levels and Type 1 T-helper cellular immune responses.

Conclusion: The ID93 + GLA-SE vaccine induced antigen-specific cellular and humoral immune responses, with an acceptable safety profile in previously healthy, BCG-vaccinated, Mycobacterium tuberculosis-uninfected adult healthcare workers.

Trial registration: This clinical trial was retrospectively registered on 16 January 2019 at Clinicaltrials.gov (NCT03806686).

Keywords: GLA-SE; Immunogenicity; Safety; Subunit vaccine; Tuberculosis.

Fig. 1

Study design and trial profile. a Study design and scheduled follow-ups and blood collections. Safety assessment of ID93 + GLA-SE recipients (cohorts 1 and 2) compared with placebo recipients (cohort 3) was conducted following three administrations at days 0, 28, and 56, and follow-ups for 12 months (421 days) from the final vaccination. Blood samples for immunogenicity assessment of ID93 + GLA-SE recipients compared with placebo recipients were collected on days 0 (baseline), 28, 56, 84, and 421. b Eligible participants were randomly assigned in a 1:1:1 ratio to one of three treatment groups to receive either 2 μg ID93 + 5 μg GLA-SE (cohort 1), 10 μg ID93 + 5 μg GLA-SE (cohort 2), or 0.9% normal saline placebo (cohort 3) on days 0, 28, and 56

Fig. 2

Immunogenicity assessment of antigen-specific interferon-γ (IFN-γ)-secreting cells. ID93-specific IFN-γ producing T cells using ELISpot. PBMCs from blood samples obtained before vaccination (day 0) and on days 28, 56, 84, and 421 after vaccination were stimulated with ID93 fusion protein in vitro. Results are shown for subjects vaccinated with 2 μg ID93 + 5 μg GLA-SE (cohort 1), 10 μg ID93 + 5 μg GLA-SE (cohort 2), or a saline placebo (cohort 3). a Data are represented as the mean and standard deviation and b each box extends from the 25th to 75th percentile, and the line in the middle of the box represents the median value. The whiskers go down to the minimum value and extend to the maximum value. Values were considered significantly different if p < 0.05 within the group, as indicated by *p < 0.05, **p < 0.01, or ****p < 0.0001

Fig. 3

Antigen-specific cytokine(s) positive CD4⁺ T cells from stimulated cryopreserved peripheral blood mononuclear cells. Blood samples were obtained before each vaccination (days 0, 28, and 56) and at 4 weeks and 12 months after the final vaccination (days 84 and 421). a The percentages of ID93-specific CD4⁺ T cells producing any of the three T-helper type 1 (Th1) cytokines, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2) (single producer, double producers, and triple producers) were measured in PBMC stimulated with ID93 antigen using intracellular cytokine staining and flow cytometry from each study participant. b The percentages of ID93 specific CD8⁺ T-cell responses. Values were considered significantly different if p < 0.05, as indicated by *p < 0.05 or ****p < 0.0001. For distribution of multifunctional CD4⁺ T cells by visits, the data is displayed from the two cohorts administered ID93 + GLA-SE; c cohort 1 and d cohort 2. Data are presented as the percentage frequency of ID93-specific CD4⁺ T cells expressing either 4, 3, 2, or 1 immune marker combination(s) including IFN-γ, IL-2, TNF-α, and CD40L at days 0, 28, 56, 84, and 421 for each cohort. Pie charts represent the mean proportions of cells expressing (after in vitro stimulation) any single marker and combination of IFN-γ, IL-2, TNF-α, and CD40L marker-positive CD4⁺ T cells of the total immune marker-expressing CD4⁺ T-cell response, at days 84 and 421 after vaccination. Paired responses of immune marker-positive CD4⁺ T cells on days 0, 28, 56, 84, and 421 after vaccination are shown in c cohort 1 and d cohort 2