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

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.


Inclusion criteria
To participate in the study, a volunteer must meet all of the following criteria: 1. Ability to understand the research requirements, signed informed consent form and consent to any restrictions applicable during the study. 2. The age of volunteers is from 18 to 49 years inclusive at the time of signing the informed consent. 3. Volunteers who are completely healthy based on a medical assessment, including medical history, physical examination, and laboratory examination.
4. Absence of signs of lung disease, confirmed by chest x-ray. 5. Body mass index (BMI) from 18 to 30 kg / m2, inclusive. 6. For female volunteers: women are eligible if they are not pregnant (pregnancy test (test strip) is negative at screening and on the day 0), no lactation, and at least one of the following conditions applies: a) no reproductive potential or b) women with preserved reproductive potential who agree to follow contraceptive recommendations throughout the study. 7. BCG vaccination was performed, which is documented in the medical history or the presence of a scar. 8. Positive result of PPD skin test: induration ≥ 5 mm and ≤ 9 mm. 9. The absence of markers of the immune response to the mycobacterial proteins ESAT6 and CFP10 in the Diaskintest and QuantiFERON TB Gold ELISA tests simultaneously at screening. Immune response to that proteins characterize the probable contact with M. tuberculosis prior to the start of the study. 10. No fact of living or working with someone diagnosed with TB within 3 months prior to day 0 of the study. 11. Absence of malignant neoplasms at the moment and within 5 years prior to inclusion in the study. 12. Absence of malignant blood diseases.

Noninclusion criteria
Volunteers who have at least one of the criteria listed below should not be included in the study: 1. Presence of symptoms of acute disease, including temperature in the armpit > 37.5 °C, within 5 days before the start of the study and on day 0 of the study. 2. History or presence of tuberculosis, including extrapulmonary tuberculosis. 3. Negative PPD skin test (<5 mm) or hyperergic positive PPD skin test results (> 9 mm). 4. Positive or questionable result in the Diaskintest and / or QuantiFERON TB Gold ELISA tests. 5. History or presence of autoimmune diseases or immunosuppression, or family history of congenital or hereditary immunodeficiency. 6. Positive test results for HIV-1/2 antibodies, HBsAg or hepatitis C antibodies at screening. 7. Use of immunosuppressive or other immunomodulatory medications within 42 days prior to day 0 of the study. 8. Use of immunoglobulin or blood products within 180 days before day 0 of the study, or scheduled administration during the study. 9. Use of any investigational drug or investigational vaccine within 90 days prior to the day of screening, or planned participation in other clinical trials during the study. 10. Use of antibacterial drugs within 14 days before day 0 of the study (oral administration) or within 28 days before day 0 of the study (parenteral administration).
11. Use of the study GamTBvac vaccine at any time prior to day 0 of the study. 12. Planned use/administration of the registered vaccine within 28 days before and 28 days after vaccination with the investigational vaccine. 13. Planned surgical intervention (on a scheduled basis) during the study. 14. History or laboratory evidence of any possible immunodeficiency condition.
15. History of allergic diseases or reactions that may be aggravated by any component of the investigational vaccine. 16. History of diseases that could compromise the safety of the study participant, including but not limited to: impairment of lung function in any lung disease, heart or kidney failure, neurological disease, epilepsy or infant seizures, diabetes, cancer. 17. History or presence of any systemic disease or any chronic disease that, in the opinion of the investigator, may affect the assessment of the safety or reactogenicity or immunogenicity of the investigational vaccine. 18. History of chronic alcohol or drug abuse. 19. History or presence of diseases or skin features that, in the opinion of the investigator, may affect the assessment of reactions at the injection site (diseases: skin malignancies, allergic and eczematous skin diseases; features: congenital or acquired benign skin lesions (nevus), scars, decorative body modifications (permanent (persistent) drawing, tattoos) applied drawings). 20. Participation in any other clinical study within the past 90 days. 21. Blood donation (450 ml or more of blood or plasma) less than 2 months before inclusion in the study. 22. History of allergic reactions to animal proteins and a tuberculin allergen.