A Study to Evaluate the Efficacy, Safety and Immunogenicity of MTBVAC in Adolescents and Adults Living in a TB Endemic Region.

Phase 2b, double-blind, randomized, placebo-controlled, safety and efficacy study in 5,500 healthy adults and adolescents. Participants will be enrolled based on IGRA status at baseline into an IGRA-positive cohort (n=4,300) or an IGRA-negative cohort (n=1,200). Most participants are likely to have received previous BCG vaccination in infancy. The investigational product is MTBVAC administered intradermally at 5x105 CFU.

Participants meeting the enrolment criteria will be randomized, in a 1:1 ratio if baseline IGRA-positive or in a 3:1 ratio if baseline IGRA-negative, to receive a single dose of MTBVAC or placebo administered intradermally on Study Day 1.

Participants will be followed up for efficacy following vaccination via regular visits or contacts to screen for possible TB. Participants will also be trained to recognize signs and symptoms consistent with pulmonary TB disease and to report them for clinical evaluation. Participants with clinical presumption of pulmonary TB will be assessed with confirmatory diagnostic testing using a Nucleic Acid Amplification Test (Xpert MTB/RIF Ultra assay) and microbiological culture in sputum sampled on 3 separate days within a 1 week period. Participants diagnosed with pulmonary TB will be referred for TB treatment according to local clinical practice.

Only HIV-negative participants will be eligible for enrolment. Participants will be tested for HIV seroconversion at the end of each year of follow-up and at the presumptive TB visits. Participants who test positive for HIV will be referred for TB preventive treatment and antiretroviral treatment according to local clinical practice.

A safety sub-cohort of approximately 660 participants (330 in each study arm) from the IGRA-positive cohort and 225 participants (150 MTBVAC and 75 placebo recipients) from the IGRA-negative cohort will be randomly selected for follow-up for solicited adverse events (AEs) and selected biochemistry and haematology. Additionally, an immunogenicity sub-cohort of approximately 90 participants (60 in the MTBVAC and 30 in the placebo arm) from the IGRA-positive cohort and 90 participants (60 in the MTBVAC and 30 in the placebo arm) from the IGRA-negative cohort will be randomly selected for specific immunogenicity assessments. All participants in the immunogenicity sub-cohort will participate in the safety sub-cohort. The sub-cohort randomization procedures will attempt to evenly distribute participants between adolescents (i.e., age 14 through 17) and adults (i.e., age 18 through 45) and among clinical research centres. The strategy for participant sub-cohort selection and randomization will be described in the Study Operations Manual (SOM) and Statistical Analysis Plan (SAP).

Inclusion criteria

• Is male or female aged 14 through 45 years on Study Day 1.
• Has completed the written (or thumb printed and witnessed) informed consent process (participants older than 18 years) or has completed the written parental consent and participant assent process (participants younger than 18 years) before any study-related procedures were performed.
• Participants who, in the opinion of the investigatory, can and will comply with the requirements of the protocol (e.g., to stay in contact with the Clinical Research Centre (CRC), return for follow-up visits)
• Has general good health as confirmed by medical history and physical examination.
• All participants born female who are engaging in sexual activity that could lead to pregnancy must commit to use an acceptable method of contraception from 21 days prior to Study Day 1 and for the 2 months after vaccination. Acceptable contraception includes:

• Condoms (male or female) with or without spermicide
• Diaphragm or cervical cap with spermicide
• Intrauterine device
• Hormonal contraception (combined estrogen and progestogen, or progestogen-only), including contraceptive implant or injectable
• Successful vasectomy in the male partner, considered successful if a woman reports that a male partner has:

documentation of azoospermia by microscopy (1 year ago) or a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy

• Not of reproductive potential, such as having undergone hysterectomy, bilateral oophorectomy or tubal ligation, postmenopausal (any age and amenorrhea for at least 6 months and a serum follicle stimulating hormone (FSH) level > 40 IU/L), surgically sterile.
• Sexual abstinence. All participants born female who are not heterosexually active at screening must agree to utilize an acceptable method of contraception if they become heterosexually active as outlined above.
• All male participants should agree to use barrier contraception with their female partners for at least 2 weeks after vaccination.
• Has not shared the same enclosed living space with someone diagnosed with TB for one or more nights or for frequent or extended daytime periods during the 6 months prior to Study Day 1.
• HIV negative at screening.
• Negative clinical screening questionnaire and Xpert MTB/RIF negative sputum sample for pulmonary TB disease at screening.

Exclusion criteria

• Acute illness and/or axillary temperature ≥37.5°C on Study Day 1.
• Current suspicion or evidence (including but not limited to sputum Xpert MTB/RIF positive) of active TB disease at any CRC. An attempt must be made to obtain sputum from each participant; persons who are sputum unproductive will be assumed to be Xpert MTB/RIF negative.
• History of previous TB disease and/or treatment for TB disease.
• History of TB preventative therapy, not including BCG vaccination.
• Received any investigational drug or investigational vaccine within 42 days before Study Day 1, or planned use during the study period.
• Planned administration/administration of a licensed vaccine not foreseen by the study protocol in the period starting 28 days before Study Day 1 and ending 28 days after vaccine administration.
• Prior receipt of any investigational TB vaccine candidate before Study Day 1. Note: receipt of placebo in a previous TB vaccine trial will not exclude a participant from participation if documentation is available and the Medical Monitor gives approval.
• Chronic administration of immunosuppressive medication within 42 days before Study Day 1 (inhaled and topical corticosteroids are permitted).
• Any confirmed or suspected immunosuppressive, immunodeficient, or autoimmune condition based on medical history and physical examination (no laboratory testing required).
• Concurrent, or planned participation in any other investigational study during the study period. (Concurrent participation in an observational trial not requiring blood or tissue sample collection is not an exclusion.)
• Received immunoglobulin or blood products within 42 days before Study Day 1, or planned administration during the study period.
• History or any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
• Pregnant or lactating/nursing female, or positive urine pregnancy test during screening or pre-vaccination on Study Day 1.
• Indeterminate IGRA test result at screening.
• Any current, or history of, medication use or medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, might compromise the safety of the participant or make it unlikely that the participant will comply with the protocol.