A Randomized, Placebo-controlled, Observer-blind, Phase 2 Study to Evaluate Safety and Immunogenicity of the Investigational M72/AS01E Mycobacterium Tuberculosis (Mtb) Vaccine in Virally Suppressed, Antiretroviral-treated Participants With Human Immunodeficiency Virus (HIV)
Phase: PHASE2
Conditions: Human Immunodeficiency Virus
Sponsor: Gates Medical Research Institute



CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
2 
 
Version 3 Sponsor Signatory 
 
 
See appended electronic signature page 
 
 M.D. Clinical Development Leader 
Bill & Melinda Gates Medical Research Institute 
  
 
Date 
 
 
 
 
 
 
 
 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
3 
Table of Content 
Title Page ........................................................................................................................................1 
Table of Content .............................................................................................................................3 
Tables, Figures, Appendices..........................................................................................................6 
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schedule of Activities .....................................................................................................11 
2. 
Introduction ...................................................................................................................14 
2.1. 
Background .....................................................................................................................15 
2.2. 
Study Rationale ...............................................................................................................17 
2.3. 
Benefit/Risk Assessment ................................................................................................17 
3. 
Objectives and Endpoints ............................................................................................20 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.2. 
Scientific Rationale for Study Design ............................................................................22 
4.3. 
Justification for Adjuvant System and Dose...................................................................22 
4.4. 
End of Study Definition ..................................................................................................23 
5. 
Study Population ...........................................................................................................23 
5.1. 
Inclusion Criteria ............................................................................................................24 
5.2. 
Exclusion Criteria ...........................................................................................................25 
5.3. 
Screen Failures ................................................................................................................26 
6. 
Study Intervention ........................................................................................................27 
6.1. 
Study Interventions Administered ..................................................................................27 
6.1.1. 
Administration ................................................................................................................27 
6.1.2. 
Preparation/Handling/Storage/Accountability ................................................................28 
6.1.3. 
Vaccine Administration Error .........................................................................................28 
6.2. 
Measures to Minimize Bias: Randomization and Blinding ............................................29 
6.2.1. 
Randomization ................................................................................................................29 
6.2.2. 
Masking...........................................................................................................................29 
6.2.3. 
Blind Break .....................................................................................................................29 
6.3. 
Study Intervention Compliance ......................................................................................30 
6.4. 
Concomitant Therapy .....................................................................................................30 
6.5. 
Dose Modification ..........................................................................................................30 
6.6. 
Intervention after the End of the Study ...........................................................................31 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................31 
7.1. 
Discontinuation of / Withdrawal from Study Intervention .............................................31 
7.1.1. 
Contraindications to the Second Dose ............................................................................31 
7.2. 
Participant Withdrawal from the Study ..........................................................................32 
7.3. 
Lost to Follow-up............................................................................................................33 
7.4. 
Pausing Guidelines .........................................................................................................33 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
4 
7.5. 
COVID-19 Contingency Plans .......................................................................................34 
8. 
Study Assessments and Procedures.............................................................................35 
8.1. 
Efficacy Assessments/Immunogenicity ..........................................................................36 
8.1.1. 
Humoral Immunogenicity ...............................................................................................36 
8.1.2. 
Cell-Mediated Immune Responses .................................................................................36 
8.1.3. 
Subset Assessments ........................................................................................................36 
8.2. 
Safety Assessments .........................................................................................................37 
8.2.1. 
Physical Examination and Medical History ....................................................................37 
8.2.1.1. 
Interim History and Focused Physical Examination ..........................................38 
8.2.2. 
Pregnancy Status Assessment .........................................................................................38 
8.2.3. 
Pre- and Post-Study Intervention Safety Monitoring......................................................38 
8.2.4. 
Diary Card and Daily Temperature Monitoring .............................................................38 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................39 
8.2.6. 
HIV Antibody Assessment and HIV Viral Load Assessment ........................................40 
8.2.7. 
QFT assessment for TB ..................................................................................................40 
8.2.8. 
Sputum Xpert MTB/RIF .................................................................................................41 
8.3. 
Adverse Events and Serious Adverse Events .................................................................41 
8.3.1. 
Time Period and Frequency for Collecting AE, SAE, and 
Pregnancy Information....................................................................................................41 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................42 
8.3.3. 
Follow-up of AEs ............................................................................................................42 
8.3.3.1. 
AE Intensity ........................................................................................................42 
8.3.3.2. 
AE Causality ......................................................................................................42 
8.3.3.3. 
AE Resolution ....................................................................................................42 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................43 
8.3.5. 
Death Events ...................................................................................................................43 
8.3.6. 
Mtb Infection and Disease ..............................................................................................43 
8.3.7. 
HIV RNA and CD4+ T Cell Count Analysis .................................................................44 
8.4. 
Treatment of Overdose ...................................................................................................44 
8.5. 
Pharmacokinetics ............................................................................................................44 
8.6. 
Pharmacodynamics .........................................................................................................44 
8.7. 
Exploratory Biomarkers ..................................................................................................44 
8.8. 
Health Economics ...........................................................................................................45 
9. 
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Hypotheses .....................................................................................................45 
9.2. 
Sample Size Determination ............................................................................................45 
9.3. 
Populations for Analyses ................................................................................................46 
9.4. 
Statistical Analyses .........................................................................................................46 
9.4.1. 
Humoral Immunogenicity Analyses ...............................................................................48 
9.4.2. 
Cell-mediated Immune response.....................................................................................49 
9.4.3. 
Exploratory analyses .......................................................................................................49 
9.4.4. 
Subgroup Analyses .........................................................................................................49 
9.4.5. 
Demographic and Compliance Analyses ........................................................................49 
9.5. 
Interim Analyses .............................................................................................................49 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
5 
9.5.1. 
Independent Data Monitoring Committee (IDMC) ........................................................49 
9.5.2. 
Informed Consent and Assent Process ............................................................................50 
9.5.2.1. 
Informed Consent forms .....................................................................................51 
9.5.3. 
Data Protection................................................................................................................51 
9.5.4. 
Dissemination of Clinical Study Data.............................................................................51 
9.5.5. 
Data Quality Assurance ..................................................................................................51 
9.5.6. 
Source Documents ..........................................................................................................52 
9.5.7. 
Study and Site Closure ....................................................................................................52 
9.5.8. 
Publication Policy ...........................................................................................................53 
9.6. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................54 
9.6.1. 
Definition of AE .............................................................................................................54 
9.6.2. 
Definition of SAE ...........................................................................................................55 
9.6.3. 
Definition of SUSAR ......................................................................................................56 
9.6.4. 
Definition of AESI ..........................................................................................................56 
9.6.5. 
Recording and Follow-Up of AE and/or SAE ................................................................58 
9.6.5.1. 
Assessment of Intensity ......................................................................................59 
9.6.5.2. 
Assessment of Causality .....................................................................................59 
9.6.5.3. 
Assessment of Expectedness of SAEs ...............................................................60 
9.6.5.4. 
Assessment of Outcome .....................................................................................60 
9.6.6. 
SAEs and AESIs Reporting ............................................................................................60 
9.6.7. 
Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.1 Preferred Term Codes for pIMDs .............................................................63 
9.7. 
Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................................................70 
9.8. 
Toxicity Table .................................................................................................................72 
10. 
References ....................................................................................................................105 
11. 
Amendment History ...................................................................................................106 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
6 
Tables, Figures, Appendices  
 
Table 1: Objectives and Endpoints ................................................................................................. 9 
Table 2: Schedule of Activities (SoA) .......................................................................................... 12 
Table 3: Objectives and Endpoints ............................................................................................... 20 
Table 4: Study Interventions ......................................................................................................... 27 
Table 5: Collection Period for all AEs and Pregnancies ............................................................... 41 
Table 6: Statistically significant differences in geometric mean concentrations (GMCs) between 
the two treatment groups for varying sample sizes ....................................................................... 45 
Table 7: Populations for Analyses ................................................................................................ 46 
Table 8: Summary of Endpoints and Analyses ............................................................................. 47 
 
Figure 1: Study Schema ................................................................................................................ 11 
Figure 2: Geometric mean concentrations of antibodies against M72 ......................................... 17 
 
Appendix 1 .................................................................................................................................... 54 
Appendix 2 .................................................................................................................................... 70 
Appendix 3 .................................................................................................................................... 72 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
7 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase   
ART 
anti-retroviral therapy 
AST 
aspartate aminotransferase 
BARC SA 
Bio Analytical Research Corporation, Republic of South Africa 
βHCG  
beta human chorionic gonadotropin 
BCG 
Bacille Calmette-Guerin 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CoP 
correlate of protection 
CoR 
correlate of risk 
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
EDC 
electronic data capture  
GCP  
Good Clinical Practices 
GMC 
geometric mean concentration 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
ICS 
intracellular cytokine staining 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN-γ  
interferon gamma  
IL 
interleukin 
IM 
Intramuscular(ly) 
IRB 
Institutional Review Board 
IRIS 
immune reconstitution inflammatory syndrome  
IVRS 
interactive voice response system  
IWRS 
interactive web response system  
LAR 
legally acceptable representative 
M72/AS01E 
candidate (experimental) TB vaccine  
mL 
milliliter 
µL 
microliter 
Mtb 
Mycobacterium tuberculosis 
NA 
not applicable 
OI 
opportunistic infection 
PBMC 
peripheral blood mononuclear cells 
PI 
Principal investigator 
pIMD 
potential immune-mediated disease 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
8 
PPD 
purified protein derivative 
QFT assay 
QuantiFERON®-TB Gold Plus assay 
RNA 
ribonucleic acid 
RSA 
Republic of South Africa 
SAE 
serious adverse event 
SAHPRA 
(Republic of) South African Health Products Regulatory 
Authority 
SAP 
statistical analysis plan 
SoA 
schedule of activities 
SUSAR 
serious, unexpected, suspected adverse drug reactions 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
TPT 
TB preventive therapy  
WBC 
white blood cell 
WHO 
World Health Organization 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
9 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A randomized, placebo-controlled, observer-blind, phase 2 study to evaluate 
safety and immunogenicity of the investigational M72/AS01E Mycobacterium tuberculosis (Mtb) 
vaccine in virally suppressed, antiretroviral-treated participants with human immunodeficiency 
virus (HIV) 
Short Title: Safety and immunogenicity of a TB vaccine M72/AS01E in participants with well-
controlled HIV 
Rationale: 
Published phase 1 and 2 randomized, controlled trials evaluating M72/AS01E vaccination in 
individuals with HIV who were receiving antiretroviral therapy (ART) show that a 2-dose 
schedule of the vaccine given one month apart is well-tolerated and immunogenic in this 
population. This current study intends to confirm that the vaccine is safe, well-tolerated, and 
immunogenic in a larger population of people with virally suppressed HIV infection in a 
tuberculosis (TB) endemic region.  
Table 1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and 
reactogenicity of M72/AS01E 
vaccination 
• 
Solicited adverse events (AEs) through 7 days post each dose of study 
intervention 
• 
Unsolicited AEs through 28 days post each dose of study intervention 
• 
All serious adverse events (SAEs) through end of study 
Secondary  
• 
To assess the safety of 
M72/AS01E vaccination 
• 
Potential immune-mediated diseases (pIMDs) through end of study 
• 
Safety laboratory assessments grade 3 or above through end of study 
• 
To assess the humoral 
immunogenicity of M72/AS01E 
vaccination 
• 
M72-specific antibody titers at Day 1, Day 29, Day 57, Day 210 and 
Day 390 
 
• 
To assess the cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses measured by expression of IFN- or IL-2 using intracellular 
cytokine staining (ICS) at Day 1, Day 57 and Day 390  
Exploratory 
• 
To further explore cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses measured by expression of IFN- or IL-2 by ICS at Day 29 
and Day 210 
• 
Polyfunctionality of M72-specific CD4+ and CD8+ T-cell responses 
measured by co-expression of multiple functional markers by ICS 
• 
To assess HIV viral load post-
M72/AS01E vaccination 
• 
Frequencies of participants with confirmed HIV ribonucleic acid 
([RNA]>200 copies/mL) at Day 57, Day 210 and Day 390 
• 
To assess changes in CD4+ T 
cell count from baseline 
• 
Mean changes in CD4+ T cell count from baseline to Day 57, Day 210 
and Day 390 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
10 
Objectives 
Endpoints 
• 
To describe the incidence of 
suspected TB disease and 
laboratory-confirmed 
pulmonary TB disease 
• 
Suspected TB during the study   
• 
Laboratory-confirmed pulmonary TB during the study 
Other exploratory endpoints may include, but are not limited to, assessing functional antibody profiles in 
response to vaccination, vaccine-induced changes in innate and myeloid cell populations, and vaccine-induced 
changes in transcriptomic, proteomic or metabolomic profiles. 
CD= cluster of differentiation 
Overall Design 
Disclosure statement: This is randomized, observer-blind, placebo-controlled, clinical trial of 
M72/AS01E tuberculosis vaccine vs. placebo in approximately 400 males and females between 
16 to 35 years of age inclusive, who are living with HIV infection, and are virally suppressed 
(i.e., viral load < 200 copies per mL) on ART.  
Interventional model: Participants will be randomly assigned 1:1, to one of two groups in 
parallel for the duration of the study.  
Intervention groups: 2 study groups (M72/AS01E group and placebo group), will each receive 2 
vaccinations administered intramuscularly (IM) in the deltoid muscle, preferably of the non-
dominant arm, one month apart (at Day 1 and Day 29).  
- 
M72/AS01E group: A 0.5 mL dose of M72/AS01E contains 10µg M72 reconstituted with 
AS01E, a GSK proprietary adjuvant system containing 25 µg MPL (3-O-desacyl-4-
monophosphoryl lipid A produced by GSK), 25 µg QS-21 (Quillaja saponaria Molina, 
fraction 21). The vaccine will be administered at Day 1 and Day 29. 
- 
Placebo group: Each dose contains 0.5 mL saline (0.9% NaCl). The placebo will be 
administered at Day 1 and Day 29. 
Primary purpose: To assess the safety as well as immunogenicity of M72/AS01E vaccine in 
participants with virally suppressed HIV infection on ART 
Safety and immunogenicity outcomes will be followed for 12 months after the second 
vaccination (end of study) for each randomized participant. 
Masking: The study is observer-blind: participants, sponsor, contract research organization 
(CRO) clinical team, laboratory, investigators and site staff will be blinded to the randomization. 
An Independent Data Monitoring Committee (IDMC) will review unblinded data. The 
investigational pharmacist preparing study interventions will be unblinded but will not perform 
other study duties. 
Safety Monitoring: An IDMC will be established to oversee the safety of this study. The IDMC 
will review unblinded safety data during regular scheduled safety review meetings, and may 
request additional information, or a pause in recruitment and vaccination, while safety data are 
being evaluated.  
Number of participants: Approximately 400 participants will be enrolled. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
 
       Version 3.0 
26 February 2021 
11 
Randomization: Participants will be randomized 1:1, stratified by site, and QuantiFERON-TB 
Gold Plus (QFT) status, based on results at screening. 
Adverse events of special interest (AESIs): Protocol-defined potential immune-mediated 
diseases will be assessed throughout the study.  
Analysis: The final analysis will occur after all participants have reached the end of the study 
(Day 390).  
Total duration of study participation: The study duration for each participant, after screening, is 
approximately 390 days, which includes, 2 vaccinations 1 month apart, and 365 days of follow-
up post dose 2. Enrollment is expected to take approximately 6 months.  
Study sites: Approximately 6 sites in the Republic of South Africa (RSA) will participate in this 
study.  
Schema: The screening visit will begin with the informed consent process. 
Approximately 400 study-eligible participants will be randomized 1:1 to receive M72/AS01E 
vaccine or placebo IM. Study procedures are outlined in Figure 1 (Schema) and Table 2 
(Schedule of activities). 
Figure 1: Study Schema 
1.2. 
Schedule of Activities 
Written informed consent must be given before any screening procedure is started. Each enrolled 
participant will have seven clinic visits after screening. Study procedures are summarized in the 
Schedule of Activities (SoA) in Synopsis Table 2. 
 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
14 
2. 
Introduction 
Worldwide, TB is one of the top 10 causes of death, and the leading cause from a single 
infectious agent (above HIV/ acquired immunodeficiency syndrome [AIDS]). An estimated 10 
million people became ill with TB in 2018, and an estimated 1.5 million people died from the 
infection, including 251,000 people also infected with HIV (WHO, 2019a).  
Seven countries accounted for 64% of the new TB cases in 2016 including India, Indonesia, 
China, Philippines, Pakistan, Nigeria, and the Republic of South Africa (RSA). In 2016, in the 
WHO African region, where this current study will be conducted, 2.5 million people became ill 
with TB and an estimated 417,000 people died from the disease (among 1.7 million globally), 
accounting for approximately 25% of TB deaths worldwide (WHO, 2019b). 
In endemic settings, HIV coinfection is the most important risk factor for developing active TB 
disease, which increases both the susceptibility to primary infection or reinfection, and the risk of 
TB reactivation for patients with latent TB. TB also has a negative impact on the immune 
response to HIV, accelerating the progression from HIV infection to AIDS (Bruchfeld, 2015). 
TB is a leading cause of death among individuals with HIV. In 2016, 40% of HIV deaths 
globally, were due to TB. Among those living with HIV infection, the risk of developing TB was 
estimated to be between 16-27 times greater than among those without HIV infection. In 2015, 
almost 60% of TB cases among people living with HIV were not diagnosed or treated, resulting 
in 390,000 TB-related deaths among this population (WHO, 2019c). 
The World Health Organization ‘End TB strategy’ calls for a global end to TB by 2035 using 
strategies such as early diagnosis, treatment, and prevention, including vaccination (WHO, 
2019d). Towards that same end, the RSA, with one of the highest per capita rates of TB, 
implemented a plan in 2012 (National Strategic Plan or NSP) to control the spread of TB. 
The Bacille Calmette–Guerin (BCG) vaccine is currently the only available TB vaccine but 
among several drawbacks, it is contra-indicated in people living with HIV except for special 
populations (e.g., newborns). HIV negatively impacts T-cell function, polarization and 
differentiation of Mtb-specific T cells, Mtb antigen presentation by dendritic cells, as well as B-
cell and antibody-response (Nemes, 2018). 
ART is the most effective preventive strategy against TB in people living with HIV, substantially 
reducing the risk irrespective of baseline CD4+ cell count, tuberculin skin test status, and 
antimycobacterial drug resistance. Even so, ART alone is not expected to control HIV-associated 
TB, since it is often started late during HIV progression and many patients already have Mtb 
infection before starting ART. Even during long-term ART, TB incidence in the RSA is still 
higher than among people not infected with HIV (Lawn, 2015). 
However, an effective TB vaccine that could provide adequate immunity against TB among 
immunocompromised individuals, including those who are living with HIV is possible. The 
GlaxoSmithKline (GSK) M72/AS01E, (10 µg formulation) is a candidate vaccine to prevent TB 
disease that has shown promising results in phase 2 studies.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
15 
2.1. 
Background 
The M72/AS01E vaccine contains the M72 recombinant fusion protein derived from two 
immunogenic M. tuberculosis antigens (Mtb32A and Mtb39A), 10 µg per dose, combined with 
GSK’s AS01E adjuvant system. The Mtb39A and Mtb32A components of the recombinant 
antigen elicited specific lymphoproliferation, interferon-γ production, or both, in those with 
latent Mtb infection and active TB. To date, approximately 2300 participants have received the 
M72/AS01E vaccine (at least 4400 doses administered).  
Two of these studies (TB-011 and TB-014) were conducted in adults living with HIV who have 
had no past or current TB disease. A total of 102 persons living with HIV were exposed to 
M72/AS01E, and of these, 62 were virally suppressed on ART. 
TB-011 was a phase I/II double-blind, randomized study in Switzerland (Thacher, 2014). All 37 
participants had to be on ART for at least 6 months with viral load < 50 copies/mL and CD4+ > 
200 cells/µL. Thirty-seven were enrolled and randomized 3:1:1 to either M72/AS01E (n=22), 
AS01E alone (n=8) or saline (n=7). Vaccines were administered at Day 0 and Day 30. Follow up 
continued for 6 months post-second vaccination.  
• 
Demographics and baseline: mean age 40 years old, 30% female, 78% Caucasian, 73% 
BCG+, 2.7% QFT+, mean purified protein derivative (PPD) skin test induration ≤5mm, 
CD4+ 605 cells/µL, nadir CD4+ 191 cells/µL. 
• 
Safety and reactogenicity: No vaccine-related SAEs or study discontinuation due to an AE; 
90% M72/AS01E participants reported pain at injection site, and about half reported fatigue 
and/or headache. Most AEs were mild or moderate in severity with infrequent grade 3 
solicited AEs (local after ≤9.1% and general after ≤7.1% of doses). Five of 22 M72/AS01E 
participants had a transient CD4 decline of >100 cells/µL one-month post first injection that 
was deemed clinically insignificant. Their CD4+ count remained above 200 cells/µL.  
• 
Three participants had a single viral load blip that was clinically insignificant (i.e., 121 
copies/mL at Day 30, and 55 and 59 copies/mL at Day 60). 
• 
Immune response: Most had vaccine-induced response of M72-specific CD4+ T cells 
expressing at least two markers among CD40L, interleukin (IL)-2, tumor necrosis factor 
(TNF)-α and interferon gamma (IFN-γ) by intracellular cytokine staining ([ICS] 89% at Day 
60 and 91% at Day 210). These responses did not differ by BCG vaccination status. There 
was no correlation between CD4+ cell counts and M72-specific CD4+ T cell responses. Pre-
existing responses at baseline were infrequent.  
• 
All individuals were anti-M72 seronegative before vaccination. Geometric mean 
concentrations (GMCs) in the M72/AS01E group was highest at Day 60 and persisted at Day 
210. All were seropositive after the second dose (Day 60) and remained so at Day 210. 
TB-014 study was a phase II double-blind, randomized study in Chennai, India (Kumarasamy, 
2016, Kumarasamy, 2018). A total of 240 participants were enrolled, 80 in each of 3 groups 
(HIV-uninfected controls, HIV+ on stable ART, and HIV+ ART-naïve). The ART-stable group 
had been on ART for at least 6 months and had CD4+ ≥ 250 cells/µL and viral load < 400 
copies/mL. The ART-naïve group were not yet eligible for ART according to standard of care, 
and had CD4+ > 350 cells/ µL and viral load 5000-80,000 copies/mL. Each group was 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
16 
randomized 1:1 to M72/AS01E vs. saline. Vaccines were administered at Day 0 and Day 30. The 
study duration was 13 months (1-year post dose 2) with a long term follow up phase to Year 3. 
• 
Demographics and baseline: Among the M72/AS01E-exposed participants with and without 
HIV (n=120): mean age 34.2 years, 32.5% female, 96.7% central/south Asian, 70.8% 
BCG+, 43.3% QFT+. Among ART-stable M72/AS01E participants: baseline viral load 150 
copies/mL and CD4+ 613 cells/µL, and nadir CD4+ 219 cells/µL. Among ART-naïve 
M72/AS01E participants: baseline viral load 29,007 copies/mL, CD4+ 517 cells/µL, and 
naïve CD4+ 476 cells/µL. 
• 
Safety and reactogenicity: Pain at injection site, fatigue and headache were the most 
common solicited AEs among M72/AS01E recipients, and were mostly mild or moderate in 
severity. Grade 3 pain was infrequent (≤7.6% of doses). Across all groups, the frequency of 
swelling of any intensity after all doses was ≤8.9% of doses, and no grade 3 swelling was 
reported. The only grade 3 general solicited AEs were headache in one ART stable 
participant and gastrointestinal symptoms in one HIV-negative participant. There were no 
significant differences in general solicited AEs between the HIV-negative, and the ART 
stable and ART-naïve HIV+ groups except more frequent fever and headaches were 
observed in the HIV-negative group.  
• 
Unsolicited AEs reporting was comparable between the M72/AS01E vs. placebo groups 
within each cohort. These AEs tended to be higher in ART-naïve cohort, followed by ART-
stable cohort and then the HIV-negative cohort. Most frequently reported AEs were 
nasopharyngitis, back pain, headache, cough, decreased appetite and pruritus. No grade 3 
unsolicited AEs were reported.  
• 
CD4 count and viral load were comparable between the M72/AS01E vaccine vs. placebo 
recipients with each cohort. 
• 
Immune response: Several participants had pre-existing M72-specific CD4+ T cell response 
by ICS (CD4+ expressing at least two markers among CD40L, IL-2, TNF-α and IFN-γ). 
Vaccine induced responses were highest at Day 37 and persisted to Year 3. Vaccine-induced 
responses in the ART stable group were significantly higher than the ART-naïve groups 
from Day 30 onwards, but comparable to the HIV-negative group, from Day 60 onwards.  
Degree of polyfunctionality of the responding CD4+ T cells tended to be higher in the QFT+ 
participants at Day 7 and Day 30, but was comparable to QFT- participants at subsequent 
time points. No M72-specific CD8+ T cell responses were observed.  
• 
Anti-M72 IgG responses peaked at Day 60 in the M72/AS01E group and persisted to year 3. 
The ART stable group had higher vaccine-induced IgG responses than the ART-naïve 
cohort but comparable to that of the HIV-negative cohort (Figure 2). The seropositivity rates 
at year 3 were 97.1% in ART stable, 66.7% in ART-naïve and 97.3% in HIV-negative 
cohorts. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
18 
in all cohorts. In the TB-014 Indian study, irrespective of cohorts, after all doses, grade 3 pain 
was reported infrequently and only in the M72/AS01E groups (≤7.6% of doses). Across groups 
and cohorts, the frequency of swelling (any intensity) after all doses was low (≤8.9% of doses) 
and no grade 3 swelling was reported. In the TB-011 Swiss study, grade 3 solicited local AEs 
were also infrequent, occurring after ≤9.1% of doses, and reported predominantly after 
M72/AS01E. 
Solicited general AEs: In both studies, headache and fever were the most frequently reported 
solicited general AEs across groups. In the India study, the only grade-3 general AEs were 
headache and gastrointestinal symptoms, reported in the ART-stable and HIV-negative cohorts, 
respectively (1 participant each, Kumarasamy, 2016). In the Swiss study, grade 3 solicited local 
and general AEs were also infrequent (occurring after ≤7.1% of doses) and reported 
predominantly after vaccination with M72/AS01E (Thacher, 2014). 
Unsolicited AEs: In the Indian study, the incidence of unsolicited AEs was generally comparable 
between the vaccine and placebo groups, and tended to be highest in the ART-naive cohort, 
followed by the ART stable cohort and then the HIV-negative cohort. Nasopharyngitis, back 
pain, headache, cough, decreased appetite, and pruritus were most frequently reported, without 
clear patterns between groups, and were all considered not clinically significant. No grade 3 
unsolicited symptoms were reported. Vaccine-related unsolicited AEs (injection-site induration 
among ART-stable participants; one participant per AE) were rare in the vaccine group and not 
reported in the placebo group (Kumarasamy, 2016). 
Participants in the Indian study who received M72/AS01E reported more AEs within 30 days of 
vaccination than those in the placebo group (67.4% versus 45.4%). This difference stemmed 
from more injection-site reactions and flu-like symptoms among M72/AS01E recipients. Such 
common, mild, and transient AEs could be taken as evidence of reactogenicity. 
In the Swiss study, nasopharyngitis and myalgia were also frequently reported (4 participants 
each/18.2%) in this group. In the AS01E alone group, the most frequently reported AEs were 
nasopharyngitis and headache (both reported in two individuals [25.0%]), and in the placebo 
group, nasopharyngitis and cough (2 subjects each/28.6%) were the most frequently reported 
AEs. 
Grade 3 unsolicited AEs were infrequently reported (in one or two individuals for a given AE) 
and only in the M72/AS01E and AS01E groups. Vaccine-related unsolicited AEs occurred only in 
the M72/AS01E group: two individuals reported feverishness or feeling hot (including one 
graded 3) and two individuals reported injection site pruritus (none graded 3), all of which 
resolved within 1–4 days. Two vaccine recipients, both in the M72/AS01E group, each reported 
one SAE unrelated to vaccination (appendicitis and cellulitis of the foot). 
In both studies, although there were some fluctuations in the levels of hematological or 
biochemical parameters over time, no clinically relevant changes or vaccine-related trends were 
observed. 
SAEs: In the Indian study, SAEs were reported by 5 HIV-positive M72/AS01E recipients (of 
whom 3 were ART-naive) and none of these were M72/AS01E vaccine-related (Kumarasamy, 
2016). There were no SAEs in the Swiss study (Thacher, 2014). 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
19 
Potential immune-mediated diseases (pIMDs): No pIMDs were reported in the two studies. 
HIV parameters: In both studies there were no clinically significant effects of vaccination on 
the median CD4+ counts or HIV viral loads. In the Indian cohort, compared to the ART-stable 
cohort, lower median CD4+ counts were reported in the ART-naive cohorts at all time-points, but 
viral loads were higher in the ART-naive cohort. In the Swiss study, there was a decreased CD4+ 
T cell count (defined as a decrease of >100 cells/mL from the previous reading), which was 
reported in five M72/AS01E recipients (22.7%) and was not considered clinically significant. 
CD4+ T cell counts in these individuals remained above 200 cells/µL throughout the study. 
Group median and the majority of individual CD4+ cell counts remained relatively constant 
during the study. 
There were no significant changes in viral load in the Indian study. In the Swiss study, HIV-1 
viral loads were undetectable at the time-points measured for all individuals except three 
M72/AS01E vaccine recipients, who reported levels exceeding 50 copies/mL at only one post-
vaccination time-point each (i.e., 121 copies/mL at Day 30, and 55 and 59 copies/mL at Day 60). 
These viral load blips were not considered clinically significant (Thacher, 2014). 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
20 
3. 
Objectives and Endpoints 
Table 3: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and 
reactogenicity of M72/AS01E 
vaccination 
• 
Solicited adverse events (AEs) through 7 days post each dose of study 
intervention 
• 
Unsolicited AEs through 28 days post each dose of study intervention 
• 
All serious adverse events (SAEs) through end of study 
Secondary  
• 
To assess the safety of 
M72/AS01E vaccination 
• 
Potential immune-mediated diseases (pIMDs) through end of study 
• 
Safety laboratory assessments grade 3 or above through end of study 
• 
To assess the humoral 
immunogenicity of M72/AS01E 
vaccination 
• 
M72-specific antibody titers at Day 1, Day 29, Day 57, Day 210 and 
Day 390 
 
• 
To assess the cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses measured by expression of IFN- or IL-2 using intracellular 
cytokine staining (ICS) at Day 1, Day 57 and Day 390  
Exploratory 
• 
To further explore cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses measured by expression of IFN- or IL-2 by ICS at Day 29 
and Day 210 
• 
Polyfunctionality of M72-specific CD4+ and CD8+ T-cell responses 
measured by co-expression of multiple functional markers by ICS 
• 
To assess HIV viral load post-
M72/AS01E vaccination 
• 
Frequencies of participants with confirmed HIV ribonucleic acid 
([RNA]>200 copies/mL) at Day 57, Day 210 and Day 390 
• 
To assess changes in CD4+ T 
cell count from baseline 
• 
Mean changes in CD4+ T cell count from baseline to Day 57, Day 210 
and Day 390 
• 
To describe the incidence of 
suspected TB disease and 
laboratory-confirmed 
pulmonary TB disease 
• 
Suspected TB during the study   
• 
Laboratory-confirmed pulmonary TB during the study 
Other exploratory endpoints may include, but are not limited to, assessing functional antibody profiles in 
response to vaccination, vaccine-induced changes in innate and myeloid cell populations, and vaccine-induced 
changes in transcriptomic, proteomic or metabolomic profiles. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
21 
4. 
Study Design 
4.1. 
Overall Design 
Disclosure statement: This is randomized, observer-blind, placebo-controlled, clinical trial of 
M72/AS01E tuberculosis vaccine vs. placebo in approximately 400 males and females between 
16 to 35 years of age inclusive, who are living with HIV infection, and are virally suppressed 
(i.e., viral load < 200 copies per mL) on ART.  
Interventional model: Participants will be randomly assigned 1:1, to one of two groups in 
parallel for the duration of the study.  
Intervention groups: 2 study groups (M72/AS01E group and placebo group), will each receive 2 
vaccinations administered IM in the deltoid muscle, preferably of the non-dominant arm, one 
month apart (at Day 1 and Day 29).  
- 
M72/AS01E group: A 0.5 mL dose of M72/AS01E contains 10µg M72 reconstituted with 
AS01E, a GSK proprietary adjuvant system containing 25 µg MPL (3-O-desacyl-4-
monophosphoryl lipid A produced by GSK), 25 µg QS-21 (Quillaja saponaria Molina, 
fraction 21). The vaccine will be administered at Day 1 and Day 29. 
- 
Placebo group: Each dose contains 0.5 mL saline (0.9% NaCl). The placebo will be 
administered at Day 1 and Day 29. 
Refer to Section 6.1 for details regarding the vaccine and placebo. 
Primary purpose: To assess the safety, as well as immunogenicity of M72/AS01E vaccine in 
participants with virally suppressed HIV infection on ART 
Safety and immunogenicity outcomes will be followed for 12 months after the second 
vaccination (end of study) for each randomized participant. 
Masking: The study is observer-blind: participants, sponsor, CRO clinical team, laboratory, 
investigators and site staff will be blinded to the randomization. An Independent Data 
Monitoring Committee (IDMC) will review unblinded data. The investigational pharmacist 
preparing study interventions will be unblinded but will not perform other study duties. Refer to 
Section 6.2.2. 
Safety Monitoring: An IDMC will be established to oversee the safety of this study. The IDMC 
will review unblinded safety data during regular scheduled safety review meetings, and may 
request additional information, or a pause in recruitment and vaccination, while safety data are 
being evaluated.  
Number of participants: Approximately 400 participants will be enrolled. 
Randomization: Participants will be randomized 1:1, stratified by site, and QuantiFERON-TB 
Gold Plus (QFT) status, based on results at screening. 
Adverse events of special interest (AESIs): Protocol-defined pIMDs will be assessed throughout 
the study.  
Analysis: The final analysis will occur after all participants have reached the end of the study 
(Day 390).  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
22 
Total duration of study participation: The study duration for each participant, after screening, is 
approximately 390 days, which includes 2 vaccinations 1 month apart, and 365 days of follow-up 
post dose 2. Enrollment is expected to take approximately 6 months. 
Study sites: Approximately 6 sites in the RSA will participate in this study.  
4.2. 
Scientific Rationale for Study Design 
This study design is similar in scope to that of the previous studies that evaluated the 
M72/AS01E vaccine in HIV positive populations (refer to Section 2.1), in order to confirm those 
results in a larger cohort of people living with HIV.  
The main inclusion criteria are that the participants with HIV infection (positive HIV antibody) 
must be on ART for at least 3 consecutive months prior to screening and have HIV RNA <200 
copies/mL and CD4 ≥200 cells/µL at screening. They must also have had TB preventive therapy 
(TPT) in the past. 
The rationale is to include healthy people living with HIV who are receiving ART. These 
selection criteria are aimed to enroll individuals at low risk for opportunistic infections (OI), 
immune reconstitution inflammatory syndrome (IRIS) and new ART-related side effects during 
the study. Stable ART for at least 3 months would reduce the risk of new onset AEs possibly 
related to the regimen. Most AEs from ART occur during the first days and weeks of its 
initiation, and any AEs resulting in regimen modifications would likely have occurred prior to 3 
months. IRIS generally occurs during the first 3 months of ART initiation as an inflammatory 
response to undiagnosed or subclinical OI. It is more common in people with low CD4+ count 
(who are excluded from this study), and can be severe and life-threatening. CD4+ count < 200 
cells/µL is considered severe immune deficiency, necessitating medications for OI prophylaxis. 
By enrolling people with CD4+ above this threshold, there is less risk for IRIS and it avoids the 
need for concomitant OI prophylaxis. Viral load < 200 copies/mL indicates successful ART. 
ART is the standard of care worldwide regardless of HIV symptoms, CD4+ counts or viral load 
levels. TPT reduces risk for TB disease and is standard of care for all people living with HIV. 
Therefore, in this study, only participants who have had TPT prior to screening will be included.  
4.3. 
Justification for Adjuvant System and Dose  
A previous study, TB-009, was conducted to evaluate the different adjuvant systems, AS01 
versus AS02, and to determine the antigen/adjuvant dose for further development. This study 
enrolled PPD positive adults with no history of TB, living in The Philippines, a TB endemic 
region. Adjuvanted vaccine formulations used were:  
• M72 (40 µg)AS01B,  
• M72 (20 µg)AS01E,  
• 
M72 (10µg)AS01E 
• M72 (10 µg)AS02D.  
This study confirmed that M72/AS01 vaccine formulations induced a higher cell-mediated 
immune response compared to M72/AS02 vaccine formulations and showed that the lower M72 
dose (10 µg) induced immune responses that were comparable to those induced by higher M72 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
23 
doses (20 and 40 µg). Furthermore, all adjuvanted vaccine formulations had a similar safety and 
reactogenicity profile.  
The low dose antigen-Adjuvant System combination M72(10µg)AS01E was thus selected as the 
TB vaccine candidate for further evaluation in clinical trials including the phase 2b TB-018 
efficacy study (Van Der Meeren, 2018). 
The schedules other than 0 and 1 month have not been explored, and this schedule was shown to 
be efficacious in Phase 2b. To minimize risk, the scientific community agreed that the 0, 1 
schedule should be maintained through Phase 3 and licensure (WHO, 2019e).  
The selection of the dose and schedule of vaccination in this protocol is also the same as in the 
previous phase 2 studies in people living with HIV (TB-011 and TB-014).  
Vaccination schedules in all previous M72/AS01E studies consisted of 2 doses given one month 
apart, except for the TB-013 study in which 100 participants (1/3) received only one dose. All 
doses were administered IM in the deltoid region of the arm or in the anterolateral thigh of 
infants (TB-013). 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she completes the final visit, 
Visit 7 (Day 390). 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Recruitment 
Participants will be recruited from communities with known high burden of TB transmission and 
disease. Good participatory practices will be followed and site staff will work closely with 
community organizations and community leaders. 
Various methods of recruitment may be used, such as community information sessions, 
advertising, referrals, word-of mouth, or solicitation through participants previously known to 
the clinical site.  
All recruitment materials will be approved by the appropriate Institutional Review Board/s 
(IRBs) or Independent Ethics Committee/s (IECs). Interested participants will be invited to 
participate in the informed consent and assent process, depending on age (see Section 9.5.2). 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
24 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria are met: 
Age 
1. Participant must be 16 to 35 years of age inclusive, at the time of signing the informed 
consent or assent. 
Type of Participant and Disease Characteristics 
2. Participant with documented HIV infection who fulfill all of the following: 
• Has reactive anti-HIV antibody at screening 
• On ART for at least 3 consecutive months at screening 
• Has documented HIV RNA <200 copies/mL at screening 
• Participants with CD4+ cell counts ≥200 cells/µL at screening 
3. Participants have had TPT in the past and are not receiving TPT at the time of screening, 
according to the judgment of the investigators 
4. Participants who are healthy as determined by medical evaluation including medical history, 
physical examination and laboratory tests 
Informed Consent 
5. Capable of giving signed informed consent and informed assent (if appropriate), which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) or informed assent form, and in this protocol (see Section 9.5.2 for details 
regarding the informed consent process). 
Sex 
6. Female participants of childbearing potential must agree not to become pregnant from the 
time of study enrollment for one year after study intervention. Women physically capable of 
pregnancy, sexually active and has no history of hysterectomy or tubal ligation or menopause 
must agree to use an effective method of avoiding pregnancy during this period. Refer to 
Section 9.7 for details. 
Additional requirements: 
7. Participants who agree to stay in contact with the study site for the duration of the study, 
provide updated contact information as necessary, and have no current plans to relocate from 
the study area for the duration of the study. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
25 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria are met: 
Medical Conditions 
1. Acute illness or fever ≥99.5°F (or 37.5C) on Day 1 
2. History of active TB disease 
3. Evidence of active TB disease with any of the following: 
• Have symptoms or signs of TB disease 
• Have a positive sputum Xpert MTB/RIF assay (only in participants with sputum 
sample at screening)  
• Are on treatment for active TB disease 
4. Evidence and/or history of clinically significant medical conditions (other than HIV 
infection) as judged by the investigator, including malignancies 
5. Any current medical, psychiatric, occupational, or substance abuse problems that, in the 
opinion of the investigator, will make it unlikely that the participant will comply with the 
protocol 
Prior/Concomitant Therapy 
6. Any medications or other therapies that may impact the immune system such as immune 
globulin, interferon, immunomodulators, cytotoxic drugs or other drugs known to be 
frequently associated with major organ toxicity as determined by the investigator, within 90 
days prior to Day 1 
7. Immunosuppressive agents including systemic steroids - prior corticosteroid therapy within 
90 days prior to Day 1 (permitted: 5mg/day prednisone equivalent, inhaled, topical, and intra-
articular corticosteroids) 
8. Receipt or donation of blood or blood products within 90 days prior to Day 1 or planned 
receipt or donation during the study period. 
9. Receipt of any vaccine in the period starting 7 days before, and ending 7 days after, each 
dose of the study vaccine. Refer to Section 6.4. 
Prior/Concurrent Clinical Study Experience 
10. Participation in an interventional clinical trial and/or receipt of any investigational drug 
within 180 days prior to signing informed consent or assent 
11. History of previous administration of experimental Mtb vaccine 
Diagnostic Assessments 
12. Safety laboratory values outside of normal range, for age and sex that are suggestive of a 
disease state (Grade 1 abnormalities, as per DAIDS toxicity table version 2.1, will not lead to 
exclusion if the investigator considers them not clinically significant.) 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
26 
13. Urinalysis abnormality greater than Grade 1 on the Toxicity Scale (with the exception of 
hematuria in a menstruating female), or urinalysis abnormality judged clinically significant 
by the investigator 
14. Current hepatitis B and/or hepatitis C infection 
15. Indeterminate QFT result 
Other Exclusions 
16. History of allergy or hypersensitivity to the study drug, excipients or related substances 
17. Shared residence with an individual who is receiving TB treatment or with someone who is 
known to have incompletely treated TB, e.g., Xpert MTB/RIF assay-positive, PCR-positive, 
culture-positive, smear-positive TB, or clinically diagnosed unconfirmed TB 
18. Female participants with any one of the following conditions: currently pregnant or 
lactating/nursing; having positive serum pregnancy test during the screening window, 
planning a pregnancy within 1 year after first dose of study intervention 
19. Individuals who are acting as study personnel or immediate family members (brother, sister, 
child, parent) or the spouse/partner of study personnel. 
20. Child in Care* 
*Defined as a child who is under the care (control or protection) of an agency, organization, 
institution or entity by the courts, the government body, acting in accordance with powers 
conferred in them by law or regulations. The definition of a child in care can include a child 
cared for by foster parents or living in a care home or institution, provided that the arrangements 
fall within the definition above. The definition of a child in care does not include a child who is 
adopted or has an appointed legal guardian. 
5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, consent status and any SAE. 
Rescreening is only permitted under the following conditions: 
• If a participant presents with an acute illness day of first study intervention, e.g., elevated 
temperature, and meets all other inclusion/exclusion criteria and is rescreened within the 
originally defined screening window (Section 1.2).  
• When there are technical difficulties with phlebotomy at screening (e.g., laboratory 
reports hemolyzed blood), technical error in running the laboratory tests, or an abnormal 
urine analysis (e.g., due to menstruation or urinary tract infection). 
Rescreened participants should be assigned the same participant number as for the initial 
screening.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
27 
Refer to Section 9.5.2 regarding consent process for rescreened participants. 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention, marketed product, placebo, or 
medical device intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Interventions Administered 
Participants randomized to the vaccine group will receive 2 doses of the M72/AS01E candidate 
vaccine which contains 10 µg of a recombinant fusion protein derived from the Mtb antigens 
Mtb32A and Mtb39A (M72), and the adjuvant, AS01E.  
A 0.5 mL dose of M72/AS01E contains 10µg M72 reconstituted with AS01E, a GSK proprietary 
adjuvant system containing 25 µg MPL (3-O-desacyl-4-monophosphoryl lipid A produced by 
GSK), 25 µg QS-21 (Quillaja saponaria Molina, fraction 21; licensed by GSK from Antigenics 
Inc., a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation), and liposomes. 
The control group will receive a 0.5mL saline (0.9% NaCl) placebo per dose.  
Table 4: Study Interventions 
 
M72/AS01E Vaccine  
Control 
Intervention Name 
M72/AS01E Mycobacterium 
tuberculosis vaccine 
Normal saline 
Unit Dose Strength 
10 µg 
Normal saline (0.9% NaCl) 
Dosage Volume 
0.5 mL per injection 
0.5 mL per injection 
Route of Administration IM injection 
IM injection  
6.1.1. 
Administration 
Both the vaccine and placebo injections will be administered IM in the deltoid muscle of the 
upper arm, preferably the non-dominant arm, using standard technique. A standard syringe and 
needle will be available locally at site. 
The M72/AS01E vaccine is slightly opaque compared to the transparent saline placebo. The 
unblinded investigational pharmacist will provide M72/AS01E and placebo to the clinic as unit-
dose syringes, which will be identified with the participant identification number, date and time 
of dose preparation, and the volume prepared. An investigator (i.e., physician) must be present in 
the clinic at the time of administration. Labels will be prepared and provided by the CRO. 
Before administering the injection, the study intervention administrator must check that the 
syringe is identified with the correct participant identification number and check the date and 
time the dose was prepared. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
28 
6.1.2. 
Preparation/Handling/Storage/Accountability 
The M72/AS01E vaccine will be supplied as a lyophilized cake for reconstitution with the AS01E 
adjuvant system.  
The normal saline placebo for injection will be prepared as described in 6.1.1. 
The vaccine must be stored between +2°C to +8°C in a secured location with no access for 
unauthorized personnel. Reconstituted vaccine must be stored between +2°C to +8°C and 
administered as soon as possible and within 8 hours after reconstitution. Any reconstituted 
vaccine not used within 8 hours must be discarded. Exposure to light should be kept to a 
minimum.  
The saline placebo must also be stored in a secured location between +2°C to +8°C with no 
access for unauthorized personnel.  
The study pharmacist (or designee) must confirm appropriate temperature conditions have been 
maintained during transit and during site storage for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. Upon receipt of 
study vaccine supplies, the authorized site staff must immediately inspect all kits for damage. 
Any damage or discrepancies from the packing list must be documented and promptly discussed 
with the sponsor and the study monitor to determine the appropriate action. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The principal investigator (PI) is responsible for study intervention accountability, reconciliation, 
and record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Authorization for any unused study vaccine and supplies to be destroyed is the responsibility of 
the sponsor. Unused supplies will be destroyed according to the facility’s SOPs or per local 
regulations. Any disposal of study vaccine conducted at the clinical site must be documented in 
the study file.  
Further guidance and information for the preparation, handling, storage and accountability are 
provided in the Study Pharmacy Manual. 
6.1.3. 
Vaccine Administration Error 
Vaccine administration error is defined as the administration of a dose of the study vaccine that 
was not intended as instructed or by a route that is different from the intended route of 
administration. Each vaccine dose will be prepared by reconstituting fully the contents of one 
vial containing the antigen with the contents of one vial of the adjuvant, and then drawing out the 
reconstituted vaccine content (0.5 mL) into the dosing syringe. In case of any deviation, the 
instructions in the pharmacy manual and the IB are to be followed. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
29 
6.2. 
Measures to Minimize Bias: Randomization and Blinding 
6.2.1. 
Randomization  
Participants will be randomized to one of two interventions (M72/AS01E or placebo) based on a 
randomly-generated sequence of participant identification (identifier) numbers (randomization 
schedule) using a validated Interactive Voice/Web Response System (IVRS/IWRS).  
Before the study is initiated, the telephone number and call-in directions for the IVRS and/or the 
log in information and instructions for the IWRS will be provided to the study sites.  
The randomization schedule will be prepared by a statistician who will not be involved in the 
analysis of the study in order to maintain the blind of the study team.  
The day of randomization for each participant will be Study Day 1. Randomization will be 
stratified by site and QFT status.  
6.2.2. 
Masking 
The study will be conducted as an observer blind study because of the difference appearances of 
the vaccine and placebo.  
The study team will remain blinded until the end of the study, and the laboratory staff will 
remain blinded until all laboratory studies have been completed. 
Only the following people will have access to treatment allocation while the study is blinded:  
• Investigational pharmacists preparing the study interventions  
• Biostatistician preparing the randomization list 
• Biostatistician preparing the IDMC data 
• IDMC members 
• Unblinded study monitors. 
All unblinded persons must take care to not reveal individual group assignments to any other 
member of the study team. The investigational pharmacist preparing study interventions, will be 
unblinded but will not perform other study duties. 
Unblinded study personnel must not participate in the evaluation of AEs. A delegation of 
authority log will be maintained by the site and will identify the individual(s) with access to 
study blinding information. 
6.2.3. 
Blind Break  
The IVRS/IWRS will be programmed with blind-breaking instructions. In addition, instructions 
on emergency unblinding in case of system outage will be provided. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s treatment 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact the sponsor prior to unblinding a participant’s treatment assignment 
unless this could delay emergency treatment of the participant. If a participant’s treatment 
assignment is unblinded, the sponsor must be notified within 24 hours after breaking the blind. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
30 
The date and reason that the blind was broken must be recorded in the source documentation and 
case report form (CRF), as applicable. 
6.3. 
Study Intervention Compliance 
Participant compliance with study intervention will be recorded on his/her CRF. 
6.4. 
Concomitant Therapy 
As part of the inclusion criteria, participants must have documentation in the CRF that they have 
been on ART for at least 3 consecutive months prior to screening and should remain on ART 
throughout the study period. Modifications of ART for clinical reasons are allowed. 
Discontinuation of ART is not cause for study withdrawal. 
Receipt of any vaccine 7 days before and 7 days after either Dose 1 or Dose 2 is prohibited 
during the study, and will lead to study withdrawal. Refer to Section 7.2.  
All vaccines received within 30 days prior to the first study vaccine administration and 
throughout the study will be recorded for each participant.  
Any prescription medication, anti-inflammatory drugs and antipyretic drugs*, or vaccine that the 
participant receives from enrollment through study must be recorded at specified timepoints as 
shown in the SoA, along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
* The use of anti-inflammatory and antipyretic medication should be discouraged during the first 
28 study days (days 1 through 28 after each dose administered). 
Information regarding all immunosuppressant therapy/medications and TB curative treatment, 
experimental drugs or vaccines, and receipt or donation of blood products will be collected and 
monitored through the last study visit. 
Note that any of these concomitant therapies or medications are not allowed in the study 
and their administration will lead to withdrawal from the study. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5. 
Dose Modification 
There are no dose modification specifications.  
All participants will receive 2 doses by injection of either M72/AS01E vaccine or placebo as 
described in Section 6.1.1. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
31 
6.6. 
Intervention after the End of the Study 
There is no intervention planned after the end of the study.  
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of / Withdrawal from Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention.  
See the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
A ‘withdrawal’ from the study treatment refers to any participant who does not receive the 
complete treatment, i.e., when no further planned dose (i.e., dose 2) is administered from the date 
of withdrawal. A participant withdrawn from the study intervention may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed (safety or 
immunogenicity) if planned in the study protocol. 
All data collected until the date of withdrawal/last contact of the participant will be used for the 
analysis. 
Information relative to premature discontinuation of the investigational vaccine will be 
documented in the CRF. The investigator will document whether the decision to discontinue 
further vaccination was made by the participant or by the investigator (or designee), as well as 
which of the following possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Other (specify). 
7.1.1. 
Contraindications to the Second Dose 
The following events constitute absolute contraindications to further administration of 
M72/AS01E or placebo. If any of these events occur during the study, the participant must not 
receive the second dose but may continue other study procedures at the discretion of the 
investigator.  
• 
Hypersensitivity reaction, including anaphylaxis, following the administration of the first 
dose 
• 
Pregnancy  
• 
Auto-immune disease  
• 
Discovery of any health condition which, in the investigator’s opinion, places the participant 
at increased risk from receipt of further investigational product; or discovery of a change in 
the participant’s status which renders him/her unable to comply with protocol-mandated 
safety follow-up. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
32 
The vaccine doses can be administered to participants with a minor illness (i.e., mild diarrhea, 
mild upper respiratory infection, etc.) without fever (fever ≥37.5°C/99.5°F oral body 
temperature, or equivalent). If the participant has fever, with or without a minor illness at the 
time scheduled for vaccination, the participant may be vaccinated at a later date, within the 
specified time window for that visit or withdrawn at the discretion of the investigator. 
7.2. 
Participant Withdrawal from the Study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any participant who did not 
come back for the concluding visit (Visit 7 [Day 390]). 
All data collected until the date of withdrawal/last contact of the participant will be used for the 
analysis. 
A participant is considered a ‘withdrawal’ from the study when no study procedure has occurred, 
no follow-up has been performed and no further information has been collected for this 
participant from the date of withdrawal/last contact. 
Information relative to the withdrawal will be documented in the CRF including date and reason. 
A withdrawal from the study because of an SAE/AE must be clearly documented in the CRF. 
Investigators will follow participants who are withdrawn from the study as result of a SAE/AE 
until resolution or stabilization of the event. 
The investigator will document whether the decision to withdraw a participant from the study 
was made by the sponsor or the investigator, as well as which of the following possible reasons 
was responsible for withdrawal: 
• 
Serious adverse event 
• 
Non-serious adverse event 
• 
Protocol violation (specify) 
• 
Consent withdrawal, not due to an adverse event* 
• 
Moved from the study area 
• 
Lost to follow-up 
• 
Other (specify). 
*If a participant withdraws consent, the reason, if specified, will be documented in the CRF. 
A participant may, at the investigator’s discretion, be withdrawn from the study if any one of the 
below conditions apply. Participants with the below conditions will be followed for safety as 
described in the protocol, without any of the protocol-required blood draws. 
• 
Development of active TB or receipt of curative anti-tuberculous therapy 
• 
Development of autoimmune disease or immunosuppression, or an AESIs 
• 
Receipt of investigational drug therapy or investigational vaccine outside of the study or 
concomitant treatment or therapies noted as exclusion criteria 
• 
Pregnancy 
• 
Receipt of any vaccine 7 days before and 7 days after either Dose 1 or Dose 2.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
33 
A participant may withdraw (or a participant’s parent or guardian (a guardian is a legally 
acceptable representative [LAR]) may withdraw the participant) from the study at any time or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
If the participant withdraws consent the sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits (3 failed visits) and is unable to be contacted by the study site (3 failed attempts 
per failed visit). 
If a participant fails to return to the clinic for a required study visit, the following actions must be 
taken. 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, telephone calls and, if necessary, a 
home visit by a member of the study team). These contact attempts should be documented in the 
participant’s medical record and the CRF. 
Should the participant continue to be unreachable, he/she will be considered lost to follow-up 
from the study.   
7.4. 
Pausing Guidelines 
Pausing guidelines are put in place to address events necessitating a pause in enrollment and in 
participant dosing, and an IDMC review. Therefore, these guidelines are in effect during the 
active enrollment and dosing period. 
Refer to Section 9.5.1 regarding the IDMC, established to oversee the safety of this study  
Any of the below conditions, if identified either by an investigator, the sponsor or the IDMC, 
will trigger a pause of the enrollment and pause of administration of study intervention until the 
IDMC has reviewed the safety data and made a recommendation on how to proceed: 
1. One report of anaphylaxis with or without bronchospasm within 4 hours of injection, 
indicative of an immediate hypersensitivity reaction to the study injection 
2. 1% of the safety population and at least two participants experience an SAE judged as related 
to study intervention by the investigator 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
34 
3. 20% of participants and at least 20 participants experience a Grade 3 or higher event related 
to study vaccine, as judged by the investigator, with the exception of expected local reactions 
or local injection site reactions that decrease to < Grade 3 within 48 hours. 
If an investigator observes that pausing guideline 1 or 2 is met, the investigator will inform the 
sponsor or delegate as soon as possible and within 24 hours of the observation. The sponsor or 
delegate will notify all study investigators and the IDMC members of the pause in enrollment as 
soon as possible and within 24 hours of receiving notification of the condition being met. The 
IDMC members will review all relevant safety data, convene an urgent ad hoc review meeting 
and make a recommendation to the sponsor with regards to maintaining the pause in enrollment 
or resuming enrollment. 
If, during one of its scheduled or ad-hoc meetings, the IDMC observes that a pausing guideline is 
met, the IDMC Chair or delegate will inform the sponsor as soon as possible and within 24 hours 
of the identification of the condition being met. If the IDMC has sufficient information to 
recommend that enrollment resume, this can be communicated to the sponsor within the same 
timeline. The sponsor or delegate will notify all study investigators of the pause in enrollment as 
soon as possible and within 24 hours of receiving notification from the IDMC. 
If the sponsor or delegate observes that a pausing guideline is met, the sponsor will notify all 
study investigators and the IDMC members of the pause in enrollment as soon as possible and 
within 24 hours. The IDMC members will review all relevant safety data, convene an urgent ad 
hoc review meeting and make a recommendation to the sponsor with regards to lifting or 
maintaining the pause in enrollment. 
The IDMC may recommend resumption of enrollment with or without changes to the protocol. 
The final decision to pause or resume study activities will always be the responsibility of the 
sponsor. All IDMC recommendations will be stored according to the IDMC Charter. 
All sponsor decisions will be documented in a memorandum to the study file. The sponsor or 
delegate is responsible for prompt communication to all relevant study sites of decisions related 
to pausing or resuming the study activities, including notification to the PI, relevant IRBs/IECs 
and regulatory authorities. 
The clinical sites will be allowed to resume activities only upon receipt of written notification 
from the sponsor. 
7.5. 
COVID-19 Contingency Plans 
In the event that coronavirus disease, COVID-19, affects the conduct of this trial, the sponsor 
will evaluate if in-person visits are necessary to fully assure the safety of trial participants and 
whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative 
location for assessment such as local labs or home visits) could be implemented when necessary 
and feasible, and would be sufficient to assure data integrity and safety of participants (FDA, 
2020; SACRA, 2020; SAPHRA, 2020). 
Any contingency plans must be sufficient to assure the safety of trial participants. Changes in 
study visit schedules, missed visits, or withdrawal of the study intervention or participant 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
35 
discontinuations may lead to missing information (e.g., for protocol-specified procedures) must 
be captured in the case report form that explains the basis of the missing data (i.e., COVID-19).  
Approaches to be used to protect trial participants and manage study conduct during possible 
disruption of the study as a result of COVID-19 control measures at study sites must be 
documented. Depending upon the nature of the changes described above, a protocol amendment 
may be required under the applicable regulations. 
Deviations because of COVID-19 will be described in the clinical study report or in a separate 
study-specific document) including but not limited to the following: 
• 
Contingency measures implemented to manage study conduct during disruption of the study 
as a result of COVID-19 control measures.  
• 
A listing of all participants affected by the COVID-19 related study disruption by unique 
participant number identifier and by investigational site, and a description of how the 
individual’s participation was altered.  
• 
Analyses and corresponding discussions that address the impact of implemented 
contingency measures (e.g., trial participant discontinuation from investigational product 
and/or study, alternative procedures used to collect critical safety and/or efficacy data) on 
the safety and efficacy results reported for the study.  
8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.2). 
Prior to any study procedure, all eligible participants will be assigned a unique participant 
identifier. This participant identifier will be used throughout the study for participant 
identification.  
Screening for eligibility assessment will occur after informed consent, and as applicable, assent, 
is obtained (see Section 9.5.2 for the consent/assent process). Eligibility for randomization will 
be based on the inclusion and exclusion criteria (described in Sections 5.1 and 5.2, respectively). 
Eligibility criteria will be checked during the screening process and prior to study intervention 
administration to ensure that all participants enrolled meet all of the inclusion criteria and none 
of the exclusion criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
To evaluate eligibility criteria, a medical history and physical examination including vital signs, 
height, and weight will be performed. In addition, safety laboratory tests (hematology and 
chemistry), and urinalysis (including microscopy) as well as a QFT TB test, sputum Xpert 
MTB/RIF assay, CD4+ cell count, HIV viral load, HIV serology, hepatitis B and C screening, 
and a serum pregnancy test (females only) will be performed. Refer to Section 8.2 for details 
regarding these procedures.  
The investigator must document confirmation of eligibility prior to randomization.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
36 
All protocol-required safety laboratory tests (hematology, chemistry, and urinalysis) as well as a 
QFT TB test, sputum Xpert MTB/RIF assay, CD4+ cell count, HIV viral load, HIV serology, 
hepatitis B and C screening, and a serum pregnancy test (females only) will be performed by the 
central laboratory, Bio Analytical Research Corporation RSA (BARC SA or similar).  
Urine pregnancy tests will be performed by the study site.  
Assays for secondary, and exploratory endpoints will be carried out in laboratories outside of the 
RSA.  
8.1. 
Efficacy Assessments/Immunogenicity 
Efficacy of the M72/AS01E vaccine will not be measured in this study. Instead, the study is 
designed to evaluate safety and immunogenicity of the vaccine. 
8.1.1. 
Humoral Immunogenicity 
Blood samples for immunogenicity evaluation of M72-specific IgG antibody in serum will be 
collected per SoA (Table 2). On Day 1 and Day 29 visits, samples will be collected prior to study 
intervention administration. Humoral M72-specific IgG antibodies will be measured by enzyme-
linked immunosorbent assay (ELISA).  
8.1.2. 
Cell-Mediated Immune Responses 
Blood samples for CMI responses will be collected as shown in the SoA (Table 2).  
On Day 1 and Day 29 visits, samples will be collected prior to study intervention administration.  
Peripheral blood mononuclear cells (PBMCs) will be isolated and analyzed using intracellular 
cytokine staining (ICS) to assess the frequency, magnitude and polyfunctionality of M72-specific 
CD4+ and CD8+ T-cell responses. M72-specific CD4+ and CD8+ T cells expressing multiple 
cytokines will be measured upon short-term in vitro stimulation of PBMCs.  
For the secondary objective, frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses will be measured by expression of IFN-γ or IL-2 at Days 1, 57 and 390 to characterize 
the vaccine-induced immune response at baseline, peak immunogenicity and long-term memory, 
respectively.  
If responses at peak or memory are lower than expected compared to historical data from 
previous M72 vaccine studies, additional timepoints may be assessed to further characterize the 
kinetics of the cellular vaccine-induced immune response in HIV-positive study participants.  
For exploratory objectives, polyfunctionality of M72-specific CD4+ and CD8+ T-cell responses 
will be measured to support the exploratory objective by analysis of the co-expression of 
multiple functional markers by ICS.  
8.1.3. 
Subset Assessments  
It may not be necessary to test all participants for immunogenicity. Strategies to sample only a 
portion of participants for immunogenicity may be considered and final plans will be 
documented in a separate statistical analysis plan prior to data unblinding.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
37 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.2). 
Safety outcomes will include: 
• 
Solicited AEs: local injection site pain, redness, and swelling, and general AEs including 
headache, fatigue, malaise, myalgia, gastrointestinal symptoms, and fever (defined as a 
temperature ≥37.5°C [99.5°F]). 
• 
Unsolicited AEs  
• 
All SAEs 
• 
Vaccination-related SAEs  
• 
pIMDs  
• 
Safety laboratory assessments ≥grade 3.  
Refer to Section 8.3 for details regarding AEs and SAEs, and Section 8.2.5 for safety laboratory 
assessments. 
8.2.1. 
Physical Examination and Medical History  
A medical history and physical examination will be conducted at screening to assess enrollment 
eligibility. Only participants who are considered healthy by the investigator will be enrolled.  
All conditions that exist prior to administration of study intervention will be recorded in the 
medical history. Day to day fluctuations in these conditions that do not represent a clinically 
significant change in the participant’s status will not necessarily be reported as AEs.  
Physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, 
gastrointestinal and neurological systems, as well as assessment of height and weight, body 
temperature, and resting vital signs (blood pressure, pulse and respiratory rate). Vital signs will 
be measured after at least 5 minutes of rest in a quiet setting without distractions. Vital signs will 
be taken prior to each dose administration. 
As part of the history/physical examination at each visit, a TB symptom/sign checklist from RSA 
TB guidelines will be used. This will include TB contact history. The TB symptom/sign checklist 
in the eCRF includes: 
• 
Cough for longer than 2 weeks 
• 
Fever for longer than 2 weeks  
• 
Fatigue for longer than 2 weeks 
• 
Night sweats for longer than 2 weeks 
• 
Loss of weight or insufficient weight gain or growth 
• 
Other. 
If TB is suspected, potential participants would be managed according to standard of care.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
38 
 
8.2.1.1. 
Interim History and Focused Physical Examination 
An interim history will be taken on Day 1 and all subsequent visits, as indicated in the SoA. A 
focused physical examination will be performed if indicated by interval history and may include 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Body 
weight will be measured at each visit. A TB symptom screen and TB contact history update will 
also be included at each visit. 
8.2.2. 
Pregnancy Status Assessment 
A serum βHCG test will be performed at screening, Day 1 (Visit 1), Day 29 (Visit 3), Day 57 
(Visit 5) and Day 210 (Visit 6) and Day 390 (Visit 7). 
A urine βHCG test will be performed at Day 1 (Visit 1, prior to enrollment and dose 1) and Day 
29 (Visit 3, prior to dose 2).  
During the study, participants will be asked about pregnancy at each time point indicated in the 
SoA (Section 1.2). If a pregnancy is reported, the investigator should inform the Medical 
Monitor within 24 hours of learning of the pregnancy and should follow the procedures outlined 
in Section 9.7. 
If a participant becomes pregnant during the study, she will be withdrawn from all study 
procedures going forward, i.e., dose administration, blood-draws and laboratory evaluations 
described in the SoA will not be performed once a participant is known to be pregnant.  
However, she will be encouraged to continue in the study for safety follow-up. 
Details of all pregnancies will be collected after the start of study intervention and until the end 
of the study. 
8.2.3. 
Pre- and Post-Study Intervention Safety Monitoring 
On Day 1 (Visit 1) and Day 29 (Visit 3), prior to vaccine/placebo administration, vital signs will 
be taken.  
Participants will remain under observation for at least 30 minutes after receiving the injection.  
Allergic reactions to vaccination are possible, therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available and a physician 
trained to recognize and treat anaphylaxis must be present in the clinic during vaccination and 
the post-vaccination monitoring period.  
8.2.4. 
Diary Card and Daily Temperature Monitoring 
On Day 1 (Visit 1) and Day 29 (Visit 3), participants will be given a diary card and receive 
guidance (training) on how to fill in the card. Participants will also receive a digital thermometer. 
The diary card will be used by the study participants to record the duration and intensity (Grade 
1, 2, 3, or 4) of solicited local and general AEs, and any unsolicited AEs, for 7 days following 
vaccination. The diary card will also allow for unsolicited AEs to be recorded. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
39 
The diary card will be collected and reviewed by the PI (or designee) 7 days after each dose, i.e., 
on Day 8 (Visit 2) and Day 36 (Visit 4). No changes to the diary card will be permitted, however, 
any verbally recalled information provided by the participant or parent or guardian/LAR during 
review of the diary card will be documented in the source document and reported as an AE. 
A memory aid will be distributed to the participant on Day 8 (Visit 2) and Day 36 (Visit 4) and 
the participant will receive guidance (training) to record any general AEs or unsolicited AEs, 
using the aid (any local injection site AE reported after Day 8 will be considered an unsolicited 
AE). 
The memory aid will be collected one month after each dose, i.e., on Day 29 (Visit 3) and Day 
57 (Visit 5). 
Memory aids and diary cards are regarded as source documents for the study. 
8.2.5. 
Clinical Safety Laboratory Assessments  
Safety laboratory assessments will be performed at screening and prior to each dose 
administration. 
Laboratory values from blood/urine sample collected at screening outside the normal range that 
are suggestive of a disease state (i.e., values greater than Grade 1) will lead to exclusion from 
study enrollment, with the exception of any grade hematuria in a menstruating female, or a 
urinalysis abnormality judged not clinically significant by the investigator. 
Refer to Section 9.8, for toxicity table for grading laboratory indices. 
Clinical safety laboratory parameters that will be evaluated at screening include: 
• 
Hematology: hemoglobin (Hgb), white blood cells (WBC), platelets 
• 
Serum chemistry: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
and total bilirubin 
• 
Urinalysis by dipstick: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase. 
• 
Urine microscopy. 
Abnormal results and findings that make the participant ineligible will be discussed with the 
participant and the participant will be referred for follow-up care with their healthcare provider if 
necessary.  
Information about the laboratory(ies), including any instructions for performing and interpreting 
specific tests, will be maintained in the investigator’s study files.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents.  
An abnormal laboratory value should be deemed clinically significant if either of the following 
conditions are met: 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
40 
• 
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from 
baseline. 
• 
The abnormality is of a degree that requires additional active management, e.g., change of 
dose, discontinuation of the drug, close observation, more frequent follow-up assessments, 
or further diagnostic investigation. 
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SoA. 
Hematology and serum chemistry will be monitored on Day 1 and Day 29. 
If laboratory values from non-protocol specified laboratory assessments require a change in 
participant management or are considered clinically significant by the investigator (e.g., AE or 
SAE), then the results must be recorded in the CRF.  
All protocol-required safety laboratory tests will be performed by the central laboratory, Bio 
Analytical Research Corporation RSA (BARC SA or similar). 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
8.2.6. 
HIV Antibody Assessment and HIV Viral Load Assessment 
To be eligible for the study, participants must have reactive anti-HIV antibody at screening and 
be on ART for at least 3 consecutive months at the time of screening and have HIV viral load 
<200 copies/mL. 
ART initiation date will be documented at screening.  
To assess that all participants have HIV viral load <200 copies/ mL on ART, an HIV viral load 
assessment (copies/mL) will be performed as shown in the SoA (Section 1.2). 
If an enrolled participant has HIV viral load> 200 copies/mL, confirmed HIV RNA rise as 
determined by the HIV viral load assessment per SoA (Section 1.2) should be managed 
according to standard of care.  
At screening, CD4+ T cell counts will be measured to ensure that all enrolled participants have 
≥200 cells/µL. 
Once enrolled, participants may remain in the study regardless of their ART status or HIV viral 
load and CD4+ T cell counts. 
8.2.7. 
QFT assessment for TB 
QuantiFERON-TB Gold Plus (QFT) testing (Cellestis Ltd., Australia) will be conducted at 
screening, and the last visit (Section 1.2).  
Participants may be enrolled in this study regardless of QFT status (positive or negative). An 
indeterminate QFT test at the screening visit would render the participant ineligible for the study. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
41 
8.2.8. 
Sputum Xpert MTB/RIF 
A single self-expectorated sputum will be collected for Xpert MTB/RIF assay from all 
participants at screening and from participants with suspected TB, at study visits. Participants 
with a positive sputum Xpert MTB/RIF assay at screening (if sputum is able to be collected) are 
ineligible for the study. All participants with a positive sputum Xpert MTB/RIF assay and/or 
suspected TB should be referred for further management per standard of care. No sputum 
induction will be done. Sputum Xpert MTB/RIF assay is not required in participants who are 
unable to produce sputum.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs, SAEs, SUSARs, and AESIs can be found in Appendix 1, Section 9.6.1, 
and 9.6.2, 9.6.3, 9.6.4, respectively. 
AEs will be reported by the participant (or, as appropriate, the participant's legally authorized 
representative). Biochemistry and/or hematology findings may also qualify as AEs if the 
investigator considers them as such. 
Study nurses and physicians are responsible for collecting and documenting information and 
events that would potentially meet the definition of an AE. However only the investigator (study 
physician) is responsible for assessment, including assignment of causality and intensity, 
reporting and management of all AEs. The investigator is responsible for following up all AEs 
regardless of their relatedness to the study intervention or study procedures, or that caused the 
participant to discontinue the study (Sections 7, 8.3.1, and 8.3.3). 
Refer to Table 5 for the required time periods for collection of each type of AE. 
8.3.1. 
Time Period and Frequency for Collecting AE, SAE, and Pregnancy 
Information 
Table 5: Collection Period for all AEs and Pregnancies 
Type of Event 
Collection Time Period 
Any AE, SAE, or AESI  
From time of ICF and/or IAF is signed until dosing 
at Day 1 
All solicited AEs  
7 days after each dose 
Unsolicited AEs  
28 days after each dose 
All SAEs, AESIs and Pregnancies 
Day 1 through Month 13 (Day 390) (end of study) 
Distribution and collection days for diary cards are shown in the SoA (Section 1.2). 
All SAEs and AESIs will be reported to the sponsor or designee within 24 hours, as indicated in 
Appendix 1, Section 9.6.6. The investigator will submit any updated SAE data to the sponsor or 
designees within 24 hours of being available 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
42 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be related to 
the study intervention or study participation, the investigator must notify the sponsor or designee 
within the same 24 hours timeline. 
8.3.2. 
Method of Detecting AEs and SAEs 
The methods of recording and follow-up of AEs and SAEs are provided in detail in Appendix 1, 
Section 9.6.5, which includes assessments of intensity, causality, expectedness and outcome of 
AEs and SAE.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading questions are the preferred method to inquire about AE occurrences.  
8.3.3. 
Follow-up of AEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, or the 
participant is lost to follow-up (as defined in Section 7.3). Refer to Section 9.6.5 for details 
regarding recording and follow-up. 
8.3.3.1. 
AE Intensity 
Unsolicited AEs will be classified by the investigator as mild (Grade 1, not interfering with 
normal daily activities), moderate (Grade 2, interfering with normal daily activities), severe 
(Grade 3, preventing normal daily activities) or potentially life-threatening (Grade 4). Refer to 
Appendix 1, Section 9.6.5.1 for details. Solicited AEs will be graded by the participant using the 
diary card. 
8.3.3.2. 
AE Causality 
All AEs will be evaluated by the PI or medically qualified designee (i.e., investigator, study 
physician) to assess the relationship between study intervention and AE. Careful medical 
judgement should be exercised to determine the level of causal relationship between an AE and 
the study intervention. The causality will be assessed as related or not related.  
The sponsor or designee will have the opportunity to confirm the seriousness and case causality 
based on the clinical judgement of the Medical Monitor and sponsor designee. If a serious 
adverse event is considered unrelated by the investigator but the sponsor believes that there is a 
reasonable possibility that the event is related, the sponsor will upgrade the case to a ‘related’ 
status. The sponsor or designee will never downgrade a case from serious to non-serious. 
Refer to Section 9.6.5.2 for details.  
8.3.3.3. 
AE Resolution 
All AEs/SAEs must be followed until resolution. Refer to Section 9.6.5.4 for details. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
43 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Refer to Section 9.6.6 for details regarding SAE reporting. 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor or delegate has a legal responsibility to notify both the local regulatory authority 
and potentially other regulatory agencies about the safety of the study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRBs/IECs, and investigators. The sponsor is 
responsible for the determination of expectedness according to the applicable version of the 
Reference Safety Information of the Investigator’s Brochure. 
All fatal and life-threatening serious unexpected suspected adverse drug reactions (SUSARs) are 
to be reported to SAHPRA within 7 calendar days after first knowledge by the sponsor or its 
delegate, with a complete report to be submitted within an additional 8 calendar days.  
Other SUSARs that are not fatal or life threatening need to be reported no later than 15 calendar 
days after first knowledge by the sponsor or delegate.  
SUSARs and other applicable safety information submitted to the applicable regulatory 
authorities will be distributed to the investigators for awareness. An investigator who receives a 
SUSAR report or other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and file it. A tracker of all such reports received from the sponsor will be 
maintained by the site. The investigator will notify the IRB/IEC, if appropriate and according to 
local requirements. IRB/IEC submissions will be conducted per the local IRB/IEC standard 
operating procedures (SOPs).   
The sponsor will prepare, distribute and submit SUSARs and other applicable reports according 
to local regulatory requirements. The CRO, on behalf of the sponsor will submit the 
corresponding reports to the regulatory authorities. 
Refer to Section 9.6.6 for details regarding SAE reporting. 
8.3.5. 
Death Events 
Any untoward medical occurrence resulting in death is reported as an SAE. The cause of death 
will be appropriately documented in the SAE report form and supporting evidence will be 
provided. 
8.3.6. 
 Mtb Infection and Disease 
Active surveillance for signs and symptoms compatible with incident TB disease, e.g., cough, 
fever, fatigue or night sweats, for longer than 2 weeks, or loss of weight, will continue 
throughout the study.  
Any cases of TB disease will be summarized. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
44 
8.3.7. 
 HIV RNA and CD4+ T Cell Count Analysis 
The proportion of participants with confirmed HIV RNA > 200 copies/mL will be summarized. 
Changes in CD4+ T cell counts will be summarized by treatment group and time point, with 95% 
confidence intervals (CIs).  
8.4. 
Treatment of Overdose 
Not applicable 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this vaccine study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Exploratory Biomarkers 
Collection and analyses of blood samples for biomarker research is an exploratory objective. 
Analytic approaches for the exploratory endpoints below will be informed by best practice and 
the most recent advances in biomarker discovery and systems biology, including the 
identification of vaccine-induced correlates of protection (CoP) in the currently planned 
retrospective analysis of TB-018 samples. Putative CoP will be tested in this trial to confirm that 
HIV infection does not interfere with the induction of CoP by vaccination. 
Exploratory endpoints may include, but are not limited to, assessing functional antibody profiles 
in response to vaccination, vaccine-induced changes in innate and myeloid cell populations, and 
vaccine-induced changes in transcriptomic, proteomic or metabolomic profiles. 
PBMC, plasma, serum and whole blood samples will be collected at time points likely to show 
peak responses for cellular, humoral, and transcriptomic responses, respectively. Refer to SoA 
Section 1.2 for specific time points and volumes for collection of samples.  
Transcriptome studies may be conducted using RNA sequencing or comparable techniques, 
which facilitate the simultaneous measurement of the relative abundances of thousands of RNA 
species resulting in a transcriptome profile for each blood sample. This will enable the evaluation 
of changes in transcriptome profiles that may correlate with biological response to vaccination. 
Plasma and/or serum may be analyzed for soluble immune mediators by quantification using 
multiplex assays. 
Samples will be stored according to local regulations at a facility selected by the sponsor. 
Collected samples will be used for protocol related biomarker research. In addition, only with the 
explicit and optional consent of study participants, samples or partial sample volumes that 
remain once a protocol-defined assay has been completed, may be stored and used for purposes 
other than protocol-related endpoints. Such “future research studies” would include assay 
development, assay quality control and development of methods related to TB research and TB 
vaccine research, including studies that pertain to the improvement, development and quality 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
45 
assurance of the lab tests described in this protocol. If future research must be conducted in 
countries other than RSA, a separate request for approval will be made to the IRB/IEC, informed 
consent/assent will be required, and is subject to laws and regulations of the RSA and to 
IRB/IEC approval.  
8.8. 
Health Economics 
Not applicable 
9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
There are no formal statistical hypotheses to support the objectives of this study. 
9.2. 
Sample Size Determination 
Safety 
With N = 200 vaccinated with M72/AS01E, there is at least 90% (80%) power to observe at least 
1 AE if the true rate is at least 1.2% (0.8%). Therefore, there is high probability to observe at 
least 1 SAE, or 1 AESI if the true AE rate is relatively low (~1%). 
M72 immunogenicity 
The sample size is not driven by the immunogenicity endpoints. Table 6 provides the power to 
show statistically significant differences in GMCs between the two treatment groups for varying 
sample sizes when the true differences are between 10% and 40% higher in the vaccine arm, and 
the coefficient of variation (CV) of the measurement is between 30% and 50%. 
Table 6: Statistically significant differences in geometric mean concentrations (GMCs) 
between the two treatment groups for varying sample sizes 
N 
 
True geometric mean increase in vaccine arm 
per group 
CV 
10% 
20% 
30% 
40% 
50 
30% 
36.0 
87.4 
99.4 
> 99.9 
 
40% 
23.0 
65.1 
92.0 
99.1 
 
50% 
16.3 
48.2 
78.7 
94.4 
100 
30% 
62.3 
99.2 
> 99.9 
> 99.9 
 
40% 
42.2 
90.8 
99.9 
> 99.9 
 
50% 
29.5 
77.0 
97.5 
> 99.9 
150 
30% 
80.3 
> 99.9 
> 99.9 
> 99.9 
 
40% 
56.6 
98.1 
> 99.9 
> 99.9 
 
50% 
41.5 
90.9 
99.8 
> 99.9 
200 
30% 
90.0 
> 99.9 
> 99.9 
> 99.9 
 
40% 
68.8 
99.7 
> 99.9 
> 99.9 
 
50% 
53.0 
97.0 
> 99.9 
> 99.9 
With N = 200 per group, there is excellent power (≥ 97%) to show statistically significant 
differences in GMCs between the two treatment groups when the true differences are at least 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
46 
20% higher in the vaccine arm, and CV of the measurement is as high as 50%. The table clearly 
shows that sample sizes lower than 200 per group are likely sufficient to show meaningful 
differences in immunogenicity between the vaccine and placebo groups. While samples will be 
collected and stored at all planned immunogenicity timepoints, strategies to test only a portion of 
participants for immunogenicity analyses may be considered. Final plans will be documented in 
a separate statistical analysis plan (SAP) prior to data unblinding. 
9.3. 
Populations for Analyses 
Analysis populations are shown in Table 7. 
Table 7: Populations for Analyses 
Population 
Description 
Randomized 
All participants randomly assigned to study intervention, a 
randomization number and date. 
Safety 
All participants randomly assigned to study intervention and who 
received the study intervention. Participants will be analyzed 
according to the intervention they actually received.  
Intention to treat (ITT) 
population 
All participants randomly assigned to study intervention and who 
received the study intervention. Participants will be analyzed 
according to the intervention they were randomized. 
Modified intention to treat 
(mITT) population. 
All participants randomly assigned to study intervention and who 
received the study intervention and who were randomly selected 
and tested for immunogenicity.. Participants will be analyzed 
according to the intervention they actually received. 
Per Protocol (PP) 
population 
All participants randomly assigned to study intervention, who 
received the study interventions as planned and did not 
substantially deviate from the protocol procedures.   
Participants who substantially deviated will be identified prior to 
database lock and unblinding.  
Participants will be analyzed according to the intervention they 
actually received. 
Per-Protocol for 
Immunogenicity 
Population 
All participants in PP population randomly selected to have 
immunogenicity assays performed. 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe in further detail the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
47 
Some exploratory analyses may be included in this SAP. Other exploratory endpoint analyses 
such as those centered on exploratory biomarker analyses, may be described in a separate 
exploratory scientific and statistical analysis plan (exploratory SAP). Specific objectives and 
hypotheses related to exploratory biomarker analyses will be documented in the exploratory SAP 
prior to full data unblinding and analysis. Results from the exploratory analyses may be reported 
in a separate results memo and included as an addendum to the clinical study report (CSR).  
Analyses based on study endpoints are summarized in Table 8. 
Table 8: Summary of Endpoints and Analyses 
Primary Endpoint 
Statistical Analysis  
Solicited AEs through 7 days post each dose 
of study intervention 
Unsolicited AEs through 28 days post each 
dose of study intervention  
All SAEs through end of study 
The incidence and 95% confidence intervals 
of AEs will be summarized by treatment 
group, overall, and by grade, intensity, and 
relatedness. The incidence and 95% 
confidence intervals of SAEs will be 
summarized by treatment group.  
Secondary Endpoints 
Statistical Analysis  
pIMDs through end of study 
Safety laboratory assessments grade 3 or 
above through end of study 
Summary statistics will be generated for 
pIMDs, laboratory safety tests including grade 
3 and above. 
M72-specific antibody titers at Day 1, Day 
29, Day 57, Day 210 and Day 390 
Anti-M72/AS01E seropositive rates and 
GMCs will be calculated by treatment and 
time point with exact 95% CIs. 
Frequency and magnitude of M72-specific 
CD4+ and CD8+ T-cell responses measured 
by expression of IFN- or IL-2 by ICS at Day 
1, Day 57 and Day 390 
The frequency of CD4+ T cells positive for 
IFN-γ or IL-2, by ICS, will be summarized by 
treatment group and timepoint. Median 
DMSO-subtracted cytokine responses and 
associated 95% CIs will be used to summarize 
percentage T cell responses. 
Exploratory Endpoints 
Statistical Analysis  
Frequency and magnitude of M72-specific 
CD4+ and CD8+ T-cell responses measured 
by expression of IFN-γ or IL-2 by ICS at Day 
29 and Day 210 
The frequency of CD4+ T cells positive for 
IFN-γ or IL-2, by ICS, will be summarized by 
treatment group and timepoint. Median 
DMSO-subtracted cytokine responses and 
associated 95% CIs will be used to summarize 
percentage T cell responses. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
48 
Exploratory Endpoints 
Statistical Analysis  
Polyfunctionality of M72-specific CD4+ and 
CD8+ T-cell responses measured by co-
expression of multiple functional markers by 
ICS 
Polyfunctionality will be analyzed by 
COMPASS*, and summarized by treatment 
group using functionality and/or 
polyfunctionality scores.  
Frequencies of participants with confirmed 
HIV RNA >200 copies/mL at Day 57, Day 
210 and Day 390 
Frequencies of participants with confirmed 
HIV RNA will be summarized by treatment 
group and timepoint, with associated 95% CIs 
Mean changes in CD4+ T cell count from 
baseline to Day 57, Day 210 and Day 390 
Mean changes in CD4+ T cell count will be 
summarized based on timepoints from 
baseline 
Suspected TB during the study   
 
Summary statistics will be generated for the 
incidence of suspected TB by treatment group 
and timepoint. 
Laboratory-confirmed pulmonary TB during 
the study 
Summary statistics will be generated for the 
incidence of Laboratory-confirmed pulmonary 
TB by treatment group and timepoint. 
* [Lin 2015] 
Analyses for other exploratory endpoints may include, but are not limited to: 
• 
assessing functional antibody profiles in response to vaccination 
• 
vaccine-induced changes in innate and myeloid cell populations, and  
• 
vaccine-induced changes in transcriptomic, proteomic or metabolomic profiles. 
In addition to these analyses, any observed cases of TB disease will be summarized and 
described by treatment group. 
9.4.1. 
Humoral Immunogenicity Analyses 
Anti-M72/AS01E seropositive rates and GMCs will be calculated by treatment and time point 
with exact 95% CIs. 
To formally compare GMCs between treatment groups, a linear mixed effect model will be used, 
including fixed effects for treatment and time, and a random effect for participant. Individual 
M72-specific IgG antibody titers will be log-transformed. GMCs and 95% CIs will be estimated 
from the model as the back-transformed mean estimate.  
To formally compare seropositivity rates between treatment groups, a generalized linear mixed 
effect model will be used, including fixed effects for treatment and time, and generalized 
estimating equations will be used to account for the dependence in the longitudinal binomial 
response data.  
Formal comparisons before and after study intervention (e.g., geometric mean ratios (GMR), 
differences in seropositivity rates) will be generated from the model results with 95% CIs. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
49 
9.4.2. 
Cell-mediated Immune response 
Frequency, magnitude and polyfunctionality of M72-specific CD4+ and CD8+ T-cell responses 
measured by ICS before and following vaccination at specified time points through the end of 
the study with associated CIs will be summarized. Summaries of T-cell response will be 
presented by T-cell type (CD4+ and CD8+), functionality (cytokines expressed) and by 
stimulation antigen. Summaries will include immune responses at pre- and post-study 
intervention immunology time points, and change from pre-vaccination to post-vaccination time 
points. 
Similar analysis methods will be used to compare cellular immune responses over time between 
treatment groups. 
9.4.3. 
Exploratory analyses 
Summary statistics will be generated for the incidence, by treatment group, of suspected TB 
disease and laboratory-confirmed pulmonary TB that occur throughout the study period. 
Specific objectives related to additional exploratory immunogenicity and/or exploratory 
transcriptomic, proteomic and/or metabolomic assessments will be also be examined. Specific 
objectives and hypotheses related to these analyses will be documented and if not reported with 
the final CSR, will be reported separately, and described in the SAP prior to data unblinding and 
analysis. 
9.4.4. 
Subgroup Analyses 
The consistency of results with respect to the primary and secondary objectives will be examined 
within various subgroup populations (e.g., by QFT status, sites and maybe others). Details will 
be provided in the SAP.  
9.4.5. 
Demographic and Compliance Analyses 
Demographic parameters (age, sex, and race/ethnicity) and other baseline characteristics will be 
summarized by treatment group for all participants in the safety population.  
Listings of randomized participants with protocol deviations (to be defined in the SAP) will be 
presented by treatment group. 
9.5. 
Interim Analyses  
Interim analyses are not planned.  
9.5.1. 
Independent Data Monitoring Committee (IDMC) 
The IDMC will operate according to a charter. The IDMC structure, participants and other 
details will be provided in the charter. The charter will be available prior to study start.  
The IDMC will review unblinded safety data during regular scheduled safety review meetings as 
well as the outcome of the primary and secondary analyses. The IDMC may request additional 
information, or a pause in recruitment and vaccination, while safety data are being evaluated.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
50 
During active enrollment, the IDMC will meet approximately at least once every 3 months and 
ad hoc as necessary. The IDMC review will include solicited and unsolicited AEs, as well as 
SAEs, AESIs, and any safety laboratory measurements that are grade 3 and above. All 
procedures associated with this review, including objectives, data handling, and elements to be 
included for review will be documented.  
The IDMC may request additional information, or a pause in recruitment and vaccination, while 
safety data are being evaluated. Refer to Section 7.4 for details. The IDMC will make a formal 
recommendation on the continued enrollment into the trial after each safety review. 
The IDMC charter will provide meeting information and other details.  
If study vaccine administration is paused by the Medical Monitor or the PI, the IDMC will 
convene ad hoc.  
The recommendations of the IDMC, along with the sponsor’s decision, will be communicated to 
the investigators and the IRBs/IECs and the national regulatory authorities as required. The 
sponsor or its designee agrees to abide by any directives issued by the national regulatory 
authority or the IRB/IEC. 
9.5.2. 
Informed Consent and Assent Process 
The PI or his or her representative will explain the study to the participant and, for participants 
who are minors, to his or her parent or guardian/LAR, and answer all questions regarding the 
study. The PI or designee will conduct the consent and assent discussions on an individual basis 
with each participant and parent or guardian/LAR. Adequate time will be allowed for all 
questions to be addressed. Potential participants will be interviewed to ensure that they meet all 
entry criteria relating to history. 
Participants must be informed that their participation is voluntary. Participants or their LAR will 
be required to sign a statement of informed consent (ICF) that meets the requirements of FDA 
Code of Regulations (CFR) 21 CFR 50, local regulations, International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
and the IRB/IEC or study center. 
Participants who are under the age of informed consent (less than 18 years of age) must sign an 
informed assent form (IAF) and their parent or guardian/LAR must sign an ICF prior to 
enrollment.  
The CRF must indicate that written informed consent or assent was obtained before the 
participant was enrolled in the study and the date the written consent or assent was obtained. The 
authorized person obtaining the informed consent or assent must also sign the ICF. 
Participants must be re-consented/assented to the most current version of the ICF(s) during their 
participation in the study, and any participant who previously signed an IAF, and then reaches 
the age of consent during the study, must sign a consent form at the next scheduled study visit. 
A copy of the ICF or IAF must be provided to the participant or guardian/LAR. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
51 
9.5.2.1. 
Informed Consent forms 
Informed consent for study participation  
If a participant cannot be randomized on the intended day of vaccination (e.g., if elevated 
temperature) her/she is not required to sign another ICF/IAF (as applicable), as long as re-
screening and vaccination occur within the protocol-defined window.  
The ICF and IAF contain a separate section that addresses the use of remaining mandatory 
samples for research not described in the protocol, e.g., assay development and assay quality 
control. A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for research not described in the protocol.  
Participants will be told that they are free to refuse to participate and may withdraw their consent 
or assent at any time and for any reason during the storage period. Participants will also be 
informed that laboratory tests will be run in laboratories in and outside of the RSA. 
9.5.3. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant record or dataset 
that is transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred to the sponsor. 
The participant must be informed that his or her study-related data will be used by the sponsor in 
accordance with local data protection law. The level of data disclosure must also be explained to 
the participant. 
The participant must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
9.5.4. 
Dissemination of Clinical Study Data 
Study information from this protocol will be posted on publicly available clinical trials registers 
(clinicaltrials.gov and the RSA registry [sanctr.gov.za]) before enrollment of participants begins. 
Summaries of the results of the study will also be posted on the same website. 
The final CSR will include all available safety data, immunogenicity data, clinical assessments, 
and concomitant medications through the final study visit. The database will be locked prior to 
preparation of the final CSR when all of the above data have been entered, reviewed, and all 
queries related to the data have been addressed. Modifications or additions to the analyses will be 
included in the relevant SAP. Any decisions to deviate from the planned analyses described in 
the protocol and in the SAP will be described in detail in the final CSR. The CSR will be 
reviewed and approved by the sponsor signatory and the lead PI.  
9.5.5. 
Data Quality Assurance 
All participant data relating to the study will be recorded on a printed CRF or, by an electronic 
CRF using an Electronic Data Capture (EDC) system, unless transmitted to the sponsor or 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
52 
designee electronically (e.g., laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically signing or electronically signing the CRF. 
The investigator must maintain accurate documentation that supports the information entered in 
the CRF. 
The study will be monitored regularly by the sponsor or its designee throughout the study period. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs and IAFs, pertaining to the conduct of this study 
must be retained by the investigator for 10 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
9.5.6. 
Source Documents 
Source documentation consists of existing medical records and/or study records developed and 
maintained by the investigator. Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. Diary card and memory aid are 
source documents. 
Data recorded on source documents will be transcribed onto CRFs either paper, or electronically 
using an EDC system. 
Data entered in the CRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study.  
9.5.7. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site(s) or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
53 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development. 
9.5.8. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
59 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post-mortem 
findings including histopathology, if available. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE/AESI data to the sponsor within 24 
hours of receipt of the information. 
• The onset and resolution dates of the event and medical care taken in response to the 
event will be documented.  
• AEs will be considered resolved when the condition returns to normal or returns to the 
participant’s baseline status as established on Study Day 1, or when the condition has 
stabilized with the expectation that it will remain chronic. 
• If the event has not resolved by the final study visit, it will be documented as 
“ongoing” on the CRF, however, follow-up of the SAE must continue until resolved or 
the condition has stabilized. Information recorded on the CRF must be substantiated in 
the source documents. 
• The resolution date to be recorded on the CRF is the last date on which the participant 
experienced the AE.  
9.6.5.1. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE reported during the study 
and assign it to 1 of 4 categories:  
• Mild symptoms causing no or minimal interference with usual social and functional 
activities with intervention not indicated  
• Moderate symptoms causing greater than minimal interference with usual social and 
functional activities with intervention indicated 
• Severe symptoms causing inability to perform usual social and functional activities 
with intervention or hospitalization indicated 
• Potentially life-threatening symptoms causing inability to perform basic self-care 
functions with intervention indicated to prevent permanent impairment, persistent 
disability, or death 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
9.6.5.2. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
61 
• The site will enter the SAE or AESI data into the electronic system as soon as it is 
identified. 
• All SAEs and AESIs are reported to the sponsor and to the CRO Safety team throughout 
the 12 months after study intervention administration.  
• The investigator must not wait to collect additional information to fully document the 
event before notifying the CRO Safety team of an SAE, or AESI. The initial notification 
should include the following:  
• Protocol number and name and contact number of the investigator 
• Participant ID number (and initials and date of birth, if available)  
• Date participant received study vaccine 
• Term and date of event onset  
• Current status of event  
• The investigator is responsible for expedited safety report submission to the Sponsor 
delegate and the Sponsor delegate for reporting to SAHPRA within specific time periods 
of being notified of the event. Therefore, it is important that the investigator submit 
additional information requested as soon as it becomes available. The sponsor is 
responsible for the determination of the expectedness according to the reference safety 
information section of the applicable investigator’s brochure. 
• All fatal and life-threatening adverse drug reactions and SUSARs are to be reported to 
SAHPRA with 7 calendar days after first knowledge with a complete report to be 
submitted within an additional 8 calendar days.  SUSARs that are not fatal or life 
threatening need to be reported to SAHPRA no later than 15 calendar days after first 
knowledge. The sponsor will notify the IDMC of all SUSARs within the same timelines 
the report is sent to investigators, health authorities, and other relevant parties. Any 
follow-up report will be sent with the same timelines. The principal investigator is 
responsible for the notification of such reports to the applicable IRB/IEC. 
• If the electronic system is unavailable, the site may use the paper SAE data collection 
tool (see next section) instead of the EDC, in order to report the event within 24 hours of 
becoming aware. 
• After the study is completed at a given site, the electronic data collection tool, if used, 
will be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section). 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
63 
9.6.7. 
Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 Preferred 
Term Codes for pIMDs 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Neuroinflammatory 
disorders 
Cranial nerve disorders and 
inflammations 
 
Anosmia 
10002653 
IIIrd nerve paralysis 
10021283 
IIIrd nerve paresis 
10054202 
IVth nerve paralysis 
10023110 
IVth nerve paresis 
10054201 
Trigeminal palsy 
10049788 
Trigeminal nerve paresis 
10068008 
VIth nerve paralysis 
10047641 
VIth nerve paresis 
10071044 
Facial paralysis 
10016062 
Facial paresis 
10051267 
Acoustic neuritis 
10063162 
Glossopharyngeal nerve paralysis 
10051270 
Tongue paralysis 
10043972 
Vagus nerve paralysis 
10064661 
Vocal cord paralysis 
10047674 
Vocal cord paresis 
10049234 
XIth nerve paralysis 
10048842 
Hypoglossal nerve paralysis 
10069450 
Hypoglossal nerve paresis 
10067129 
 
 
Bulbar palsy 
10006542 
Oculofacial paralysis 
10030069 
Neuritis cranial 
10029244 
Cranial nerve disorder 
10061093 
Paresis cranial nerve 
10061911 
Cranial nerve paralysis 
10061908 
Cranial nerve palsies multiple 
10011314 
Optic neuritis 
10030942 
Multiple sclerosis 
Multiple sclerosis 
10028245 
Radiologically isolated syndrome 
10079292 
Primary progressive multiple sclerosis 
10063401 
Progressive multiple sclerosis 
10053395 
Marburg's variant multiple sclerosis 
10067067 
Secondary progressive multiple sclerosis 
10063400 
Multiple sclerosis relapse 
10048393 
Relapsing multiple sclerosis 
10080700 
Multiple sclerosis relapse prophylaxis 
10070495 
Progressive relapsing multiple sclerosis 
10067063 
Relapsing-remitting multiple sclerosis 
10063399 
Tumefactive multiple sclerosis 
10078556 
Expanded disability status scale score decreased 
10071385 
Expanded disability status scale score increased 
10071384 
Myelitis / Transverse myelitis 
Myelitis transverse 
10028527 
Myelitis 
10028524 
Acute flaccid myelitis 
10082097 
Noninfectious myelitis 
10071764 
Guillain-Barré syndrome 
Guillain-Barré syndrome 
10018767 
Miller Fisher syndrome 
10049567 
Acute disseminated 
encephalomyelitis and 
demyelination (including site 
specific variants) 
Demyelination 
10012305 
Intramyelinic oedema 
10083038 
Autoimmune demyelinating disease 
10075688 
Clinically isolated syndrome 
10071068 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
64 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
 
Leukoencephalomyelitis 
10048999 
Leukoencephalopathy 
10024382 
Acute disseminated encephalomyelitis 
10000709 
Acute haemorrhagic leukoencephalitis 
10058994 
Concentric sclerosis 
10010252 
Encephalitis periaxialis diffusa 
10049020 
Limbic encephalitis 
10078012 
Neuromyelitis optica spectrum disorder 
10077875 
Neuromyelitis optica pseudo relapse 
10080353 
Autoimmune encephalopathy 
10075691 
Bickerstaff's encephalitis  
10076985 
Noninfective encephalitis 
10074712 
Encephalitis autoimmune 
10072378 
Immune-mediated encephalitis 
10083074 
Rasmussen encephalitis 
10071141 
Encephalitis allergic 
10056387 
Encephalitis brain stem 
10048997 
Encephalitis haemorrhagic 
10014589 
Encephalomyelitis 
10014619 
Noninfective encephalomyelitis 
10074713 
Encephalitis post immunisation 
10014602 
Panencephalitis 
10056332 
Encephalitis toxic 
10014607 
Chronic lymphocytic inflammation with pontine 
perivascular enhancement responsive to steroids 
10075210 
Myasthenia gravis 
Myasthenia gravis 
10028417 
Myasthenia gravis crisis 
10062758 
Ocular myasthenia 
10049168 
Myasthenic Syndrome 
10028424 
Autoimmune / Immune-mediated 
peripheral neuropathies and 
plexopathies 
Autoimmune neuropathy 
10070439 
Immune-mediated neuropathy 
10078963 
Neuritis 
10029240 
Anti-myelin-associated glycoprotein associated 
polyneuropathy 
10078324 
Subacute inflammatory demyelinating 
polyneuropathy 
10081726 
Chronic inflammatory demyelinating 
polyradiculoneuropathy 
10057645 
Lewis-Sumner syndrome 
10065580 
Demyelinating polyneuropathy 
10061811 
Polyneuropathy idiopathic progressive 
10036111 
Multifocal motor neuropathy 
10065579 
Acute motor-sensory axonal neuropathy 
10076657 
Acute motor axonal neuropathy 
10076658 
Cervical neuritis 
10008293 
Mononeuritis 
10027910 
Mononeuropathy multiplex 
10027918 
Brachial plexopathy 
10065417 
Radiculitis brachial  
10037778 
Neuralgic amyotrophy 
10029229 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
65 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Narcolepsy 
Narcolepsy 
10028713 
Musculoskeletal 
disorders 
Systemic lupus erythematosus 
Systemic lupus erythematosus 
10042945 
SLE arthritis 
10040968 
Cutaneous lupus erythematosus 
10056509 
Acute cutaneous lupus erythematosus 
10057928 
Chronic cutaneous lupus erythematosus 
10057929 
Subacute cutaneous lupus erythematosus 
10057903 
Lupus cystitis 
10074714 
Lupus encephalitis 
10025130 
Lupus endocarditis 
10058225 
Lupus enteritis 
10067738 
Lupus hepatitis 
10067737 
Lupus myocarditis 
10066391 
Lupus myositis 
10079642 
Lupus nephritis 
10025140 
Lupus pancreatitis 
10067750 
Lupus pleurisy 
10073694 
Lupus pneumonitis 
10057481 
Lupus-like syndrome 
10050551 
Neuropsychiatric lupus 
10063663 
Central nervous system lupus 
10076328 
Pericarditis lupus 
10058149 
Peritonitis lupus 
10062898 
Systemic lupus erythematosus rash 
10042946 
Systemic lupus erythematosus disease activity index 
abnormal 
10067659 
Systemic lupus erythematosus disease activity index 
decreased 
10067658 
Systemic lupus erythematosus disease activity index 
increased 
10067657 
Systemic Scleroderma (Systemic 
sclerosis) 
Scleroderma 
10039710 
Scleroderma renal crisis 
10062553 
Scleroderma associated digital ulcer 
10073229 
Reynold’s syndrome 
10070953 
Systemic sclerosis pulmonary 
10042954 
Systemic scleroderma 
10078638 
Anti-RNA polymerase III antibody increased 
10082280 
Anti-RNA polymerase III antibody positive 
10082283 
CREST syndrome 
10011380 
Muscular Autoimmune / Immune-
mediated disorders 
Polymyalgia rheumatica 
10036099 
Dermatomyositis 
10012503 
Polymyositis 
10036102 
Autoimmune myositis 
10082418 
Immune-mediated myositis 
10083073 
Juvenile polymyositis 
10076673 
Antisynthetase syndrome 
10068801 
Rheumatoid arthritis and 
associated conditions  
Rheumatoid arthritis 
10039073 
Autoimmune arthritis 
10071155 
Immune-mediated arthritis 
10083155 
Laryngeal rheumatoid arthritis 
10059669 
Rheumatoid lung 
10039081 
Rheumatoid scleritis 
10067427 
Rheumatic brain disease 
10079411 
Rheumatoid neutrophilic dermatosis 
10072362 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
66 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Rheumatoid nodule 
10048694 
Juvenile idiopathic arthritis 
10059176 
Cogan's syndrome 
10056667 
Palindromic rheumatism 
10033534 
Still's disease 
10042061 
Spondyloarthropathies 
 
Arthritis reactive 
10003267 
Reiter's syndrome 
10038294 
Ankylosing spondylitis 
10002556 
Spondylitis 
10061371 
Spondyloarthropathy 
10051265 
Juvenile spondyloarthritis 
10076675 
Enteropathic spondylitis 
10076549 
Psoriatic arthropathy 
10037162 
Juvenile psoriatic arthritis 
10076674 
Relapsing polychondritis 
Polychondritis 
10065159 
Mixed connective tissue disease 
Overlap syndrome 
10068786 
Mixed connective tissue disease 
10027754 
Gout 
Gout 
10018627 
Gouty arthritis 
10018634 
Gouty tophus 
10018641 
Gastrointestinal 
disorders 
Inflammatory Bowel disease 
Crohn's disease 
10011401 
Colitis ulcerative 
10009900 
Colitis microscopic 
10056979 
Autoimmune colitis 
10075761 
Immune-mediated enterocolitis 
10078961 
Inflammatory bowel disease 
10022102 
Arthritis enteropathic 
10003253 
Proctitis ulcerative 
10036783 
Autoimmune enteropathy 
10081456 
Autoimmune / Immune-mediated 
pancreatitis 
Autoimmune pancreatitis 
10069002 
Immune-mediated pancreatitis 
10083072 
Celiac disease 
Coeliac disease 
10009839 
Liver disorders 
Autoimmune / Immune-mediated 
hepatobiliary diseases 
 
Autoimmune hepatitis 
10003827 
Immune-mediated hepatitis 
10078962 
Biliary cirrhosis primary 
10004661 
Primary biliary cholangitis 
10080429 
Cholangitis sclerosing 
10008609 
Endocrine and 
Metabolic 
disorders 
Autoimmune / immune-mediated 
thyroid diseases 
Autoimmune hypothyroidism 
10076644 
Immune-mediated hypothyroidism 
10083075 
Atrophic thyroiditis 
10077172 
Autoimmune thyroiditis 
10049046 
Immune-mediated thyroiditis 
10083071 
Silent thyroiditis 
10079012 
Hashimoto's encephalopathy 
10069432 
Hashitoxicosis 
10067873 
Basedow's disease 
10004161 
Marine Lenhart syndrome 
10068828 
Autoimmune thyroid disorder 
10079165 
Autoimmune / Immune-mediated 
endocrinopathy (NOS) 
Autoimmune endocrine disorder 
10078953 
Immune-mediated endocrinopathy 
10078964 
Diabetes mellitus type I 
Type 1 diabetes mellitus 
10067584 
Fulminant type 1 diabetes mellitus 
10072628 
Polyglandular autoimmune 
syndrome 
Polyglandular autoimmune syndrome type I 
10036072 
Polyglandular autoimmune syndrome type II 
10036073 
Polyglandular autoimmune syndrome type III 
10064115 
Autoimmune hypophysitis 
Lymphocytic hypophysitis 
10063685 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
67 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Addison's disease 
Addison's disease 
10001130 
Skin disorders 
Psoriasis 
Psoriasis 
10037153 
Vitiligo 
Vitiligo 
10047642 
Erythema nodosum 
Erythema nodosum 
10015226 
Alopecia areata 
Alopecia areata 
10001761 
Lichen planus 
Lichen planopilaris 
10081142 
Lichen planus 
10024429 
Sweet’s syndrome 
Acute febrile neutrophilic dermatosis 
10000748 
Autoimmune / Immune-mediated 
bullous skin diseases 
Pemphigus 
10034280 
Pemphigoid 
10034277 
Dermatitis herpetiformis 
10012468 
Autoimmune dermatitis 
10075689 
Immune-mediated dermatitis 
10083156 
Localised Scleroderma 
Morphoea 
10027982 
Vasculitides 
Vasculitis and vasculitides 
Acute haemorrhagic oedema of infancy 
10070599 
Administration site vasculitis 
10075969 
Anti-neutrophil cytoplasmic antibody positive 
vasculitis 
10050894 
Aortitis 
10002921 
Application site vasculitis 
10076027 
Arteritis 
10003230 
Arteritis coronary 
10003232 
Behcet's syndrome 
10004213 
Capillaritis 
10068406 
Central nervous system vasculitis 
10081778 
Cerebral arteritis 
10008087 
Chronic pigmented purpura 
10072726 
Cutaneous vasculitis 
10011686 
Diffuse vasculitis 
10012978 
Eosinophilic granulomatosis with polyangiitis 
10078117 
Erythema induratum 
10015213 
Granulomatosis with polyangiitis 
10072579 
Haemorrhagic vasculitis 
10071252 
Henoch-Schonlein purpura 
10019617 
Henoch-Schonlein purpura nephritis 
10069440 
Hypersensitivity vasculitis  
10020764 
Injection site vasculitis 
10067995 
Kawasaki's disease 
10023320 
Langerhans' cell histiocytosis 
10069698 
Lupus vasculitis 
10058143 
MAGIC syndrome 
10078132 
Microscopic polyangiitis 
10063344 
Nodular vasculitis 
10029491 
Ocular vasculitis 
10066926 
Optic ischaemic neuropathy 
10030924 
Optic neuropathy 
10061323 
Polyarteritis nodosa 
10036024 
Pulmonary vasculitis 
10037457 
Renal arteritis 
10038373 
Renal vasculitis 
10038546 
Retinal vasculitis 
10038905 
Rheumatoid vasculitis 
10048628 
Segmented hyalinising vasculitis 
10067527 
Takayasu's arteritis 
10043097 
Temporal arteritis 
10043207 
Thromboangiitis obliterans 
10043540 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
68 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Urticarial vasculitis 
10048820 
Vaccination site vasculitis 
10076191 
Vascular purpura 
10047097 
Vasculitic rash 
10047111 
Vasculitic ulcer 
10075714 
Vasculitis 
10047115 
Vasculitis gastrointestinal 
10048319 
Vasculitis necrotising 
10047124 
Other 
Stevens-Johnson syndrome 
Stevens-Johnson syndrome 
10042033 
Erythema multiforme 
10015218 
Toxic epidermal necrolysis 
10044223 
SJS-TEN overlap 
10083164 
Blood autoimmune / immune-
mediated disoders 
Autoimmune anaemia 
10080243 
Autoimmune haemolytic anaemia 
10073785 
Warm type haemolytic anaemia 
10047822 
Cold type haemolytic anaemia 
10009868 
Coombs positive haemolytic anaemia 
10010941 
Evans syndrome 
10053873 
Immune thrombocytopenic purpura  
10074667 
Thrombocytopenic purpura 
10043561 
Thrombotic thrombocytopenic purpura 
10043648 
Autoimmune aplastic anaemia 
10071576 
Autoimmune neutropenia 
10055128 
Autoimmune pancytopenia 
10069509 
Immune-mediated pancytopenia 
10083004 
Antiphospholipid syndrome 
10002817 
Pernicious anaemia 
10034695 
Autoimmune / immune-mediated 
glomerulonephritis 
Glomerulonephritis rapidly progressive 
10018378 
IgA nephropathy 
10021263 
IgM nephropathy 
10077209 
C1q nephropathy 
10081461 
Glomerulonephritis membranous 
10018372 
Glomerulonephritis membranoproliferative 
10018370 
Membranous-like glomerulopathy with masked IgG-
kappa deposits 
10083098 
Mesangioproliferative glomerulonephritis 
10066453 
Anti-glomerular basement membrane disease 
10081981 
Autoimmune nephritis 
10077087 
Immune-mediated nephritis 
10083070 
Chronic autoimmune glomerulonephritis 
10073016 
Tubulointerstitial nephritis and uveitis syndrome 
10069034 
Ocular autoimmune / immune-
mediated diseases 
Uveitis 
10046851 
Vogt-Koyanagi-Harada disease 
10082001 
Ocular pemphigoid 
10067776 
Autoimmune retinopathy 
10071578 
Acute macular outer retinopathy 
10079367 
Autoimmune uveitis 
10075690 
Immune-mediated uveitis 
10083069 
Autoimmune eye disorder 
10081123 
Autoimmune / immune-mediated 
heart disease 
Autoimmune myocarditis 
10064539 
Immune-mediated myocarditis 
10082606 
Autoimmune pericarditis 
10079058 
Sarcoidosis 
Sarcoidosis 
10039486 
Pulmonary sarcoidosis 
10037430 
Neurosarcoidosis 
10078011 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
69 
Event 
Category 
Immune-Mediated 
Disorder 
MedDRA PT 
PT Code 
Cutaneous sarcoidosis 
10011674 
Liver sarcoidosis 
10068664 
Muscular sarcoidosis 
10028390 
Ocular sarcoidosis 
10065700 
Sjögren’s syndrome 
Sjogren's syndrome 
10040767 
Autoimmune lung disease 
Idiopathic pulmonary fibrosis 
10021240 
Idiopathic interstitial pneumonia 
10078268 
Interstitial lung disease 
10022611 
Pulmonary fibrosis 
10037383 
Autoimmune lung disease 
10080701 
Immune-mediated pneumonitis 
10082452 
Goodpasture’s syndrome 
Goodpasture’s syndrome 
10018620 
Raynaud's phenomenon 
Raynaud's phenomenon 
10037912 
 
 
 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
70 
Appendix 2 
9.7. 
Contraceptive Guidance and Collection of Pregnancy Information 
Definitions: 
Female of Childbearing Potential (FOCBP) 
A female is considered fertile following menarche. If fertility is uncertain (e.g., amenorrhea in 
adolescents) and a menstrual cycle cannot be confirmed before first dose of study intervention, 
additional evaluation should be considered. If in doubt, the participant should be considered 
fertile. 
Women in the following categories are not considered FOCBP 
1. Premenarchal 
2. Documented hysterectomy, bilateral salpingectomy or bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
Contraception Guidance: 
Women physically capable of pregnancy must agree to use an acceptable method of avoiding 
pregnancy for one year after the start of study intervention.  
Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per 
year when used consistently and correctly and when applicable, in accordance with the product 
label.  
Effective methods include contraceptive intrauterine device or system, subdermal contraceptive 
implant, progestogen injections, progestogen only oral contraceptive pills, combined estrogen 
and progestogen oral contraceptive pills, percutaneous contraceptive patch, and contraceptive 
vaginal ring.  
Routinely counsel females to use condoms for dual protection against pregnancy and to avoid 
transmission of HIV and other sexually transmitted infections at all scheduled study visits. 
Adequate contraception does not apply to participants of child-bearing potential with same sex 
partners, when this is their preferred and usual lifestyle. 
Collection and Reporting Pregnancy Information 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded and 
submitted to the sponsor within 24 hours of learning of a participant's pregnancy.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
71 
• The health status of the mother and child, the date of delivery, and the child’s sex, 
birth weight and multiparity should be recorded and be reported to the Medical 
Monitor after delivery. If delivery occurs before the last scheduled study visit, the 
participant should continue to be followed to determine the outcome of the 
pregnancy, and for SAEs through the final study visit unless withdrawal of consent 
has occurred. If delivery occurs after the final study visit, the investigator should 
attempt to maintain contact with the participant to obtain information after delivery. 
• The investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor. Generally, follow-up will not 
be required for longer than 6 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.  
• Any post-study pregnancy-related SAE considered related to the study intervention 
by the investigator will be reported to the sponsor. While the investigator is not 
obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting.  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
72 
Appendix 3 
9.8. 
Toxicity Table 
Modified from Division of AIDS Table for Grading the Intensity (severity) of Adult and 
Pediatric Adverse Events Version 2.1, July 2017 
Parameter  
Grade 1 
Mild  
Grade 2 Moderate  
Grade 3 Severe  
Grade 4  
Potentially  
Life-Threatening 
ESTIMATING INTENSITY GRADE  
Clinical 
adverse event 
NOT 
identified 
elsewhere in 
the Grading 
Table   
Mild symptoms  
causing no or 
minimal 
interference 
with  
usual social & 
functional 
activities  
with 
intervention  
not indicated  
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social &  
functional activities  
with intervention  
indicated 
Severe symptoms 
causing inability to 
perform usual 
social & functional 
activities, with 
intervention or 
hospitalization 
indicated 
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions, with 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
95 
1 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
2 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section 
3 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.  
4 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:   
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
105 
10. 
References 
Bruchfeld, J, Correia-Neves, M, Källenius G. Tuberculosis and HIV Coinfection. Cold Spring 
Harb Perspect Med. 2015;5(7): a017871. doi: 10.1101/cshperspect.a017871.  
Food and Drug Administration (FDA) 2020. FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and 
Institutional Review Boards. 
Kumarasamy N, Poongulali S, Bollaerts A, Moris, P, et al. A randomized, controlled safety and 
immunogenicity trial of the M72/AS01 candidate tuberculosis vaccine in HIV-positive Indian 
adults. Medicine. 2016;95(3):e2459. 
Kumarasamy N, Poongulali S, Beulah F, Akite J, et al. Long-term safety and immunogenicity of 
the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults. 
Medicine. 2018;97:45(e13120). 
Lawn SD, Wilkinson RJ. ART and prevention of HIV-associated tuberculosis. The Lancet. 2(6): 
Pe221-e222, June 01, 2015. 
Lin L, Finak G, Ushey K, et al. COMPASS identifies T-cell subsets correlated with clinical 
outcomes. Nat Biotechnol. 2015;33(6):610-6. 
Nemes E, Scriba T, Hatherill M. Prospects for a vaccine to prevent HIV-related tuberculosis. 
Current Opinion in HIV and AIDS. 2018;13(6):522–527. 
South African Clinical Research Association (SACRA). SACRA Clinical Trials Suggested 
Business Continuity Plan: Response to COVID-19. Version 1. 16 March 2020. 
South African Health Products Regulatory Authority (SAHPRA). Update for interaction with 
SAHPRA. Accessed 30 March 2020. http://www.sahpra.org.za/be-prepared-for-covid-19 
Thacher E, Cavassini M, Audran R, Thierry A-C, et al. Safety and immunogenicity of the 
M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral 
therapy: a phase I/II, randomized trial. AIDS. 2014;28:1769-1781. 
Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, et al. Phase 2b Controlled Trial of 
M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med. 2018;379:1621-34. 
World Health Organization (WHO). 2019a. Tuberculosis key facts. Accessed 26 Dec 2019 
https://www.who.int/news-room/fact-sheets/detail/tuberculosis.  
World Health Organization (WHO) 2019b. Regional office for Africa. Tuberculosis. 
https://www.afro.who.int/health-topics/tuberculosis-tb. 
World Health Organization (WHO) 2019c. Tuberculosis and HIV. 
https://www.who.int/hiv/topics/tb/en/. 
World Health Organization (WHO) 2019d. End TB Strategy 
https://www.who.int/tb/post2015_TBstrategy.pdf. 
World Health Organization (WHO) 2019e. Executive Summary: M72/AS01E Tuberculosis 
Vaccine Candidate: Consensus-Generating Consultation on the Development Pathway. 30-31 
July, Geneva, Switzerland  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
106 
11. 
Amendment History 
Rationale for Version 3 dated final draft 02 February 2021 
Protocol Version 2.0 dated 01 May 2020 was the first version to be approved by SAHPRA and 
the Ethics Committee and used by the sites. First screening visit was on 09 Nov 2020 with the 
first randomization/dosing on 17 Nov 2020.   
Protocol Version 3.0 is the first amendment to the protocol after study start. Version 3 was 
prepared to reflect that assays for secondary and exploratory endpoints will be carried out in 
laboratories outside of the RSA. These assays were originally intended to be performed in the 
RSA. For cellular responses, the sponsor was not able to identify a vendor who was able to 
consistently provide the services needed (18 color flow cytometry under Good Clinical 
Laboratory Practice [GCLP] conditions) in the RSA. For humoral responses, the laboratory was 
chosen in order to provide continuity with the assay used for previous studies, and that laboratory 
has provided the ELISA data for most of the previous M72 studies, in addition to having the 
most experience with the assay. Because of this, the informed consent and informed assent forms 
were also amended, and participants already enrolled will be reconsented. 
Clinical data were being collected for TB disease but there was no Sputum Xpert MTB/RIF 
assay to confirm the case and there was no objective to describe the incidence so Xpert 
MTB/RIF assay for suspected TB and a corresponding objective was added. Timepoints to assess 
the CD4+ and CD8+ T cell responses were split into secondary and exploratory endpoints.  
Following the secondary endpoints analyses, if responses at peak or memory are lower than 
expected compared to historical data from previous M72 vaccine studies, additional timepoints 
may be assessed as exploratory analysis to further characterize the kinetics of the cellular 
vaccine-induced immune response. Polyfunctionality of M72-specific CD4+ and CD8+ T-cell 
responses was moved from secondary to exploratory endpoint to support the exploratory cellular 
immunogenicity objective. 
Other changes were made in response to site’s request for clarity, or to correct an error. 
A detailed summary of changes from Version 2 to Version 3 are listed below. 
Header change: Version 2 3 
Footer change: 01 May 2020 to final draft 02 February 2021  
Title page: Legal Registered Address:  
One Kendall Square 
Building 600, Suite 6-301 
Cambridge, MA 02139 
245 Main Street, Cambridge, MA 02142 
 
Approval Date: 01 May 2020 final draft 02 February 2021 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
107 
Page 2 sponsor signatory: Version 3 Sponsor Signatory 
Alemnew Dagnew Jintanat Ananworanich, M.D. Clinical Development Leader 
Table 1 and Table 3: Objectives and Endpoints 
Objectives 
Endpoints 
Secondary  
• 
To assess the safety of 
M72/AS01E vaccination 
• 
Potential immune-mediated diseases (pIMDs) through end of study 
• 
Safety laboratory assessments grade 3 or above through end of study 
• 
To assess the humoral 
immunogenicity of M72/AS01E 
vaccination 
• 
M72-specific antibody titers concentrations pre  and post  
vaccination through the end of the study at Day 1, Day 29, Day 
57, Day 210 and Day 390 
• 
To assess the cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency, and magnitude and polyfunctionality of M72-specific 
CD4*+ and CD8+ T-cell responses measured by expression of IFN- 
or IL-2 using intracellular cytokine staining (ICS) pre  and post  
vaccination through the end of the study at Day 1, Day 57 and 
Day 390  
Exploratory 
• 
To further explore cellular 
immunogenicity of M72/AS01E 
vaccination 
• 
Frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses measured by expression of IFN-γ or IL-2 by ICS at Day 
29 and Day 210 
• 
Polyfunctionality of M72-specific CD4+ and CD8+ T-cell responses 
measured by co-expression of multiple functional markers by ICS 
• 
To assess HIV viral load post-
M72/AS01E vaccination 
• 
Frequencies of participants with confirmed HIV ribonucleic acid 
([RNA]>200 copies/mL) at Day 57, Day 210 and Day 390 
• 
To assess changes in CD4+ T 
cell count from baseline 
• 
Mean changes in CD4+ T cell count from baseline to Day 57, Day 210 
and Day 390 
• 
To describe the incidence of 
suspected TB disease and 
laboratory-confirmed 
pulmonary TB disease 
• 
Suspected TB during the study   
• 
Laboratory-confirmed pulmonary TB during the study 
Other exploratory endpoints may include, but are not limited to, assessing functional antibody profiles in 
response to vaccination, vaccine-induced changes in innate and myeloid cell populations, and vaccine-induced 
changes in transcriptomic, proteomic or metabolomic profiles. 
(note that the * was deleted from table and here) *CD= cluster of differentiation 
Throughout: corrected ie to i.e. and eg to e.g. 
Synopsis and Section 4.1 
 Masking: Site staff preparing and administering study interventions, including the pharmacist, 
will be unblinded but will not perform other study duties. The investigational pharmacist 
preparing study interventions will be unblinded but will not perform other study duties. 
In Section 4.1, added: Refer to Section 6.2.2. 
Randomization: added comma after status (QFT) status, based on results at screening. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
109 
values prior to the administration of the second dose (and not to determine eligibility for second dose 
administration).  
Added space between sentences: All blood volumes are approximate. Total amount of whole blood... 
Note that the sponsor will evaluate whether alternative methods for safety assessments… 
Section 2.1 Background TB-014: yYear 3 
Section 5.2: Exclusion Criteria: capitalized the word Assessment: Diagnostic Aassessments 
Added new number 9. Receipt of any vaccine in the period starting 7 days before, and ending 7 
days after, each dose of the study vaccine. Refer to Section 6.4 
Renumbered criteria starting with Prior/Concurrent Clinical Study Experience, changed 9 to 
10, 10 to 11, etc.  
Added new number 15 under diagnostic assessments: Indeterminate QFT result  
Renumbered criteria under “Other Exclusions to 16 – 20 (previously 14 – 18). 
New 17. Corrected typographical error: deleted extra “,” in TB,, e.g., 
New 18. Female participant……study product intervention (for consistency) 
New 20. Corrected spelling error *Defined as provided that the arrangements falls within the… 
 Section 5.3 Screen Failures 
• When there are technical difficulties with phlebotomy at screening (e.g., laboratory 
reports hemolyzed blood).), technical error in running the laboratory tests, or an 
abnormal urine analysis (e.g., due to menstruation or urinary tract infection). 
Section 6.1.1 Administration 
Before administering the injection, the study intervention administrator must inspect the syringe 
and vaccine volume, checking that the syringe is identified with the correct participant 
identification number and checking the date and time the dose was prepared. 
Section 6.1.2 Preparation/Handling/Storage/Accountability 
Further guidance and information for the preparation, handling, storage and accountability are 
provided in the Study ReferencePharmacy Manual. 
Section 6.1.3 Vaccine Administration Error 
Each vaccine dose will be prepared by reconstituting fully the contents of one vial containing the 
antigen with the contents of one vial of the adjuvant, and then drawing out the reconstituted 
vaccine content (0.5 mL) fully into the dosing syringe. 
 Section 6.2.2 Masking 
All unblinded persons must take care to not reveal individual group assignments to any other 
member of the study team. The investigational pharmacist preparing study interventions will 
be unblinded but will not perform other study duties. Designated unblinded site staff will 
prepare the vaccine in a blinded manner (the kits and doses are provided in a blinded manner).  

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
110 
A delegation of authority log will be maintained by the site and will identify the individual(s) 
authorized to function as the study vaccine manager, i.e., individuals with access to study 
blinding information. 
 Section 6.4 Concomitant Therapy 
* The use of anti-inflammatory and antipyretic medication should be discouraged during the first 
28 study days (Ddays 1 through 28) after each dose administered). 
Added: Receipt of any vaccine 7 days before and 7 days after either Dose 1 or Dose 2 is 
prohibited during the study, and will lead to study withdrawal. Refer to Section 7.2. 
Section 7.2 changed title of section: Participant Discontinuation/Withdrawal from the Study 
(changed because discontinuation not mentioned in this subsection). 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
Added new bullet after pregnancy bullet:  Receipt of any vaccine 7 days before and 7 days after 
Dose 1 and after Dose 2 
Section 7.3 Title: Lost to Follow-up; added hyphen in follow-up 
Section 8. Study Assessments and Procedures 
In addition, safety laboratory tests (hematology and chemistry), and urinalysis) (including 
microscopy) as well as a QFT TB test, sputum Xpert MTB/RIF assay, CD4+ cell count, HIV 
viral load, HIV serology, hepatitis B and C screening, and a serum pregnancy test (females only)  
All protocol-required safety laboratory tests (hematology, chemistry, and urinalysis) as well as 
a QFT TB test, sputum Xpert MTB/RIF assay, CD4+ cell count, HIV viral load, HIV serology, 
hepatitis B and C screening, and a serum pregnancy test (females only) will be performed by 
the central laboratory, Bio Analytical Research Corporation RSA (BARC SA or similar).  
Urine pregnancy tests will be performed by the study site.  
Assays for secondary and exploratory endpoints will be carried out in laboratories outside of 
the RSA.  
Section 8.1.1. Humoral Immunogenicity added text:  
…(Table 2). On Day 1 and Day 29 visits, samples will be collected prior to study intervention 
administration.  
Section 8.1.2. Cell-Mediated Immune Responses 
On Day 1 and Day 29 visits, samples will be collected prior to study intervention 
administration.  
For the secondary objective, frequency and magnitude of M72-specific CD4+ and CD8+ T-cell 
responses will be measured by expression of IFN-γ or IL-2 at Days 1, 57 and 390 to 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
111 
characterize the vaccine-induced immune response at baseline, peak immunogenicity and 
long-term memory, respectively.  
If responses at peak or memory are lower than expected compared to historical data from 
previous M72 vaccine studies, additional timepoints may be assessed to further characterize 
the kinetics of the cellular vaccine-induced immune response in HIV-positive study 
participants.  
For exploratory objectives, polyfunctionality of M72-specific CD4+ and CD8+ T-cell 
responses will be measured to support the exploratory objective by analysis of the co-
expression of multiple functional markers by ICS. 
Section 8.2.1. Physical Examination and Medical History 
As part of screening, the history/physical examination at each visit, a TB symptom/sign checklist from 
RSA TB guidelines will be used. This will include TB contact history. If TB is suspected, potential 
participants would be managed according to standard of care. The TB symptom/sign checklist in the 
eCRF includes: 
• 
Cough for longer than 2 weeks 
• 
Fever for longer than 2 weeks  
• 
Fatigue for longer than 2 weeks 
• 
Night sweats for longer than 2 weeks 
• 
Loss of weight or insufficient weight gain or growth 
• 
Other. 
If TB is suspected, potential participants would be managed according to standard of care. 
Section 8.2.4. Diary Card and Daily Temperature Monitoring 
The diary card will be collected and reviewed by the PI (or designee) on 7 days after each dose, 
i.e.ie, on Day 8 (Visit 2) and Day 36 (Visit 4). No changes to the diary card will be permitted, 
Section 8.2.5. Clinical Safety Laboratory Assessments 
• 
Urinalysis by dipstick: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase, by dipstick 
• 
Urine microscopy. 
Section 8.2.8. Sputum Xpert MTB/RIF 
A single self-expectorated sputum will be collected for Xpert MTB/RIF assay at screening from 
all participants at screening, and from participants with suspected TB, at study visits. 
Participants with a positive sputum Xpert MTB/RIF assay at screening (if sputum is able to be 
collected) are ineligible for the study. and. All participants with a positive sputum Xpert 
MTB/RIF assay and/or suspected TB should be referred for further management per standard of 
care. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
112 
Section 8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the participant (or, as appropriate, the participant's legally authorized 
representative). Biochemistry and/or hematology findings may also qualify as AEs if the 
investigator considers them as such. 
All SAEs and AESIs, will be collected through the end of the study.  
Refer to Table 5 for the required time periods for collection of each type of AE. 
Section 8.3.1 added ”and Pregnancy” to title: Time Period and Frequency for Collecting AE, 
and SAE, and Pregnancy Information 
Added table number and title: Table 5 Collection Period for all AEs and Pregnancies 
Type of Event 
Collection Time Period 
Any AE, SAE, or AESI  
From time of ICF and/or IAF is signed until 
dosing at Day 1 
All solicited AEs  
7 days after each dose Day 1 through Day 7 
(inclusive) after each dose 
Unsolicited AEs  
28 days after each dose Day 1 through Day 28 
(inclusive) after each dose 
All SAEs, AESIs and Pregnancies 
Day 1 through Month 13 (Day 390) (end of study) 
Medical conditions that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF, 
not the AE section. 
Section 8.3.3.1 AE Intensity 
Unsolicited AEs will be….. 
Solicited AEs will be graded by the participant using the diary card. 
Section 8.3.3.2.  AE Causality 
The sponsor or designee will never downgrade a case from serious to non-serious, or related to 
not related.  
Section 8.7   Exploratory Biomarkers 
If future research must be conducted in countries other than RSA, a separate request for 
approval will be made to the IRB/IEC, informed consent/assent will be required, and is subject 
to laws and regulations of the RSA and to IRB/IEC approval. 
Numbering of table changes:  
Section 9.2, Table 5 changed to Table 6. 
Section 9.3, Table 6 changed to Table 7. 
Section 9.4, Table 7 changed to Table 8. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
113 
Section 9.3 Table 7  
Population 
Description 
Randomized 
All participants randomly assigned to study intervention, a 
randomization number and date. 
Modified intention to treat 
(mITT) population. 
All participants randomly assigned to study intervention and who 
received the study intervention and who were randomly selected 
and tested for immunogenicity. Participants will be analyzed 
according to the intervention they actually received. 
Per-Protocol for 
Immunogenicity 
Population 
All participants in PP population randomly selected to have 
immunogenicity assays performed. 
Section 9.4 Statistical Analyses, Table 8: Summary of Endpoints and Analyses 
Secondary Endpoints 
Statistical Analysis  
M72-specific antibody titer pre  and post  
vaccination through the end of the study at 
Day 1, Day 29, Day 57, Day 210 and Day 
390  
Anti-M72/AS01E seropositive rates and 
GMCs will be calculated by treatment and 
time point with exact 95% CIs. 
 
Frequency, and magnitude and 
polyfunctionality of M72-specific CD4+ and 
CD8+ T-cell responses measured by 
expression of IFN-γ or IL-2 by ICS pre- and 
post- vaccination through the end of the 
study at Day 1, Day 57 and Day 390 
The frequency of CD4+ T cells positive for 
IFN-γ or IL-2, by ICS, will be summarized by 
treatment group and timepoint. Median 
DMSO-subtracted cytokine responses and 
associated 95% CIs will be used to summarize 
percentage T cell responses. 
Exploratory Endpoints 
Statistical Analysis  
Frequency and magnitude of M72-specific 
CD4+ and CD8+ T-cell responses measured 
by expression of IFN-γ or IL-2 by ICS at 
Day 29 and Day 210 
The frequency of CD4+ T cells positive for 
IFN-γ or IL-2, by ICS, will be summarized 
by treatment group and timepoint. Median 
DMSO-subtracted cytokine responses and 
associated 95% CIs will be used to 
summarize percentage T cell responses. 
Polyfunctionality of M72-specific CD4+ and 
CD8+ T-cell responses measured by co-
expression of multiple functional markers by 
ICS 
Polyfunctionality will be analyzed by 
COMPASS*, and summarized by treatment 
group using functionality and/or 
polyfunctionality scores. 
Suspected TB during the study   
 
Summary statistics will be generated for the 
incidence of suspected TB by treatment 
group and timepoint. 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
114 
Laboratory-confirmed pulmonary TB during 
the study 
Summary statistics will be generated for the 
incidence of Laboratory-confirmed 
pulmonary TB by treatment group and 
timepoint. 
* [Lin 2015] 
Section 9.4.3. Exploratory analyses 
Summary statistics will be generated for the incidence, by treatment group, of suspected TB 
disease and laboratory-confirmed pulmonary TB that occur throughout the study period. 
Section 9.5.2.1 Informed Consent forms 
Laboratory assays for primary and secondary endpoints will be carried out in the RSA.  
Participants will also be informed that laboratory tests will be run in laboratories in and 
outside of the RSA. 
Section 9.6.5   Recording and Follow-Up of AE and/or SAE 
Study product changed to study intervention 
Section 9.7   Contraceptive Guidance and Collection of Pregnancy Information 
Contraception Guidance: 
Added “after the start of”: Women physically capable of pregnancy must agree to use an 
acceptable method of avoiding pregnancy for one year after the start of study intervention.  
Collection and Reporting Pregnancy Information 
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy. 
Section 9.8 Toxicity Table: 
page 74: added the subscript 1 before the note:  1 Blood pressure norms for children < 18 … 
page 78: added the subscript 1 before the note:  1 Definition: A disorder characterized by …  
page 83: added rows for osteopenia and for osteoporosis ≥ 30 years of age 
≥ 30 years of age 
BMD t-score-2.5 to -1 
NA  
NA  
NA  
≥ 30 years of age 
NA 
BMD t-score  
< -2.5 
Pathologic fracture (e.g., 
compression fracture 
causing loss of vertebral 
height)  
Pathologic fracture 
causing life-
threatening 
consequences  
page 97: added the subscript 1 before the note:  1 Injection Site Erythema or Redness should be … 
page 101: added the subscript 1 before the note: 1 Creatinine clearance- Use the applicable… 
Section 10 References 

CONFIDENTIAL                                                           Protocol Gates MRI TBV02-202 
 
 
 
          
         Version 3.0 
26 February 2021 
115 
Added: Lin L, Finak G, Ushey K, et al. COMPASS identifies T-cell subsets correlated with 
clinical outcomes. Nat Biotechnol. 2015 Jun;33(6):610-6. doi: 10.1038/nbt.3187. Epub 2015 
May 25. 

Signature Page for TBV02-202 Protocol Version 3.0 v4.0
Document Number: TBV02-CLIN-000005 v4.0
Approval
Clinical Development
26-Feb-2021 20:30:40 GMT+0000