A Randomized, Placebo Controlled, Observer-Blind, Phase IIb Study to Evaluate the Efficacy, Safety, and Immunogenicity of BCG Revaccination in Healthy Adolescents for the Prevention of Sustained Infection With Mycobacterium Tuberculosis
Phase: PHASE2
Conditions: Tuberculosis
Sponsor: Gates Medical Research Institute

Title of the study - Bacille Calmette Guerin (BCG) Revaccination of 
Healthy Adolescents for the Prevention of Mycobacterium Tuberculosis 
Sustained Infection 
NCT number - NCT04152161 
Document date - 21 July 2023 

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Protocol Gates MRI-TBV01-201 
  Version 7, 21 July 2023 
Gates Medical Research Institute 
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Title Page 
Protocol Title: A Randomized, Placebo Controlled, Observer-Blind, Phase IIb Study to Evaluate 
the Efficacy, Safety, and Immunogenicity of BCG revaccination in Healthy Adolescents for the 
Prevention of Sustained Infection with Mycobacterium tuberculosis 
Protocol Number: Gates MRI-TBV01-201 
Short Title: BCG Revaccination of Healthy Adolescents for the prevention of Mycobacterium 
tuberculosis sustained infection 
Sponsor Name: Bill & Melinda Gates Medical Research Institute (Gates MRI) 
Legal Registered Address: Bill & Melinda Gates Medical Research Institute  
One Kendall Square, Building 600, Suite 6-301, Cambridge MA 02139 
Amendment Version 7: 21 July 2023 

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Gates Medical Research Institute 
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NOTE 
This study was paused for screening and randomization by the sponsor, effective 19 March 2020, 
due to the Coronavirus Disease 2019 (COVID-19) pandemic.  
Screening and randomization resumed in July, 2020. Refer to Section 7.4, COVID-19 
Contingency Plans for details regarding study pause due to COVID-19. 
 
 

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DOCUMENT HISTORY  
Document 
Date 
Original Version 1 pre-IRB review 14 Feb 2019 
Version 2 pre-IRB review 
21 Feb 2019 
Version 3 pre- IRB review 
27 Feb2019  
Version 4 
25 June 2019 (Version used at Study Start) 
Version 5 
11 May 2020 
(Modified to Version 6 before presented to the IRBs or SAHPRA) 
Version 6 
23 June 2020        
Version 7 
21 July 2023 

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Protocol Gates MRI-TBV01-201 
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SUMMARY OF CHANGES  
A high-level summary of the major changes incorporated into this protocol Version 7 are shown 
below.  
Section 
Number 
Summary of Change 
Rationale for Change 
Table 1 and  
Section 3 
Objectives and 
Endpoints  
Updated primary and the first secondary efficacy 
endpoint text to delete IFN-γ concentration cut-off 
value 
Replaced “an IFN-γ concentration cut-off value of 
0.35 IU/mL” with “positive QFT test results” 
 
 
 
Added “at least” 118 events to the primary endpoint. 
Changed the wording to 
indicate that the assay is 
used according to the 
manufacturer’s instructions. 
The conditions that need to 
be met for a valid positive 
result are best described in 
the package insert. 
Added to allow for 
flexibility in the timing of 
the analysis. 
 
Moved secondary objective (“To evaluate the 
efficacy and durability of efficacy, and associated 
endpoint”) to first exploratory objective.  
Revised the text associated with endpoint for primary 
QFT conversion  
New text:  
 …at the time of primary endpoint analysis, and after 
a follow-up of 36- and 48-months post vaccination, 
using an alternative definition of conversion as a 
change in IFN-γ concentration from <0.35 IU/mL to 
≥4 IU/mL (initial conversion only) 
Previous version:  
..based on a QFT IFN-γ concentration cut-off value 
of 4 IU/mL at the time of primary 
endpoint analysis, and after a minimum 
follow-up of 36- and 48-months post 
vaccination, based on IFN-γ 
concentration cut-off value of 4 IU/mL 
(initial conversion only) 
The endpoint which 
includes a threshold of 4 
IU/mL for QFT positivity, 
does not conform to the 
language in the package 
insert and we therefore 
considered declaring this as 
an exploratory endpoint 
more appropriate.  
First secondary objective - edited endpoint wording 
for the efficacy and durability of efficacy against 
sustained Mtb infection 
For clarification 

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Section 
Number 
Summary of Change 
Rationale for Change 
New text: Sustained QFT conversion based on 
positive QFT test results (initial conversion and QFT-
positive at 3- and 6-months PC) with a follow-up of 
36- and 48-months post vaccination. 
Previous version: Sustained QFT conversion based 
on an IFN-γ concentration cut-off value of 0.35 
IU/mL (initial conversion and QFT-positive at 3- and 
6-months PC) with a minimum follow-up of 36- and 
48-months post vaccination 
Section 1.3 
SoA and Table 
4 
The Month 54 visit was deleted from SoA and Table 
4, and footnotes updated accordingly.  
Footnote for HIV testing corrected to add the word 
“suspected” to HIV testing at screening, and M12, 
24, 36, 48, and if TB is suspected. A column for 
Suspected TB visits was added. 
Correction for consistency 
with text in Section 8.3.6. 
Suspected TB column added 
for clarification 
Section 4.1 
Scientific 
Rationale for 
Study Design 
Updated wording to reflect changes in endpoint text 
For clarification 
Section 4.3 
End of Study 
Definition 
Changed the end of study definition to remove 
follow-up at Months 51 and 54 for participants who 
have their initial QFT seroconversion at Month 48. A 
participant is considered to have completed the study 
if he/she completes the final visit at Month 48. The 
end of the study is defined as the date of the last visit 
of the last participant in the study or last scheduled 
procedure shown in the SoA for the last participant in 
the trial. The primary endpoint is reached when at 
least 118 participants have converted from a 
negative to positive QFT result, sustaining 
positivity for at least 6 months post initial 
conversion. 
The study will end after the 
Month 48 visit is completed.  
 
Clarification for when the 
primary endpoint is met. 

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Section 
Number 
Summary of Change 
Rationale for Change 
Section 7.2. 
Discontinuation/
Withdrawal from 
the Study 
Removed pregnancy from bulleted list of reasons for 
investigator-instigated withdrawals and removed 
pregnancy text 
 
 
Edited text regarding participant withdrawal and 
required procedures  
Pregnancy alone is not a 
reason for study withdrawal. 
Post study start pregnancy 
will lead to cancellation of 
further blood draws. 
Clarified text regarding 
procedures to be performed 
if participant is not 
withdrawn. 
Section 8.1.1 
Evaluation of 
initial Mtb 
infection and 
sustained 
infection 
New text: Mtb infection is defined for this 
protocol as QFT conversion from a negative to 
positive test, as per the manufacturer’s QFT-GIT 
package insert.  
Sustained Mtb infection is defined for this 
protocol as sustained QFT conversion from a 
negative to positive test, with initial conversion 
at any time after a first negative QFT result, post 
randomization (Day 71 or subsequent visit if Day 
71 result is not available), and remaining QFT-
positive at 3- and 6-months PC. 
Previous text: Mtb infection is defined for this 
protocol as QFT conversion from a negative to 
positive test, using the manufacturer’s 
recommended threshold of 0.35 IU/mL, at any 
time-point. 
Sustained Mtb infection is defined for this 
protocol as sustained QFT conversion from a 
negative to positive test, using the 
manufacturer’s recommended IFN- 
concentration cut-off value of 0.35 IU/mL, with 
initial conversion at any time after Day 71 testing 
and remaining QFT-positive at 3- and 6-months 
PC.  
Clarification of Mtb 
infection and sustained 
infection definitions. 
 
Section 8.2.2 
Pregnancy 
Assessment  
Added “and Follow-up” to the subsection title  
Added text here to indicate that pregnancy after study 
start does not lead to withdrawal but that blood draws 
are not performed during pregnancy. Once pregnancy 
Stated above.  

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Section 
Number 
Summary of Change 
Rationale for Change 
ends, QFT and HIV blood draws can resume, per PI 
discretion, but all other blood draws are cancelled. 
Section 8.3.6 
Latent TB 
infection  
Updated wording to state that TPT either by referral 
or offered at site.  
 
To allow for flexibility for 
sites to refer participants for 
TPT  
Table 9 
Populations for 
Analyses 
Revised mITT population description text to include 
participants who may have missed the Day 71 visit. 
Revised PP text  
New text: All participants in the mITT population 
who did not substantially deviate from the protocol 
procedures. 
Previous version: All participants randomly 
assigned to study intervention, who received the 
study intervention, are QFT negative at the Day 
71 visit, and did not substantially deviate from 
the protocol procedures. 
mITT population definition edited to specify that 
participants will be analyzed according to the 
intervention to which they were randomized 
instead of to the intervention they actually 
received. 
 
PP definition was modified to “All participants 
in the mITT population who did not substantially 
deviate from the protocol procedures and who 
received the treatment to which they were 
randomized.” 
For clarification 
Table 10 
Summary of 
Primary and 
Secondary 
Endpoints and 
Analyses 
and Section 
9.4.1.2 
Secondary and 
Exploratory 
Revised text  
 
For consistency to reflect 
changes made to the 
Objectives and Endpoints 
Table 

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Section 
Number 
Summary of Change 
Rationale for Change 
Efficacy 
Endpoint 
Analyses 
Section 9.4.1.1 
Primary 
Endpoint 
Analyses 
Edited sustained QFT conversion definition to 
remove “based on an assay threshold of 0.35 IU/mL” 
Timing of primary efficacy analysis edited to include 
the option to combine the primary analysis and the 
Month 36 efficacy analysis if at least 118 events are 
reached within 6 months before the Month 36 visit is 
planned to occur. 
For consistency with 
changes made to primary 
endpoint 
Timing of primary analysis 
updated for flexibility 
Interim 
Analysis 
Section 9.4.6 
Removed this IA section and content and moved text 
regarding IDMC to a new separate subheading: 
Independent Data Monitoring Committee (IDMC)  
The interim analysis was 
included in the original 
protocol to allow Gates 
MRI/BMGF to make the 
decision as to whether we 
would run a similar study in 
other countries.  
A second revaccination 
study will not be conducted 
and therefore, an interim 
analysis was not required 
and was not performed. 
Section 10.2.6 
SAEs, AESIs, 
Serious ADRs, 
and SUSAR 
Reporting  
Removed reference to “Immediately Reportable 
Event Form” 
This form will not be used.  
Section 10.3  
Deleted elective termination of pregnancy from 
pregnancy complications and specified that AE 
and SAE reporting periods apply as described in 
reporting sections. 
Clarified text regarding 
pregnancy complications 
and reporting of 
pregnancies. 
Refer to Summary of Section 12 for version history and list of changes for previous versions. 

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Amendment Version 7 Signature Page 
 
See appended electronic signature page 
 
 

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Table of Contents 
 
Title Page ........................................................................................................................................1 
Document History ..........................................................................................................................3 
Summary of Changes .....................................................................................................................4 
Table of Contents .........................................................................................................................10 
List of Tables ................................................................................................................................14 
List of Figures ...............................................................................................................................14 
1. 
Protocol Summary ........................................................................................................17 
1.1. 
Synopsis ..........................................................................................................................17 
1.2. 
Schema ............................................................................................................................21 
1.3. 
Schedule of Activities (SoA) ..........................................................................................22 
2. 
Introduction ...................................................................................................................28 
2.1. 
Study Rationale ...............................................................................................................28 
2.1.1. 
Rationale for addition of COVID-19 related study objectives .......................................29 
2.2. 
Background .....................................................................................................................30 
2.3. 
Benefit/Risk Assessment ................................................................................................30 
3. 
Objectives and Endpoints ............................................................................................33 
4. 
Study Design ..................................................................................................................35 
4.1. 
Scientific Rationale for Study Design ............................................................................36 
4.2. 
Justification for Dose ......................................................................................................38 
4.3. 
End of Study Definition ..................................................................................................38 
5. 
Study Population ...........................................................................................................38 
5.1. 
Inclusion Criteria ............................................................................................................39 
5.2. 
Exclusion Criteria ...........................................................................................................39 
5.3. 
Lifestyle Considerations .................................................................................................41 
5.4. 
Screen Failures ................................................................................................................41 
6. 
Study Intervention ........................................................................................................41 
6.1. 
Study Intervention(s) Administered................................................................................41 
6.1.1. 
BCG Vaccine ..................................................................................................................42 
6.1.2. 
Placebo ............................................................................................................................42 
6.1.3. 
Administration ................................................................................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................44 
6.3.1. 
Randomization ................................................................................................................44 
6.3.2. 
Masking...........................................................................................................................44 
6.3.3. 
Blind Break .....................................................................................................................45 

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6.4. 
Study Intervention Compliance ......................................................................................45 
6.5. 
Concomitant Therapy .....................................................................................................45 
6.6. 
Dose Modification ..........................................................................................................45 
6.7. 
Intervention after the End of the Study ...........................................................................46 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal and COVID-19 Contingency 
Plans ...............................................................................................................................46 
7.1. 
Discontinuation of Study Intervention ............................................................................46 
7.1.1. 
Pausing Rules for Study ..................................................................................................46 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................47 
7.3. 
Lost to Follow-up............................................................................................................48 
7.4. 
COVID-19 Contingency Plans .......................................................................................48 
7.4.1. 
Rationale and Plan ..........................................................................................................48 
7.4.2. 
Enrollment of new participants and status of previously enrolled 
participants ......................................................................................................................49 
7.4.3. 
Study visits for enrolled subjects ....................................................................................50 
7.4.4. 
Addition of exploratory objectives and endpoints related to 
COVID-19.......................................................................................................................51 
7.4.4.1. 
Serology for COVID-19 .....................................................................................51 
7.4.4.2. 
Diagnostic test for SARS-CoV-2 .......................................................................51 
7.4.5. 
Changes to the definition of the mITT cohort for efficacy .............................................51 
7.4.6. 
Protocol deviations related to COVID-19.......................................................................52 
7.4.7. 
Informed consent and re-consent ....................................................................................52 
7.4.8. 
Safety precautions for trial staff after enrollment resumes .............................................52 
7.4.9. 
References .......................................................................................................................52 
8. 
Study Assessments and Procedures.............................................................................52 
8.1. 
Efficacy Assessments .....................................................................................................53 
8.1.1. 
Evaluation of initial Mtb infection and sustained infection ............................................53 
8.2. 
Safety Assessments .........................................................................................................54 
8.2.1. 
Physical Examination and Medical History ....................................................................54 
8.2.1.1. 
Interim History and Focused Physical Examination ..........................................55 
8.2.2. 
Pregnancy Status Assessment and Follow-Up ................................................................55 
8.2.3. 
Pre- and Post-Study Intervention Safety Monitoring......................................................55 
8.2.4. 
Diary Card and Daily Temperature Monitoring .............................................................55 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................56 
8.2.6. 
Injection Site Examination ..............................................................................................57 
8.2.7. 
Participant Follow-Up .....................................................................................................57 
8.3. 
Adverse Events and Serious Adverse Events .................................................................58 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................58 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................59 
8.3.3. 
Follow-up of AEs ............................................................................................................59 
8.3.3.1. 
AE Intensity ........................................................................................................59 

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8.3.3.2. 
AE Causality ......................................................................................................59 
8.3.3.3. 
AE Resolution ....................................................................................................60 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................60 
8.3.5. 
Death Events ...................................................................................................................60 
8.3.6. 
Latent TB infection and TB disease................................................................................61 
8.4. 
Treatment of Overdose ...................................................................................................61 
8.5. 
Pharmacokinetics ............................................................................................................61 
8.6. 
Pharmacodynamics .........................................................................................................62 
8.7. 
Genetics ..........................................................................................................................62 
8.8. 
Biomarkers ......................................................................................................................62 
8.8.1. 
Immunological Assessments ...........................................................................................63 
8.8.2. 
Subset Assessment ..........................................................................................................63 
8.9. 
Health Economics ...........................................................................................................63 
9. 
Statistical Considerations .............................................................................................63 
9.1. 
Statistical Hypotheses .....................................................................................................64 
9.2. 
Sample Size Determination ............................................................................................64 
9.3. 
Populations for Analyses ................................................................................................66 
9.4. 
Statistical Analyses .........................................................................................................66 
9.4.1. 
Efficacy Analyses ...........................................................................................................68 
9.4.1.1. 
Primary Endpoint Analyses ................................................................................68 
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoint Analyses ..................................68 
9.4.1.2.1. Multiplicity ................................................................................................. 69 
9.4.2. 
Safety Analyses ...............................................................................................................69 
9.4.3. 
Immunogenicity and Exploratory Biomarker Analyses .................................................70 
9.4.3.1. 
Immune Response by ICS ..................................................................................70 
9.4.3.2. 
Other Exploratory Analyses ...............................................................................70 
9.4.4. 
Subgroup Analyses .........................................................................................................70 
9.4.5. 
Demographic and Compliance Analyses ........................................................................71 
9.4.6. 
Independent Data Monitoring Committee (IDMC) ........................................................71 
9.4.7. 
National Regulatory Authority .......................................................................................71 
10. 
Supporting Documentation and Operational Considerations ..................................72 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................72 
10.1.1. Regulatory and Ethical Considerations ...........................................................................72 
10.1.2. Study Oversight ..............................................................................................................72 
10.1.3. Financial Disclosure........................................................................................................73 
10.1.4. Informed Consent Process ..............................................................................................73 
10.1.4.1. 
Informed Consent forms .....................................................................................74 
10.1.5. Data Protection................................................................................................................75 
10.1.6. Dissemination of Clinical Study Data.............................................................................75 
10.1.7. Data Quality Assurance ..................................................................................................75 
10.1.8. Source Documents ..........................................................................................................76 

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10.1.9. Study and Site Closure ....................................................................................................76 
10.1.10. Publication Policy ...........................................................................................................77 
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................77 
10.2.1. Definition of AE .............................................................................................................77 
10.2.2. Definition of SAE ...........................................................................................................79 
10.2.3. Definition of Serious ADR and SUSAR .........................................................................80 
10.2.4. Definition of AESI ..........................................................................................................80 
10.2.5. Recording and Follow-Up of AE and/or SAE ................................................................80 
10.2.5.1. 
Assessment of Intensity ......................................................................................82 
10.2.5.2. 
Assessment of Causality .....................................................................................82 
10.2.5.3. 
Assessment of Expectedness ..............................................................................83 
10.2.5.4. 
Assessment of Outcome .....................................................................................83 
10.2.6. SAEs, AESIs, Serious ADRs, and SUSAR Reporting ...................................................83 
10.3. 
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................87 
10.4. 
Appendix 4: Genetics......................................................................................................88 
10.5. 
Appendix 5: Toxicity Table ............................................................................................89 
11. 
References .....................................................................................................................120 
12. 
Version History .............................................................................................................122 

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List of Tables 
 
Table 1:  
Objectives and Endpoints .................................................................................. 17 
Table 2: Scheduled Visits and Activities ...................................................................................... 22 
Table 3: Schedule of Activities Post QFT Conversion at the Month 6 Visit or Thereafter .......... 26 
Table 4: Study Visit Intervals ....................................................................................................... 27 
Table 5: Objectives and Endpoints ............................................................................................... 33 
Table 6: Study Interventions ......................................................................................................... 42 
Table 7: Guidance for visits missed due to COVID-19-related restrictions, once in-person study 
visits become feasible ................................................................................................................... 50 
Table 8: Sample Size Requirements to Ensure 75%-80% Probability of Performing the Primary 
Analysis within 3.5 years .............................................................................................................. 65 
Table 9: Populations for Analyses ................................................................................................ 66 
Table 10: Summary of Primary and Secondary Endpoints and Analyses .................................... 67 
Table 11: Scheduled Visits and Activities .................................................................................. 126 
Table 12: Study Visit Intervals ................................................................................................... 127 
 
List of Figures 
Figure 1: Outline of Study Procedures.......................................................................................... 21 
Figure 2: SAE and SUSAR Reporting Scheme ............................................................................ 86 
 

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List of Abbreviations 
ADR 
(serious) adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase   
AST 
aspartate aminotransferase 
BARC SA 
Bio Analytical Research Corporation, South Africa 
βHCG  
beta human chorionic gonadotropin 
BCG 
Bacille Calmette Guerin 
BMI 
body mass index 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CFU 
Colony-forming units 
CoP 
correlate of protection 
CoR 
correlate of risk 
COVID-19 
Coronavirus Disease 2019  
CRF 
case report form 
CSR 
clinical study report 
DNA 
deoxyribonucleic acid 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
GCP  
Good Clinical Practices 
GMRI 
Gates Foundation Medical Research Institute 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
ICS 
intracellular cytokine staining 
ID 
intradermal 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN-γ  
interferon gamma  
IL 
interleukin 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IVRS 
interactive voice response system  
IWRS 
interactive web response system  
LAR 
legally acceptable representative 
LLN 
lower limit of normal 
LTBI 
latent TB infection 
mL 
milliliter 

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mITT 
modified intention to treat 
Mtb 
Mycobacterium tuberculosis 
NA 
not applicable 
NK cells 
natural killer cells 
NTM  
non-tuberculous mycobacteria 
NTP 
(South African) National TB Program  
PBMC 
peripheral blood mononuclear cells 
PC 
post conversion 
PCR test 
polymerase chain reaction test 
POD 
Prevention of disease 
POSI 
Prevention of sustained Mtb infection 
PP 
Per protocol 
QFT-GIT assay 
QuantiFERON-Gold in Tube assay 
QFT assay 
QuantiFERON®-TB Gold Plus assay 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAHPRA 
South African Health Products Regulatory Authority 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Coronavirus-2 
SATVI 
South African Tuberculosis Vaccine Initiative 
SoA 
schedule of activities 
SUSAR 
suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TNF 
tumor necrosis factor 
TST 
tuberculin skin test 
ULN  
upper limit of normal 
VE 
vaccine efficacy 
WBC 
white blood cell 
WHO 
World Health Organization 
Yr  
Year 

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1. 
Protocol Summary 
1.1. Synopsis 
Protocol Title: A Randomized, Placebo Controlled, Observer-Blind Phase IIb Study to Evaluate 
the Safety, Immunogenicity, and Efficacy of BCG revaccination in Healthy Adolescents for the 
Prevention of Sustained Infection with Mycobacterium tuberculosis 
Short Title: BCG Revaccination of Healthy Adolescents for the prevention of Mycobacterium 
tuberculosis sustained infection 
Rationale: Recently published results from a Phase 2 study evaluating Bacillus Calmette-Guerin 
(BCG) revaccination in healthy adolescents in South Africa suggest that BCG revaccination of 
adolescents 12 to 17 years of age may lead to prevention of sustained Mycobacterium 
tuberculosis (Mtb) infection (POSI) over a 24 month period following vaccination, as assessed 
by sustained QuantiFERON-TB Gold® in-Tube (QFT GIT) conversion (i.e., initial QFT 
conversion and remaining QFT positive at three and six months post conversion [PC]) (Nemes, 
2018).  
This current study intends to i) confirm that BCG revaccination protects against sustained Mtb 
infection in a larger independent study, ii) assess the duration of protection through 48 months 
post revaccination, iii) evaluate BCG revaccination in children ten years of age and above and iv) 
identify/validate biomarkers that correlate with  risk for or protection against transient and/or 
sustained Mtb infection, as assessed by QuantiFERON plus (QFT) assay, which is the newer 
version of the QFT GIT assay. 
Table 1:  
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To demonstrate the efficacy of BCG 
revaccination against sustained Mtb 
infection versus placebo in previously 
BCG vaccinated QFT negative, healthy 
adolescents (event-driven analysis) 
• Sustained QFT conversion (at least 118 
events) based on positive QFT test results 
(initial conversion and QFT-positive at 3- 
and 6-months PC) 
Secondary 
• To evaluate the durability of efficacy of 
BCG revaccination against sustained Mtb 
infection versus placebo in previously 
BCG vaccinated, QFT negative, healthy 
adolescents 
• Sustained QFT conversion based on 
positive QFT test results (initial 
conversion and QFT-positive at 3- and 6-
months PC) with a follow-up of 36- and 
48-months post vaccination 

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Objectives 
Endpoints 
Secondary, continued… 
• To evaluate the safety and reactogenicity 
of BCG revaccination in previously BCG 
vaccinated, QFT negative healthy 
adolescents 
• Solicited adverse events (AEs) through 7 
days post vaccination 
• Unsolicited AEs through 28 days post 
vaccination 
• All serious adverse events (SAEs) and 
adverse events of special interest (AESIs) 
through Month 6 
• Serious adverse drug reactions (Serious 
ADRs) through the end of the study 
Exploratory 
• To evaluate the efficacy and durability of 
efficacy of BCG revaccination against 
primary Mtb infection post vaccination 
versus placebo in previously BCG 
vaccinated, QFT negative healthy 
adolescents 
• Primary QFT conversion at the time of 
primary endpoint analysis, and after a 
follow-up of 36- and 48-months post 
vaccination, using an alternative definition 
of conversion as a change in IFN-γ 
concentration from <0.35 IU/mL to ≥4 
IU/mL (initial conversion only)  
• To evaluate the efficacy and durability of 
efficacy of BCG revaccination against 
primary and sustained Mtb infection post 
vaccination versus placebo in previously 
BCG vaccinated, QFT negative healthy 
adolescents, based on alternate QFT IFN-γ 
concentration cut-off values 
• Primary and sustained QFT conversion at 
the time of primary endpoint analysis, and 
after a follow-up of 36- and 48-months 
post vaccination, based on a definition of 
primary and sustained conversions using  
exploratory IFN-γ concentration  threshold 
values  
• To assess the immunogenicity of BCG 
revaccination 
• Frequency of Mtb-, BCG- and/or non-
tuberculous mycobacteria (NTM)-specific 
cluster of differentiation (CD)4 T cells 
expressing one or more cytokines, e.g., 
IFN-γ, tumor necrosis factor (TNF)-α, 
interleukin (IL)-2 and/or IL-22 by 
intracellular cytokine staining (ICS) 
 

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Objectives 
Endpoints 
Exploratory, continued… 
• To describe host attributes and host 
responses to vaccination  
• To describe host attributes and host 
responses following QFT conversion  
• To explore and/or develop candidate 
correlates of risk (CoRs) and correlates of 
protection (CoPs) 
• To detect and describe incident TB disease 
• To characterize Mtb isolates 
• To describe COVID-19 among study 
participants who present with suspected 
COVID-19  
• To describe the serostatus of SARS-CoV-2 
infection  
Endpoints may include: 
• Genetic markers and sequences 
• Transcriptomics and gene expression 
markers 
• Proteomics 
• Antibody analyses 
• Cellular analyses (eg, natural killer cells 
[NK cells], B cells, T cells, myeloid cells) 
• Signs and symptoms of illness, by 
treatment group 
• SARS-CoV-2 nucleic acid amplification 
from nasal or oropharyngeal sample  
• Serological tests for SARS-CoV-2, by 
treatment group 
Refer to Section 7.4 for COVID-19 Pandemic contingency plans. 
Overall Design: 
• Disclosure Statement: This is a randomized, placebo controlled, observer-blind, 
phase IIb study with two arms (BCG vaccine and saline placebo). An independent 
data monitoring committee (IDMC) will be established to oversee the safety of this 
study. 
• Intervention model: Participants will be randomly assigned equally to one of two 
groups in parallel for the duration of the study. 
• Intervention Groups: 2 study groups (BCG group and placebo group) will each 
receive a single intradermal (ID) injection: 
o BCG group will receive one dose of BCG vaccine (Bacillus Calmette-Guerin SSI, 
Danish strain 1331, live attenuated 2-8 x 105 colony forming units (cfu) in a 
0.1mL volume ID injection  
o Placebo group will receive one dose of saline control in a 0.1mL volume ID 
injection 
• Primary Purpose: Intervention (BCG revaccination) is being evaluated for POSI (see 
Section 2.1 and Section 4.1 for details). 
• Masking: Participants, sponsor, investigators, contract research organization (CRO) 
clinical team, laboratory, and clinical staff are blinded to intervention (BCG vs 

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placebo) until primary endpoint analyses are performed. BCG vaccine recipients and 
clinical staff at the sites may inadvertently become unblinded as soon as a BCG 
lesion develops. Refer to Section 6.3.2 for masking details. 
• Number of Participants: Approximately 5625 participants will be screened to enroll 
and randomize 1800 healthy participants 1:1 to receive either a single dose of BCG 
vaccine intradermally or a single dose of normal saline placebo intradermally on Day 
1. Randomization will be stratified by age strata (10-11 years old, 12-14 years old, 
and > 14 years old), sex, study site, and school cluster, to account for expected 
differences in incidence rates. Refer to 6.3.1 for details. 
• A subset of 80 participants (the first 80 10-12-year-old participants who are enrolled 
at the SATVI site) will be included for whole blood ICS analysis to assess frequency 
of Mtb-, BCG- or NTM-specific CD4 T cells expressing one or more cytokines, e.g., 
IFN-γ, TNF-, IL-2 and/or IL-22. 
• Wash-out period: A 70-day wash-out period will be used to identify participants who 
may have been infected with Mtb just prior to or soon after enrollment. Participants 
who convert to QFT positive at Day 71 (or if missed or not feasible, at the next 
feasible visit) will not be asked to return for PC Day 28 and PC Day 84 visits and 
will be excluded from the primary mITT efficacy analysis but will be followed for 
safety and efficacy to End-of-Study.  
• Total duration of study participation: Each participant will remain in the study for a 
minimum of 4 years. Enrollment, originally expected to take place over a 1-year 
period, will be extended as necessary due to COVID-19 pandemic-related 
restrictions. Refer to 7.4.2 for COVID-19 pandemic contingency plans with regard to 
participant enrollment, and other details. 
• Safety Monitoring: An IDMC will be established to oversee the safety of this study, 
and will also review and monitor the primary and secondary efficacy results. The 
IDMC will review unblinded safety data on a regular basis. During active 
enrollment, the IDMC will meet at least once every three months. Once enrollment is 
complete, the IDMC will meet at least twice a year. The IDMC review will include 
solicited and unsolicited AEs, as well as SAEs and AESIs. The IDMC may request 
additional information, or a pause in recruitment and vaccination, while safety data 
are being evaluated. The IDMC will make a formal recommendation on the 
continued enrollment into the trial after each safety review. Each participant will be 
followed for safety for a minimum of 6 months after vaccination.  
• Study sites: Five or more sites in South Africa will participate in this study. 
• Participants will be asked to consent to extended passive follow-up for TB disease 
(using the National TB Programme electronic TB register) for up to 10 years post 
end of study. 

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Table 4: Study Visit Intervals 
Study Visits 
Length of Interval 
Allowed Interval 
Screening  
Day -28 to Day -1 
Day -28 to Day -1 
Day 1 
NA 
Day 1 
Day 8 
Day 1 plus 7 days  
Day 8 to Day 11 
Day 29 
Day 1 plus 28 days  
Day 29 to Day 35 
Day 71 
Day 1 plus 70 days  
Day 71 to Day 78 
Month 6, M12, 18 …M48 
Day 1 plus 6 (12, 18, …) 
calendar months 
6 (12, 18, …48) calendar 
months from Day 1 ±14 days  
PC28 
Date of QFT conversion plus 
28 days 
Day 28 to Day 35 post QFT 
conversion 
PC84 
Date of QFT conversion plus 
84 days 
Day 84 to Day 98 post QFT 
conversion 
NA = not applicable  
Note that after Day 71, timepoints and intervals will be measured in calendar months. 
Refer to Section 7.4 for intervals based on COVID-19 contingency plans. 

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2. 
Introduction 
Worldwide, tuberculosis (TB) is one of the top 10 causes of death and the leading cause from a 
single infectious agent. In 2017, TB caused an estimated 1.3 million deaths among HIV-negative 
people and there were an additional 300,000 deaths from TB among HIV-positive people. It is 
estimated that 10 million people developed TB disease in 2017: 5.8 million men, 3.2 million 
women and 1.0 million children: the average case fatality rate of TB is 16% [WHO 2018].  
TB is seen in all countries and age groups, but overall, 90% of new cases globally occur in 
people aged 15 years or above. Thirty high TB burden countries accounted for 87% of the 
world’s cases. The severity of national epidemics varies widely among countries and within 
countries.  
Burden of disease in South Africa 
The national incidence of TB in South Africa is estimated at 322,000 (230,000 to 428,000) new 
cases in 2017, i.e., an incidence rate of 567 per 100 000 population, one of the highest estimated 
rates based on the World Health Organization (WHO) Global TB report [WHO 2018]. Cohort 
studies in the Western Cape province showed that the prevalence of Mtb infection increases 
quickly in adolescence and that about half of the adolescents are latently infected with Mtb, with 
demographic and poverty-related socio-economic factors predicting the risk of TB infection 
[Mahomed 2011; Nemes 2018]. A recent study, largely enrolled in the Worcester region of the 
Western Cape, reported QFT-GIT conversion rates of approximately 10% per year [Nemes 
2018].  
Adolescents who are QFT-GIT positive have an almost three-fold higher incidence of active TB 
disease in subsequent years, compared to QFT-GIT negative adolescents (0.64 vs 0.22 per 100 
person-years) [Mahomed 2011]. However, the highest risk of TB disease occurs in adolescents 
with recent QFT-GIT conversion. Their TB disease incidence was 8 times higher than the rate in 
adolescents who had remained QFT-GIT negative (1.46 vs 0.17 per 100 person-years) 
[Machingaidze 2012]. Therefore, QFT-GIT conversion is an important indicator for the risk to 
develop active TB.  
2.1. Study Rationale 
The recently published Aeras Phase 2b study C-040-404 (Aeras 404 study) evaluated the vaccine 
efficacy (VE) of BCG revaccination in healthy 12 to 17-year-old HIV-negative participants in 
South Africa against initial QuantiFERON-TB Gold in tube ® (QFT-GIT) conversion, a 
surrogate for primary Mtb infection. The study did not meet its primary endpoint but reported 
45% VE against sustained QFT-GIT conversion, i.e., initial QFT-GIT conversion and remaining 
QFT-GIT positive at 3- and 6-months PC, as a surrogate for sustained latent Mtb infection 
[Nemes 2018].This finding is encouraging as QFT reversion (from QFT-positive to QFT-
negative) is thought to be indicative of successful immune control of the initial infection. 
Treatment of latent TB infection (LTBI) patients with Isoniazid (INH) has been reported to 
significantly decrease IFN- concentrations in the QuantiFERON TB Plus (QFT) assay, 
suggesting that IFN- concentrations may correlate with the bacillary load in LTBI [Petruccioli 
2018]. 

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The current study aims to confirm the findings of the previous BCG revaccination study. The 
study will be conducted at sites in the Western Cape province, where the initial finding of 
protection was observed, and additional site(s) in other provinces. The study aims to extend the 
findings of the previous study by modifying three of its aspects: Firstly, the study will enroll 
adolescents from ten years of age (rather than 12 years of age), aiming to increase the proportion 
of QFT-negative participants among the population screened for inclusion and to generate safety 
and immunogenicity data in an age range that could potentially be considered for revaccination 
of a majority QFT-negative population in high-transmission settings. Secondly, the duration of 
follow-up will be extended from two years to 4 years in order to assess the duration of protection 
from sustained infection. Thirdly, biospecimens will be collected 4- and 12-weeks post QFT 
conversion to characterize potential differences in the immune response between participants 
who develop sustained conversion versus reversion. 
The study described here intends to demonstrate that BCG revaccination of healthy HIV-
negative adolescents leads to POSI, as assessed by sustained QFT conversion. Although it 
remains to be demonstrated that POSI will translate to prevention of disease (POD), it is 
biologically plausible to argue that successful immune control of the initial Mtb infection is 
likely to reduce the risk of progression to active disease. The goal of this study is to generate the 
evidence needed to inform whether a POD trial in QFT-negative is justified and necessary. 
2.1.1. 
Rationale for addition of COVID-19 related study objectives 
The Government of South Africa declared the COVID-19 pandemic a National Disaster on 15 
March 2020 and the Sponsor of this study issued a pause for enrollment on 17 March 2020, 
effective 19 March 2020.  
The Government of South Africa subsequently ordered a lockdown (stay-at-home order) for 
three weeks on 26 March 2020 and subsequently extended it for an additional two weeks, 
through the end of April, 2020. Under the lockdown, most trial participants are not able to come 
to the investigational site for protocol-specified visits.  
Since 1 May 2020, South Africa has employed a system of alert levels at the provincial and, in 
some cases, the district level. Criteria based on the rate of infection as well as health system 
capacity are used by the National Command Council to determine the alert level. 
Enrollment into this study can only resume once the Government, local IRBs, investigators, and 
the sponsor agree that it is acceptable to resume enrollment. Enrollment may also need to be 
paused again in the future, depending on the COVID-19 situation at national, province and 
district level. 
Study investigators and study sites have defined infection control measures for COVID-19 that 
need to be implemented prior to resuming enrollment and are consulting with IRBs to determine 
the conditions that would allow for enrollment to continue. 
The study investigators and study sponsor agreed to add two exploratory COVID-19 endpoints to 
this study. Firstly, in order to describe COVID-19 among the study population, to differentiate 
COVID-19 from pulmonary TB, and to minimize risks to participants and staff, a diagnostic test 
for SARS-CoV-2 (based on nucleic acid amplification) will be performed if a participant 
presents with suspected COVID-19. A description of the frequency and symptomatology of 

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COVID-19 by treatment group is of great scientific interest as BCG-induced trained immunity 
has been hypothesized to potentially offer protection from progression to severe COVID-19. 
BCG vaccination is currently being tested as a prophylactic intervention against COVID-19 
(NCT04327206 and additional studies). 
Secondly, to describe the penetrance of SARS-CoV-2 infection in the communities that 
participate in this study, SARS-CoV-2 serology will be performed once every six months for a 
duration of 24 months. This will aid our understanding of virus transmission in the communities 
we work in and may allow a better understanding of the frequency of asymptomatic illness. 
2.2. Background 
BCG vaccination at birth is part of the South African National Routine Immunization Schedule 
and prevents severe forms of TB in childhood. BCG revaccination of children is not 
recommended in the Republic of South Africa but has been practiced in a number of countries. 
BCG revaccination appears to be safe and well tolerated in adolescents and young adults [Nemes 
2018; Pereira 2012; Petruccioli 2018, Rodrigues 2005; Bottiger 1983]. A trial of BCG 
revaccination in 2,997 fourteen to fifteen-year-old Swedish adolescents reported open 
vaccination lesions in 4% of vaccines who received the Danish BCG vaccine that will be used in 
this trial [Bottiger 1983].  
Currently there is no consensus with regards to the efficacy or effectiveness of BCG 
revaccination for the prevention of TB disease. The recent Phase 2b study evaluating BCG 
revaccination in South Africa suggested that BCG revaccination may confer POSI for at least 
two years following vaccination. Previous cluster-randomized, open label, uncontrolled trials in 
Brazil [Petruccioli 2018; Rodrigues 2005; Cunha 2008; Barreto 2011] and a randomized, 
placebo-controlled trial in Malawi [Fine 1996] did not find statistically significant efficacy in the 
per protocol population for the prevention of TB disease following BCG revaccination. 
Differences in populations (no screening for tuberculin skin test [TST] or IFN-γ release assay 
status), age, geography, climate, force of infection and the prevalence of infection with NTM are 
being discussed as potential root causes for the observed differences in VE following BCG 
revaccination. Indeed, 33% (95% CI 4%-53%) VE was observed for the prevention of TB in 
children who were revaccinated before the age of 11 years at one of two Brazilian sites with 
lower NTM prevalence [Barreto 2011]. 
This current study intends to i) confirm that BCG revaccination protects against sustained Mtb 
infection in a larger independent study, ii) assess the duration of protection through 48 months, 
iii) evaluate BCG revaccination in children 10 years of age and above and iv) identify/validate 
biomarkers that correlate with the risk for or protection against transient and/or sustained Mtb 
infection, as assessed by QFT. 
2.3. Benefit/Risk Assessment 
The benefits and risks of BCG vaccination with the Danish BCG Vaccine SSI, manufactured by 
AJ Vaccines, Copenhagen, Denmark, are well documented in the South African package insert. 
The approved AJ Vaccines package insert serves as Reference Safety Information.  
An IDMC will monitor safety data on a regular basis. 

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With regards to BCG vaccination of older children and adolescents, a recent randomized 
controlled trial conducted in South Africa reported that BCG revaccination was well tolerated in 
adolescents 12 to 17 years of age and had a VE against sustained QFT conversion of 45% 
[Nemes 2018]. A population-based case–control study in the United Kingdom (UK) evaluated 
protection against TB following primary BCG vaccination of children aged 12–13 years.VE 
against TB was 51% (95% CI 21, 69%) at 10–15 years after vaccination and 57% (CI 33, 72%) 
at 15–20 years after vaccination [Mangtani 2017]. 
With regards to AEs following vaccination, a local reaction is normal after BCG. A small tender 
red swelling appears at the site of the injection which gradually changes to a small vesicle. An 
ulcer may appear 2 to 4 weeks after vaccination. The reaction usually subsides within two to five 
months and in practically all children leaves a superficial scar 2 – 10 mm in diameter. Transient 
enlargement of the regional lymph nodes (< 1 cm) is normal. Enlargement of axillary lymph 
nodes may be seen less frequently in the months following immunization.  
Suppurative lymphadenitis may occur less frequently. This is a benign condition which heals 
spontaneously, although often only slowly.  
As stated in the BCG vaccine package insert, side-effects include: 
Infections and Infestations  
Less frequent: Osteomyelitis, Suppurative lymphadenitis, Injection site abscess  
Blood and the lymphatic system disorders  
Less frequent: Enlargement of axillary lymph nodes > 1 cm may appear following immunization.  
Inflammation of gland, sometimes with abscesses and release of fluid from the swellings. 
Immune system disorders 
Less frequent: Anaphylactic reaction, Allergic reaction  
Nervous system disorders 
Less frequent: Headache 
Skin and subcutaneous tissue disorders  
Less frequent: Lupus types of reaction and keloid formation may occur.  
Musculoskeletal, connective tissue and bone disorders 
Less frequent: Osteitis  
General disorders and administrative site conditions  
Less frequent: Inadvertent subcutaneous injection produces abscess formation and may lead to 
ugly retracted scars. Disseminated BCG disease may occur, particularly in immuno-suppressed 
individuals.  
Less frequent: Fever, injection site ulceration, injection site discharge. 

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Other side effects  
Less frequent: Several allergic reactions (such as redness of the face and neck, swelling of the 
face, throat or neck, skin rash, breathing difficulties and collapse) can occur. These often start 
very soon after injection.  
Less frequent: Infection with the bacteria in the vaccine (Mycobacterium bovis BCG) can occur, 
that can spread through the body, including to the bones. This does not usually happen in people 
who are otherwise healthy, but it has been reported. These infections need to be treated in a 
similar way to the treatment of TB. 

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3. 
Objectives and Endpoints 
Table 5: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To demonstrate the efficacy of BCG 
revaccination against sustained Mtb 
infection versus placebo in previously 
BCG vaccinated QFT negative, healthy 
adolescents (event-driven analysis) 
• Sustained QFT conversion (at least 118 
events) based on positive QFT test results 
(initial conversion and QFT-positive at 3- 
and 6-months PC) 
Secondary 
• To evaluate the durability of efficacy of 
BCG revaccination against sustained Mtb 
infection versus placebo in previously 
BCG vaccinated, QFT negative, healthy 
adolescents 
• Sustained QFT conversion based on 
positive QFT test results (initial 
conversion and QFT-positive at 3- and 6-
months PC) with a follow-up of 36- and 
48-months post vaccination 
• To evaluate the safety and reactogenicity 
of BCG revaccination in previously BCG 
vaccinated, QFT negative healthy 
adolescents 
• Solicited adverse events (AEs) through 7 
days post vaccination 
• Unsolicited AEs through 28 days post 
vaccination 
• All serious adverse events (SAEs) and 
adverse events of special interest (AESIs) 
through Month 6 
• Serious adverse drug reactions (Serious 
ADRs) through the end of the study 
Exploratory 
• To evaluate the efficacy and durability of 
efficacy of BCG revaccination against 
primary Mtb infection post vaccination 
versus placebo in previously BCG 
vaccinated, QFT negative healthy 
adolescents 
• Primary QFT conversion at the time of 
primary endpoint analysis, and after a 
follow-up of 36- and 48-months post 
vaccination, using an alternative definition 
of conversion as a change in IFN-γ 
concentration from <0.35 IU/mL to ≥4 
IU/mL (initial conversion only)  
• To evaluate the efficacy and durability of 
efficacy of BCG revaccination against 
primary and sustained Mtb infection post 
vaccination versus placebo in previously 
BCG vaccinated, QFT negative healthy 
adolescents, based on alternate QFT IFN-γ 
concentration cut-off values 
• Primary and sustained QFT conversion at 
the time of primary endpoint analysis, and 
after a follow-up of 36- and 48-months 
post vaccination, based on a definition of 
primary and sustained conversions using  
exploratory IFN-γ concentration  threshold 
values  

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Objectives 
Endpoints 
Exploratory, continued… 
• To assess the immunogenicity of BCG 
revaccination 
• Frequency of Mtb-, BCG- and/or non-
tuberculous mycobacteria (NTM)-specific 
cluster of differentiation (CD)4 T cells 
expressing one or more cytokines, e.g., 
IFN-γ, tumor necrosis factor (TNF)-α, 
interleukin (IL)-2 and/or IL-22 by 
intracellular cytokine staining (ICS) 
 
• To describe host attributes and host 
responses to vaccination  
• To describe host attributes and host 
responses following QFT conversion  
• To explore and/or develop candidate 
correlates of risk (CoRs) and correlates of 
protection (CoPs) 
• To detect and describe incident TB disease 
• To characterize Mtb isolates 
• To describe COVID-19 among study 
participants who present with suspected 
COVID-19  
• To describe the serostatus of SARS-CoV-2 
infection  
Endpoints may include: 
• Genetic markers and sequences 
• Transcriptomics and gene expression 
markers 
• Proteomics 
• Antibody analyses 
• Cellular analyses (eg, natural killer cells 
[NK cells], B cells, T cells, myeloid cells) 
• Signs and symptoms of illness, by 
treatment group 
• SARS-CoV-2 nucleic acid amplification 
from nasal or oropharyngeal sample  
• Serological tests for SARS-CoV-2, by 
treatment group 
Refer to Section 7.4 for COVID-19 Pandemic contingency plans. 
 
 

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4. 
Study Design 
Overall Design: 
• Disclosure Statement: This is a randomized, placebo controlled, observer-blind, 
phase IIb study with two arms (BCG vaccine and saline placebo). An IDMC will be 
established to oversee the safety of this study. 
• Intervention model: Participants will be randomly assigned equally to one of two 
groups in parallel for the duration of the study. 
• Intervention Groups: 2 study groups (BCG group and placebo group) will each 
receive a single ID injection: 
o BCG group will receive one dose of BCG vaccine (Bacillus Calmette-Guerin SSI, 
Danish strain 1331, live attenuated 2-8 x 105 cfu in a 0.1mL volume ID injection  
o Placebo group will receive one dose of saline control in a 0.1mL volume ID 
injection 
• Primary Purpose: Intervention (BCG revaccination) is being evaluated for POSI (see 
Section 2.1 and Section 4.1 for details). 
• Masking: Participants, sponsor, investigators, CRO clinical team, laboratory, and 
clinical staff are blinded to intervention (BCG vs placebo) until primary endpoint 
analyses are performed. BCG vaccine recipients and clinical staff at the sites may 
inadvertently become unblinded as soon as a BCG lesion develops. Refer to Section 
6.3.2 for masking details. 
• Number of Participants: Approximately 5625 participants will be screened to enroll 
and randomize 1800 healthy participants 1:1 to receive either a single dose of BCG 
vaccine intradermally or a single dose of normal saline placebo intradermally on Day 
1. Randomization will be stratified by age strata (10-11 years old, 12-14 years old, 
and > 14 years old), sex, study site, and school cluster, to account for expected 
differences in incidence rates. Refer to 6.3.1 for details. 
• A subset of 80 participants (the first 80 10-12-year-old participants who are enrolled 
at the SATVI site) will be included for whole blood ICS analysis to assess frequency 
of Mtb-, BCG- or NTM-specific CD4 T cells expressing one or more cytokines, e.g., 
IFN-γ, TNF-, IL-2 and/or IL-22. 
• Wash-out period: A 70-day wash-out period will be used to identify participants who 
may have been infected with Mtb just prior to or soon after enrollment. Participants 
who convert to QFT positive at Day 71 (or if missed or not feasible, at the next 
feasible visit) will not be asked to return for PC Day 28 and PC Day 84 visits and 
will be excluded from the primary mITT efficacy analysis but will be followed for 
safety and efficacy to End-of-Study.  
• Total duration of study participation: Each participant will remain in the study for a 
minimum of 4 years. Enrollment, originally expected to take place over a 1-year 

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period, will be extended as necessary due to COVID-19 pandemic-related 
restrictions. 
• Refer to Section 7.4 for COVID-19 pandemic contingency plans with regard to 
participant enrollment, and other details. 
• Safety Monitoring: An IDMC will be established to oversee the safety of this study, 
and will also review and monitor the primary and secondary efficacy results. The 
IDMC will review unblinded safety data on a regular basis. During active 
enrollment, the IDMC will meet at least once every three months. Once enrollment is 
complete, the IDMC will meet at least twice a year. The IDMC review will include 
solicited and unsolicited AEs, as well as SAEs and AESIs. The IDMC may request 
additional information, or a pause in recruitment and vaccination, while safety data 
are being evaluated. The IDMC will make a formal recommendation on the 
continued enrollment into the trial after each safety review. Each participant will be 
followed for safety for a minimum of 6 months after vaccination.  
• Study sites: Five or more sites in South Africa will participate in this study. 
• Participants will be asked to consent to extended passive follow-up for TB disease 
(using the National TB Programme electronic TB register) for up to 10 years post 
end of study. 
4.1. Scientific Rationale for Study Design 
The recently published Aeras 404 study evaluated the VE of BCG revaccination in healthy 12 to 
17-year-old HIV-negative participants in South Africa against initial QuantiFERON-TB Gold in 
tube® (QFT-GIT) conversion, a surrogate for primary Mtb infection. The study did not meet its 
primary endpoint but reported 45% VE against sustained QFT-GIT conversion, i.e., initial QFT-
GIT conversion and remaining QFT-GIT positive at 3- and 6-months PC, as a surrogate for 
sustained latent Mtb infection [Nemes 2018]. This finding is encouraging as QFT reversion 
(from QFT-positive to QFT-negative) is thought to be indicative of successful immune control of 
the initial infection, and thus POSI could potentially translate into prevention of disease.  
The current study is designed to confirm the results of the Aeras 404 study in a larger population 
by evaluating whether BCG revaccination confers POSI. Eligible clinical trial participants are 
randomized 1:1 to receive either BCG vaccine or placebo intradermally.  
The study design is observer blinded to enable unbiased assessment of adverse events until a 
BCG lesion develops, thus unblinding the majority of BCG vaccine recipients and the clinical 
team at the sites. Care will be taken to keep the blind for all other staff, including all laboratory 
staff and the sponsor staff. Sponsor staff may become aware of individual treatment assignments 
during the course of data review; however, precautions will be taken to limit exposure of sponsor 
staff to unblinded data. 
Placebo control is used to a) allow unbiased safety assessment and b) to enable demonstration of 
vaccine efficacy for POSI. 
Participants who convert to QFT-positive at Day 71 will be excluded from the modified intention 
to treat efficacy analyses and the per protocol immunogenicity analyses as they may have been 

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infected with Mtb prior to or shortly after revaccination. However, these participants will 
continue study participation with all study procedures through the end of the study. 
The primary endpoint in this study, sustained QFT conversion (initial conversion and QFT-
positive at both 3- and 6-months PC), is the same as the secondary endpoint in the Aeras 404 
study. The intention of our study is to demonstrate VE against POSI with statistical criteria that 
are typically used for pivotal efficacy trials (ie, 90% power, alpha 2.5%).  
The duration of follow-up with semiannual QFT-testing is 4 years, as compared to two years in 
the Aeras 404 study. The longer follow-up will enable us to assess the duration of protection past 
24 months as a secondary objective, and the statistical analysis plan will include duration of 
protection analyses. 
The study intends to enroll adolescents from 10 years of age since the previous trial found that 
approximately half of the adolescents 12 to 17 years of age are already infected with Mtb, as 
assessed by QFT. Since this intervention aims to prevent sustained infection, it would therefore 
be meaningful to implement in an age group in which the majority are uninfected. 
Another secondary endpoint is to evaluate the efficacy and durability of efficacy of BCG 
revaccination against primary Mtb infection post vaccination using an alternative definition of 
conversion as a change in IFN-γ concentration from <0.35 IU/mL to ≥4 IU/mL (initial 
conversion only). In the Aeras 404 study, the QFT-GIT assay was used and a vaccine efficacy of 
~45% was observed for this endpoint.  
The rationale for this end-point is that QFT conversion above this threshold was associated with 
an increased risk of tuberculosis disease in infants and adults [Andrews 2017; Winje 2018, a 
finding that was consistent with predictions from studies in animal models [Andersen 2007]. 
Therefore, this alternative conversion threshold will be evaluated as a secondary exploratory 
objective in this trial. The QFT-GIT assay has limitations as a test for Mtb infection, due to intra-
participant and dynamic variability around the threshold recommended by the manufacturer (Pai, 
2012; Mazurek et al, 2010). QFT-GIT assay variability appears maximal in low burden settings 
with low rates of Mtb infection. Findings from high TB burden settings with high risk of Mtb 
infection, such as South Africa, where the rate of QFT-GIT conversion is similar to the expected 
rate of TST conversion, are in contrast to the pattern observed in serial testing of low risk study 
populations, where the rate of QFT-GIT conversion has been unexpectedly high compared to 
TST [Pai 2012; Zwerling 2013].  
In this current study the QuantiFERON®-TB-Gold-Plus assay (QFT) will be used, which is the 
updated version of the QFT-GIT assay. 
Optimum use of QFT conversion as a surrogate for Mtb infection, and potentially as a correlate 
of risk for progression to disease, requires further exploration of the effect of alternative QFT 
conversion thresholds in multiple populations and in high and low burden countries. For 
example, it has been shown that individuals who had a change in QFT-GIT IFN- values from 
less than 0.2 to greater than 0.7 IU/mL had 10-fold higher tuberculosis incidence rates than those 
who maintained values less than 0.2 IU/mL over 2 years (P = 0.0003). By contrast, “uncertain” 
converters, with at least one of serial QFT-GIT results between 0.2 and 0.7 IU/mL, were not at 

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higher risk than nonconverters (P = 0.229; Nemes, 2018). Therefore, other conversion thresholds 
will be evaluated as exploratory objectives, similar to Nemes et al. 
4.2. Justification for Dose 
The BCG vaccine is licensed in South Africa. The dosage used in this study is the same as that of 
the licensed vaccine.  
4.3. End of Study Definition 
A participant is considered to have completed the study if he/she completes the final visit at 
Month 48. The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial. 
The primary endpoint is reached when at least 118 participants have converted from a negative 
to positive QFT result, sustaining positivity for at least 6 months post initial conversion. The 
study will continue after the primary endpoint has been reached, and will conclude when all 
participants have completed the Month 48 visit, or discontinued the study. Participants with an 
initial conversion at Month 48 will not be evaluated for sustained conversion. 
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 and schools with known high burden of TB 
transmission and disease. Good participatory practices will be followed and site staff will work 
closely with community organizations, community leaders, parent organizations, teachers and 
school and Department of Education officials. 
Various methods of recruitment may be used, such as community and classroom 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. 

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5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age:  
1. ≥ 10 years and ≤ 18 years on Study Day 1 
Health and Medical Characteristics: 
2. General good health, confirmed by medical history and physical examination 
3. Vaccinated with BCG at least 5 years ago, documented through medical history or by 
presence of healed BCG scar 
4. Tests QFT negative at screening 
5. For female participants: not pregnant and agrees to avoid pregnancy throughout the first 12 
months of the study. Women physically capable of pregnancy must agree to use an 
acceptable method of avoiding pregnancy during this period. Acceptable methods of 
avoiding pregnancy include sexual abstinence (not engaging in sexual intercourse), a 
confirmed sterile partner, or at least 2 contraception methods from the following list: male 
or female condom, diaphragm, intrauterine devices (IUDs), hormonal contraceptive (oral, 
injection, transdermal patch, or implant). Refer to Appendix 3, Section 10.3, for details.  
Specific Additional Requirements: 
6. Agrees to stay in contact with the study site for the duration of the study, provide updated 
contact information as necessary, and has no current plans to move from the study area for 
the duration of the study 
Informed Consent: 
7. Capable of giving signed informed consent/assent as described in Appendix 1, Section 
10.1.4 and completes the written informed consent/assent process. 
5.2. Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions and History: 
8. Acute illness on Study Day 1 (refer to Section 5.4 for additional details). NOTE: This is a 
temporary exclusion for which the subject may be re-evaluated. 
9. Body temperature 37.5C on Study Day 1 (refer to Section 5.4 for additional details). 
NOTE: This is a temporary exclusion for which the subject may be re-evaluated. 
10. History or evidence of any clinically significant disease, including severe eczema and severe 
asthma, or any acute or chronic illness that might affect the safety, immunogenicity, or 
efficacy of study vaccine in the opinion of the investigator  
11. 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 
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12. History of autoimmune disease  
13. History or evidence of active TB disease  
14. History or laboratory evidence of any past or present possible immunodeficiency state 
including, but not limited to, any laboratory indication of HIV-1 infection 
15. History of allergic disease that is likely to be exacerbated by any component of the study 
vaccine 
Prior/Concomitant Therapy  
16. History of treatment for active TB disease or history of latent Mtb infection 
17. Received a TST within 6 months prior to Study Day 1 
18. Received immunosuppressive treatment, e.g., chemotherapy, biologics or radiation therapy, 
or used immunosuppressive medication (daily steroid equivalent of ≥5mg prednisone) 
within 42 days before Study Day 1. Inhaled and topical corticosteroids are permitted.  
19. Received immunoglobulin or blood products within 42 days before Study Day 1 
20. Planned administration/administration of a licensed vaccine in the period starting 28 days 
before and ending 28 days after Study Day 1  
Prior/Concurrent Clinical Study Experience 
21. Received investigational TB vaccine at any time prior to Study Day 1  
22. Received any investigational drug therapy or investigational vaccine within 180 days before 
Study Day 1, or planned participation in any other clinical trial using investigational product 
during the study period 
Diagnostic assessments 
23. Laboratory values from the most recent blood collected prior to randomization outside the 
normal range that are suggestive of a disease state. Grade 1 abnormalities (as per DAIDS 
toxicity table version 2.1) do not lead to exclusion if the investigator considers them not 
clinically significant: 
24. 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 
Other Exclusions 
25. 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. 
26. Child in Care* 
27. Female participants currently pregnant or lactating/nursing; or positive serum pregnancy test 
during screening or on Day 1, prior to vaccination, or planning a pregnancy within the first 
12 months after study intervention. Refer to Appendix 3, Section 10.3 for details. 

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*Child in Care is 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 who is cared for by foster parents or living in a care home or institution, provided that the 
arrangements falls 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. The definition of a child in care does 
include a child who is cared for by family members – other than parents – who have not gone 
through formal legal adoption/guardian processes. 
5.3. Lifestyle Considerations 
No restrictions are required. 
5.4. 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, and any AE or SAE from the time 
of consent. 
Screening assessments can be done at any time during the screening interval, except for the 
written informed consent, which must be completed prior to any screening procedure. 
If a participant presents with an acute illness (e.g., elevated temperature, acute respiratory or 
gastrointestinal illness, UTI) or an abnormal urinalysis (e.g., due to menstruation or urinary tract 
infection), repeat procedures, with the exception of blood collection (unless allowed as described 
in section 8), may be performed as long as they are completed within the screening window. 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. Study Intervention(s) Administered 
Two interventions will be used in this study: participants will receive either BCG vaccine or 
placebo intradermally. On Study Day 1, study participants will receive their injection after 
randomization and baseline immunology blood collection and other required assessments are 
performed. 
Participants randomized to the BCG group will receive a single 0.1mL volume of BCG vaccine, 
administered intradermally in the deltoid region of the upper arm. Participants randomized to the 
Control group will receive a single 0.1 mL volume of normal saline, administered intradermally 
in deltoid region of the upper arm. 

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Table 6: Study Interventions 
 
BCG licensed Vaccine  
Control 
Intervention Name 
BCG vaccine SSI 
Normal saline 
Unit Dose Strength(s) 
2 to 8 x 105 cfu  
normal saline (0.9% NaCl) 
Dosage Volume 
0.1 mL, single injection 
0.1 mL, single injection  
Route of Administration ID injection  
ID injection  
6.1.1. 
BCG Vaccine  
The BCG vaccine used in this study, Danish BCG vaccine SSI, is manufactured by AJ Vaccines, 
Copenhagen, Denmark. The vaccine is registered and distributed in South Africa by the Biovac 
Institute (15 Alexandra Road, Pinelands, Cape Town), for prevention of TB in children and 
adults, and is included in their national immunization program. The AJ Vaccine’s BCG vaccine 
is the licensed SSI BCG Danish 1331 vaccine.  
The BCG Vaccine SSI is supplied as a freeze-dried (lyophilized) powder containing live 
attenuated M. bovis BCG, Danish BCG strain 1331 and sodium glutamate stabilizer. The vaccine 
powder, which is in an amber vial, is white and crystalline.  
The vaccine is commercially supplied as a pack of 10 vials. Each vial contains 2-8 million 
colony forming units of BCG, to be reconstituted with 1mL of the diluent, diluted Sauton SSI, to 
derive 10 adult doses of 0.1mL each. 
The diluted Sauton SSI diluent contains magnesium sulfate, heptahydrate, dipotassium 
phosphate, citric acid monohydrate, L-asparagine monohydrate, ferric ammonium citrate and 
glycerol 85%, and water for injections.  
The diluent is in a clear vial and is a clear, colorless solution without visible particles. The 
diluent is also supplied by the Biovac Institute in South Africa and commercially supplied as a 
pack of 10 vials.  
6.1.2. 
Placebo  
The placebo control is normal saline, 0.9% NaCl, as commercially available for injection in 
South Africa. A volume of 0.1mL of normal saline is administered intradermally.  
6.1.3. 
Administration  
Administration procedures for the BCG vaccine are found in the package insert. The placebo 
control will be administered in the same manner. The placebo will be administered intradermally 
into the deltoid region of the upper arm using standard technique and a fine short needle with a 
short bevel (25 G/0,50 mm or 26 G/0,45 mm). BCG is slightly opaque compared to the 
transparent saline placebo. 
The unblinded investigational pharmacist will provide BCG and placebo to the clinic as unit-
dose syringes with a masking label, which will be identified with the participant identification 

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number, date and time of dose preparation, and the volume prepared. An investigator (ie, 
physician) must be present in the clinic at the time of administration.  
Before administering the injection, the study intervention administrator must inspect the syringe, 
checking that the syringe is identified with the correct participant identification number and 
checking the date and time the dose was prepared. 
6.2. Preparation/Handling/Storage/Accountability 
Further guidance and information for the preparation, handling, storage and accountability are 
provided in the Study Reference Manual. 
Refer to 6.1.1 for preparing the BCG vaccine for administration. Vaccine will be prepared as per 
the manufacturer’s recommendations by the study pharmacist. All of the participating sites have 
investigational pharmacies and will use an unblinded pharmacist. Once the vaccine is prepared, 
the pharmacist will cover the vaccine syringe content with a blinding label so that the clinical 
staff remains blinded. Vaccine will NOT be administered by the study pharmacist. 
Placebo will be prepared as in Section 6.1.2. 
BCG must be stored at 2°C to 8°C in a secured location with no access for unauthorized 
personnel. Reconstituted vaccine may be kept at 2°C to 8°C for up to 6 hours in the original vial. 
Exposure to light should be kept to a minimum. Any reconstituted vaccine not used within six 
hours must be discarded. 
The saline placebo will be stored in a secured location at 2°C to 8°C in the study pharmacy.  
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 unblinded investigational pharmacist 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.  

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6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization  
Participants will be randomized to one of two interventions (BCG 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 age strata (10-11 years old, 12-14 years old, and > 14 years old), sex, study site, and 
school cluster, to account for expected differences in incidence rates.  
To minimize risk of study failure by maximizing consistency of study assumptions with 
available literature data, the overall proportion of patients randomized in the youngest age strata 
(10-11 years old), and outside the Western Cape Province will be actively monitored and capped 
at approximately 10% and 20% of the randomized study population, respectively. 
6.3.2. 
Masking 
The study will be conducted as an observer blind study until the primary endpoint has been 
reached and primary endpoint analyses are completed. While the study is blinded, sponsor staff 
may become aware of individual treatment assignments during the course of data review, 
however, precautions will be taken to limit exposure of sponsor staff to unblinded data. 
Following completion of primary endpoint analyses, the study team will be unblinded but 
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.  
Unblinded study personnel must not participate in the evaluation of adverse events. 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. 

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After primary endpoint analyses are completed – likely more than two years after completion of 
enrollment– the study will be unblinded to CRO staff and the sponsor to reduce the complexity 
of statistical analyses for IDMC and other data reviews. Site staff, laboratory staff, and 
participants will remain blinded. 
Because of the unique local reaction to BCG vaccination, the site staff and participant will 
become aware of study intervention allocation if and when a BCG lesion develops.  
6.3.3. 
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, during the observer-blind period (prior to completion of primary 
endpoint analyses), the sponsor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation and case 
report form (CRF), as applicable. 
6.4. Study Intervention Compliance 
Participant compliance with study intervention will be recorded on his/her CRF. 
6.5. Concomitant Therapy 
Any prescription medication, anti-inflammatory drugs and antipyretic drugs*, or vaccine that the 
participant receives from enrollment through study Day 71 must be recorded 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 (Day 1 through Day 28). 
Information regarding all immunosuppressant therapy/medications and any TB medication 
(curative or preventive) will be collected through the last study visit.  
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6. Dose Modification 
There are no dose modification specifications.  
All participants will receive either 1 dose (injection) of BCG or 1 dose of placebo as described in 
Section 6.1. 

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6.7. 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 and COVID-19 Contingency Plans 
Refer to Section 7.4, COVID-19 Contingency Plans for details regarding study pause due to 
COVID-19. 
7.1. Discontinuation of Study Intervention 
This is a single dose study. Therefore, there is no plan to discontinue a participant from any 
additional doses.  
7.1.1. 
Pausing Rules for 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. 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 BCG vaccination by the investigator 
3. 20% of participants and at least ten participants experience a Grade 3 or higher event 
related to BCG vaccination, as judged by the investigator, with the exception of 
expected local BCG reactions or local injection site reactions that decrease to < 
Grade 3 within 48 hours. 
If an investigator observes that pausing rule 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 rule 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 at the same time. 
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 is met, the sponsor will notify all study 
investigators and the IDMC members of the pause in enrollment as soon as possible and within 

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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. 
7.2. Participant Discontinuation/Withdrawal from the Study 
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 possible, a discontinuation visit should be scheduled for any participant who wishes to 
discontinue or withdraw from the study. At this visit, topics around subject safety as well as the 
use of already collected biospecimens will be discussed. 
The time and reason for withdrawal should be noted in the space provided for this purpose in the 
CRF. Participants who are withdrawn because of occurrence of AE should be clearly 
distinguished from participants who are withdrawn for other reasons. Participants who are 
withdrawn will be followed up for an AE until the event resolves or stabilizes.  
Refer to Appendix 1, Section 10.1.4 regarding the informed consent process. 
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 and the CRF. 
A participant may, at the investigator’s discretion, be withdrawn from the study if any one of the 
below conditions apply. If not withdrawn, participants with the below conditions will be 
followed as described in the protocol, including all required blood draws. 
• Development of active TB or receipt of curative anti-tuberculous therapy 
• Development of autoimmune disease or immunosuppression, or an AE of special 
interest  
• Receipt of investigational drug therapy or investigational vaccine (other than study 
injection) 
No replacements are planned for the withdrawals in the study. 

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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). 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit. 
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. COVID-19 Contingency Plans 
7.4.1. 
Rationale and Plan 
The Coronavirus Disease 2019 (COVID-19) pandemic has impacted the world since the 
beginning of 2020, severely affecting people and societies around the globe. 
This study was paused for enrollment by the sponsor, effective 19 March 2020, in order to 
support social distancing and to help health care professionals address COVID-19.  
At the time of the enrollment pause, 349 participants had received investigational product (BCG 
or placebo) and were on-study. 
The Government of South Africa declared a National Disaster on 15 March 2020 and ordered a 
first lockdown (stay-at-home order) on 26 March 2020. Under the lockdown, most trial 
participants are not able to come to the investigational site for protocol-specified visits. The 
sponsor and investigators therefore needed to change study procedures and agreed on telephone 
contacts as an alternative to study visits for safety assessments, for the duration of the 
Government restrictions, and/or risks that prevent in-person study visits, as judged by the site PI. 
In accordance with the SAHPRA Policy on Conduct of Clinical Trials of Health Products during 
the Current COVID-19 Pandemic, issued 25 March 2020, this protocol amendment reflects the 
new and modified processes that were put in place in response to COVID-19. This protocol 
amendment, therefore, accommodates the changes related to the pandemic that needed to take 
place in order to continue the study in a manner that minimizes any immediate hazards, and also 
allows for more flexibility to capture study endpoints, and adds an assessment of SARS-CoV-2 
infection and COVID-19 disease. 

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Changes in study visit procedures, missed visits, and participant discontinuations may lead to 
missing information (e.g., for protocol-specified procedures). We will capture as much 
information as possible in the case report form and explain the basis of the missing data.  
Approaches used to protect trial participants and to manage study conduct during the COVID-19 
pandemic, as well as control measures at study sites, will be documented.  
Protocol deviations due to the COVID-19 pandemic 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., alternative procedures used to collect critical safety and/or 
efficacy data) on the safety and efficacy results reported for the study.  
Study aspects affected by the study pause due to the COVID-19 pandemic are addressed in the 
following subsections.  
7.4.2. 
Enrollment of new participants and status of previously enrolled participants 
Enrollment was paused by the sponsor effective 19 March 2020 due to COVID-19 and will only 
resume once IRBs, investigators and the Sponsor agree that it is acceptable to resume study 
enrollment.  
Many of the 349 participants on-study at the time of the lockdown will miss study visits and 
blood draws. A subset of these participants may not be eligible for inclusion in the primary 
endpoint analyses. In order to meet the primary study objective, the final sample size will be 
determined and documented once enrollment has resumed and we can understand the impact of 
the pause on the ability to address the primary objectives. The total randomized population may 
increase to a maximum of 2150 participants.  
Participants who were screened but not randomized because the study was paused prior to 
randomization will be offered re-screening when enrollment resumes. Re-screening will also be 
allowed for any participant who screen-fails due to potential future COVID-19-related 
restrictions to movement or enrollment.  
Participants who are offered re-screening due to COVID-19 will be assigned a new participant 
identifier (PID), and the new PID will be linked to the previously used PID to avoid double 
counting of the total number and percent failure of screened participants. Information collected 
from the re-screening will become the source information to be used to determine eligibility.  
Extension of the estimated duration of enrollment (and therefore the overall estimated duration 
of the trial) will be required since the study was paused. 

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7.4.3. 
Study visits for enrolled subjects  
The preference for study follow-up is to maintain in person study visits when it is acceptable and 
feasible to do so. Alternatively, follow-up visits can be performed by phone or another type of 
remote contact and will be captured in a consistent manner within the CRFs. 
When participants are able to return to the site for onsite visits, they may be asked to complete 
visit assessments and procedures at a time point that is not specified in the protocol, in order to 
collect missing data and to perform missed procedures (e.g., blood draw or diary card collection). 
Once in-person visits become feasible, investigators will need to assess what visit the participant 
should be assigned to, based on guidelines in Table 7.  
Refer to Section 7.4.5, regarding impact on mITT cohort for efficacy. 
Table 7: Guidance for visits missed due to COVID-19-related restrictions, once in-person 
study visits become feasible 
Screening visit  Re-screening will be allowed if participants were unable to attend the Day 1 study 
visit due to COVID-19 restrictions or if they were previously screened but not 
randomized before the study was paused due to the COVID-19 pandemic. 
Day 8 visit 
If the interval between Day 1 and Day 8 visits is longer than 11 days, the PI will 
decide whether to invite the participant for a late Day 8 visit or wait until the date of 
a later scheduled visit (e.g., Day 29, Day 71, or Month 6, etc.). Participants should 
be seen sooner rather than later, to ensure appropriate safety follow-up. 
At that visit, investigators will collect data for the missed Day 8 visit, if possible. 
For example, the diary card should be collected, and data entered into the Day 8 
visit CRF form with the actual diary card collection date.  
Day 29 visit  
If the interval between Day 1 and Day 29 visit is longer than 35 days, the PI will 
decide whether to invite the participant for a late Day 29 visit or wait until the date 
of a later scheduled visit (e.g., Day 71, Month 6, etc.). Participants should be seen 
sooner rather than later, to ensure appropriate safety follow-up. 
At that visit, investigators will collect data for the missed Day 29 visit, if possible. 
For example, the memory aid should be collected, and data entered into the Day 29 
visit CRF form with the actual memory aid collection date. The Day 29 blood draw 
should not be performed if the visit occurs after Day 35.  
Day 71 visit 
If the Day 71 visit was missed, the visit will be scheduled as soon as possible, in 
order to obtain the blood sample that determines eligibility of the mITT cohort 
(see Section 7.4.5). The Day 71 blood draw should be performed, regardless of 
when the Day 71 visit occurs. 
Month 6 visit 
and later visits 
If the Month 6 visit or later visits are missed, the participant should be seen soon 
after in-person study visits become feasible. At that visit, investigators will collect 
data for missed visits, if possible. 

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7.4.4. 
Addition of exploratory objectives and endpoints related to COVID-19 
The following exploratory objectives were added:  
• To describe COVID-19 among study participants who present with suspected COVID-19  
• To describe the serostatus of SARS-CoV-2 infection.  
7.4.4.1. Serology for COVID-19  
In order to describe the penetrance of SARS-CoV-2 infection in the communities that participate 
in this study, SARS-CoV-2 serology will be performed once every six months for a duration of 
24 months. For enrolled participants, serology will be done on a blood sample drawn at the 
earliest possible study visit (e.g., the Month 6 or Month 12 visit, etc.) and at four subsequent 
biannual study visits.  
For participants who are screened after SAHPRA and ethics committee approval of the Gates 
MRI-TBV01-201 Amendment Version 5, a blood sample will be collected at the screening visit, 
and at the Month 6, 12, 18 and Month 24 visits.  
7.4.4.2. Diagnostic test for SARS-CoV-2  
In order to describe signs and symptoms of COVID-19 among the study population, a diagnostic 
test for SARS-CoV-2 (based on nucleic acid amplification) will be performed if a participant 
presents with suspected COVID-19 (e.g., respiratory or febrile illness, anosmia, etc.). Signs and 
symptoms of illness are described as per investigator assessment (e.g., temperature, respiratory 
rate, oxygen saturation, medication, etc.). 
A nasal or oropharyngeal sample will be obtained (e.g., swab, brush, scraping, or saliva) for the 
COVID-19 diagnostic test. 
7.4.5. 
Changes to the definition of the mITT cohort for efficacy 
Protocol version 4 (prior to COVID-19) defined a 70-day “wash-out” period to identify 
participants who may have been infected with Mtb just prior to or soon after enrollment and 
stated that participants who convert to QFT positive at Day 71 would be excluded from the 
primary mITT efficacy analysis.  
Because of COVID-19, most of the study participants enrolled less than 70 days prior to the 
pause on March 19, 2020, missed or will miss their Day 71 visit. The amended protocol, Version 
5, defines that participants who missed their Day 71 visit may be eligible for inclusion in the 
mITT cohort if they test QFT-negative, and are excluded from the mITT cohort if they test QFT-
positive, at the first study visit after the COVID-19 related pause is lifted (e.g., late Day 71 visit 
or Month 6 visit). The mITT analysis will take the duration of follow-up after the QFT-negative 
test into consideration for the primary analysis. 
The impact on data eligibility for certain protocol-defined analyses (e.g., mITT analysis) will be 
addressed in the Statistical Analysis Plan (SAP). Clear rules for how data obtained during out-of-
window study visits will be used in endpoint analyses will be defined in the SAP. 

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7.4.6. 
Protocol deviations related to COVID-19  
Tracking of all protocol deviations related to COVID-19 will be done proactively by sites and all 
parties involved. Deviations may include delayed participant visits, missed assessments, etc. Site 
staff will clearly document all COVID-19-related deviations in detail in participant source 
documentation, as well as in annotations in the EDC system, to ensure clarity for statistical 
analyses and clinical study reporting. 
7.4.7. 
Informed consent and re-consent 
Participants who were enrolled into the study will be re-consented/assented into the study so that 
they are aware of the protocol changes. 
Newly screened participants will be asked to sign the current consent/assent form which captures 
applicable protocol changes.  
7.4.8. 
Safety precautions for trial staff after enrollment resumes  
Principal Investigators and site personnel have a critical role in the conduct of the study to ensure 
safety of the trial participants and site staff. The sponsor, clinical research organizations, and 
principal investigators should adhere to applicable guidelines on measures to control 
transmission of COVID-19. Investigators and site staff should develop and implement site-
specific procedures and processes as appropriate.  
7.4.9. 
References 
South African Clinical Research Association (SACRA) Clinical Trials Suggested Business 
Continuity Plan_COVID-19_Version 1; 16 March 2020. 
SAHPRA Policy on Conduct of Clinical Trials of Health Products During the Current COVID-
19 Pandemic; 25 March 2020 (adapted from: FDA’s Guidance on Conduct of Clinical Trials of 
Medicinal Products During the COVID-19 Pandemic;18 March 2020). 
8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
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. Screening assessments can be done at any time during the period, except for the 
written informed consent, which must be completed prior to any screening procedure. Eligibility 
for randomization will be based on the inclusion and exclusion criteria described in Sections 5.1 
and 5.2. 
Eligibility criteria will be checked during the screening process and prior to vaccine/placebo 
administration to ensure that all participants enrolled meet all of the inclusion criteria and none 

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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, medical history, physical examination including vital signs, and 
height and weight will be performed. In addition, safety laboratory tests (hematology, chemistry, 
and urinalysis) as well as a QFT TB test, HIV test, and a serum pregnancy test (females only) 
will be performed.  
Repeat collection and testing 
Note that if a blood sample collected for screening cannot be evaluated (e.g., insufficient 
volume; damaged, hemolytic or lost sample, etc.) a second (repeat) blood collection is permitted 
to enable evaluation of study eligibility.  
The repeat blood collection must occur within the protocol-defined screening visit window. If a 
screening blood sample was successfully run and has a reported result to determine eligibility, a 
second (repeat) blood collection is not permitted. 
A second sample for urinalysis may also be repeated if the screening sample is unevaluable or if 
it is abnormal due to menstruation or suspected urinary tract infection. Urinary tract infection 
should be resolved prior to the repeat urinalysis and the repeat test must be performed during the 
screening interval. If repeat urinalysis is abnormal, participant will be a screen failure.  
In addition, if the blood sample for QFT collected at any time point after screening is 
unevaluable, collection of a second (repeat) blood sample is also permitted to enable evaluation 
of the primary efficacy endpoint. The repeat blood collection must occur within the protocol-
defined visit window.  
If the QFT sample was successfully run and has a reported result, including “indeterminate”, 
collection of a second (repeat) blood sample is not permitted. 
Details regarding these procedures are provided in the subsections to follow.  
If a planned study visit or planned study procedure (e.g., blood draw) cannot be performed 
because the participant has an acute illness or cannot access the study site (refer to Section 7.4 
for COVID-19 related restrictions), the missed visit should be rescheduled as soon as feasible. 
Unscheduled visits should only take place as necessary and data from unscheduled study visits 
should be captured in the EDC.  
The investigator must document confirmation of eligibility prior to randomization.  
8.1. Efficacy Assessments 
8.1.1. 
Evaluation of initial Mtb infection and sustained infection 
Mtb infection is defined for this protocol as QFT conversion from a negative to positive test, 
as per the manufacturer’s QFT-GIT package insert.  
Sustained Mtb infection is defined for this protocol as sustained QFT conversion from a negative 
to positive test, with initial conversion at any time after a first negative QFT result, post 

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randomization (Day 71 or subsequent visit if Day 71 result is not available), and remaining QFT-
positive at 3- and 6-months PC. 
QFT assays will be performed on blood samples collected from all participants at screening, 
at the Day 71 visit (end of the wash-out period), and every 6 months (counting from Day 1) 
through Month 48. In addition, participants who have QFT conversion will have one 
additional QFT assay done three months PC.  
An additional exploratory endpoint will be to evaluate alternative threshold values for QFT 
conversion. 
Details on these endpoint cut-off values will be included in the statistical analysis plan. 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.  
Safety outcomes will include: 
• Solicited AEs (including local injection site pain, redness, and swelling, and general 
AEs (headache, fatigue, gastrointestinal symptoms, and fever). 
• Unsolicited AEs  
• All SAEs 
• Vaccination-related SAEs (serious ADRs). 
AEs will be collected from the time informed consent is obtained. 
Refer to Appendix 2, Section 10.2 for details regarding AEs and SAEs. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness.  
Adherence to the study protocol, including those specified in the SoA, is essential and required 
for study conduct. 
8.2.1. 
Physical Examination and Medical History  
A medical history and physical examination will be conducted at screening to assess enrollment 
eligibility. Medical history will include questions regarding acute respiratory illness, febrile 
illness, and anosmia, e.g., due to SARS-CoV-2, influenza, or other respiratory agents.  
Only participants that are considered as healthy by the investigator will be enrolled. 
Medical conditions that exist prior to the screening visit 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, 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. 

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Height and body weight will be measured at screening, Day 1, and every six months thereafter.  
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. Interim medical 
history will also include questions regarding acute respiratory illness, febrile illness, anosmia, 
etc, e.g., due to SARS-CoV-2, influenza, or other respiratory agents.  
8.2.2. 
Pregnancy Status Assessment and Follow-Up 
A serum βHCG test will be performed at screening, and a urine βHCG test will be performed at 
Day 1 (prior to enrollment) and any time during the study if a pregnancy is suspected.  
During the study, participants will be asked about pregnancy at each time point indicated in the 
SoA (Section 1.3). 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 Appendix 3, Section 10.3. 
If a participant becomes pregnant during the study, she may continue in the study at the 
investigator’s discretion. If she continues study participation, she will be followed for all safety 
assessments, but no blood will be collected for the study during pregnancy. Once the pregnancy 
has ended, only blood draws for QFT and HIV tests are allowed. 
 
A participant who becomes pregnant during the study will be followed during the gestation 
period, and after the delivery to collect information on the health of the participant and the 
newborn. Details of the pregnancy will be collected (refer to Section 10.3, Collection and 
Reporting Pregnancy Information). If delivery occurs after the final study visit, the investigator 
should attempt to maintain contact with the participant to obtain the information. 
8.2.3. 
Pre- and Post-Study Intervention Safety Monitoring 
On Day 1, 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, participants will be given a diary card and receive guidance on how to fill in the card. 
Participants will also receive a digital thermometer. 
The diary card will be used by the study participants or parent or guardian/LAR to record the 
duration and intensity (Grade 1, 2, 3, or 4) of solicited local and general AEs for 7 days 
following vaccination. The diary card will also allow for unsolicited AEs to be recorded. 

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The diary card will be collected and reviewed by the PI (or designee) on Day 8. 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, as applicable. Any participant-reported Grade 4 event 
will be assessed by the investigator. 
A memory aid will be distributed to the participant at the Day 8 visit and the participant will be 
instructed to record unsolicited adverse events using the aid. The memory aid will be collected at 
the Day 29 visit.  
8.2.5. 
Clinical Safety Laboratory Assessments  
Safety laboratory assessments will be performed at screening. Refer to the SoA Section Table 2. 
Laboratory values from the most recent blood sample collected prior to randomization outside 
the normal range that are suggestive of a disease state (ie, 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 Appendix 5, Section 10.5 for toxicity table for grading for each laboratory test.  
Grade 1 abnormalities will not lead to exclusion if the investigator does not consider them 
clinically significant.  
Clinical safety laboratory parameters that will be evaluated at screening include: 
• Hematology: Complete blood count (hemoglobin, platelets and white blood cells) 
and absolute counts for neutrophils, lymphocytes, and monocytes 
• Serum chemistry: ALT, AST, alkaline phosphatase, total bilirubin, creatinine, blood 
urea nitrogen (BUN)  
• Urinalysis: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase by dipstick. 
Refer to Repeat Collection and Testing in Section 8 for unevaluable blood samples. 
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.  
All screening laboratory specimens will be processed according to laboratory SOPs available 
from the clinical laboratory(ies) designated for the study. 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. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition. 

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All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SoA. 
If laboratory values from non-protocol specified laboratory assessments require a change in 
participant management or are considered clinically significant by the investigator (eg, 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 South Africa (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. 
Injection Site Examination 
A local reaction is normal after BCG. Site of injection examinations will be performed from Day 
8 through Month 6 to evaluate the observed local reactions. As stated in the BCG SSI vaccine 
package insert (South Africa): 
• A small tender red swelling appears at the site of the injection which gradually 
changes to a small vesicle. An ulcer may appear 2 to 4 weeks after vaccination. An 
adherent dressing is not recommended.  
• The reaction usually subsides within two to five months and in practically all 
children leaves a superficial scar 2 – 10 mm in diameter.  
• Transient enlargement of the regional lymph nodes (< 1 cm) is normal.  
• Enlargement of axillary lymph nodes may be seen less frequently in the months 
following immunisation. Suppurative lymphadenitis may occur less frequently. This 
is a benign condition which heals spontaneously, although often only slowly.  
The presence and maximum diameter of injection site reactions will be recorded as follows:  
• Redness, swelling, or induration ≤20 mm is considered as anticipated. 
• Redness, swelling, or induration >20 mm is reported as an AE. 
• Papule, vesicle, pustule, ulcer, or scar ≤5 mm is considered as anticipated. 
• Papule, vesicle, pustule, ulcer, or scar >5 mm is reported as an AE. 
The presence and maximum diameter of homolateral axillary lymph nodes larger than 1 cm will 
be recorded. 
8.2.7. 
Participant Follow-Up 
Participants will be instructed to contact a study team member to report new or worsening AEs, 
as well as new diagnoses, and to come to the study clinic if medical attention is needed. 
For emergencies and other unscheduled visits to a medical facility other than the study clinic, 
medical records will, to the extent possible, be obtained by the investigator. 

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For participants who attend school, study visits will be scheduled outside of school hours 
whenever possible. Participants will be asked about the occurrence of AEs and SAEs, 
concomitant prescription medications/vaccinations, and change in general health status and any 
other change in status that may affect the participant’s participation, as indicated in the SoA. 
An HIV blood sample will be collected for HIV testing at screening and again yearly, with pre-
and post-test HIV counseling. HIV counseling will be performed by study staff. In addition, any 
participant suspected of having TB disease (see Section 8.3.6) will be tested for HIV at the time 
of diagnosis or as soon as possible following suspicion of TB disease.  
All deviations from protocol procedures, evaluations, and/or visits will be documented.  
8.3. Adverse Events and Serious Adverse Events 
The definitions of AEs, SAEs, serious ADRs, SUSARs, and adverse events of special interest 
(AESIs) can be found in Appendix 2, Section 10.2.1, and 10.2.2, 10.2.3, 10.2.4, 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. 
SAEs that the investigator assessed as related to vaccination will be collected throughout the 
study. 
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 AEs that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Type of Event 
Collection Time Period 
All solicited AEs  
Day 1 through Day 7 (inclusive) 
Unsolicited AEs  
Screening through Day 28 (inclusive)* 
All SAEs and AESIs 
Screening through Month 6* 
Serious ADRs 
Day 1 through the end of the study  
*Refer to the SoA, Section 1.3 for collection of AEs from time of signed consent. 
Distribution and collection days for diary cards are shown in the SoA (Section 1.3). 

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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. 
All SAEs and AESIs will be reported to the sponsor or designee within 24 hours, as indicated in 
Appendix 2, Section 10.2.6. The investigator will submit any updated SAE data to the sponsor or 
designees within 24 hours of it being available. 
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 2, 
Section 10.2.5, 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 Appendix 2, Section 10.2.5. 
8.3.3.1. AE Intensity 
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 2, 
Section 10.2.5.1 and Appendix 5 for details. Note that a body temperature between 37.5°C and 
37.9°C, can be captured as an AE, at the PI’s discretion.  
8.3.3.2. AE Causality 
All AEs will be evaluated by the PI or medically qualified designee (ie, 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, or 
related to not related. 

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Refer to Appendix 2, Section 10.2.5.2 for details. Expectedness of AEs is defined in Appendix 2, 
Section 10.2.5.3. 
8.3.3.3. AE Resolution 
All AEs/SAEs must be followed until resolution. Refer to Appendix 2, Section 10.2.5.4 for 
details. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Refer to Appendix 2, Section 10.2.6 for details regarding SAE reporting. 
For the purposes of regulatory reporting, this study will be conducted like a post-marketing 
study, as the product used is a marketed product approved in the country. 
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. 
All fatal and life-threatening SUSARs are to be reported to South African Health Products 
Regulatory Authority (SAHPRA) within 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. 
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 CRO will be maintained by the site. The PI will notify the IRB/IEC, if 
appropriate and according to local requirements. IRB/IEC submissions will be conducted per the 
local IRB/IEC SOP.  
The sponsor will prepare, distribute and submit SUSAR reports according to local regulatory 
requirements. The CRO, on behalf of the sponsor will submit the SUSAR reports to SAHPRA. 
Refer to Appendix 2, Section 10.2.6 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. 

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8.3.6. 
Latent TB infection and TB disease 
Participants in this trial will be managed according to current national and/or international 
guidelines, in accordance with ethical standards. A recent international guideline (Latent 
tuberculosis infection. Updated and consolidated guidelines for programmatic management. 
[WHO, 2018b]) recommends that in countries with a high TB incidence, children aged ≥ 5 years, 
adolescents and adults who are household contacts of people with bacteriologically confirmed 
pulmonary TB who are found not to have active TB may be given preventive therapy 
(Conditional recommendation, low-quality evidence. New recommendation). Household contact 
is used in this context as a proxy for possible Mtb infection, and associated risk for progression 
to TB disease, in countries where testing for infection is not routine. 
This trial will test adolescent participants for sustained Mtb infection using the QFT assay. Since 
it would be illogical to offer preventive therapy based on household contact status when serial 
QFT results are available, all participants with sustained QFT conversion will either be referred 
for TB preventive therapy (TPT) regardless of whether or not they are household contacts of a 
confirmed TB case, or be offered TPT by the site. Participants with transient QFT conversion, 
i.e., participants who’s initial QFT positive result reverts to negative within 6 months, will not be 
referred for preventive therapy. 
All participants who are QFT positive (from screening throughout study period) will be educated 
on the symptoms of TB and the benefits of early diagnosis and treatment.  
Active surveillance for signs and symptoms compatible with incident TB disease, e.g., cough, 
fever, fatigue or night sweats, for longer than two weeks, or loss of weight / insufficient weight 
gain or growth, will continue throughout the study.  
Participants with suspected TB disease will be tested for HIV infection and will be asked to 
provide two sputum samples or other appropriate samples for smear microscopy, mycobacterial 
culture, and GeneXpert. 
Participants with a microbiological, radiological, and/or clinical diagnosis of TB disease will be 
referred to the NTP for TB treatment which is provided free of charge by the NTP. 
A bacteriologically confirmed case of active TB disease will be defined as clinical evidence of 
TB with positive Mtb mycobacteria growth indicator tube culture, or GeneXpert MTB/rifampicin 
(Cepheid, USA), from sputum or an extra-pulmonary site. 
A clinical case of active TB disease will be defined as clinical and/or radiographic evidence of 
active TB disease that is not bacteriologically confirmed. 
8.4. Treatment of Overdose 
If a dosing error occurs, the investigator, safety physician and medical monitor need to be 
informed as soon as possible. 
8.5. Pharmacokinetics 
PK parameters are not evaluated in this vaccine study. 

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8.6. Pharmacodynamics 
Pharmacodynamic parameters (other than characterization of the immune response to 
vaccination) are not evaluated in this vaccine study. 
8.7. Genetics  
Germline genetic information may be assessed to aid in the interpretation of study results related 
to the host response to BCG vaccination and to Mtb infection. Germline genetic analyses may 
include HLA typing, Fc receptor and NK cell genotyping, and assessment of other genetic 
information that may influence vaccine-induced and infection-induced responses, as well as 
susceptibility to infectious diseases. Germline genetic information will not be used for analyses 
related to paternity, ancestry or hereditary diseases. See Appendix 4, Section 10.4 regarding 
information for use and analysis of DNA samples. 
8.8. Biomarkers 
Collection and analyses of blood samples for biomarker research and identification of potential 
correlates of risk for and correlates of protection from sustained Mtb infection is an essential part 
of this study. Analytic approaches for the exploratory endpoints below will be informed by best 
practice and the most recent advances in biomarker discovery and systems biology. 
Exploratory analyses of host characteristics, as well as host responses following vaccination, that 
correlate with the risk of transient and/or sustained QFT conversion will be conducted. Specific 
objectives and hypotheses related to these analyses will be documented and reported in a 
separate scientific and statistical analysis plan, prior to full unblinding of data associated with 
these exploratory analyses. 
Exploratory endpoints may include proteomics, antibody analyses and cellular analyses (eg, NK 
cells, B cells, T cells), as well as candidate CoP and CoR identified in other studies. 
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 1.3 for specific time points and volumes for collection of samples. If an effect of 
vaccination is seen on infection with Mtb, immunologic assays may be conducted to search for 
correlates of risk or protection. Functional assays such as mycobacterial growth inhibition may 
also be conducted.  
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 relating the 
prevention of initial and sustained QFT conversion. 
Biomarkers studies using DNA-sequencing technologies such as Assay for Transposase-
Accessible Chromatin with high throughput Sequencing (ATAC-seq) may be used to identify 
accessible chromatin sequences from small cell numbers, e.g., PBMCs, to generate epigenomic 
profiles of immune cells. Histone modification and other epigenetic modifications that are 
potentially affected by vaccination and/or Mtb infection may be analyzed. These genetic and 

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epigenetic studies aim to identify correlates of risk and correlates of protection for Mtb infection, 
for sustained Mtb infection, and TB disease. If any CoRs or CoPs are identified in other studies, 
validity of such correlates may be tested using data from this this study. 
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 tuberculosis research 
and TB vaccine research, including studies that pertain to the improvement, development and 
quality assurance of the lab tests described in this protocol. Such future research is subject to 
laws and regulations of South Africa and is subject to IRB/IEC approval.  
Refer to Appendix 4, Section 10.4 regarding use/analysis of DNA.  
8.8.1. 
Immunological Assessments  
Immunological outcomes may include ICS on PBMC and whole blood, phenotyping of cell 
subsets by flow cytometry, transcriptomics and genetic or epigenetics studies using RNA and/or 
DNA extracted from whole blood or white blood cells, and quantification of soluble immune 
mediators by multiplex assays. 
The assessment of immune responses to vaccine may include the frequency of Mtb-, BCG- 
and/or NTM-specific CD4 T cells positive for markers such as IFN-γ, TNF-, IL-2 and/or IL-22. 
Responses will be measured by flow cytometry in the ICS assay.  
Antibody titers against BCG may also be measured using ELISA, multiplex assays or functional 
assays (eg, mycobacterial killing assays etc). 
8.8.2. 
Subset Assessment 
For a subset of the first 80 10- to 12-year-old participants enrolled at the SATVI site, ICS will be 
performed directly ex vivo after stimulation of whole blood. Site staff will use the Study 
Reference Manual (provided separately) for further instructions and additional information on 
specimen collection and processing. All blood volumes in the table are approximate. 
Note that the type of assays performed will be based on the most current information available at 
the time of analysis.  
8.9. Health Economics 
This section is not applicable. 
9. 
Statistical Considerations 

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9.1. Statistical Hypotheses 
Primary: Revaccination with BCG reduces the risk of sustained Mtb infection versus placebo in 
previously BCG vaccinated, QFT negative healthy adolescents. 
Secondary:   
• Revaccination with BCG reduces the risk of sustained Mtb infection versus placebo in 
previously BCG vaccinated, QFT negative healthy adolescents, with VE durability that 
lasts at least 36 months in all participants. 
• Revaccination with BCG reduces the risk of sustained Mtb infection versus placebo in 
previously BCG vaccinated, QFT negative healthy adolescents, with VE durability that 
lasts 48 months in all participants. 
9.2. Sample Size Determination 
The primary analysis will be triggered when the number of required events to achieve 90% 
power with a 1-sided alpha of 2.5% has been accrued. If the true vaccine efficacy is 45%, at least 
118 sustained QFT conversion events are required for the primary analysis. Additional sample 
size considerations were based on the following assumptions: It will take one year to fully enroll 
the study, 7% of enrolled participants will be ineligible for the mITT efficacy population due to a 
positive QFT assay result at Day 71, an expected 8-10% per year will convert to QFT positive in 
the placebo arm, 70% of initial conversions are expected to remain sustained, 5% on average loss 
to follow-up per year and 45% VE. 
The proposed sample size was determined based on targeting relatively high probability (~80%) 
of obtaining 118 sustained conversion events within 3.5 years of study start. The probability of 
obtaining 118 sustained conversion events within 3 and 3.5 years of study start are shown in 
Table 8 for sample sizes ranging from 600 to 800 in the mITT efficacy population. Due to 
COVID-19 related restrictions, it will take longer to complete enrollment and to reach the 
number of events needed for analyses. After accounting for the expected 7% expected to be 
ineligible for the mITT efficacy population due to a positive QFT assay result at Day 71, the 
table shows that randomizing approximately 800 participants to each treatment group is 
sufficient to detect a true VE of at least 45% under the specified assumptions, resulting in ~80% 
probability to accrue 118 events within 3.5 years of study initiation when the attack rate is as low 
as 8%. Since it is expected that approximately 12% of the population enrolled will be 10- or 11-
year-old adolescents, where there is limited information on the attack rate and potential VE, a 
further inflation of the required 800 participants per group by 12% resulted in a final proposed 
sample size of 900 participants per group, or 1800 participants total. 
Approximately 6720 participants will be screened to enroll and randomize up to 2150 
participants.  

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9.3. Populations for Analyses 
Analysis populations are shown in Table 9. 
Table 9: Populations for Analyses 
Population 
Description 
Modified intention to treat 
(mITT) efficacy 
population 
All participants randomly assigned to study intervention, who 
received the study intervention and are QFT negative at the Day 
71 visit, or if the Day 71 study visit was missed, or the QFT 
result was not available, the first study visit post Day 71 for 
which a QFT result is available. Participants will be analyzed 
according to the intervention to which they were randomized.  
Intention to treat (ITT) 
efficacy population 
All participants randomly assigned to study intervention and who 
received the study intervention. Participants will be analyzed 
according to the intervention to which they were randomized. 
Per Protocol (PP) efficacy 
population 
All participants in the mITT population who did not substantially 
deviate from the protocol procedures and who received the 
treatment to which they were randomized 
Participants who substantially deviated will be identified prior to 
database lock and unblinding. 
 
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.  
9.4. Statistical Analyses 
A detailed statistical analysis plan (SAP) centered on primary and secondary endpoints will be 
developed and finalized prior to initiation of enrollment and will further describe the participant 
populations to be included in each analysis, details of the statistical methods, including 
procedures for accounting for missing, unused, and spurious data. Some exploratory analyses 
may be included in this SAP. Analyses are summarized in Table 10. 
Exploratory endpoint analyses, in particular those centered on immunogenicity and exploratory 
biomarker analyses, will be described in a separate exploratory scientific and statistical analysis 
plan (exploratory SSAP). Specific objectives and hypotheses related to exploratory biomarker 
analyses will be documented in this exploratory SSAP 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).  

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Table 10: Summary of Primary and Secondary Endpoints and Analyses 
Endpoint 
Statistical Analysis  
Primary: 
Sustained QFT conversion based 
on positive QFT test results 
(initial conversion and QFT-
positive at 3- and 6-months PC) 
The primary analysis will be triggered when at least 118 
sustained Mtb infection events in the mITT efficacy 
population are accrued. 
A log-rank test, stratified by sex and age group (10-11 
years old, 12-14 years old, and > 14 years old), will be 
used to evaluate differences in the distributions of event 
times between the BCG vaccination and placebo groups. 
The primary hypothesis will be met if the 1-sided p-value 
associated with evaluating whether the event free 
distribution is longer in the BCG vaccination group relative 
the placebo group is less than or equal to 0.025. Hazard 
ratios and 95% confidence intervals will be estimated using 
a stratified Cox proportional hazards regression model. 
Secondary: 
Sustained QFT conversion based 
on positive QFT test results 
(initial conversion and QFT-
positive at 3- and 6-months PC) 
with a follow-up of 36- and 48-
months post vaccination 
Two durability analyses will be performed, the first after 
all participants have at least 36 months of follow-up and 
the second after all participants have 48 months of follow-
up.  
Log-rank tests, stratified by sex and age group (10-11 years 
old, 12-14 years old, and > 14 years old), will be used to 
evaluate differences in the distributions of event times 
between the BCG vaccination and placebo groups. The 
secondary hypotheses will be met if the 1-sided p-value 
associated with evaluating whether the event free 
distribution is longer in the BCG vaccination group relative 
the placebo group is less than or equal to 0.025. Hazard 
ratios and 95% confidence intervals will be estimated using 
stratified Cox proportional hazards regression models. 

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Endpoint 
Statistical Analysis  
Secondary, continued 
 
Safety endpoints post 
vaccination 
Solicited AEs through 7 days  
Unsolicited AEs through 28 
days  
All SAEs and AESIs through 
Month 6 
Serious ADRs through the end 
of the 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. Summary statistics will be generated for 
raw laboratory safety tests, as well as for changes from 
baseline, as deemed clinically appropriate.  
 
9.4.1. 
Efficacy Analyses 
9.4.1.1. Primary Endpoint Analyses 
The primary efficacy outcome measure is sustained QFT conversion, defined as an initial 
positive QFT test, and sustained positive tests at both 3- and 6-months after primary conversion. 
To assess the vaccine efficacy on this primary endpoint, an event driven analysis will be utilized.  
The primary analysis will occur when at least 118 sustained Mtb infection events occur in the 
mITT efficacy population. If at least 118 sustained QFT conversion events are reached within a 
6- month period prior to all participants completing 36 months of follow up, then the primary 
analysis and the Month 36 secondary endpoint analysis may be combined into a single analysis 
to occur after all participants have completed the Month 36 visit.  
A log-rank test, stratified by sex and age group (10-11 years old, 12-14 years old, and > 14 years 
old), will be used to evaluate differences in the distributions of event times between the BCG 
vaccination and placebo groups. The primary hypothesis will be met if the 1-sided p-value 
associated with evaluating whether the event free distribution is longer in the BCG vaccination 
group relative the placebo group is less than or equal to 0.025. Hazard ratios and 95% confidence 
intervals will be estimated using a Cox proportional hazards regression model, adjusting for sex 
and age group. 
9.4.1.2. Secondary and Exploratory Efficacy Endpoint Analyses 
To address the secondary objectives (sustained QFT conversion based on positive QFT test 
results with a follow-up of 36- and 48-months post vaccination), two analyses will be performed 
to assess the durability of efficacy against sustained Mtb infection post vaccination. The first 
analysis will be performed subsequent to the initial primary analysis after all participants have at 
least 36 months of follow-up, and the second analysis will be performed subsequent to the initial 
and 36-month analysis, after all participants have 48 months of follow-up. However, as noted 
above, depending on the timing of the sustained conversion events, the 36-month analysis may 
be combined with the primary analysis. 

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Again, stratified log-rank tests will be used to evaluate differences in the distributions of event 
times between the BCG vaccination and placebo groups; and hazard ratios and 95% confidence 
intervals will be estimated from Cox regression models, adjusted for sex and age group.  
If the one-sided p-value after all participants have 36 months of follow-up is less than or equal to 
0.025, durability after all participants have 48 months of follow-up will be assessed. 
As such, durability after all participants have reached 36- and 48-months of follow-up will only 
be concluded if statistically significant differences in event times between the BCG vaccination 
and placebo arms were met at all prior time points evaluated. Failure to meet the primary or 36- 
month durability hypothesis will not result in a formal early stopping of the study. 
Exploratory analyses will be performed similarly using an alternative definition of conversion as 
a change in IFN-γ concentration from <0.35 IU/mL to ≥4 IU/mL. 
Further similar exploratory analyses will be performed for various primary and sustained Mtb 
infection post vaccination endpoints, conversion defined by various exploratory QFT IFN-γ 
concentration thresholds (other than the package-insert defined 0.35 IU/mL value in the QFT 
assay). In addition, similar analyses will be performed using the ITT and PP efficacy populations 
to assess the robustness of results. 
9.4.1.2.1. Multiplicity 
To account for multiple testing, a step-down approach will be utilized to preserve the overall 
Type I error at a one-sided 2.5% for the primary and first secondary hypotheses. Specifically, if 
the one-sided p-value associated with the primary hypothesis of BCG vaccine efficacy relative to 
placebo is less than or equal to 0.025, the durability of the vaccine efficacy after all participants 
have 36 months of follow-up will be formally assessed.  
9.4.2. 
Safety Analyses 
The incidence and 95% confidence intervals of solicited AEs through 7 days post vaccination, 
unsolicited AEs through 28 days post vaccination, all SAEs and AESIs through 6 months post 
vaccination, and related SAEs throughout the entire study duration will be summarized by 
treatment group.  
For all presentations of adverse events, additional summaries based on reporting period of AEs 
following each study vaccination may also be presented.  
The number and percentage of participants with AEs will be summarized by Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT). 
Additional summaries will present the number and percentage of participants with adverse events 
by intensity and by relationship to study vaccine; each participant will be counted once per 
preferred term at the greatest intensity or most related state recorded for that term.  
Separate summaries of the number and percentage of participants with solicited AEs will also be 
presented. Solicited AEs will also be summarized by intensity and relationship to study vaccine; 
each participant will be counted once per preferred term at the greatest intensity or most related 
state recorded for that term.  

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Summary statistics will be generated for raw laboratory safety test results, as well as for changes 
from baseline, as deemed clinically appropriate.  
Depending on the safety parameter, the difference from baseline will either be computed on the 
original scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline).  
Summary statistics for continuous parameters will be presented by treatment regimen for all pre- 
and post-vaccination assessments and for change from pre-vaccination to post-vaccination 
assessments.  
9.4.3. 
Immunogenicity and Exploratory Biomarker Analyses  
9.4.3.1. Immune Response by ICS 
To evaluate the immunogenicity of BCG revaccination, frequency of CD4 T cells positive for 
one or more cytokines, e.g., IFNγ, IL-2, IL-22, and/or TNF-α by ICS, will be summarized by 
treatment group and timepoint. 
Median DMSO-subtracted cytokine responses and associated 95% confidence intervals (CI) or 
other descriptive statistics as appropriate will be used to summarize percentage T cell responses. 
Summaries of T cell response will be presented by T cell type (CD4 and CD8) and by 
stimulation antigen. Summaries will include immune responses at pre- and post-vaccination 
immunology time points, and change from pre-vaccination to post-vaccination time points. 
For the first 80 10-12-year-old participants enrolled at the SATVI site, whole blood ICS will be 
conducted as an immunologic endpoint and will measure the frequencies and patterns of CD4 
and CD8 T cells expressing one or more cytokines following stimulation of whole blood with 
viable BCG from the vaccine vial. Analysis of these results will be performed as outlined above. 
9.4.3.2. Other Exploratory Analyses 
The SARS-CoV-2 serostatus will be summarized overall, as well as by time and treatment group. 
Among participants who present with suspected COVID-19, the proportion of participants with 
positive nucleic acid amplification will be summarized overall and by treatment group. Signs and 
symptoms of disease will be described for each participant. 
Further exploratory analyses related to host characteristics and responses to vaccination and or 
Mtb infection will also be examined. Specific objectives and hypotheses related to these analyses 
will be documented and reported in a separate scientific and statistical analysis plan prior to full 
unblinding and analysis of data associated with these exploratory analyses. 
9.4.4. 
Subgroup Analyses 
The consistency of results with respect to the primary and secondary objectives will be examined 
within various subgroup populations (eg, site, sex, and age group). Details will be provided in 
the SAP.  

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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 will be presented by treatment 
group. 
9.4.6. 
Independent Data Monitoring Committee (IDMC) 
The IDMC will be established to oversee the safety of this study and to review results from the 
primary data analysis (after at least 118 sustained Mtb infection events occur in the mITT 
efficacy population), and the secondary analysis (after all participants have 36 months of follow-
up). Refer to Sections 9.4.1.1 and 9.4.1.2, for primary and secondary endpoint analyses, 
respectively.  
The independent 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.  
During active enrollment, the IDMC will meet at least once every 3 months and ad hoc as 
necessary. Once enrollment is complete, the IDMC will meet at least twice a year and ad hoc as 
necessary. The IDMC review will include solicited and unsolicited AEs, as well as SAEs. 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. 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. 
9.4.7. 
National Regulatory Authority 
SAHPRA receives all expedited safety reports for clinical trials and has the authority to 
terminate, suspend or require changes to a clinical trial. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, and other relevant documents (eg, diary 
cards) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
10.1.2. 
Study Oversight 
The study sponsor, the institution through which the research is performed and all members of 
the PI’s clinical team and the national regulatory authority share responsibility for ensuring the 
safety of participants in this trial. 
The PI will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently, in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH and GCP guidelines, SAHPRA Regulations, the IRB/IEC, and 
all other applicable country and local regulations 
• Closely monitoring study participants and taking whatever measures necessary to 
ensure their safety. The PI may delay an individual’s study vaccine administration or 
pause study vaccine administration altogether if the investigator is concerned that the 
study vaccine might place a participant or participants at significant risk. Where 
specified, the responsibilities of the PI may be delegated to a medically qualified 

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team member (designee). The investigator determines intensity and causality with 
respect to the study vaccine for each AE. 
The sponsor has an institutional responsibility to ensure participant safety and is ultimately 
accountable for safety oversight. Medical monitors and the IDMC play an important role in this 
regard and support the sponsor. 
The Medical Monitor is the sponsor’s representative and is a physician. The Medical Monitor: 
• reviews the safety of the product for protocols in a specific region and, in 
consultation with the sponsor, determines expectedness of AEs.  
• is responsible for safety oversight in-country and plays an important role in the 
reporting of serious ADRs, SAEs, pregnancies, and other important safety 
information, as described in the protocol 
• in consultation with the sponsor, may assess the intensity and causality for AEs and 
may upgrade the degree of intensity and causality determined by the PI or designee 
The Medical Monitor, like the PI, will be blinded until primary endpoint analyses are completed, 
unless emergency unblinding is required.  
The Institutional Review Board or Ethics Committee has institutional responsibility for the safety 
of research participants. The Institutional Review Board or Ethics Committee has the authority to 
terminate, suspend or require changes to a clinical trial. 
The national regulatory authority, SAHPRA, has the authority to terminate, suspend or require 
changes to a clinical trial. 
10.1.3. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.4. 
Informed Consent Process 
Written informed consent and assent will be obtained prior to conducting any study-related 
procedures.  
Participants must be informed that their participation is voluntary. The PI or designee will 
explain the study to the participant and, for participants who are minors, to his/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. 

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10.1.4.1. Informed Consent forms 
Informed consent for study participation  
Participants or parent or guardian/LAR will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center.  
The informed consent form will be obtained by the use of a written informed consent form (ICF) 
approved by the IRB/IEC and signed and dated by the parent or guardian/LAR of participants 
less than 18 years of age. Consent for HIV testing and genetic testing will also be obtained prior 
to enrollment. 
Participants 18 years of age at the time of consent will also be asked to sign a consent form.  
Similarly, informed assent from participants who are 10 to 17 years of age will be obtained by 
the use of a written assent form approved by the IRB/IEC and signed and dated by the participant 
at the time of assent.  
Other consents will be presented to the participant and parent or guardian/LAR which are 
optional and if not signed, would not exclude the participant from the study: 
• Consent for storage and testing of samples for research not described in the protocol.  
• Consent to participant in Extended Follow-up for the National TB Registry. 
A copy of the signed consent and assent forms shall be given to the participant and parent or 
guardian/LAR prior to conducting any study-related procedures. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If there is a change to the ICF during the conduct of the study, participants must be re-consented 
to the most current version of the ICF. Participants who become 18 years of age during the study 
(those who previously signed an assent form) will be asked to sign an informed consent form 
following their 18th birthday. 
Any withdrawal of consent for sample testing will be documented in the CRF. 
If a participant cannot be randomized on the intended day of vaccination (eg, if elevated 
temperature) her/she is not required to sign another ICF, as long as re-screening and vaccination 
occur within the protocol-defined window.  
Laboratory assays for primary and secondary endpoints will be carried out in South Africa. 
Participants will be informed that some of the assays for exploratory endpoints may be carried 
out in laboratories outside South Africa. 
The ICF will 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.  

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Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period.  
All participants will be asked to give specific consent to allow the sponsor (or contract partner) 
to use the samples for future research. Any sample testing will be in line with the consent of the 
participant and/or parent or guardian/LAR. 
Consent will also be requested for extended passive follow-up on the TB registry after end of 
study. 
10.1.5. 
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/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/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. 
10.1.6. 
Dissemination of Clinical Study Data 
Study information from this protocol will be posted on publicly available clinical trials registers 
(clinicaltrials.gov and the South African registry [sanctr.gov.za]) before enrollment of 
participants begins. 
The final study report 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 study report 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 statistical analysis plan. Any decisions to deviate 
from the planned analyses described in the protocol and in the statistical analysis plan will be 
described in detail in the final study report.  
The final clinical study report will be reviewed and approved by the sponsor signatory and the 
PI.  
Summaries of the results of the study will also be posted on the same website. 
10.1.7. 
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 
designee electronically (eg, laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically signing or electronically signing the CRF. 

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The investigator must maintain accurate documentation (Appendix 1, Section 10.1.8) 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 (eg, 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, 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. 
10.1.8. 
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. 
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.  
For the purpose of monitoring and auditing the study, source documentation will consist of 
existing medical records and/or study records developed and maintained by the investigator. 
10.1.9. 
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 
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. 

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• 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.  
 
10.2.5.1. 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, as defined in Appendix 5 Section 10.5:  
Note that a body temperature between 37.5°C and 37.9°C, can be captured as an AE, at the 
PI’s discretion. 
• 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. 
10.2.5.2. Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• An AE/SAE is considered related to study intervention if there is a reasonable 
possibility that the study intervention contributed to the AE. 
• Not-related means there is no reasonable possibility that the AE is causally related to 
administration of the study intervention. There are other more likely causes for the AE.  
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 

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• 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:  
o Protocol number and name and contact number of the investigator 
o Participant ID number (and initials and date of birth, if available) 
o Date participant received study vaccine 
o SAE term and date of event onset  
o Current status of SAE. 
• The investigator is responsible for expedited safety report submission to the Sponsor 
delegate and the Sponsor delegate reports 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.  
• All fatal and life-threatening 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. Other 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, IRB/IEC and other relevant parties. Any follow-up report will be sent 
with the same timelines.  
• 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). 
• Contacts for SAE reporting and for all safety personnel are contained in the Team 
Contact List which will be stored on site in the Site Regulatory Binder and maintained 
by the study sponsor. 
• Refer to Section 1.3 for the reporting schema. 

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10.3. 
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions: 
Female of Childbearing Potential (FOCBP) 
A female is considered fertile following menarche. If fertility is uncertain (eg, 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 
o 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 study intervention.  
Acceptable methods of avoiding pregnancy include:  
• sexual abstinence (not engaging in sexual intercourse)  
• a confirmed sterile partner 
OR at least 2 of the below contraceptive methods: 
• hormonal contraceptives (oral, injection, transdermal patch, or implant),  
• IUD 
• male or female condom 
• diaphragm. 
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.  

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• The health status of the mother and child, the date of delivery, and the child’s sex, birth 
weight and parity 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 will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs. AE and SAE reporting periods apply as specified in Section 8.3.1. 
• 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.  
10.4. 
Appendix 4: Genetics 
Use/Analysis of DNA 
o Genetic variation may impact a participant’s response to study intervention, susceptibility 
to infection, progression to disease and severity of disease. Variable response to study 
intervention may be due to genetic determinants that impact vaccine responses. Therefore, 
where local regulations and IRB/IEC allow, a blood sample may be used for genetic 
analyses, from participants with a valid consent for genetic analyses only. 
o Germline genetic analyses may include HLA typing, Fc receptor and NK cell genotyping, 
and assessment of other genetic information that may influence vaccine-induced and 
infection-induced responses, as well as susceptibility to infectious diseases. Germline 
genetic information will not be used for analyses related to paternity, ancestry or hereditary 
diseases. 
o The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand study disease or related conditions. 
o The results of genetic analyses may be reported in the CSR or in a separate study summary. 
o The sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 

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10.5. 
Appendix 5: 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  

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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 

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11. 
References 
Andersen P, Doherty T, Pai M, et al. The prognosis of latent tuberculosis: can disease be 
predicted? TRENDS in Mol Med. 2007;13(5):175-82.  
Andrews J, Nemes E, Tameris M, et al. Serial QuantiFERON testing and tuberculosis disease 
risk among young children: an observational cohort study. Lancet Respir Med. 2017;4:282-290. 
doi: 10.1016/S2213-2600(17)30060-7. 
Bottiger M, de Verdier C, Lind A, et al. A comparative study of Danish (Statens Seruminstitut), 
Glaxo and Behringwerke vaccines--revaccination of schoolchildren. J Biological Standardization 
1983;11:1-12. 
Barreto ML, Pereira SM, Pilger D, et al. Evidence of an effect of BCG revaccination on 
incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC 
cluster-randomised trial. Vaccine. 2011;29(31):4875-7. doi: 10.1016/j. PMID 21616115 
Cunha SS, Alexander N, Barreto ML, et al. BCG Revaccination Does Not Protect Against 
Leprosy in the Brazilian Amazon: A Cluster Randomised Trial. PLoS Negl Trop Dis. 
2008;2(2):e167. doi:10.1371/journal.pntd. PMID 18270542 
Fine P, Clayton, D, Colston M, et al (Karonga Prevention Trial Group). Randomised controlled 
trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine 
for prevention of leprosy and tuberculosis in Malawi. Lancet. 1996;348(9019);17-24. 
DOI:https://doi.org/10.1016/S0140-6736(96)02166-6. PMID 8691924 
Machingaidze S, Verver S, Mulenga H, et al. Predictive value of recent QuantiFERON 
conversion for tuberculosis disease in adolescents. Am J Respir Crit Care Med 2012;186:1051-6. 
Mahomed H, Hawkridge T, Verver S, et al. The tuberculin skin test versus QuantiFERON TB 
Gold in predicting tuberculosis disease in an adolescent cohort study in South Africa. PLoS One 
2011;6(3):e17984. 
Mangtani, P; Nguipdop-Djomo, P; Keogh, et al. The duration of protection of school-aged BCG 
vaccination in England: a population-based case-control study. Inter. J of epidemiol 
2017;47(1):193-201. ISSN 0300-5771 DOI: https://doi.org/10.1093/ije/dyx141 
Mazurek G, Jereb J, Vernon A, et. al.Updated Guidelines for Using Interferon Gamma Release 
Assays to Detect Mycobacterium tuberculosis Infection --- United States, 2010 
Recommendations and Reports. MMWR 2010;59(RR05):1-25. 
Nemes E, H. Geldenhuys, V. Rozot, KT, et al. Prevention of M. tuberculosis Infection with 
H4:IC31 Vaccine or BCG Revaccination. N Engl J Med 2018;379:138-49. 
Pai M. Serial testing with TB interferon-gamma release assays: toward a nuanced 
understanding. Chest 2012;142:1366-1367.  
Pereira SM, Barreto ML, Pilger D, Cruz AA, Sant'Anna C, et al. Effectiveness and cost 
effectiveness of first BCG vaccination against tuberculosis in school-age children without 
previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial. Lancet Infect Dis 
2012;12:300-306.  

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Petruccioli E, Chiacchio T, Vanini V. Effect of therapy on Quantiferon-Plus response in patients 
with active and latent tuberculosis infection. Sci Rep. 2018;8(1):15626. 
Rodrigues LC, Pereira SM, Cunha SS, Genser B, et al. Effect of BCG revaccination on incidence 
of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomized trial. 
Lancet 2005;366:1290-95. PMID 16214599. 
WHO. Global Tuberculosis Report 2018. Geneva:World Health Organization, 2018. 
WHO. Latent tuberculosis infection. Updated and consolidated guidelines for programmatic 
management. World Health Organization. 2018b. WHO/CDS/TB/2018.4. 
https://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/ 
Winje B, White R, Syre H, et al. Stratification by interferon-γ release assay level predicts risk of 
incident TB. Thorax. 2018;Apr 5. pii: thoraxjnl-2017-211147. doi: 10.1136/thoraxjnl-2017-
211147. 
Zwerling A, Benedetti A, Cojocariu M, McIntosh F, Pietrangelo F, et al. Repeat IGRA testing in 
Canadian health workers: conversions or unexplained variability? PLoS One. 2013;8:e54748. 
 

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12. 
Version History 
Versions prior to study start 
Pre-IRB review: 
• Version 1: 14 Feb 2019 
• Version 2: 21-Feb-2019: Minor change from Version 1: added grade 4 to Sections 8.2.4 
and 8.3.3.1 to align with Appendix 2) 
• Version 3: 27-Feb-2019: minor change from Version 2: Randomization will be stratified 
by age strata (10-11 years old, 12-14 years old, and > 14 years old), sex, study site, and 
school cluster (SATVI site only)(if participants are students) or area of residence for 
non-students), to account for expected differences in incidence rates  
Post IRB reviews: 
• Version 4: 25 June 2019: Changes from Version 3 include (new text indicated here by 
bold, italics):  
o Throughout protocol: Revised unblinding to occur after completion of primary 
endpoint analyses.  
o SoA and Section 8.2.1: Added that height and body weight will be measured at 
Day 1 and every six months thereafter 
o  SoA and Section 8.2.6: Removed Day 1 injection site examination (edited: Site 
of injection examinations will be performed from Day 8 through Month 6). 
o Section 4.1, Scientific Rationale for Study Design: Added text for clarity 
regarding blinding: Care will be taken to keep the blind for all other staff, 
including all laboratory staff and the sponsor staff. Sponsor staff may become 
aware of individual treatment assignments during the course of data review, 
however, precautions will be taken to limit exposure of sponsor staff to 
unblinded data. 
o Section 5.2: Clarified exclusion criterion #25 by adding text: Shared residence 
with an individual who is receiving TB treatment or with someone who is known 
to have incompletely treated TB, e.g., PCR-positive, culture-positive, smear-
positive, or clinically diagnosed unconfirmed TB. 
o Section 5.2: Clarified exclusion criterion #26 by adding text to clarify child in 
care definition – Child in care is defined as … 
The definition of a child in care does include a child cared for by family 
members - other than parents - who have not gone through formal legal 
adoption/guardian processes. 
o Section 6.1.3, Administration: Edited for clarity regarding blinding: 
Administration procedures for the BCG vaccine are found in the package insert. 

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The placebo control will be administered in the same manner in this observer 
blind study… The unblinded investigational pharmacist will provide BCG and 
placebo to the clinic as unit-dose syringes with a masking label, which will be 
identified with… . Before administering the injection, the study intervention 
administrator must inspect the syringe, and vaccine volume, checking that the 
syringe…. 
o Section 6.2, Preparation/Handling/Storage/Accountability., Clarified as follows: 
Vaccine will be prepared and administered as per the manufacturer’s 
recommendations by the study pharmacist from multi-dose vials and dispensed 
according to the package insert.  
The saline placebo will be stored in a secured location at room temperature or 2°C 
to 8°C in the study pharmacy.  
o Section 6.3.2, Masking text was updated to reflect unblinding and to reflect that 
sponsor staff may also become aware of individual treatment assignments during 
the course of data review. by adding text: The study will be conducted as an 
observer blind study until the primary endpoint has been reached and primary 
endpoint analyses are completed. While the study is blinded, sponsor staff may 
become aware of individual treatment assignments during the course of data 
review, however, precautions will be taken to limit exposure of sponsor staff to 
unblinded data. Following completion of primary endpoint analyses, the study 
team will be unblinded but laboratory staff will remain blinded until all 
laboratory studies have been completed. . meaning neither the clinical study 
team, laboratory staff, sponsor, CRO staff, nor participants will know the 
treatment allocation (BCG or placebo) administered on Day 1.  
Added this sentence to indicate approximate timeframe for completion of primary 
endpoint analyses: After primary endpoint analyses are completed – likely more 
than two years after completion of enrollment - the study will be unblinded to 
reduce the complexity of statistical analyses for IDMC and other data reviews. 
o Section 6.3.3. Blind Break: edited sentence for clarity by adding text: If a 
participant’s treatment assignment is unblinded, during the observer-blind period 
(prior to completion of primary endpoint analyses), the sponsor must be notified 
within 24 hours after breaking the blind. 
o Section 8.1.1. Evaluation of infection: deleted text since it does not represent the 
processing of the QFT samples as agreed with our central lab, BARC: The QFT 
assay will be run in a central laboratory. The initial incubations will be performed 
at the clinical sites using a well defined procedure. QFT tubes will be centrifuged 
at the site after incubation, plasma will be transferred to vials and frozen before 
being shipped to the central laboratory. 
o Section 8.2.5, Clinical Safety Lab Assessments: Removed analysis of red blood 
cells, eosinophils and basophils and removed testing at local laboratories (all 
safety analyses will be performed at the central laboratory). Edited the text: If 
laboratory values from non-protocol specified laboratory assessments performed 

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at the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (eg, 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 South Africa (BARC SA or 
similar). Local laboratory results are only required in the event that the central 
laboratory results are not available in time for either study intervention 
administration and/or response evaluation. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the 
CRF. 
o  Section 8.2.6, Site of Injection site examination: reworded for clarity: These 
reactions will be recorded as expected AEs. The presence and maximum 
diameter of injection site swelling, vesicle, ulcer and/or scar will be 
recorded.The presence and maximum diameter of homolateral axillary lymph 
nodes larger than 1cm will be recorded. 
o Section 8.2.7, Participant follow-up, edited text for clarity: An HIV blood sample 
will be collected for HIV testing at screening and again yearly, with pre-and post-
test HIV counseling. HIV counseling will be performed by study staff. In 
addition, any participant diagnosed with TB disease (see Section 8.3.6) will be 
tested for HIV 8 weeks after the at the time of diagnosis or as soon as possible 
following diagnosis of TB disease.  
o Section 8.3.1, Table Time period for Collecting AE and SAE information: deleted 
row injection site examination since that is not applicable here. 
o  Section 8.8, Biomarkers: edited for clarity: Specific objectives and hypotheses 
related to these analyses will be documented and reported in a separate scientific 
and statistical analysis plan, prior to data full unblinding of data associated with 
these exploratory analyses. 
o  Section 9.4.3.2 Other Exploratory Analyses: Specific objectives and hypotheses 
related to these analyses will be documented and reported in a separate scientific 
and statistical analysis plan prior to data full unblinding and analysis of data 
associated with these exploratory analyses. 
o Section 10.1.2 Study Oversight: Edited for clarity: The Medical Monitor, like the 
PI, will be blinded until primary endpoint analyses are completed, unless 
emergency unblinding is required.  
o Section 10.1.6, Dissemination of Clinical Study Data: Edited for clarity based on 
change to unblinding The database will be locked prior to unblinding and 
preparation of the final study report when all of the above data have been entered, 
reviewed, and all queries related to the data have been addressed. 

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o Section 10.2.6 SAEs, AESIs, and Serious ADR Reporting, Other Events 
Requiring Immediate Reporting: The investigator must report the following 
events by scanning and emailing, eCRF entry, or faxing the appropriate form to 
the CRO Safety Team within 24 hours of becoming aware of the event 
o Section 10.5 Toxicity table row Cardiac Troponin I, as defined by local laboratory. 
Version 5, 11 May 2020 
Updated protocol to address changes following March 2020 study pause due to COVID-19 
pandemic to allow for flexibility in visits and other COVID-19 related issues. 
Changes from Amendment 4 (first version approved by IRB) to Amendment 5 by 
section 
New text indicated with bold italics 
1. Title page and signature page: Amendment Version 4 changed to Version 5 
Added text NOTE: This study was paused for screening and randomization by the 
sponsor, effective 19 March 2020, due to the Coronavirus Disease 2019 (COVID-19) 
pandemic. Refer to Section 7.4, COVID-19 Contingency Plans for details regarding 
study pause due to COVID-19. 
2. List of abbreviations added COVID-19, PCR test, SARS-CoV-2, SUSAR, and corrected 
GMRI from Gates Foundation to Bill and Melinda Gates 
3. Synopsis 1.1 and Section 3: edited as follows: 
Rationale (synopsis only): edited text : …post conversion [PC]) (Nemes, 2018).  
Then throughout document, replaced post conversion with PC. 
Added two COVID-19 exploratory objectives and 3 endpoints as shown: 
Objectives  
Endpoints 
• To describe COVID-19 among 
study participants who present 
with suspected COVID-19  
• To describe the serostatus of 
SARS-CoV-2 infection  
• Signs and symptoms of illness, by 
treatment group 
• SARS-CoV-2 nucleic acid 
amplification from nasal or 
oropharyngeal sample  
• Serological tests for SARS-CoV-2 by 
treatment group 
4. Added text below table: Refer to Section 7.4 for COVID-19 Pandemic contingency plans. 
5. Synopsis 1.1 and Section 4 Study design-Overall design 
• Total duration of study participation: …Enrollment is originally expected to take 
place over a 1-year period, will be extended as necessary due to COVID-19 
pandemic-related restrictions.  

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11. Section 2.1.1 added section and text 
2.1.1 Rationale for addition of COVID-19 related study objectives 
The Government of South Africa declared the COVID-19 pandemic a National 
Disaster on 15 March 2020 and the Sponsor of this study issued a pause for 
enrollment on 17 March 2020, effective 19 March 2020.  
The Government of South Africa subsequently ordered a lockdown (stay-at-home 
order) for three weeks on 26 March 2020 and subsequently extended it for an 
additional two weeks, through the end of April, 2020. Under the lockdown, most trial 
participants are not able to come to the investigational site for protocol-specified visits.  
Since 1 May 2020, South Africa has employed a system of alert levels at the provincial 
and, in some cases, the district level. Criteria based on the rate of infection as well as 
health system capacity are used by the National Command Council to determine the 
alert level. 
Enrollment into this study can only resume once the Government, local IRBs, 
investigators and the sponsor agree that it is acceptable to resume enrollment. 
Enrollment may also need to be paused again in the future, depending on the COVID-
19 situation at national, province and district level. 
Study investigators and study sites have defined infection control measures for 
COVID-19 that need to be implemented prior to resuming enrollment and are 
consulting with IRBs to determine the conditions that would allow for enrollment to 
continue. 
The study investigators and study sponsor agreed to add two exploratory COVID-19 
endpoints to this study. Firstly, in order to describe COVID-19 among the study 
population, to differentiate COVID-19 from pulmonary TB, and to minimize risks to 
participants and staff, a diagnostic test for SARS-CoV-2 (based on nucleic acid 
amplification) will be performed if a participant presents with suspected COVID-19. A 
description of the frequency and symptomatology of COVID-19 by treatment group is 
of great scientific interest as BCG-induced trained immunity has been hypothesized to 
potentially offer protection from progression to severe COVID-19. BCG vaccination is 
currently being tested as a prophylactic intervention against COVID-19 
(NCT04327206 and additional studies). 
Secondly, to describe the penetrance of SARS-CoV-2 infection in the communities 
that participate in this study, SARS-CoV-2 serology will be performed once every six 
months for a duration of 24 months. This will aid our understanding of virus 
transmission in the communities we work in and may allow a better understanding of 
the frequency of asymptomatic illness. 
12. Section 4 and 1.1:  Study sites: Five Two or more sites in South Africa will participate in 
this study. 
13. Section 4.1 Scientific Rationale for Study Design 

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Participants who convert to QFT-positive at Day 70 71 will be excluded from the modified 
intention to treat efficacy analyses and the per protocol immunogenicity analyses as they may 
have been infected with Mtb prior to or shortly after revaccination. 
14. Section 5.2 Exclusion Criteria 
Medical Conditions and History: 
8.Acute illness on Study Day 1 (refer to Section 5.4 regarding rescreening) 
Other Exclusions 
25. 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. 
15. Section 5.4 Screen failures 
Minimal information includes demography, screen failure details, eligibility criteria, and 
any AE or SAE from the time of consent. 
Rescreening is permitted only if a participant presents with an acute illness (e.g., elevated 
temperature, acute respiratory or gastrointestinal illness, UTI) or an abnormal urine 
analysis due to menstruation. or urinary tract infection), and meets all other 
inclusion/exclusion criteria and is rescreened within the originally defined interval 
screening window (Section 1.3). 
Rescreened Pparticipants who are rescreened within the allowed interval, should be 
assigned the same participant number as for the initial screening. Refer to Appendix 1, 
Section 10.1.4 regarding consent process for rescreened subjects. Refer to Section 7.4.2 for 
rescreening due to COVID-19. 
16. Section 6.2 Preparation/Handling/Storage/Accountability 
Vaccine will be prepared as per the manufacturer’s recommendations by the study 
pharmacist. from multi dose vials and dispensed according to the package insert. All of the 
participating sites have investigational pharmacies and will use an unblinded pharmacist. 
Once the vaccine is prepared, the pharmacist will cover the vaccine syringe content with a 
blinding label so that the clinical staff remains blinded. Vaccine will NOT be administered 
by the study pharmacist. 
BCG must be stored at 2°C to 8°C in a secured location with no access for unauthorized 
personnel. Reconstituted vaccine may be kept at 2°C to 8°C for up to 6 hours in the original 
vial.  
17. Section 6.3 Randomization  
To minimize risk of study failure by maximizing consistency of study assumptions with 
available literature data, the overall proportion of patients randomized in the youngest age 
strata (10-11 years old) and outside the Western Cape Province will be actively monitored 

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and capped at approximately 10% and 20% of the randomized study population, 
respectively. 180 subjects and 360 subjects, respectively. 
18. Section 7 Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal 
Added: Refer to Section 7.4, COVID-19 Contingency Plans for details regarding study 
pause due to COVID-19. 
19. Section 7.1.1 Pausing Rules for Study 
• 2.  1% of the safety population and at least two participants experience an SAE 
judged as related to BCG vaccination by the investigator 
• 3. 20% of participants and at least ten participants experience a Grade 3 or higher 
event related to BCG vaccination study vaccine, as judged by the investigator, with 
the exception of expected local BCG reactions or local injection site reactions that 
decrease to < Grade 3 within 48 hours. 
20. Added Section 7.4 COVID-19 Contingency Plans 
COVID-19 Contingency Plans 
7.4.1 Rationale and Plan 
The Coronavirus Disease 2019 (COVID-19) pandemic has impacted the world since the beginning of 
2020, severely affecting people and societies around the globe. 
This study was paused for enrollment by the sponsor, effective 19 March 2020, in order to support social 
distancing and to help health care professionals address COVID-19.  
At the time of the enrollment pause, 349 participants had received investigational product (BCG or 
placebo) and were on-study. 
The Government of South Africa declared a National Disaster on 15 March 2020 and ordered a first 
lockdown (stay-at-home order) on 26 March 2020. Under the lockdown, most trial participants are not 
able to come to the investigational site for protocol-specified visits. The sponsor and investigators 
therefore needed to change study procedures and agreed on telephone contacts as an alternative to study 
visits for safety assessments, for the duration of the Government restrictions, and/or risks that prevent in-
person study visits, as judged by the site PI. 
In accordance with the SAHPRA Policy on Conduct of Clinical Trials of Health Products During the 
Current COVID-19 Pandemic, issued 25 March 2020, this protocol amendment reflects the new and 
modified processes that were put in place in response to COVID-19. This protocol amendment, therefore,  
accommodates the changes related to the pandemic that needed to take place in order to continue the 
study in a manner that minimizes any immediate hazards, and also allows for more flexibility to capture 
study endpoints, and adds an assessment of SARS-CoV-2 infection and COVID-19 disease. 
Changes in study visit procedures, missed visits, and participant discontinuations may lead to missing 
information (e.g., for protocol-specified procedures). We will capture as much information as possible in 
the case report form and explain the basis of the missing data.  
Approaches used to protect trial participants and to manage study conduct during the COVID-19 
pandemic, as well as control measures at study sites, will be documented.  
Protocol deviations due to the COVID-19 pandemic will be described in the clinical study report (or in a 
separate study-specific document) including but not limited to the following: 

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• 
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., alternative procedures used to collect critical safety and/or efficacy data) on the safety 
and efficacy results reported for the study.  
Study aspects affected by the study pause due to the COVID-19 pandemic are addressed in the following 
subsections.  
7.4.2 Enrollment of new participants and status of previously enrolled participants 
Enrollment was paused by the sponsor effective 19 March 2020 due to COVID-19 and will only resume 
once IRBs, investigators and the Sponsor agree that it is acceptable to resume study enrollment.  
Many of the 349 participants on-study at the time of the lockdown will miss study visits and blood draws. 
A subset of these participants may not be eligible for inclusion in the primary endpoint analyses. In order 
to meet the primary study objective, the final sample size will be determined and documented once 
enrollment has resumed and we can understand the impact of the pause on the ability to address the 
primary objectives. The total randomized population may increase to a maximum of 2150 participants.  
Participants who were screened but not randomized because the study was paused prior to randomization 
will be offered re-screening when enrollment resumes. Re-screening will also be allowed for any 
participant who screen-fails due to potential future COVID-19-related restrictions to movement or 
enrollment.  
Participants who are offered re-screening due to COVID-19 will be assigned a new participant identifier 
(PID), and the new PID will be linked to the previously used PID to avoid double counting of the total 
number and percent failure of screened participants. Information collected from the re-screening will 
become the source information to be used to determine eligibility.  
Extension of the estimated duration of enrollment (and therefore the overall estimated duration of the 
trial) will be required since the study was paused. 
7.4.3 Study visits for enrolled subjects  
The preference for study follow-up is to maintain in person study visits when it is acceptable and feasible 
to do so. Alternatively, follow-up visits can be performed by phone or another type of remote contact and 
will be captured in a consistent manner within the CRFs. 
When participants are able to return to the site for onsite visits, they may be asked to complete visit 
assessments and procedures at a time point that is not specified in the protocol, in order to collect missing 
data and to perform missed procedures (e.g., blood draw or diary card collection). Once in-person visits 
become feasible, investigators will need to assess what visit the participant should be assigned to, based on 
guidelines in Table 7.  
Refer to Section 7.4.5 regarding impact on mITT cohort for efficacy. 
Table 6: Guidance for visits missed due to COVID-19-related restrictions, once in-person study visits 
become feasible 
Screening 
visit  
Re-screening will be allowed if participants were unable to attend the Day 1 study visit 
due to COVID-19 restrictions or if they were previously screened but not randomized 
before the study was paused due to the COVID-19 pandemic. 
Day 8 
visit 
If the interval between Day 1 and Day 8 visits is longer than 11 days, the PI will decide 
whether to invite the participant for a late Day 8 visit or wait until the date of a later 

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scheduled visit (e.g., Day 29, Day 71, or Month 6, etc.). Participants should be seen sooner 
rather than later, to ensure appropriate safety follow-up. 
At that visit, investigators will collect data for the missed Day 8 visit, if possible. For 
example, the diary card should be collected and data entered into the Day 8 visit CRF 
form with the actual diary card collection date.  
Day 29 
visit  
If the interval between Day 1 and Day 29 visit is longer than 35 days, the PI will decide 
whether to invite the participant for a late Day 29 visit or wait until the date of a later 
scheduled visit (e.g., Day 71, Month 6, etc.). Participants should be seen sooner rather 
than later, to ensure appropriate safety follow-up. 
At that visit, investigators will collect data for the missed Day 29 visit, if possible. For 
example, the memory aid should be collected and data entered into the Day 29 visit CRF 
form with the actual memory aid collection date. The Day 29 blood draw should not be 
performed if the visit occurs after Day 35.  
Day 71 
visit 
If the Day 71 visit was missed, the visit will be scheduled as soon as possible, in order to 
obtain the blood sample that determines eligibility of the mITT cohort (see Section 7.4.5). 
The Day 71 blood draw should be performed, regardless of when the Day 71 visit occurs. 
Month 6 
visit and 
later visits 
If the Month 6 visit or later visits are missed, the participant should be seen soon after in-
person study visits become feasible. At that visit, investigators will collect data for missed 
visits, if possible. 
 
7.4.4 Addition of exploratory objectives and endpoints related to COVID-19 
The following exploratory objectives were added:  
• 
To describe COVID-19 among study participants who present with suspected COVID-19  
• 
To describe the serostatus of SARS-CoV-2 infection.  
7.4.4.1 Serology for COVID-19  
In order to describe the penetrance of SARS-CoV-2 infection in the communities that participate in this study, 
SARS-CoV-2 serology will be performed once every six months for a duration of 24 months. For enrolled 
participants, serology will be done on a blood sample drawn at the earliest possible study visit (e.g., the Month 6 
or Month 12 visit, etc.) and at four subsequent biannual study visits.  
For participants who are screened after SAHPRA and ethics committee approval of the Gates MRI-TBV01-201 
Amendment Version 5, a blood sample will be collected at the screening visit, and at the Month 6, 12, 18 and 
Month 24 visits.  
7.4.4.2.Diagnostic test for SARS-CoV-2  
In order to describe signs and symptoms of COVID-19 among the study population, a diagnostic test for SARS-
CoV-2 (based on nucleic acid amplification) will be performed if a participant presents with suspected COVID-19 
( e.g., respiratory or febrile illness, anosmia, etc.). Signs and symptoms of illness are described as per investigator 
assessment (e.g., temperature, respiratory rate, oxygen saturation, medication, etc.). 
A nasal or oropharyngeal sample will be obtained (e.g., swab, brush, scraping, or saliva) for the COVID-19 
diagnostic test. 
7.4.5 Changes to the definition of the mITT cohort for efficacy 

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Protocol version 4 (prior to COVID-19) defined a 70-day “wash-out” period to identify participants who may 
have been infected with Mtb just prior to or soon after enrollment and stated that participants who convert to 
QFT positive at Day 71 would be excluded from the primary mITT efficacy analysis.  
Because of COVID-19, most of the study participants enrolled less than 70 days prior to the pause on March 19, 
2020, missed or will miss their Day 71 visit. The amended protocol, Version 5, defines that participants who 
missed their Day 71 visit may be eligible for inclusion in the mITT cohort if they test QFT-negative, and are 
excluded from the mITT cohort if they test QFT-positive, at the first study visit after the COVID-19 related pause 
is lifted (e.g., late Day 71 visit or Month 6 visit). The mITT analysis will take the duration of follow-up after the 
QFT-negative test into consideration for the primary analysis. 
The impact on data eligibility for certain protocol-defined analyses (e.g., mITT analysis) will be addressed in the 
Statistical Analysis Plan (SAP). Clear rules for how data obtained during out-of-window study visits will be used 
in endpoint analyses will be defined in the SAP. 
7.4.6 Protocol deviations related to COVID-19  
Tracking of all protocol deviations related to COVID-19 will be done proactively by sites and all parties involved. 
Deviations may include delayed participant visits, missed assessments, etc. Site staff will clearly document all 
COVID-19-related deviations in detail in participant source documentation, as well as in annotations in the EDC 
system, to ensure clarity for statistical analyses and clinical study reporting. 
7.4.7 Informed consent and re-consent 
Participants who were enrolled into the study will be re-consented/assented into the study so that they are aware 
of the protocol changes. 
Newly screened participants, will be asked to sign the current consent/assent form which captures applicable 
protocol changes.  
7.4.8 Safety precautions for trial staff after enrollment resumes  
Principal Investigators and site personnel have a critical role in the conduct of the study to ensure safety of the 
trial participants and site staff. The sponsor, clinical research organizations, and principal investigators should 
adhere to applicable guidelines on measures to control transmission of COVID-19. Investigators and site staff 
should develop and implement site-specific procedures and processes as appropriate.  
7.4.9 References 
South African Clinical Research Association (SACRA) Clinical Trials Suggested Business Continuity 
Plan_COVID-19_Version 1; 16 March 2020. 
SAHPRA Policy on Conduct of Clinical Trials of Health Products During the Current COVID-19 Pandemic; 25 
March 2020 (adapted from: FDA’s Guidance on Conduct of Clinical Trials of Medicinal Products During the 
COVID-19 Pandemic;18 March 2020). 
21. Section 8: Study Assessments and Procedures 
To evaluate eligibility criteria, and a medical history, and physical examination including 
vital signs, and height and weight will be performed.  
Added: If a planned study visit or planned study procedure (e.g., blood draw) cannot be 
performed because the participant has an acute illness or cannot access the study site (refer to 
Section 7.4 for COVID-19 related restrictions), the missed visit should be rescheduled as soon 
as feasible. Unscheduled visits should only take place as necessary and data from unscheduled 
study visits should be captured in the EDC.  
22. Section 8.1.1 Evaluation of initial Mtb infection and sustained infection 

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QFT assays will be performed on blood samples collected from all participants at screening, on 
at the Day 71 visit (end of the wash-out period), and every 6 months (counting from Day 1) 
through Month 48. 
23. 8.2 Safety Assessments 
Added: AEs will be collected from the time informed consent is obtained. 
24. 8.2.1 Physical Examination and Medical History  
Added: Medical history will include questions regarding acute respiratory illness, febrile 
illness, and anosmia, e.g., due to SARS-CoV-2, influenza or other respiratory agents.  
All Medical conditions that exist prior to the screening visit administration of study intervention 
will be recorded in the medical history.  
Added: Height and body weight will be measured at screening, Day 1, and every six months 
thereafter.  
25. Section 8.2.1.1 Interim History and Focused Physical Examination 
Added sentence: Interim medical history will also include questions regarding acute 
respiratory illness, febrile illness, anosmia, etc, e.g., due to SARS-CoV-2, influenza or other 
respiratory agents.  
26. Section 8.2.2 Pregnancy Status Assessment 
If a pregnancy occurs after study start, Ddetails of the pregnancy all pregnancies will be 
collected (refer to Section 10.3, Collection and Reporting Pregnancy Information).after the 
start of study intervention and until the end of the study. If delivery occurs after the final study 
visit, the investigator should attempt to maintain contact with the participant to obtain the 
information.  
27. Section 8.2.4 Diary Card and Daily Temperature Monitoring 
On Day 1, participants will be given a diary card and receive guidance on how to fill in the card. 
Participants will also receive a digital thermometer. 
The diary card will be used by the study participants/ or parent or guardian/LAR to record the 
duration and intensity (Grade 1, 2, 3, or 4) of solicited local and general AEs for 7 days 
following vaccination. The diary card will also allow for unsolicited AEs to be recorded. 
The diary card will be collected and reviewed by the PI (or designee) on Day 8. 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, as applicable. Any participant-reported Grade 4 event 
will be assessed by the investigator. 
28. 
Section 8.2.5 Clinical Safety Laboratory Assessments  

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Added: Safety laboratory assessments will be performed at screening. Refer to the SoA Section 
Table 2. 
29. Section 8.2.6 Title of section changed from Site of Injection Examination to Injection Site 
of Examination 
Added: The presence and maximum diameter of injection site reactions will be recorded as 
follows: 
• Redness, swelling, or induration ≤20 mm is considered as anticipated. 
• Redness, swelling, or induration >20 mm is reported as an AE. 
• Papule, vesicle, pustule, ulcer, or scar ≤5 mm is considered as anticipated. 
• Papule, vesicle, pustule, ulcer, or scar >5 mm is reported as an AE. 
This text was formatted in header style and was changed to normal text: The presence and 
maximum diameter of homolateral axillary lymph nodes larger than 1cm will be recorded. 
30. Section 8.3 added SUSARs to first sentence.. The definitions of AEs, SAEs, serious ADRs, 
SUSARs, and adverse events of special interest … 
31. Section 8.3.1 Time Period and Frequency for Collecting AE and SAE Information 
Unsolicited AEs 
Screening through Day 28 (inclusive)* 
All SAEs and AESIs 
Screening through Month 6* 
*Refer to the SoA Section 1.3 for collection of AEs from time of signed consent. 
32. Section 8.3.3.1 AE Intensity 
Added: Section 10.2.5.1 and Appendix 5 for details. Note that a body temperature between 
37.5°C and 37.9°C, can be captured as an AE, at the PI’s discretion. 
33. Section 8.3.4 Regulatory Reporting Requirements for SAEs 
Changed serious ADR to SUSAR 
All fatal and life-threatening serious ADR SUSARs are to be reported to South African Health 
Products Regulatory Authority (SAHPRA) within 7 calendar days after first knowledge with a 
complete report to be submitted within an additional 8 calendar days. Serious ADRs SUSARs 
that are not fatal or life threatening need to be reported to SAHPRA no later than 15 calendar 
days after first knowledge. An investigator who receives a Serious ADRs 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 CRO will be maintained by the site. The PI 
will notify the IRB/IEC, if appropriate and according to local requirements. IRB/IEC 
submissions will be conducted per the local IRB/IEC SOP.  

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The sponsor will prepare, distribute and submit Serious ADRs SUSAR reports according to local 
regulatory requirements. The CRO, on behalf of the sponsor will submit the Serious ADRs 
SUSAR reports to SAHPRA. 
34. Section 8.3.6 Latent TB infection: edited as follows 
Participants in this trial will be managed according to current national and/or international 
guidelines, in accordance with ethical standards. The South African National TB Programme 
(NTP) does not currently recommend preventive therapy for HIV-uninfected adults and children 
older than 5 years of age with asymptomatic (latent) Mtb infection, due to the high risk of 
reinfection after completion of preventive therapy. However, a A recent international guideline 
(Latent tuberculosis infection. Updated and consolidated guidelines for programmatic… 
35. Section 8.4 Treatment of Overdose 
Not applicable If a dosing error occurs, the investigator, safety physician and medical monitor 
need to be informed as soon as possible. 
36. Section 9.2 Sample Size Determination 
Added Due to COVID-19 related restrictions, it will take longer to complete enrollment and to 
reach the number of events needed for analyses. 
Approximately 5625 participants will be screened to enroll and randomize 1800 healthy 
participants 1:1 to either intervention arm.Approximately 6720 participants will be screened to 
enroll and randomize up to 2150 participants.  
Table 6 re-numbered to Table 7. 
37. Section 9.3 Table 7 re-numbered to Table 8.  
Table 8: under Description edited text for mITT and per Protocol: All participants randomly 
assigned to study intervention, who received the study intervention and are QFT negative at the 
Day 71 visit. 
38. Section 9.4 Statistical Analyses 
Table 8 re-numbered to Table 9. 
39. Section 9.4.3.2 Other Exploratory Analyses 
Added 
The SARS-CoV-2 serostatus will be summarized overall, as well as by time and treatment 
group. Among participants who present with suspected COVID-19, the proportion of 
participants with positive nucleic acid amplification will be summarized overall and by 
treatment group. Signs and symptoms of disease will be described for each participant. 
40. Section 10.2.3. 
edited section title: Definition of Serious Adverse Drug Reaction (Serious 
ADR and SUSAR 

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Edited text: When an adverse event is judged to be serious and related to an investigational 
product, it is a serious ADR and is subject to expedited reporting based on the parameters of this 
study. A serious unexpected suspected adverse drug reaction is referred to as a SUSAR. Refer 
to Section 10.2.6 for the different reporting requirements. 
41. Section 10.2.5.1 Assessment of Intensity 
Added: Note that a body temperature between 37.5°C and 37.9°C, can be captured as an AE, 
at the PI’s discretion. 
42. Section 10.2.6.SAEs, AESIs, and Serious ADR, and SUSAR Reporting 
• All fatal and life-threatening adverse drug reactions (ADRs) 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. Serious ADRs Other 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 Serious ADRs 
SUSARs within the same timelines the report is sent to investigators, health authorities, 
IRB/IEC and other relevant parties.  
43. Figure 2 title edited: SAE and Serious ADR SUSAR Reporting Scheme and same change in 
bottom 2 boxes in figure.  
44. Section 10.3 Appendix 3 Contraceptive Guidance and Collection of Pregnancy Information 
Edited:  
• 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. 

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 New version  
Injection Site 
Erythema or 
Redness1 
 Report only one  
> 15 years of 
age  
  
2.1 to < 5 cm 
in diameter  
≥5 to <10 cm in 
max diameter 
   ≥  5    < 100 
cm2 surface 
area OR 
Symptoms  
causing 
greater than 
minimal 
interference 
with usual 
social & 
functional 
activities  
≥ 0                
OR  
 ≥100 cm2 surface 
area  
OR Phlebitis OR  
Sterile abscess OR  
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities  
Potentially 
life-
threatening 
consequences 
(eg, abscess, 
exfoliative 
dermatitis, 
necrosis 
involving 
dermis or 
deeper tissue) 
OR 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness1 Report 
only one  
 
≤ 15 years of 
age  
 .       ≤ 
2.5 cm in 
diameter  
> 2.5 cm in 
diameter with 
< 50% surface 
area of the 
extremity 
segment 
involved (eg, 
upper arm or 
thigh)  
≥ 50% surface area 
of the extremity 
segment involved 
(eg, upper arm or 
thigh) OR Phlebitis 
OR Sterile abscess  
Potentially 
life-
threatening 
consequences 
(eg, abscess, 
exfoliative 
dermatitis, 
necrosis 
involving 
dermis or 
deeper tissue) 
OR 
Hospitalization 
indicated 
 
Note: Minor typos were corrected throughout. 

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 f changed to h and  g changed to i 
Section 5.2 Exclusion criteria:  
8. Acute illness on Study Day 1 (refer to Section 5.4 regarding rescreening for additional 
details). NOTE: This is a temporary exclusion for which the subject may be re-evaluated. 
9. Body temperature 37.5C on Study Day 1 (refer to Section 5.4 for additional details). 
NOTE: This is a temporary exclusion for which the subject may be re-evaluated. 
Section 5.4 Screen Failures 
Rescreening is permitted only if a participant presents with an acute illness (e.g., elevated 
temperature, acute respiratory or gastrointestinal illness, UTI) or an abnormal urine analysis 
(e.g., due to menstruation or urinary tract infection), and meets all other inclusion/exclusion 
criteria and is rescreened within the originally defined interval (Section 1.3). 
Participants who are rescreened within the allowed interval, should be assigned the same 
participant number as for the initial screening. Refer to Appendix 1, Section 10.1.4 regarding 
consent process for rescreened subjects. Refer to Section 7.4.2 for rescreening due to COVID 19. 
Screening assessments can be done at any time during the screening interval, except for the 
written informed consent, which must be completed prior to any screening procedure. 
If a participant presents with an acute illness (e.g., elevated temperature, acute respiratory or 
gastrointestinal illness, UTI) or an abnormal urinalysis (e.g., due to menstruation or urinary 
tract infection), repeat  procedures, with the exception of blood collection (unless allowed as 
described in section 8), may be performed as long as they are completed within the screening 
window. 
Figure 1 Outline of study procedures- screening timepoints corrected to be consistent with SoA 
table (Day -28 to Day 7 corrected to Day -28 to Day -1) 
Section 7. 
Edited the title: Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal and COVID-19 Contingency Plans 
Section 8 Study Assessments and Procedures 
Added: Screening assessments can be done at any time during the period, except for the 
written informed consent, which must be completed prior to any screening procedure. 
Repeat collection and testing 
Note that if a blood sample collected for screening cannot be evaluated (e.g., insufficient 
volume; damaged, hemolytic, or lost sample, etc.) a second (repeat) blood collection is 
permitted to enable evaluation of study eligibility.  
The repeat blood collection must occur within the protocol-defined screening visit window. If a 
screening blood sample was successfully run and has a reported result to determine eligibility, 
a second (repeat) blood collection is not permitted. 
A second sample for urinalysis may also be repeated if the screening sample is unevaluable or 
if it is abnormal due to menstruation or suspected urinary tract infection. Urinary tract 

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infection should be resolved prior to the repeat urinalysis and the repeat test must be 
performed during the screening interval. If repeat urinalysis is abnormal, participant will be a 
screen failure.  
In addition, if the blood sample for QFT collected at any time point after screening is 
unevaluable, collection of a second (repeat) blood sample is also permitted to enable 
evaluation of the primary efficacy endpoint. The repeat blood collection must occur within the 
protocol-defined visit window.  
If the QFT sample was successfully run and has a reported result, including “indeterminate”, 
collection of a second (repeat) blood sample is not permitted. 
Section 8.2.5: Clinical Safety Laboratory Assessments: Added Refer to Repeat Collection and 
Testing in Section 8 for unevaluable blood samples. 
 
Version 7: 21 July 2023 
Refer to high level summary of changes on page 4. 
All changes, including minor changes, are provided in the track changes version.