The study will commence with a dose-escalation and age de-escalation study in healthy adults and adolescents from the previous Entebbe Mother and Baby Study (EMaBS) in Entebbe, Uganda, focusing on ChAdOx1 85A, to provide safety data for ChAdOx1 85A in this population. These measures are not required for MVA85A since this vaccine has been more widely used, including among adolescents in Uganda, and the dose has been standardised. ChAdOx1 85A dose escalation and age de-escalation will be followed by a Phase IIa randomised trial comparing the immunogenicity of ChAdOx1 85A and MVA85A with the immunogenicity of BCG revaccination. ChAdOx1 85A and MVA85A will be administered via the intramuscular route. The target dose for the Phase IIa trial is 2.5x10^10 viral particles (vp) because the lower dose is expected to have lower immunogenicity, based on the Oxford study, TB034. Data from the Oxford study suggest that this dose will be well tolerated. However, if this dose is not tolerated then the lower dose will be used. The dose of MVA85A will be 1 x 10^8 plaque-forming units (pfu) in the groups in which it is given. There will be 6 study groups with 3 to 30 volunteers in each group.

Dose escalation for ChAdOx1 85A in adults Group 1:

The first three adults will receive ChAdOx1 85A at 5 x10^9 vp.

Group 2:

The next three adults will be enrolled after safety data has been reviewed by the trial management team to one week after ChAdOx1 85A vaccination in group 1. These adults will receive ChAdOx1 85A at 2.5 x10^10 vp.

Age de-escalation and dose escalation for ChAdOx1 85A in adolescents Group 3:

The first three adolescents will be enrolled after safety data has been reviewed to one week after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 5 x10^9 vp Group 4. The next three adolescents will be enrolled after safety data has been reviewed to one week after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 2.5 x10^10 vp.

Randomised comparison of ChAdOx1 85A-MVA85A versus BCG revaccination:

Once safety data has been reviewed for groups 1 to 4 to one week post ChAdOx1 85A vaccination, recruitment to the randomised trial will commence. Sixty adolescents will be randomised, 30 (group 5) to receive ChAdOx1 85A at 2.5 x10^10 vp followed by MVA85A boost and 30 (group 6) to receive BCG revaccination.

BCG will be obtained from the Serum Institute of India, an approved provider for Uganda, and used at the standard dose of 0.1mL. BCG will be given intradermally.

This trial will be financed by a research grant from Medical Research Council. The reference number of the grant held by MRC-UKRI is MC_UU_00027/5.

Inclusion Criteria:

• Resident within the study area and planning to be resident in the study area for the duration of the study or participants with documented good attendance who are willing to attend as required
• Participant in the Entebbe Mother and Baby Study; healthy; aged 12 to 17 [or, for adults, a parent or guardian of a participant; healthy; aged 18 to 49]
• Documented immunisation within two weeks of birth with BCG Russia (BCG-I strain from Moscow, Serum Institute of India, India) [adolescents only]
• BCG scar or documented previous BCG immunisation [adults only]
• No relevant findings in medical history or on physical examination
• Written informed consent by parent or guardian [or by the volunteer themselves, for adults]
• Written informed assent by subject [for adolescents]
• Agreed to refrain from blood donation during the trial [adults only; adolescents under age 18 are not eligible to give blood]
• Agree to avoid pregnancy for the duration of the trial (female only)
• Able and willing (in the Investigator's opinion) to comply with all the study requirements

Exclusion Criteria:

• Clinical, radiological, or laboratory evidence of current active TB disease
• Laboratory evidence at screening of latent M.tb infection as indicated by a positive ELISPOT response to ESAT6 or CFP10 antigens
• Previous treatment for active or latent tuberculosis infection
• Shared a residence with an individual who has started on anti-tuberculosis treatment, or been diagnosed with culture or smear-positive pulmonary tuberculosis, within six months prior to day 0
• Received a TST within 90 days prior to day 0
• Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer, cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness, drug or alcohol abuse
• History of serious psychiatric condition or disorder
• Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents within 2 months prior to enrollment
• History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the study vaccine, including eggs
• Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study
• Positive HBsAg, HCV or HIV antibodies
• Use of an investigational medicinal product or non-registered drug, live vaccine, or medical device other than the study vaccine for 30 days prior to dosing with the study vaccine, or planned use during the study period
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned trial vaccination date
• Female currently lactating, confirmed pregnancy or intention to become pregnant during the trial period
• Screening blood sample positive for malaria by microscopy

This will be an open label trial as it will not be possible to blind either volunteers or clinic staff to the allocation. However, laboratory staff will be blinded to the allocation of the volunteers as they undertake the immunological assays.