Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults

Abstract

Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses (p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults.

Fig. 1. Screening, enrollment, randomization, and follow-up of study participants.

Of 93 subjects screened, 48 met the study criteria and were enrolled and randomly assigned to two treatment groups. Treatment Group 1 comprised 23 participants receiving the thermostable single-vial ID93 + GLA-SE vaccine; Treatment Group 2 comprised 25 participants receiving the non-thermostable two-vial ID93 + GLA-SE vaccine. The safety population represents participants receiving at least one injection. The per-protocol population represents participants that completed the study according to plan.

Fig. 2. ID93-specific antibody responses in serum and B-cell responses in PBMCs.

n = 20–25 biologically independent samples depending on treatment group and time point, see Supplementary Table 1. a Serum antibody response rate was calculated as at least a fourfold increase in ID93-specific IgG from baseline as measured by ELISA. Response rates were compared using Fisher’s exact test. Differences were detected based on a two-sided test and p ≤ 0.05 (α = 0.05) with Bonferroni adjustment to account for the multiple time points. b–i Data were compared between the two treatment groups using the Wilcoxon rank-sum test with Bonferroni adjustment to account for the multiple time points. b Fold changes in ID93-specific total IgG in serum from baseline as measured by ELISA. **p = 0.0023 (Study Day 70), *p = 0.0495 (Study Day 84). c Longitudinal plot of group MEPT for ID93-specific total IgG in serum as measured by ELISA. **p = 0.0061. d–g Longitudinal plots of group MEPT ID93-specific IgG subclasses in serum as measured by ELISA. d IgG1. **p = 0.0032 (Study Day 70), **p = 0.0040 (Study Day 84). e IgG2. f IgG3. g IgG4. h Enumeration of ID93-specific IgG-secreting cells in PBMC samples as measured by ELISpot assay. **p = 0.0085. i Enumeration of ID93-specific IgG memory B cells in PBMC samples as measured by ELISpot assay. Mean values are represented by symbols, and error bars show the 95% CI on the mean. Asterisks indicate a statistically significant difference (*p < 0.05, **p < 0.01) between treatment groups at that time point after correction for multiple comparisons. Source data are provided as a Source Data file.

Fig. 3. ID93-specific T cell responses in PBMCs.

n = 16–25 biologically independent samples depending on treatment group and time point, see Supplementary Tables 2–4. a IFN-γ response rate by ELISpot assay using ID93-stimulated PBMCs and calculated by MIMOSA as a change from baseline using background-subtracted SFUs. b Enumeration of ID93-stimulated IFN-γ-secreting cells in PBMC samples as measured by ELISpot assay. c IL-10 response rate by ELISpot assay using ID93-stimulated PBMCs and calculated by MIMOSA as a change from baseline using background-subtracted SFUs. d Enumeration of ID93-stimulated IL-10-secreting cells in PBMC samples as measured by ELISpot assay. e Response rate by ICS of CD4⁺ T cells expressing Any Two cytokines among CD154, TNF, IFN-γ, IL-2, IL-21, and IL-4 calculated by MIMOSA as a change from baseline using background-subtracted frequencies and total counts. f Frequencies of ID93-stimulated CD4⁺ T cells expressing Any Two cytokines in PBMC samples as measured by ICS. g Single cytokine and polyfunctional cytokine CD4⁺ T cell phenotype at Study Days 70 and 84 as measured by ICS. Proportions of ID93-stimulated CD4⁺ T cells expressing different single cytokines and cytokine combinations at Study Days 70 and 84 represented by median frequencies. The pie chart area is proportional to the total median frequencies for each readout. a, c, e Response rate plots show mean values represented by symbols, and error bars show the 95% CI on the mean. Response rates were compared using Fisher’s exact test. Differences were detected based on a two-sided test and p ≤ 0.05 (α = 0.05) with Bonferroni adjustments to account for the multiple time points. b, d, f Dot plots represent all background-subtracted values as symbols, with solid lines representing median values and error bars representing the interquartile range. Data were compared between the two treatment groups using the Wilcoxon rank-sum test with Bonferroni adjustment to account for the multiple time points. Source data are provided as a Source Data file.