Study of the Safety and Efficacy of the Subunit Recombinant Tuberculosis Vaccine GamTBvac

A Multicenter, Double-blind, Randomized, Placebo-controlled Study of the Safety and Efficacy of the GamTBvac Recombinant Subunit Tuberculosis Vaccine for the Prevention of Non-HIV-associated Pulmonary Tuberculosis in Volunteers Aged 18 Years and Older.

This study is a multicenter, double-blind, randomized, placebo-controlled Phase III trial designed to evaluate the efficacy and safety of the GamTBvac recombinant subunit tuberculosis vaccine for the prevention of active non-HIV-associated pulmonary tuberculosis.

The study is divided into three stages. A total of 9,500 volunteers are planned to be enrolled in the study.

Stage 1: A total of 354 volunteers with no history of pulmonary tuberculosis will be enrolled. Volunteers will be randomized in a 1:1 ratio into one of two groups receiving either GamTBvac or placebo. Within each group, stratification will be performed according to the presence or absence of a risk factor (smoking). Based on the results of this stage, the safety of the GamTBvac vaccine will be evaluated according to the criteria specified in the study objectives for Stage 1.

Stage 2: A total of 2,146 volunteers with a history of active pulmonary tuberculosis that resulted in cure without residual changes or with minor residual changes, without aggravating factors, and who at the time of participation are registered and under follow-up in Dispensary Group III will be enrolled. Volunteers will be randomized in a 1:1 ratio into one of two groups receiving either GamTBvac or placebo. Based on the results of this stage, the prophylactic efficacy and safety of the GamTBvac vaccine will be evaluated according to the criteria specified in the study objectives for Stage 2.

In the absence of statistically significant data on vaccine efficacy by Visit 6 (24 months ± 30 days), the study will proceed to Stage 3. In the event that statistically significant data on the prophylactic efficacy of GamTBvac are obtained by Visit 6 (24 months ± 30 days), the study will be terminated.

Stage 3: Up to 7,000 volunteers with no history of active pulmonary tuberculosis will be enrolled. Volunteers will be randomized in a 1:1 ratio into one of two groups receiving either GamTBvac or placebo. Within each group, stratification will be performed according to the presence or absence of a risk factor (smoking). Based on the results of this stage, the safety and prophylactic efficacy of the GamTBvac vaccine will be evaluated according to the criteria specified in the study objectives for Stage 3.

Inclusion Criteria:

1. Male and female volunteers aged ≥ 18 years.

2. Absence of active tuberculosis, confirmed by chest X ray or chest computed tomography (CT), clinical evaluation, and laboratory findings.

3. For the purpose of additional safety evaluations of the investigational product in Stage I: no history of active respiratory tuberculosis.

4. For the purpose of the primary and secondary efficacy and safety evaluations in Stage II: a history of active respiratory tuberculosis with documented cure, with no residual changes or only minor residual changes without aggravating factors, and the volunteer must have been transferred to and remain under Group III dispensary follow up (clinical Group III*) for tuberculosis at the time of study enrollment.

5. For the purpose of the primary efficacy and safety evaluations in Stage III: no history of active respiratory tuberculosis.

6. Body mass index (BMI) 18.5 - 30 kg/m² (inclusive), calculated as weight/height² (Quetelet index).

7. Written informed consent obtained from the volunteer to participate in the study in accordance with applicable laws and regulations.

8. Prior BCG vaccination, as documented in the medical records or confirmed by the presence of a BCG scar.

9. For volunteers without a history of active pulmonary tuberculosis: negative immune response markers to mycobacterial proteins ESAT 6 and CFP 10 (indicating no prior probable contact with M. tuberculosis before study entry), as assessed by Diaskintest® and Mantoux test. For volunteers with a history of active respiratory tuberculosis that has resolved with cure and no residual or only minor residual changes without aggravating factors, and who are under Group III dispensary follow up at the time of enrollment, testing for ESAT 6/CFP 10 immune markers is not an inclusion/exclusion criterion.

10. Negative pregnancy test for female volunteers of childbearing potential at screening and on the day of first vaccination.

11. Agreement by male participants and female participants of childbearing potential to use adequate contraception (dual barrier method: male or female condom combined with hormonal contraception [oral, vaginal, or transdermal], or use of a condom or diaphragm with spermicide) throughout the entire vaccination period and for 1 month after the last vaccination. Exceptions: surgically sterile individuals (for > 6 months) or postmenopausal individuals (for > 12 months).

12. Agreement by male participants to refrain from sperm donation throughout the entire vaccination period and for 1 month after the last vaccination.

    • According to the Russian tuberculosis clinical classification, Group III dispensary registration applies to individuals cured of tuberculosis who are at low risk of relapse and require regular follow-up monitoring.

Non-inclusion criteria:

1. Positive test results for HIV-1/2 antibodies, HBsAg, or hepatitis C virus antibodies at screening (results obtained no later than 30 days prior to study enrollment may be used);
2. History of extrapulmonary tuberculosis, with the exception of bronchial tuberculosis;
3. History of chronic non-infectious respiratory diseases, including idiopathic pulmonary fibrosis (IPF), bronchial asthma, severe or very severe chronic obstructive pulmonary disease (COPD), or pulmonary hypertension;
4. Presence of family contact with a tuberculosis patient at the time of the study;
5. Incarceration in a penal institution within 24 months prior to study enrollment;
6. Clinically significant ECG abnormalities at screening;
7. History of significant allergic conditions (bronchial asthma, history of anaphylactic reactions);
8. Hypersensitivity to any component of the investigational product or placebo; history of drug intolerance;
9. Presence of any disease or use of any medication that, in the investigator's opinion, may interfere with the assessment of vaccine safety or efficacy;
10. History or physical/laboratory findings suggestive of any possible immunodeficiency condition;
11. History of any autoimmune disease (including systemic lupus erythematosus, type 1 diabetes mellitus, etc.);
12. Regular use (for more than 2 weeks) of immunosuppressants or other immunomodulating drugs within 6 months prior to the study enrollment (with the exception of inhaled or topical corticosteroids);
13. Use of immunoglobulin or blood products within 3 months prior to or planned use during the study enrollment;
14. Use of antibacterial (including anti-tuberculosis) drugs within 14 days prior to vaccination orally and/or within 28 days prior to vaccination (parenterally);
15. Pregnancy, breastfeeding, refusal to use a double-barrier method of contraception, participation of a woman in an oocyte donation program;
16. Inability of the volunteer to understand the objectives, goals, and design of the study; known inability to comply with the protocol-specified plan, visit schedule, and procedures;
17. Participation in clinical trials of medicinal products within 3 months prior to the study enrollment, or planned participation in another clinical trial;
18. Previous receipt of the GamTBvac vaccine and/or participation in clinical trials of any experimental anti-tuberculosis vaccines;
19. Any vaccination or planned vaccination within less than one month prior to the first vaccination in this study or within one month after each vaccination in this study;
20. Confirmed history of alcoholism, drug addiction, or substance abuse;
21. Positive urine drug test for narcotic and psychotropic substances;
22. Positive ethanol test (in exhaled breath)/using saliva test strips.

Exclusion Criteria:

Participation of a volunteer in the study may be terminated for the following reasons:

1. Development of tuberculosis of any localization, including respiratory tuberculosis, or recurrence of respiratory tuberculosis.
2. The investigator determines that the volunteer should be withdrawn in the volunteer's best interest.
3. Occurrence of a serious adverse event (SAE) related to the investigational vaccine.
4. Non-compliance by the volunteer with the study participation requirements.
5. Retusal to cooperate or non-compliance by the participant.
6. Enrollment of the participant in violation of the protocol's inclusion/non-inclusion criteria.
7. Development of any other significant adverse events.
8. Deterioration of the volunteer's health status.
9. Initiation of another investigational product by the volunteer.
10. Major protocol violations that may affect the volunteer's safety or the integrity of the study data.