Study to Evaluate the Efficacy of GlaxoSmithKline (GSK) Biologicals' Candidate Tuberculosis (TB) Vaccine in Adults

The incidence rate of definite pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 1 = subject with clinical suspicion of pulmonary TB disease\*, with Mycobacterium tuberculosis (Mtb) complex identified from sputum specimen, taken before initiation of TB treatment, by Xpert MTB/RIF (Nucleic Acid Amplification Test to detect Mtb complex and resistance to rifampicin in sputum samples) and/or microbiological culture and confirmed Human Immunodeficiency Virus (HIV)-negative at the time of TB diagnosis. \*Clinical suspicion of pulmonary TB defined as subject presenting with 1 or more of the following symptoms: unexplained cough \> 2 weeks, unexplained fever \> 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.

Time frame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first

Population: Analysis was performed on the According-to-Protocol cohort for efficacy which included all subjects who received all vaccinations according to protocol procedures within specified intervals that contributed time at risk in the follow-up period starting one month post dose 2 (Day 60).

The frequency of M72-specific CD4 + T-cells per million cells were identified after in vitro stimulation expressing any combination of immune markers ( Interleukin-2 (IL-2), cluster of differentiation 40-ligand (CD40-L), tumor necrosis factor alpha (TNF-) and interferon-gamma (IFN-) after background subtraction for each treatment group.

Time frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 immune result documented.

The frequency of M72-specific CD8 + T-cells per million cells were identified after in vitro stimulation expressing any combination of immune markers ( Interleukin-2 (IL-2), cluster of differentiation 40-ligand (CD40-L), tumor necrosis factor alpha (TNF-) and interferon-gamma (IFN-) after background subtraction for each treatment group.

Time frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 immune result documented.

The incidence rate of Clinical TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 5 = a subject for whom a clinician has diagnosed TB disease and has decided to treat the patient with TB treatment.

Time frame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first

Population: Analysis was performed on the According-to-Protocol cohort for efficacy which included all subjects who received all vaccinations according to protocol procedures within specified intervals that contributed time at risk in the follow-up period starting one month post dose 2 (Day 60).

The incidence rate of definite pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 3 = a subject with clinical suspicion\* of pulmonary TB disease, with Mtb complex identified from a sputum specimen, taken up to four weeks after initiation of TB treatment, by Xpert MTB/RIF and/or microbiological culture and confirmed HIV-negative at the time of TB diagnosis.\*Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough \> 2 weeks, unexplained fever \> 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.

Time frame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first

Population: Analysis was performed on the According-to-Protocol cohort for efficacy which included all subjects who received all vaccinations according to protocol procedures within specified intervals that contributed time at risk in the follow-up period starting one month post dose 2 (Day 60).

The incidence rate of definite Xpert MTB/Rif positive pulmonary TB disease, expressed in terms of 100 Person-years rate, was calculated as the number of subjects reporting at least one case (n) in a group over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 2 = a subject with clinical suspicion\* of pulmonary TB disease, with Mtb complex identified from a sputum specimen, taken before initiation of TB treatment, by Xpert MTB/RIF and confirmed HIV-negative at the time of TB diagnosis. \*Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough \> 2 weeks, unexplained fever \> 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.

Time frame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first

Population: Analysis was performed on the According-to-Protocol cohort for efficacy which included all subjects who received all vaccinations according to protocol procedures within specified intervals that contributed time at risk in the follow-up period starting one month post dose 2 (Day 60).

The incidence rate of Microbiological pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 4 = a subject with clinical suspicion\* of pulmonary TB disease, with Mtb complex identified from a sputum specimen, taken up to four weeks after initiation of TB treatment, by Xpert MTB/RIF and/or microbiological culture.\*Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough \> 2 weeks, unexplained fever \> 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.

Time frame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first

Population: Analysis was performed on the According-to-Protocol cohort for efficacy which included all subjects who received all vaccinations according to protocol procedures within specified intervals that contributed time at risk in the follow-up period starting one month post dose 2 (Day 60).

Mycobacterium tuberculosis M72-specific antibody geometric mean concentrations (GMCs) with exact 95% Confidence Interval (CI) were measured by Enzyme Linked Immuno Sorbent Assay (ELISA) and expressed in ELISA unit per milliliter (EU/mL). The cut-off of the assay was 2.8 EU/mL. The Geometric Mean Concentration (GMC) calculations were performed by taking the anti-log of the mean of the log10 concentration transformations. For descriptive statistics purposes only, antibody concentrations below the cut-off value of the assay was given an arbitrary value of half the cut-off value for the purpose of GMC calculation.

Time frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 cell-mediated immune result documented.

A seronegative subject was a subject whose antibody concentration was below 2.8 EU/mL, while a seropositive subject was a subject whose antibody concentration was greater than or equal to 2.8 EU/mL.

Time frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 cell-mediated immune result documented.

Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

Time frame: From Day 0 to 6 months post-dose 2 (i.e. at Month 7)

Population: Analysis was performed on the Total Vaccinated cohort which included all vaccinated subjects with at least one dose administered.

Assessed solicited general symptoms were fatigue, fever \[defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)\], respiratory symptoms (including cough, blood in sputum, purulent sputum, shortness of breath or difficulties breathing, chest wall pain) headache, malaise and myalgia. Any = occurrence of the symptom regardless of intensity grade and relation to vaccination.

Time frame: During the 7-day follow-up period (i.e.: day of vaccination and 6 subsequent days) after each vaccine dose

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 vaccination dose documented.

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Any redness/swelling symptom was scored as injection site redness/swelling with a diameter equal or larger than (≥) 20 millimeters (mm).

Time frame: During the 7-day follow-up period (i.e. day of vaccination and 6 subsequent days) after each vaccine dose

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 vaccination dose documented.

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

Time frame: During the 30-day follow-up period following vaccination, across doses (i.e. day of vaccination and 29 subsequent days after each vaccine dose)

Population: Analysis was performed on the Total Vaccinated cohort which included all vaccinated subjects with at least one dose administered.

Abnormal laboratory values include haematological abnormalities (haemoglobin level, white blood cells and platelets) and biochemical abnormalities (alanine aminotransferase, aspartate aminotransferase and creatinine). Grading was defined based on the Food and Drug Administration \[FDA\], 2007. Guidance for Industry, Toxicity Grading Scale for Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Alanine Aminotransferase = ALA; Aspartate Aminotransferase = ASP; Creatinine = CREA; Hemoglobin (Change from baseline) = HEM (baseline); Hemoglobin (decrease) = HEM (decrease); Leukocytes (White Blood Cells) (Decrease) = WBC (decrease); Leukocytes (White Blood Cells) (Increase) = WBC (increase); Platelets = PLA; Total Bilirubin = BIL.

Time frame: Days 0, 7, 30 and 37

Population: Analysis was performed on the safety and immunogenicity sub-cohort (i.e. about 150 subjects enrolled in each group and from 2 of the 3 countries \[the third country study start was delayed as awaiting regulatory approval\]) which included subjects with at least 1 laboratory value documented.

Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: From Day 0 up to Year 3 (during the entire study period)

Population: Analysis was performed on the Total Vaccinated cohort which included all vaccinated subjects with at least one dose administered.