Safety and Immunogenicity of the GamTBvac, the Recombinant Subunit Tuberculosis Vaccine Candidate: A Phase II, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study

Abstract

GamTBvac is a candidate tuberculosis vaccine with two fusion proteins, containing Ag85a, ESAT6, CFP10, and a dextran-binding domain (DBD). Phase II of a double-blind, randomized, multicenter, placebo-controlled study in parallel groups in healthy adults to evaluate the safety and immunogenicity of GamTBvac in 180 previously-vaccinated with Bacillus Calmette-Guérin vaccine (BCG) healthy volunteers without Mycobacterium tuberculosis (MTB) infection was conducted. The dose (0.5 mL) of either the study drug or a placebo was administered subcutaneously twice with an 8-week interval. At eight timepoints from 14 to 150 days, whole blood and sera were assayed. Antigen-specific T-cell responses were measured by an in-house interferon-gamma release assay (IGRA-test), the QuantiFERON (QTF) test, and intracellular cytokine staining (ICS). For antibody response detection, the bead-based multiplex immunoassay (MIA) was applied. The vaccine confirmed an acceptable safety profile previously shown in a first-in-human clinical study. After stimulation with both fusions, the highest median level of INF-γ was detected on day 21. The GamTBvac vaccine induced antigen-specific interferon-gamma release, Th1 cytokine-expressing CD4⁺ T-cells, and IgG responses and results support further clinical testing of GamTBvac.

Keywords: BCG booster; clinical trials; safety and immunogenicity; subunit vaccine; tuberculosis.

Figure 1

Dynamics of interferon gamma (INF-γ) production after whole-blood stimulation in volunteers and the placebo group, performed with an in-house INF-γ release assay (IGRA) on study days 0, 21, 57, 64, 78, 87, 120, and 150. (A). Stimulation of samples with DBD-Ag85a; (B). Stimulation of samples with DBD-ESAT6-CFP10; medians and interquartile ranges are shown. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 2

Cytokine expression profiles of CD4⁺ T-cells following stimulation with GamTBvac components in the vaccine recipients’ group. (A). Stimulation of samples with DBD-Ag85a; (B). Stimulation of samples with DBD-ESAT6-CFP10. Black arrows indicate specific CD4⁺ T-cells responses that differ significantly from those in the placebo group with a minimum p < 0.05. Medians and interquartile ranges are shown. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 3

IgG antibody profiles after the immunization with GamTBvac specific to DBD-Ag85a and DBD-ESAT6-CFP10 (A), and individual vaccine components (B,C) in the group of vaccine recipients. ** p < 0.01, **** p < 0.0001, ns—not significant.

Figure 4

Humoral responses to vaccine fusions and their components in the immunized volunteers’ group on days 21 and 78. (A). Percentage ratio of positive/negative IgG responses to fusion DBD-Ag85a (fDA) is represented in the left dot plots. Percentage ratio of positive/negative IgG responses to fDA and its components is illustrated in the right dot plots. (B). Similar plots for fusion DBD-ESAT6-CFP10 (fDEC).