Open Label, Dose Escalation and Age De-escalation for ChAdOx1 85A in Ugandan Adults and Adolescents, Followed by a Phase IIa Randomised, Open-label Trial Among Adolescents Comparing ChAdOx1 85A Prime Followed by MVA 85A Boost Versus BCG Re-vaccination.
Phase: PHASE1
Conditions: Safety, Immunogenicity
Sponsor: University of Oxford

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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CLINICAL TRIAL PROTOCOL 
 
Trial title:  Open label, dose escalation and age de-escalation for ChAdOx1 85A in Ugandan 
adults and adolescents, followed by a Phase IIa randomised, open-label trial among 
adolescents comparing ChAdOx1 85A prime followed by MVA85A boost versus BCG re-
vaccination 
Short title: EMaBS1 TB Vaccine Study 
 
Trial Reference: TB042 
UVRI/REC Ref: GC/127/17/09/621 
UNCST Ref: HS 2346 
National Drug Authority Ref: CTA0063 
LSHTM Ref: 14598 
OXTREC Ref:  2-18 
Date and Version No: 21st Oct 2020, version 4.1 
 
Chief Investigator: 
Helen McShane 
Principal Investigator:  
Alison Elliott 
Other Investigators:  
Anne Wajja, Pontiano Kaleebu 
Trial Site:  
Entebbe Hospital and MRC/UVRI and LSHTM Uganda Research 
Unit 
Sponsor:  
University of Oxford 
Funder:  
Medical Research Council, UK 
 
 
 
 
                                                          
 
 
1 EMABS: Entebbe Mother and Baby Study 

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Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committees 
and other regulatory bodies. This information cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of Professors 
Helen McShane and Alison Elliott.  
 
Statement of Compliance  
The trial will be conducted in compliance with the protocol, the International Conference on 
Harmonisation Good Clinical Practice Guideline E6 (R2) (ICH-GCP), Medicines for Human Use (Clinical 
Trial) Regulations 2004 (as amended) and all other applicable regulatory requirements.  
 
 
Chief Investigator approval and agreement 
I hereby approve this version of the protocol and declare no conflict of interest: 
Conflict of interest details: None 
 
Chief Investigator:   
  
 
 
 
   Date: 21 Oct 2020 
Helen McShane, Chief Investigator, University of Oxford 
 
 
 
Principal Investigator Agreement 
I have read the trial protocol and agree to conduct the trial in compliance with the protocol, the 
International Conference on Harmonisation Good Clinical Practice Guideline E6 (R1) (ICH-GCP) and all 
applicable regulatory requirements.  
 
I declare no conflict of interest: 
Conflict of interest details: None 
 
Principal Investigator:   
   
 
 
   Date: 21 Oct 2020 
Alison Elliott, Principal Investigator, MRC/UVRI and LSHTM Uganda Research Unit 
 
 
 
 

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TABLE OF CONTENTS 
 
 
1. 
AMENDMENT HISTORY ...................................................................................... 7 
2. 
KEY TRIAL CONTACTS AND ROLES .................................................................... 15 
3. 
SYNOPSIS ........................................................................................................ 17 
3.1. 
Trial Synopsis ......................................................................................................................... 17 
3.2. 
Schedule of visits and procedures for groups 1-4 ................................................................. 19 
3.3. 
Schedule of visits and procedures for groups 5 and 6 .......................................................... 20 
4. 
ABBREVIATIONS .............................................................................................. 22 
5. 
BACKGROUND AND RATIONALE ....................................................................... 23 
5.1. 
Context .................................................................................................................................. 23 
5.1.1. 
BCG revaccination of adolescents in Uganda ............................................................... 24 
5.1.2. 
Description and pre-clinical experience of MVA and MVA85A .................................... 24 
5.1.3. 
Clinical studies with MVA85A ....................................................................................... 24 
5.1.4. 
Description and pre-clinical experience of ChAdOx1 and ChAdOx1 85A ..................... 29 
5.1.5. 
Clinical studies with ChAdOx1 85A ............................................................................... 29 
5.2. 
Goal ....................................................................................................................................... 31 
5.3. 
Hypothesis ............................................................................................................................. 31 
5.4. 
Risks and Benefits ................................................................................................................. 31 
5.4.1. 
Potential risks ................................................................................................................ 31 
5.4.2. 
Potential benefits .......................................................................................................... 32 
6. 
OBJECTIVES AND OUTCOME MEASURES........................................................... 33 
Primary Objective .......................................................................................................................... 33 
7. 
TRIAL DESIGN .................................................................................................. 34 
7.1. 
Trial Numbers and Groups .................................................................................................... 34 
7.2. 
Recruitment .......................................................................................................................... 35 
7.3. 
Informed Consent ................................................................................................................. 35 
7.4. 
Inclusion Criteria ................................................................................................................... 36 
7.5. 
Exclusion Criteria ................................................................................................................... 36 
7.6. 
Screening and Eligibility Assessment .................................................................................... 38 
7.7. 
Enrolment ............................................................................................................................. 38 
7.8. 
Randomisation and blinding ................................................................................................. 39 
7.9. 
Timepoints ............................................................................................................................ 39 
7.10. 
Sample handling .................................................................................................................... 40 
7.11. 
Vaccination Postponement Criteria ...................................................................................... 40 
7.12. 
Discontinuation / Withdrawal Criteria .................................................................................. 40 

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7.13. 
Discontinuation of the trial ................................................................................................... 41 
7.14. 
End of Study Definition ......................................................................................................... 41 
8. 
CLINICAL PROCEDURES .................................................................................... 41 
8.1. 
Schedule of Attendance ........................................................................................................ 41 
8.2. 
Observations ......................................................................................................................... 41 
8.3. 
Blood tests, urine and stool analysis ..................................................................................... 41 
8.4. 
Study visits ............................................................................................................................ 42 
8.4.1. 
Screening visit ............................................................................................................... 42 
8.4.2. 
Day 0: Enrolment and vaccination visit ......................................................................... 43 
8.4.3. 
Vaccination (D0) ............................................................................................................ 43 
8.4.1. 
Subsequent visits .......................................................................................................... 43 
8.4.2. 
MVA85A booster immunisation.................................................................................... 44 
9. 
INVESTIGATIONAL PRODUCTS .......................................................................... 44 
9.1. 
ChAdOx1 85A ........................................................................................................................ 44 
9.1.1. 
ChAdOx1 85A Description ............................................................................................. 44 
9.1.2. 
Supply and Storage of ChAdOx1 85A ............................................................................ 44 
9.1.3. 
Formulation of ChAdOx1 85A ....................................................................................... 44 
9.1.4. 
Dispensing and administration of ChAdOx1 85A .......................................................... 45 
9.2. 
MVA85A ................................................................................................................................ 45 
9.2.1. 
MVA85A Description ..................................................................................................... 45 
9.2.2. 
Formulation of MVA85A ............................................................................................... 45 
9.2.3. 
Storage of MVA85A ....................................................................................................... 45 
9.2.4. 
Dispensing and administration of MVA85A .................................................................. 46 
9.3. 
Vaccine accountability and disposal ..................................................................................... 46 
10. 
ASSESSMENT OF SAFETY .................................................................................. 46 
10.1. 
Interim Safety Review ........................................................................................................... 46 
10.1.1. 
Holding criteria .............................................................................................................. 46 
10.2. 
Definitions ............................................................................................................................. 47 
10.2.1. 
Adverse Event (AE) ........................................................................................................ 47 
10.2.2. 
Adverse Reaction (AR)................................................................................................... 47 
10.2.3. 
Unexpected Adverse Reaction ...................................................................................... 48 
10.2.4. 
Serious Adverse Event (SAE) ......................................................................................... 48 
10.2.5. 
Serious Adverse Reaction (SAR) .................................................................................... 48 
10.2.6. 
Suspected Unexpected Serious Adverse Reaction (SUSAR).......................................... 48 
10.3. 
Expected Serious Adverse Events ......................................................................................... 48 
10.4. 
Causality Assessment ............................................................................................................ 48 
10.5. 
Reporting Procedures for All Adverse Events ....................................................................... 49 

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10.5.1. 
Reporting Procedures for Serious AEs .......................................................................... 50 
10.5.2. 
Reporting Procedures for SARs ..................................................................................... 50 
10.5.3. 
Reporting Procedures for SUSARs ................................................................................. 50 
10.5.4. 
Development Safety Update Report ............................................................................. 50 
10.6. 
Assessment of Severity ......................................................................................................... 50 
10.7. 
Procedures to be followed in the event of abnormal findings ............................................. 51 
10.8. 
Data and Safety Monitoring Board (DSMB) .......................................................................... 52 
11. 
STATISTICS ....................................................................................................... 52 
12. 
DATA MANAGEMENT ...................................................................................... 52 
12.1. 
Source Data ........................................................................................................................... 52 
12.2. 
Access to Data ....................................................................................................................... 53 
12.3. 
Data Recording and Record Keeping .................................................................................... 53 
13. 
QUALITY ASSURANCE PROCEDURES ................................................................. 53 
13.1. 
Quality Assurance ................................................................................................................. 53 
13.2. 
Monitoring ............................................................................................................................ 54 
14. 
SERIOUS BREACHES AND PROTOCOL VIOLATIONS ............................................ 54 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................. 54 
15.1. 
Declaration of Helsinki .......................................................................................................... 54 
15.2. 
Good Clinical Practice ........................................................................................................... 54 
15.3. 
Approvals .............................................................................................................................. 54 
15.4. 
Reporting............................................................................................................................... 55 
15.5. 
Volunteer Confidentiality ...................................................................................................... 55 
15.6. 
Expenses and Benefits .......................................................................................................... 55 
16. 
FINANCE AND INSURANCE ............................................................................... 55 
16.1. 
Funding ................................................................................................................................. 55 
16.2. 
Indemnity .............................................................................................................................. 55 
16.3. 
Insurance ............................................................................................................................... 56 
17. 
PUBLICATION POLICY ....................................................................................... 56 
18. 
REFERENCES .................................................................................................... 57 
 
 
 
 

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TABLES 
Table 1.1. Schedule of trial procedures groups 1-4 .............................................................................. 19 
Table 1.2. Schedule of trial procedures groups 5-6 .............................................................................. 21 
Table 2. Summary of clinical trials of MVA85A ..................................................................................... 28 
Table 3.  TB034 trial design ................................................................................................................... 30 
Table 4. Objectives and Outcome Measures ........................................................................................ 33 
Table 5. Trial groups .............................................................................................................................. 35 
Table 6. Solicited AEs as collected on post vaccination diary cards ..................................................... 43 
Table 7. Guidelines for assessing the relationship of vaccine administration to an AE ....................... 49 
Table 8. Routinely solicited adverse events .......................................................................................... 49 
Table 9. Severity grading criteria for local adverse events ................................................................... 51 
Table 10. Severity grading criteria for physical observations ............................................................... 51 
Table 11. Severity grading criteria for respiratory and systemic AEs ................................................... 51 
 
 

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1. AMENDMENT HISTORY 
Protocol v4.1 Non Substantial Amendment/NDA, UVRI REC, UNCST and OxTREC Resubmission 
Section  
From  
Changed To 
3.3 
Schedule of visits and procedures for groups 5 
and 6  
Timelines (days): Screening, 0, 2, 14, 28, 56-140, 
63-147, 84-168, 140-224, 224-308 
Timeline (weeks): 0, 2, 4, 8-20, 9-21, 12-24, 20-
32, 32-44 
 
Schedule of visits and procedures for groups 5 
and 6  
Timelines (days): Screening, 0, 2, 14, 28, 56-365, 
63-372, 84-393, 140-449, 224-533 
Timeline (weeks): 0, 2, 4, 8-52, 9-53, 12-56, 20-
64, 32-76 
 
7.9 
Follow up period 
The follow up period for those enrolled after the 
COVID 19 lockdown will be 24 weeks after first 
vaccination and 24 weeks after booster 
vaccination for those enrolled before the 
lockdown in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. Due to the 
nearly three months COVID-19 lockdown and 
halting of trial activities, participants who had 
already been enrolled in the trial by that time 
will have a later MVA85A vaccination boost 
ranging of up to 20 weeks (instead of 8 weeks) 
after initial vaccination with ChAdox1 85A. Their 
subsequent follow up visits will be at day 7, day 
28, 3 months and 6 months post boost 
vaccination. Their follow up visits will therefore 
fall within the following ranges of 63-147, 84-
168, 140-224 and 224-308 days.   
Follow up period 
The follow up period for those enrolled after the 
COVID 19 lockdown will be 24 weeks after first 
vaccination and 24 weeks after booster 
vaccination for those enrolled before the 
lockdown in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. Due to the 
nearly three months COVID-19 lockdown and 
halting of trial activities, participants who had 
already been enrolled in the trial by that time 
will have a later MVA85A vaccination boost 
ranging of up to 52 weeks (instead of 8 weeks) 
after initial vaccination with ChAdox1 85A. Their 
subsequent follow up visits will be at day 7, day 
28, 3 months and 6 months post boost 
vaccination. Their follow up visits will therefore 
fall within the following ranges of 63-372, 84-
393, 140-449 and 224-533 days.   
8.4.2 
MVA85A booster immunisation 
Volunteers in group 5 will be asked to attend 
between day 56 and day 140 for booster 
immunisation with MVA85A [volunteers in 
group 6 will also be asked to attend on this date, 
but only to provide the samples indicated]. For 
participants who were enrolled in the trial prior 
to the COVID-19 lockdown, this boost visit will 
fall between day 56 and day 140 after enrolment 
into the trial while for newly enrolled 
participants, the boost will be done on day 56.    
    
 
MVA85A booster immunisation 
Volunteers in group 5 will be asked to attend 
between day 56 and day 365 for booster 
immunisation with MVA85A [volunteers in 
group 6 will also be asked to attend on this date, 
but only to provide the samples indicated]. For 
participants who were enrolled in the trial prior 
to the COVID-19 lockdown, this boost visit will 
fall between day 56 and day 365 after enrolment 
into the trial while for newly enrolled 
participants, the boost will be done on day 56.    
 
 
 
 
 

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Protocol v4.0 Substantial Amendment/NDA, UVRI REC, UNCST and OxTREC Resubmission 
Section  
From  
Changed To 
3.3 
Schedule of visits and procedures for groups 5 
and 6  
 
Timelines (days): Screening, 0, 2, 14, 28, 56, 63, 
84, 168, 365 
Timeline (weeks): 0, 2, 4, 8, 9, 12, 24 
 
Schedule of visits and procedures for groups 5 
and 6  
Timelines (days): Screening, 0, 2, 14, 28, 56-140, 
63-147, 84-168, 140-224, 224-308 
Timeline (weeks): 0, 2, 4, 8-20, 9-21, 12-24, 20-
32, 32-44 
 
7.9 
Follow up period 
The follow up period will be 24 weeks for groups 
1-4, one year for groups 5 and 6, after first 
vaccination in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval.  
Follow up period 
The follow up period for those enrolled after the 
COVID 19 lockdown will be 24 weeks after first 
vaccination and 24 weeks after booster 
vaccination for those enrolled before the 
lockdown in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. Due to the 
nearly three months COVID-19 lockdown and 
halting of trial activities, participants who had 
already been enrolled in the trial by that time 
will have a later MVA85A vaccination boost 
ranging of up to 20 weeks (instead of 8 weeks) 
after initial vaccination with ChAdox1 85A. Their 
subsequent follow up visits will be at day 7, day 
28, 3 months and 6 months post boost 
vaccination. Their follow up visits will therefore 
fall within the following ranges of 63-147, 84-
168, 140-224 and 224-308 days.  Newly enrolled 
participants into Group 5 will follow the original 
schedule of the MVA85A boost at day 56 and 
subsequent follow up visits on days 63, 84, 140 
and 224.  
 
8.4.2 
MVA85A booster immunisation 
Volunteers in group 5 will be asked to attend on 
day 56 for booster immunisation with MVA85A 
[volunteers in group 6 will also be asked to 
attend on this date, but only to provide the 
samples indicated]. 
    
 
MVA85A booster immunisation 
Volunteers in group 5 will be asked to attend 
between day 56 and day 140 for booster 
immunisation with MVA85A [volunteers in 
group 6 will also be asked to attend on this date, 
but only to provide the samples indicated]. For 
participants who were enrolled in the trial prior 
to the COVID-19 lockdown, this boost visit will 
fall between day 56 and day 140 after enrolment 
into the trial while for newly enrolled 
participants, the boost will be done on day 56.    
 
 
 
 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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Protocol v3.1 Non Substantial Amendment/UVRI REC, UNCST and OxTREC Resubmission 
Section  
From  
Changed To 
2. KEY TRIAL 
CONTACTS 
AND ROLES 
Project 
Managers: 
Dr Rebecca Powell Doherty 
Dr Ingrid Cabrera Puig 
 
 
 
 
 
7.9 
Follow up period 
The follow up period will be 24 weeks for groups 
1-4, one year for groups 5 and 6, after first 
vaccination in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. All follow up 
visits will last approximately 15 to 30 minutes. 
Follow up period 
The follow up period will be 24 weeks for groups 
1-4, one year for groups 5 and 6, after first 
vaccination in accordance with findings from 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. All follow up 
visits will last approximately 15 to 30 minutes. 
Most of the participants are currently in 
secondary school which are either day or 
boarding. For logistical and time management 
purposes as well as to minimize disruption of 
their studies, participants in boarding schools 
will be offered the option of having follow up 
visits done at the school premises. A qualified 
clinician and nurse will visit the school with the 
necessary supplies and equipment for the visit 
on the said date. The clinician will examine and 
assess the participant while the nurse will draw 
blood and collect the relevant samples for that 
visit. The trial team will seek permission and a 
formal introductory letter from the district 
education officials to the school management 
for access to the schools. The team will secure 
suitable space for these activities. The team will 
ensure the participant is in good health 
condition before departing from the school. The 
trial contact phone number will be availed to the 
school to follow up on any concerns.        
8.1 
 
8.1 Schedule of Attendance 
All volunteers will have the same schedule of 
clinic attendances and procedures as indicated 
in the Schedules of Visits and Procedures 
(section 3). The total volume of blood donated 
during the study will be 160mL. Additional visits 
or procedures may be performed at the 
discretion of the investigators, e.g., further 
medical history and physical examination, or 
urine microscopy in the event of positive 
urinalysis.  
8.1 Schedule of Attendance 
All volunteers will have the same schedule of 
clinic attendances and procedures as indicated 
in the Schedules of Visits and Procedures 
(section 3). The total volume of blood donated 
during the study will be 160mL. Additional visits 
or procedures may be performed at the 
discretion of the investigators, e.g., further 
medical history and physical examination, or 
urine microscopy in the event of positive 
urinalysis. Participants will be offered the option 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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of having follow up visits done at school as 
detailed in section 7.9.  
8.4.1 
8.4.1 Subsequent visits 
All volunteers will be asked to attend as per the 
Schedule of Visits and Procedures in section 3.  
On visits other than for vaccination the 
volunteers will be assessed for local and 
systemic adverse events, using paper diary 
cards, interim history, physical examination and 
blood tests at the time-points indicated in the 
Schedule of Visits and Procedures (Section 3). 
Blood will also be taken for assessments of 
immunogenicity and exploratory immunology 
analysis.  
8.4.1 Subsequent visits 
All volunteers will be asked to attend as per the 
Schedule of Visits and Procedures in section 3.  
On visits other than for vaccination the 
volunteers will be assessed for local and 
systemic adverse events, using paper diary 
cards, interim history, physical examination and 
blood tests at the time-points indicated in the 
Schedule of Visits and Procedures (Section 3). 
Blood will also be taken for assessments of 
immunogenicity and exploratory immunology 
analysis. These follow up visits may be done at 
school (see section 7.9).  
 
 
 
Protocol v3.0 Substantial Amendment/UVRI REC, UNCST and OxTREC Resubmission 
Section 
From  
Changed To 
3.3 
Blood Vol (mL) at Screening= 36mL and 
Enrolment= 0mL 
Blood Vol (mL) at Screening= 26mL and 
Enrolment= 10mL 
5.4.1 
1. Venepuncture  
Localised bruising and discomfort can occur at 
the site of venepuncture. Infrequently fainting 
may occur. The total volume of blood drawn 
over a 6-month period will be 143mL, which 
should not compromise these otherwise healthy 
volunteers.  
1. Venepuncture  
Localised bruising and discomfort can occur at 
the site of venepuncture. Infrequently fainting 
may occur. The total volume of blood drawn 
over a 6-month period will be 160mL, which 
should not compromise these otherwise 
healthy volunteers.  
8.1 
All volunteers will have the same schedule of 
clinic attendances and procedures as indicated 
in the Schedules of Visits and Procedures 
(section 3). The total volume of blood donated 
during the study will be 143mL. Additional visits 
or procedures may be performed at the 
discretion of the investigators, e.g., further 
medical history and physical examination, or 
urine microscopy in the event of positive 
urinalysis. 
 
All volunteers will have the same schedule of 
clinic attendances and procedures as indicated 
in the Schedules of Visits and Procedures 
(section 3). The total volume of blood donated 
during the study will be 160mL. Additional 
visits or procedures may be performed at the 
discretion of the investigators, e.g., further 
medical history and physical examination, or 
urine microscopy in the event of positive 
urinalysis. 
 
 
 
Protocol v2.0 Substantial Amendment 
Section 
From  
Changed To 
7.2 
In 2018, they will be aged 11 to 15 years. 
In 2018, they will be aged 12 to 17 years. 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
 Page 11 of 59 
7.2 
Using the EMaBS databases, we will identify 
participants who have no known chronic illness 
(such as HIV infection or sickle cell disease), who 
are still resident in the original study catchment 
area and who received immunisation within two 
weeks of birth with BCG Russia (BCG-I strain 
from Moscow, Serum Institute of India, India; 
the strain used for most EMaBS infants). 
Using the EMaBS databases, we will identify 
participants who have no known chronic 
illness (such as HIV infection or sickle cell 
disease), who are either still resident in the 
original study catchment area or participants 
with documented good attendance who are 
willing to attend as required and who received 
immunisation within two weeks of birth with 
BCG Russia (BCG-I strain from Moscow, Serum 
Institute of India, India; the strain used for 
most EMaBS infants). 
 
7.4 
• 
Resident within the study area and planning 
to be resident in the study area for the 
duration of the study 
 
• 
Resident within the study area and 
planning to be resident in the study area 
for the duration of the study or 
participants 
with 
documented 
good 
attendance who are willing to attend as 
required 
7.4 
• 
Participant in the Entebbe Mother and Baby 
Study; healthy; aged 11 to 14 [or, for adults, 
a parent or guardian of a participant; 
healthy; aged 18 to 49] 
• 
Participant in the Entebbe Mother and 
Baby Study; healthy; aged 12 to 17 [or, for 
adults, a parent or guardian of a 
participant; healthy; aged 18 to 49] 
7.8 
The randomisation code will be generated by 
the trial statistician. 
The randomisation code will be generated by 
an independent  statistician. 
8.3 
• 
Biochemistry: Sodium, Potassium, Urea, 
Creatinine, Albumin, Liver Function Tests 
(ALT, AST, ALP, GGT) 
• 
Biochemistry: Sodium, Potassium, Urea, 
Creatinine, Albumin, Liver Function Tests 
(ALT, ALP, GGT) 
16.3 
The University of Oxford has a specialist 
insurance policy in place which would operate in 
the event of any volunteer suffering harm as a 
result of their involvement in the research 
(Newline Underwriting Management Ltd, at 
Lloyd’s of London and a local insurance 
company. 
 
The University of Oxford has a specialist 
insurance policy in place which would operate 
in the event of any volunteer suffering harm as 
a result of their involvement in the research 
(Newline Underwriting Management Ltd, at 
Lloyd’s of London and a local insurance 
company, Jubilee Insurance Ltd. 
 
 
 
Protocol v1.3 Substantial/Non-substantial Amendment/UVRI REC and UNCST Resubmission 
Section 
From  
Changed To 
Page 1, 
sections 2, 
3.1, 12.3 and 
16.1 
MRC/UVRI Uganda Research Unit on AIDS 
MRC/UVRI and LSHTM Uganda Research Unit 
8.4.3 
Group 5 adolescents will be given ChAdOx1 
85A at 2.5 x1010 vp intramuscularly 
 
Group 5 adolescents will be given ChAdOx1 
85A at 2.5 x1010 vp intramuscularly followed 
by 
MVA85A 
boost 
at 
1 
x 
108 
pfu 
intramuscularly on day 56 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
 Page 12 of 59 
15.6 
Volunteers will be compensated pro rata for 
their time, travel and for trial procedures while 
participating in the trial, amounting to a total of 
approximately £70, depending on the exact 
number of visits, site of recruitment and 
whether any repeat or additional visits are 
necessary. 
Volunteers will be compensated pro rata for 
their time, travel and for trial procedures while 
participating in the trial, amounting to a total 
of approximately £70 or 350,000 UGX (30,000 
UGX per visit), depending on the exact number 
of visits, site of recruitment and whether any 
repeat or additional visits are necessary. 
16.2 
If any volunteer is harmed as a result of this trial, 
medical care will be provided by Entebbe 
Hospital, or a referral hospital in Uganda if 
required.  
 If any volunteer is harmed as a result of this 
trial, medical care will be provided by Entebbe 
Hospital, or a referral hospital in Uganda if 
required. The sponsor should provide care 
until complete cure or stabilization of a 
research related injury. The injured research 
participant shall be given the best care 
available within the country for the research 
related injury. Research participants shall not 
be required to waive their legal rights for 
redress in courts of law.  
16.3 
The University of Oxford has a specialist 
insurance policy in place which would operate in 
the event of any volunteer suffering harm as a 
result of their involvement in the research 
(Newline Underwriting Management Ltd, at 
Lloyd’s of London). 
 
The University of Oxford has a specialist 
insurance policy in place which would operate 
in the event of any volunteer suffering harm as 
a result of their involvement in the research 
(Newline Underwriting Management Ltd, at 
Lloyd’s of London and a local insurance 
company. 
 
 
Protocol v1.2 OxTREC Resubmission 
Section 
From  
Changed To 
7.8 
The randomisation code will be generated by 
the trial statistician, using a block size of 6. 
The randomisation code will be generated by 
the trial statistician. 
2 
Samantha Vermaak, Dr Alison Lawrie 
Dr Rebecca Powell Doherty, Dr Alison Lawrie 
 
 
Protocol v1.1 Substantial/Non-substantial Amendment 
Section 
From  
Changed To 
4 
LSC (Local Safety Committee) deleted 
DSMB (Data and Safety Monitoring Board) 
added 
7.2 
[Addition] 
A consultative group of selected parents will be 
set up; this group will advise us on issues such as 
the timing of activities in relation to the school 
year. 
7.9 
The Local Safety Committee will be consulted 
if there are any issues of concern. 
The data and safety monitoring board (DSMB) 
will be consulted if there are any issues of 
concern. 
7.9 
The follow up period will be six months after 
first vaccination in accordance with findings 
from previous studies in which adequate 
The follow up period will be 24 weeks for groups 
1-4, one year for groups 5 and 6, after first 
vaccination in accordance with findings from 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
 Page 13 of 59 
safety 
data 
and 
reliable 
markers 
of 
immunogenicity have been obtained in this 
time interval. All follow up visits will last 
approximately 15 to 30 minutes. 
previous studies in which adequate safety data 
and reliable markers of immunogenicity have 
been obtained in this time interval. All follow up 
visits will last approximately 15 to 30 minutes. 
7.12 
The 
Local 
Safety 
Monitor 
(LSM) 
may 
recommend withdrawal of volunteers. 
Deleted, this role has been replaced by the 
DSMB 
10.1 
In addition, the Phase IIa randomised trial will 
be held, and the LSM will be consulted, if any 
of the following holding criteria occurs. 
In addition, the Phase IIa randomised trial will be 
held, and the DSMB will be consulted, if any of 
the following holding criteria occurs. 
 
10.1 
In addition to these pre-defined criteria, the 
study can be put on hold upon advice of the 
Local Safety Monitor, Chief Investigator, 
Principal 
Investigator, 
Study 
Sponsor, 
Regulatory Authority, Ethical Committee(s) or 
Local Safety Committee, for any single event or 
combination of multiple events which, in their 
professional opinion, jeopardise the safety of 
the volunteers or the reliability of the data. 
In addition to these pre-defined criteria, the 
study can be put on hold upon advice of the 
Chief Investigator, Principal Investigator, Study 
Sponsor, 
Regulatory 
Authority, 
Ethical 
Committee(s) or DSMB, for any single event or 
combination of multiple events which, in their 
professional opinion, jeopardise the safety of 
the volunteers or the reliability of the data. 
10.5.1 
The local safety monitor (LSM) will be notified 
of SAEs that are deemed possibly, probably or 
definitely related to study interventions; the 
LSM will be notified immediately (within 24 
hours) of the Investigators’ being aware of 
their occurrence. 
The data and safety monitoring board (DSMB) 
will be notified of SAEs that are deemed 
possibly, probably or definitely related to study 
interventions; the DSMB will be notified 
immediately 
(within 
24 
hours) 
of 
the 
Investigators’ being aware of their occurrence. 
10.5.1 
SAEs 
will 
not 
normally 
be 
reported 
immediately to the Oxford or LSHTM ethical 
committee(s) unless there is a clinically 
important increase in occurrence rate, an 
unexpected outcome, or a new event that is 
likely to affect safety of trial volunteers, at the 
discretion of the Chief Investigator and/or 
LSM. 
SAEs will not normally be reported immediately 
to the Oxford or LSHTM ethical committee(s) 
unless there is a clinically important increase in 
occurrence rate, an unexpected outcome, or a 
new event that is likely to affect safety of trial 
volunteers, at the discretion of the Chief 
Investigator and/or DSMB. 
10.8 
Local Safety Committee 
A Local Safety Committee (LSC) will be 
appointed 
to 
provide 
real-time 
safety 
oversight. The LSC will be notified within 24 
hours of the Investigators’ being aware of the 
occurrence of SAEs. The LSC has the power to 
place the trial on hold if deemed necessary 
following a trial intervention-related SAE. The 
LSC will be chaired by clinician experienced in 
early-phase clinical trials. There will be a 
minimum of two other appropriately qualified 
committee members. All correspondence 
between Investigator and LSC will be conveyed 
by the Chief Investigator to the trial Sponsor. 
The Chair of the LSC will be contacted for 
advice and independent review by the 
Investigator or trial Sponsor in the following 
situations: 
Data and Safety Monitoring Board (DSMB) 
A data and safety monitoring board (DSMB) will 
be appointed to provide real-time safety 
oversight. The DSMB will be notified within 24 
hours of the Investigators’ being aware of the 
occurrence of SAEs. The DSMB has the power to 
place the trial on hold if deemed necessary 
following a trial intervention-related SAE. The 
DSMB will be chaired by clinician experienced in 
early-phase clinical trials. There will be a 
minimum of two other appropriately qualified 
committee members.  Membership will include 
a statistician, and at least one Ugandan 
member. 
 
All 
correspondence 
between 
Investigator and DSMB will be conveyed by the 
Chief Investigator to the trial Sponsor. The Chair 
of the DSMB will be contacted for advice and 
independent review by the Investigator or trial 
Sponsor in the following situations: 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
 Page 14 of 59 
• 
Following any SAE deemed to be 
possibly, probably, or definitely related 
to the trial challenge agent. 
• 
Any 
other 
situation 
where 
the 
Investigator or trial Sponsor feels 
independent advice or review is 
important. 
A Data Safety Monitoring Board is not 
proposed because the trial is small and not 
blinded. 
 
• 
Following any SAE deemed to be possibly, 
probably, or definitely related to the trial 
challenge agent. 
• 
Any other situation where the Investigator 
or trial Sponsor feels independent advice or 
review is important. 
Reports will be provided to the DSMB on 
completion of recruitment to groups 1 and 2 
(adult dose escalation) before proceeding to 
group 3; and on completion of recruitment to 
groups 3 and 4 (adolescent dose escalation), 
before proceeding to the randomised trial 
(groups 5 and 6). 
15.3 
[Addition] 
The 
Ethics 
Committees 
and 
Regulatory 
Authorities for this trial comprise the Research 
Ethics Committee of the UVRI, the Oxford 
Tropical Research Ethics Committee, the Ethics 
Committee of the London School of Hygiene & 
Tropical Medicine, the Uganda National Council 
for Science and Technology and the Uganda 
National Drug Authority. 
15.6 
Volunteers will be compensated pro rata for 
their time, travel and for trial procedures while 
participating in the trial, amounting to a total 
of approximately £50, depending on the exact 
number of visits, site of recruitment and 
whether any repeat or additional visits are 
necessary. 
Volunteers will be compensated pro rata for 
their time, travel and for trial procedures while 
participating in the trial, amounting to a total of 
approximately £70, depending on the exact 
number of visits, site of recruitment and 
whether any repeat or additional visits are 
necessary.  A small gift will be given to 
participants on completion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. KEY TRIAL CONTACTS AND ROLES 
 
Clinical Trial Unit: 
 
MRC/UVRI and LSHTM Uganda Research Unit  
 
 
 
 
P.O. Box 49 
 
 
 
 
Entebbe 
 
 
 
 
Uganda 
Tel: +256 (0)417 704000 
Fax: +256 (0) 414 321137 
 
Chief Investigator: 
 
Professor Helen McShane 
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), The 
Jenner Institute, University of Oxford, Churchill Hospital, Oxford OX3 
7LE 
 
 
 
 
Tel: +44 (0)1865 617606 
 
 
 
 
Fax: +44 (0)1865 617998 
 
 
 
 
Email: helen.mcshane@ndm.ox.ac.uk 
 
Principal Investigator:  
Alison Elliott 
 
 
 
 
MRC/UVRI and LSHTM Uganda Research Unit 
 
 
 
 
Tel: +256 (0)417 704000 
Fax: +256 (0) 414 321137 
 
 
 
 
Email: alison.elliott@mrcuganda.org; alison.elliott@lshtm.ac.uk  
 
Other Investigators: 
 
Anne Wajja 
 
 
 
 
MRC/UVRI and LSHTM Uganda Research Unit 
Pontiano Kaleebu 
MRC/UVRI and LSHTM Uganda Research Unit 
Lead Nurse: 
 
 
Florence Akello 
 
 
 
 
MRC/UVRI and LSHTM Uganda Research Unit 
 
 
 
Collaborators:  
 
Dr Moses Muwanga 
 
 
 
 
Medical Superintendent 
 
 
 
 
Entebbe Hospital 
 
 
 
 
P.O. Box 29 
 
 
 
 
Entebbe 
 
 
 
 
Uganda 
 
 
 
 
Email: docmuwanga@yahoo.com 
 
Project Managers: 
 
Dr Ingrid Cabrera Puig, Dr Alison Lawrie 
CCVTM 
 
Jacent Nassuuna 
MRC/UVRI and LSHTM Uganda Research Unit 
 
Immunologists:  
 
Dr Iman Satti 
 
 
 
 
The Jenner Institute 
 
 
 
 
Old Road Campus Research Building 
 
 
 
 
Roosevelt Drive, Headington  

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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Oxford, OX3 7DQ 
 
 
 
 
Tel: +44 (0)1865 617623 
 
 
 
 
Fax: +44 (0)1865 617608 
 
 
 
 
Email: iman.satti@ndm.ox.ac.uk 
 
 
 
 
 
Rachel Tanner 
 
 
 
 
The Jenner Institute 
 
Ms Beatrice Nassanga 
 
 
 
 
MRC/UVRI and LSHTM Uganda Research Unit 
 
 
 
 
 
Dr Stephen Cose 
 
 
 
 
MRC/UVRI and LSHTM Uganda Research Unit 
 
 
Statistician: 
 
 
Dr Emily Webb 
 
 
 
 
London School of Hygiene & Tropical Medicine 
 
 
 
 
Keppel Street 
 
 
 
 
London WC1E 7HT 
 
 
 
 
Tel: +44 (0)20 7927 2012 
 
 
 
 
E-mail: emily.webb@lshtm.ac.uk  
 
Sponsor:  
 
 
Clinical Trials & Research Governance 
 
 
 
 
Joint Research Office, University of Oxford 
 
 
 
 
Block 60, Churchill Hospital 
 
 
 
 
Old Road, Headington 
 
 
 
 
Oxford, OX3 7LE 
 
Monitor: 
 
 
Dr Annet Nanvubya 
Coordinator 
Reciprocal Monitoring Scheme, 
East African Centre for Clinical Research 
Entebbe 
Uganda 
Tel: +256 (0)772 722 377 or +256 (0)772 592717 
Email: A.Nanvubya@iavi.or.ug 
 
 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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3. SYNOPSIS 
3.1. Trial Synopsis 
Trial Title 
Open label, dose escalation and age de-escalation for ChAdOx1 85A, followed by a 
Phase IIa randomised, open-label trial among adolescents comparing ChAdOx1 
85A prime followed by MVA85A boost versus BCG re-vaccination 
Trial Identifier 
TB042 
Trial Centres 
MRC/UVRI and LSHTM Uganda Research Unit 
P.O. Box 49 
Entebbe 
Uganda 
Tel: +256 (0)417 704000 
Fax: +256 (0) 414 321137 
Clinical Phase 
Phase IIa 
Design 
Open label, dose escalation and age de-escalation for ChAdOx1 85A followed by  
a randomised, open-label trial among adolescents, comparing ChAdOx1 85A prime 
followed by MVA85A boost versus BCG re-vaccination 
Trial participants 
Adolescents participating in the Entebbe Mother and Baby Study (EMaBS) birth 
cohort and their parents 
Planned Sample Size 
Total: 72 healthy, previously BCG-vaccinated volunteers receiving either ChAdOx1 
85A intramuscularly at different doses, or a prime-boost regimen of ChAdOx1 85A 
intramuscularly followed by MVA85A intramuscularly, or BCG re-vaccination 
intradermally.   
 
Dose escalation in adults 
Group 1: 3 adults who are parents of EMaBS participants, to receive ChAdOx1 85A 
at 5 x109 vp  
Group 2: 3 adults who are parents of EMaBS participants, to receive ChAdOx1 85A 
at 2.5 x1010 vp  
 
Age de-escalation and dose escalation in adolescents 
Group 3: 3 adolescents who are EMaBS participants, to receive ChAdOx1 85A at 5 
x109 vp  
Group 4:  3 adolescents who are EMaBS participants, to receive ChAdOx1 85A at 
2.5 x1010 vp  
 
Randomised comparison of ChAdOx1 85A-MVA85A versus BCG revaccination 
Group 5: 30 adolescents who are EMaBS participants, to receive ChAdOx1 85A at 
2.5 x1010 vp followed by MVA85A boost 
Group 6: 30 adolescents who are EMaBS participants, to receive BCG revaccination 
 
Vaccination Schedule 
ChAdOx1 85A or BCG revaccination on day zero; where applicable MVA85A on day 
56 
Follow-up Duration 
24 weeks after vaccination for groups 1-4; one year after first vaccination for 
groups 5 and 6 
Trial Interventions 
Intramuscular or intradermal vaccination 
Venepuncture 
Trial Duration 
Estimated 30 months 
Planned Trial Period 
Prospective start date for enrolment 01.02.2018 
 
Objectives 
Outcome Measures 
Primary 
To evaluate the safety and 
immunogenicity of ChAdOx1 85A – 
MVA85A prime-boost vaccination in 
Ugandan adolescents 
Actively and passively collected data on 
adverse events 
T-cell Interferon- ELIspot response to 
antigen 85A and PPD 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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Secondary 
To further characterise immunogenicity 
of ChAdOx1 85A – MVA85A prime-boost 
vaccination in Ugandan adolescents 
Antibody response to antigen 85A and 
PPD; exploratory immunology including 
flow cytometry, gene expression, and 
mycobacterial growth inhibition assays 
Tertiary 
1. To compare the response to 
ChAdOx1 85A – MVA85A prime-
boost vaccination with the response 
to BCG revaccination in Ugandan 
adolescents 
2. To compare the response to 
ChAdOx1 85A – MVA85A prime-
boost vaccination in Ugandan 
adolescents with the response in 
Oxford adults 
3. To investigate pre-immunisation 
epidemiological and immunological 
characteristics associated with the 
immune response induced by 
ChAdOx1 85A – MVA85A prime-
boost vaccination in Ugandan 
adolescents 
T-cell Interferon- ELIspot response to 
antigen 85A and PPD 
 
Antibody response to antigen 85A and 
PPD; exploratory immunology including 
flow cytometry, gene expression, and 
mycobacterial growth inhibition assays 
Investigational products 
Investigational products: ChAdOx1 85A, MVA85A 
Comparator: Bacille Calmette Guerin (BCG); strain in use in Uganda at the time of 
the trial 
Dose(s) 
ChAdOx1 85A:  5x109 vp and 2.5x1010 vp 
MVA85A: 1x108 pfu 
BCG: 0.1 ml 
Route of administration 
ChAdOx1 85A:  intramuscular needle injection in the deltoid region of the arm 
MVA85A:  intramuscular needle injection in the deltoid region of the arm 
BCG: intradermal needle injection in the deltoid region of the arm 
Allocation Method 
Group 1: the first three adults will receive ChAdOx1 85A at 5 x109 vp  
Group 2: the next three adults will receive ChAdOx1 85A at 2.5 x1010 vp  
 
Group 3: the first three adolescents will receive ChAdOx1 85A at 5 x109 vp  
Group 4: the next three adolescents will receive ChAdOx1 85A at 2.5 x1010 vp  
 
Thereafter, 60 adolescents will be randomised, 30 (group 5) to receive ChAdOx1 
85A at 2.5 x1010 vp followed by MVA85A boost and 30 (group 6) to receive BCG 
revaccination 
 
 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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3.2. Schedule of visits and procedures for groups 1-4 
Visit number 
1 
2 
3 
4 
5 
6 
7 
Timeline (days)* 
Screening 
0  
2 
14 
28 
56 
168 
Timeline (weeks)* 
 
0 
 
2 
4 
8 
24 
Time windows (days) 
-90 to -7 
 
+1 
+3 
+5 
+5 
+14 
Vaccination, ChAdOx1 85A  
 
x 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
Review contra-indications  
x 
x 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
Medical history 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Physical examination 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
 
 
 
 
 
β-HCG urine test (female only) 
x 
x 
 
 
 
 
 
Stool parasitology 
x 
x 
x 
 
 
 
x 
Anthelminthic treatment 
 
 
 
 
 
x 
 
Local & systemic 
events/reactions 
 
x 
x 
x 
x 
x 
x 
Diary cards provided 
 
x 
 
 
 
 
 
Diary cards collected 
 
 
 
x 
 
 
 
Biochemistry (4mL)**/*** 
x 
 
 
x 
 
 
 
HBV, HCV, HIV (6mL) 
x 
 
 
 
 
 
 
Haematology: full blood count 
and storage (2mL) 
x 
 
x 
x 
 
 
 
Mansonella perstans (1mL)*** 
x 
 
 
 
 
 
x 
Malaria RDT/slide; PCR (1mL) 
x 
x*** 
 
x 
x 
 
x 
Assessments of 
immunogenicity and 
exploratory immunology incl 
ELISpot (10-20mL)**** 
x 
x 
x 
x 
x 
x 
x 
Gene expression (2mL) 
x 
 
x 
 
 
 
  
Blood vol (mL) 
36 
0 
6 
28 
9 
5 
24 
Cumulative blood vol (mL) 
36 
36 
42 
70 
79 
84 
108 
 
X  
Event scheduled to occur 
(X) 
If considered necessary, emphasising any complaint or change in medications 
* 
Timeline is approximate only, as exact timings ( windows periods) of visits relate to the actual (not intended) 
date of the previous visit 
** 
Urea & electrolytes, liver function tests 
*** 
Repeated on vaccination day if delay from screening is more than 28 days 
**** 
Exploratory immunology blood volume will be guided by guidelines from Harvard Mass General, where a 
maximum of 3ml/kg body weight is taken at any one time point and not more than 3ml/kg is taken over any 8 
week period (ref http://www.drgreene.com/21_1616.html.) These guidelines have been followed in previous 
studies vaccinating adolescents and children with MVA85A (in South Africa [1]).The total blood volume planned is 
84 ml over the initial intensive sampling period of 8 weeks. Revision of sample volumes based on weight will only 
be required for children who weigh less than 28 kg; the average weight of children aged 11 is expected to be 
greater than 35kg, with greater weights for older children. 
Table 1.1. Schedule of trial procedures groups 1-4 
 
 
 
 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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Schedule of visits and procedures for groups 5 and 6  
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Timeline (days)* 
Screening 
0  
2 
14 
28 
56-
365a 
63-
372 a 
84-
393 a 
140-
449a 
224-
533a 
Timeline (weeks)* 
 
0 
 
2 
4 
8-52 
9-53 
12-56 
20-64 
32-76 
Time windows (days) 
-90 to -7 
 
+1 
+3 
+5 
+5 
+1 
+5 
+5 
+14 
Vaccination,  
ChAdOx1 85A or BCG 
 
x 
 
 
 
 
 
 
 
 
Vaccination, MVA85A§ 
 
 
 
 
 
x§ 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
x 
 
 
 
 
 
 
 
 
Review contra-
indications  
x 
x 
 
 
 
x 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Physical examination 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
β-HCG urine test 
(female only) 
x 
x 
 
 
 
x 
 
 
 
 
Stool parasitology 
x 
x 
x 
 
 
 
 
 
 
x  
Anthelminthic 
treatment 
 
 
 
 
 
 
 
x 
 
 
Local & systemic 
events/reactions 
 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Diary cards provided 
 
x 
 
 
 
x 
 
 
 
 
Diary cards collected 
 
 
 
x 
 
 
x 
 
 
 
Biochemistry 
(4mL)**/*** 
x 
 
 
x 
 
x 
x 
 
 
 
HBV, HCV, HIV (6mL) 
x 
 
 
 
 
 
 
 
 
 
Haematology: full blood 
count and storage (2mL) 
x 
 
x 
x 
 
x 
x 
 
x 
x  
Mansonella perstans 
(1mL)*** 
x 
 
 
 
 
 
 
 
 
x  
Malaria RDT/slide; PCR 
(1mL) 
x 
x*** 
 
x 
x 
x 
 
x 
 
x  
Assessments of 
immunogenicity and 
exploratory 
immunology incl ELISpot 
(10-20mL)**** 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Gene expression (2mL) 
x 
 
x 
 
 
 
 
 
 
 
Blood vol (mL) 
26 
 10 
16 
28 
5 
13 
28 
5 
5 
24 
Cumulative blood vol 
(mL) 
26 
36 
52 
80 
85 
98 
126 
131 
136 
160 
 
X  
Event scheduled to occur 
(X) 
If considered necessary, emphasising any complaint or change in medications 
* 
Timeline is approximate only, as exact timings ( windows periods) of visits relate to the actual (not intended) 
date of the previous visit 
§ 
Group 5 only   
** 
Urea & electrolytes, liver function tests 
*** 
Repeated on vaccination day if delay from screening is more than 28 days 
**** 
Exploratory immunology blood volume will be guided by guidelines from Harvard Mass General, where a 
maximum of 3ml/kg body weight is taken at any one time point and not more than 3ml/kg is taken over any 8 
week period (ref http://www.drgreene.com/21_1616.html.) These guidelines have been followed in previous 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
 Page 21 of 59 
studies vaccinating adolescents and children with MVA85A (in South Africa [1]).The total blood volume planned is 
98 ml over the initial intensive sampling period of 8 weeks. Revision of sample volumes based on weight will only 
be required for children who weigh less than 33 kg; the average weight of children aged 11 is expected to be 
greater than 35kg, with greater weights for older children. 
a 
Participants will have variable follow up days depending on whether they were enrolled before or after the 
COVID 19 lockdown 
Table 1.2. Schedule of trial procedures groups 5-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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4. ABBREVIATIONS 
AE 
Adverse Event 
 
AR 
 
Adverse Reaction 
BCG 
 
Bacille Calmette-Guérin 
β-HCG 
 
Beta - Human Chorionic Gonadotropin 
CBF 
 
Clinical Biomanufacturing Facility, University of Oxford 
CCVTM 
 
Centre for Clinical Vaccinology and Tropical Medicine 
CFU 
 
Colony-forming unit 
ChAdOx1 
 
Chimpanzee Adenovirus vector  
CI 
 
Chief Investigator 
COVID-19  
Corona Virus Disease 
CRF 
 
Case Report Form 
DNA 
 
Deoxyribonucleic Acid 
DSMB 
 
Data and Safety Monitoring Board 
ELISpot 
 
Enzyme-linked Immunospot 
EMaBS 
 
Entebbe Mother and Baby Study 
FBC 
 
Full Blood Count 
GCP 
 
Good Clinical Practice 
HBsAg 
 
Hepatitis B Surface Antigen 
HBV 
 
Hepatitis B Virus 
HCV 
 
Hepatitis C Virus 
HIV 
 
Human Immunodeficiency Virus 
HLA 
 
Human Leukocyte Antigen 
ICH 
 
International Committee on Harmonisation 
ID 
 
Intradermal 
IDT 
 
IDT Biologika GmbH 
IFN-ɣ 
 
Interferon Gamma 
IGRA 
 
Interferon-Gamma Release Assay 
IM 
 
Intramuscular 
LFT 
 
Liver Function Test 
MHRA 
 
Medicines & Healthcare Regulatory Authority 
M.tb 
 
Mycobacterium tuberculosis 
MVA 
 
Modified vaccinia Virus Ankara 
REC 
 
Research Ethics Committee 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SmPC 
 
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
Tuberculosis 
TMF 
 
Trial Master File 
TST 
 
Tuberculin skin test 
U&Es 
 
Urea & Electrolytes 
 
 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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5. BACKGROUND AND RATIONALE 
5.1. Context 
Mycobacterium tuberculosis (M.tb) is a pathogen with worldwide preponderance which infects 
humans causing tuberculosis (TB), a transmissible disease resulting in very high mortality and 
morbidity. A third of the world’s population is latently infected with M.tb, and these people carry a 
10% lifetime risk of developing active life-threatening disease [2]. In 2015, there were 10.4 million new 
cases worldwide and 1.4 million people died of TB [3]. Co-infection with human immunodeficiency 
virus (HIV) greatly increases risk of TB reactivation and death [4, 5]. Diagnosis is challenging and drug 
treatment can be prolonged, harmful, costly and complex. For these reasons an effective vaccine is a 
global public health priority. An effective vaccine could revolutionise TB control [6]. 
The Bacille Calmette-Guérin (BCG) vaccine is the only licensed M.tb vaccine and it has been 
administered globally to several billion people over a 90 year period [7]. BCG is effective in preventing 
disseminated TB disease including tuberculous meningitis in childhood [5, 8, 9] but, against pulmonary 
tuberculosis, its efficacy varies. Infectious, sputum smear positive, pulmonary disease classically 
emerges in adolescents and young adults and this is what drives the continuing epidemic [10]. Thus 
booster immunisation against TB in adolescence is an important strategy [11]. 
The variability in efficacy of BCG is associated with latitude. It ranges from 94% in Danish school 
children to 0% in some studies in the tropics [12]. Studies on BCG immunisation in young adults from 
the UK and Malawi showed reduced immunogenicity in Malawi [13]. However, variability has also 
been observed within the tropics.  In Brazil, BCG immunisation in adolescents (whether first dose or 
booster dose) conferred benefit against tuberculosis in Salvador (a tropical, coastal city), but not in 
Manaus (an inland city, close to the equator, in the Amazon basin) [14].   At first, differential exposure 
to non-tuberculous mycobacteria (NTM) was considered the most probable explanation for these 
regional differences [15]. Later, recognition of the complexity of the geographical distribution of NTM, 
and variable cross-reactivity of NTM species with BCG, led to the suggestion that other forms of 
“environmental sensitisation” might also impact BCG immunogenicity in adolescence [14]. 
Recently, heterologous “prime-boost” vaccination strategies, in which different candidate vaccines 
expressing antigens in common are given weeks or months apart, have generated strong and 
sustained cellular immune responses correlating with an M.tb protective effect in preclinical animal 
models. In such a “prime-boost” strategy, BCG can act as the priming vaccine. Indeed, continued use 
of BCG in infants in endemic settings is desirable because of the protection it affords against severe 
disease in infancy and early childhood. Candidate TB vaccine MVA85A (recombinant modified Vaccinia 
Ankara virus expressing the immunodominant M.tb protein, antigen 85A) has been considered as a 
booster, to be given after BCG either in infancy, or in adolescence, but this vaccine has not shown 
efficacy when used as a booster in South African infants [16] or in HIV-positive adults [17] and also 
shows lower immunogenicity in Africa than in Europe [18, 19].   
Lack of efficacy of MVA85A alone as a boost to BCG immunisation suggests that more immunogenic 
vaccination regimens are required. Compared to single-dose vaccines, a prime-boost combining 
adenoviral and MVA vectors shows dramatically enhanced immunogenicity and efficacy for infections 
including malaria, and has been found safe in adults and children, including African populations [20]. 
For TB, a human adenovirus construct (Aeras-402) followed by MVA85A showed enhanced 
immunogenicity and durability of response [21]. A chimpanzee adenovirus vector encoding the M.tb 
antigen 85A, named ChAdOx1 85A, combined with MVA85A, shows enhanced immunogenicity and 
efficacy against tuberculosis in animals [22], and has just completed a phase I human trial in Oxford 
[23]. We now propose to investigate this regimen in a Phase IIa trial among adolescents in Uganda.   
Although experience on safety and immunogenicity with vaccines based on adenoviral vectors is 
accumulating for a number of infections [20, 24-27], the specific construct to be used here, ChAdOx1 
85A, has so far only been evaluated in one trial in human subjects: this was among adults in the UK.  

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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Therefore this protocol comprises an initial investigation to provide safety data among Ugandan adults 
and adolescents (dose escalation and age de-escalation) before conducting the proposed randomised 
trial in adolescents. 
5.1.1. BCG revaccination of adolescents in Uganda 
As noted above, vaccination against tuberculosis in adolescents is a key strategy for TB control 
because, epidemiologically, this is the age at which infectious, pulmonary disease emerges after a 
relatively protected period in early childhood.  BCG vaccination or re-vaccination in adolescence has 
variable efficacy by setting, and tends to be least effective in the tropics: while the underlying 
mechanism of this variability is not known, exposure to environmental, non-tuberculous mycobacteria 
may contribute, as well as a range of other infectious or environmental factors [14].  To our 
knowledge, the efficacy of BCG revaccination for adolescents in Uganda has not been tested.  BCG 
remains the only available standard against which to compare the response to new vaccines: a current 
trial in South Africa is comparing the efficacy of BCG versus a new vaccine regimen being developed 
by Aeras and Sanofi Pasteur (H4/IC31) for protection against TB infection [28].  A recent analysis 
suggests that, despite variable efficacy, BCG revaccination of adolescents is cost-effective, particularly 
among those who are not tuberculin skin test (TST) positive [29].  Because there is some potential 
benefit of BCG revaccination, but also the need for a more effective vaccine, we propose BCG 
revaccination for the comparison group in this study. 
5.1.2. Description and pre-clinical experience of MVA and MVA85A 
Modified vaccinia virus Ankara (MVA) is a highly-attenuated strain of vaccinia virus which cannot 
replicate in human cells. It is known to be highly immunogenic in UK adults but has been less 
immunogenic in African children and infants. It is suitable for use as a viral vector in a prime-boost 
regime in new vaccine development. It has an excellent safety record as it was administered 
intradermally to approximately 120,000 people during the smallpox eradication campaign [30-33], and 
has since been used in numerous clinical trials of candidate vaccines against viral, mycobacterial and 
protozoal infections [34, 35]. Meanwhile recombinant MVA vaccines administered by respiratory 
mucosal and gut mucosal routes have demonstrated protective efficacy and elicited strong immune 
responses in both rodents and non-human primates [36].  
Antigen 85A is a highly conserved antigen expressed by M.tb, BCG, and all other mycobacterial species 
sequenced to date. It is a 32-kDa protein, and is an enzyme, mycolyl transferase, which is involved in 
cell wall biosynthesis [37]. Antigen 85A is highly immunodominant in both animal and human studies 
[38-40], and protects against M.tb challenge in mice, guinea pigs and non-human primates [41, 42]. 
The recombinant MVA85A vaccine incorporates the 1176 base pair gene for antigen 85A into the viral 
DNA allowing expression of this secreted antigen.  
Experiments in mice, guinea pigs, cattle, and non-human primates have shown that a prime-boost 
schedule of vaccination with BCG followed by MVA85A, either intradermally, intramuscularly or 
mucosally, can improve protective efficacy against subsequent M.tb challenge, compared to BCG 
alone [42-45]. Animal toxicity studies using the intradermal route of administration revealed no 
differences from PBS-injected controls apart from irritation at the site of administration.  
5.1.3. Clinical studies with MVA85A 
Over 2500 volunteers have now received MVA85A, of which (in completed trials) 72 were by the 
intramuscular route, 24 by the aerosol route and the remainder intradermally. 22 phase I/II clinical 
studies of MVA85A have been completed, a further one is ongoing. These are summarised in table 2.  
MVA85A has been shown to be immunogenic as a booster vaccine in BCG-primed subjects [18]; 
however, as discussed above, a phase IIb efficacy trial in 2797 BCG-vaccinated infants in South Africa 
reported no enhancement of BCG-induced protection [16]. In this trial, the immunogenicity was 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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significantly lower than that seen in adults, and more potent routes of administration are of interest 
in the field. A phase IIb trial in HIV infected adults in South Africa and Senegal also demonstrated no 
efficacy [17]. Immunogenicity in this trial was also lower than that seen in UK adults and innovative 
ways of enhancing immunogenicity are urgently needed [17].  
To that end we are currently evaluating the safety and immunogenicity of a prime-boost regime using 
a simian adenovirus, ChAdOx1 85A prime - MVA85A boost regime.

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Protocol 
Phase 
Population 
Treatment groupsa 
Nb 
Study Status 
TB002 
Phase I open label non-
randomised 
Healthy BCG-naïve adults, 
UK 
5 x 107 pfu MVA85A (Days 0 & 21) 
14 
Completed 
GM920 
Phase I open label non-
randomised 
Healthy BCG-naïve or 
vaccinated adults, Gambia 
5 x 107 pfu MVA85A (Days 0 & 21) BCG naïve 
5 x 107 pfu MVA85A (Day 0) BCG-vaccinated 
11  
10  
Completed 
TB004 
Phase I open label non-
randomised 
Healthy BCG-naïve 
adults, UK 
1 x 106 pfu BCG prime (Day 0) 
5 x 107 pfu MVA85A boost (after 1 month) 
10 
Completed 
TB005 
Phase I open label non-
randomised 
Healthy BCG-vaccinated 
adults, UK 
5 x 107 pfu MVA85A (Day 0) 
21 
Completed 
TB007 
Phase I open label non-
randomised 
Healthy adults latently 
infected with M.tb, UK 
5 x 107 pfu MVA85A (Day 0) 
12 
Completed 
TB008 
Phase I open label non-
randomised 
Healthy BCG-naïve or 
vaccinated adults & 
adolescents, South Africa 
5 x 107 pfu MVA85A (Day 0) adults 
5 x 107 pfu MVA85A (Day 0) adolescents 
24  
12 
Completed 
TB009 
Phase I open label non-
randomised 
Healthy BCG-vaccinated 
adults, UK 
1 x 107 pfu MVA85A (Day 0) 
1 x 108 pfu MVA85A (Day 0) 
12 
12 
Completed 
TB010 
Phase I open label non-
randomised 
HIV-positive adults, UK 
5 x 107 pfu MVA85A (Day 0) 
1 x 108 pfu MVA85A (Day 0) 
10 
10 
Completed 
TB011 
Phase I open label non-
randomised 
Adults infected with M.tb, 
HIV, or both, South Africa 
5 x 107 pfu MVA85A (Day 0) TB 
5 x 107 pfu MVA85A (Day 0) HIV 
5 x 107 pfu MVA85A (Day 0) TB & HIV 
5 x 107 pfu MVA85A (Day 0) HIV on ART  
12  
12  
12 
12 
Completed 
TB012 
Phase II open label non-
randomised 
Healthy BCG-vaccinated 
infants, South Africa 
Stage 1 
EPI alone (Day 0) 
2.5 x 107 pfu MVA85A with EPI (Day 0) 
2.5 x 107 pfu MVA85A alone (Day 0)c 
EPI alone (Day 0) 
5 x 107 pfu MVA85A with EPI (Day 0) 
5 x 107 pfu MVA85A alone (Day 0)c 
Stage 2 
EPI alone 
5 x 107 pfu MVA85A with EPI (Day 0) 
5 x 107 pfu MVA85A alone (Day 0)c 
 
12 
12 
12 
12 
12 
12 
 
47 
47f 
48f 
Stage 1 
Completed 
 
 
 
 
 
Stage 2 
Completed 
 
TB014 
Phase II open label non-
randomised 
Healthy BCG-vaccinated 
children & infants, South 
Africa 
5 x 107 pfu MVA85A (Day 0) children 
2.5 x 107 pfu MVA85A (Day 0) infants 
5 x 107 pfu MVA85A (Day 0) infants 
1 x 108 pfu MVA85A (Day 0) infants 
24 
36 
36 
36 
Completed 

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Prevenar (variable dose) (Day 0) infants 
36 
TB017 
Phase I open label non-
randomised 
Healthy BCG-vaccinated 
adults, UK 
5 x 107 pfu FP85A (Day 0) 
5 x 107 pfu MVA85A (Day 0) then 5 x 107 pfu FP85A (Day 28) 
5 x 107 pfu FP85A (Day 0) then 5 x 107 pfu MVA85A (Day 28) 
12 
12 
7 
Completedd 
TB018 
Phase I open label non-
randomised 
Healthy BCG-vaccinated 
adults, UK 
1 x 108 pfu MVA85A (Day 0) 
1 x 108 pfu MVA85A (Day 0), 1g/kg deuterium-labelled glucose 
(Day 4) 
1 x 108 pfu MVA85A (Day 0), 1g/kg deuterium-labelled glucose 
(Day 10) 
4 
4 
 
4 
Completed 
TB019 
Phase I open label non-
randomised 
HIV-infected adults, 
Senegal 
1 x 108 pfu MVA85A (Day 0 & 168) 
1 x 108 pfu MVA85A (Day 0 & 168) on ART 
12 
12 
Completed 
TB020 
Phase II double blinded 
randomised 
Healthy BCG-vaccinated 
HIV-negative infants, South 
Africa 
1 x 108 pfu MVA85A (Day 0) 
Candin® (Day 0) 
1399  
1398
g 
Completed 
TB021 
Phase II double blinded 
randomised 
Healthy HIV-infected 
adults, South Africa & 
Senegal 
1 x 108 pfu MVA85A (Days 0, 168-252) 
Candin® (Days 0, 168-252) 
324i 
326i 
Completed 
TB022 
Phase I open-label 
randomised 
Healthy BCG-vaccinated 
adults, UK 
1 x 108 pfu MVA85A (IM) (Day 0) 
1 x 108 pfu MVA85A (ID) (Day 0) 
12 
12 
Completed 
TB023 
Phase I open-label non-
randomised 
Healthy BCG-naïve or 
vaccinated adults, UK 
1x108 pfu MVA85A (Day 0), BCG challenge (Day 28) 
BCG; 100µl ~ 2-8 x105 cfu 
24 
24 
Completed 
TB026 
Phase I randomised 
blinded 
Healthy BCG-vaccinated 
adults, UK 
1x108 pfu MVA85A (aerosol inhaled), saline placebo (ID)e 
1x107 pfu MVA85A (aerosol inhaled), saline placebo (ID)e 
1x107 pfu MVA85A (ID), saline placebo (aerosol inhaled)e 
2 
10 
12 
Completed 
TB028 
Phase I randomised 
blinded 
Health BCG-vaccinated 
adults, UK 
1x107 pfu MVA85A-IMX313 (ID) (Day 0) 
5x107 pfu MVA85A-IMX313 (ID) (Day 0) 
5x107 pfu MVA85A (ID) (Day 0) 
6 
12 
12 
Completed 
TB029 
Phase II randomised 
controlled trial 
Infants of HIV infected 
mothers, South Africa 
1x108 pfu MVA85A or Candin® control at birth 
BCG: 0.05ml 1-4 x 105 cfu at 8 weeks of age (HIV uninfected) 
124 
124 
Completed 
TB032 
Phase I open-label non-
randomised  
 
Healthy BCG-vaccinated 
adults, UK  
 
1 x 1011 vp AERAS-402 (Day 0 & 28) followed by 1 x 108 pfu 
MVA85A (Day 119)  
1 x 1011 vp AERAS-402 (Day 0) followed by 1 x 108 pfu MVA85A 
(Day 56)  
1 x 1011 vp AERAS-402 (Day 0, 28 and 119)  
12 
 
16h 
12 
Completed 
TB034 
Phase I open-label 
randomised trial  
Healthy BCG-vaccinated 
adults, UK  
5 x 109 vp ChAdOx1 85A (Day 0)  
2.5 x 1010 vp ChAdOx1 85A (Day 0)  
6 
12 
Completed 

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Table 2. Summary of clinical trials of MVA85A 
a. 
Intradermal route of administration unless otherwise stated 
 
 
b. 
Number of subjects is actual number enrolled for studies that have completed enrolment, and planned number of subjects for studies in which enrolment is ongoing or which are still blinded 
c. 
EPI deferred for 1 week 
d. 
Enrolment in TB017 was terminated early, due to issues with the supply of the FP85A vaccine 
e. 
Subjects blinded as to whether they received MVA85A via the ID or aerosol inhaled route 
f. 
47 subjects were randomised to receive MVA85A with EPI and 48 were randomised to receive MVA85A alone. As a result of an error, 1 subject switched groups, resulting in 48 subjects receiving MVA85A with EIP 
and 47 receiving MVA85A alone 
g. 
Two of the 1398 subjects randomised to the Candin® group were not vaccinated 
h. 
Two of these 16 subjects were vaccinated with AERAS-402 but discontinued from the study before receiving MVA85A 
i. 
One of the 324 subjects randomised to MVA85A/AERAS-485 was not vaccinated; one subject randomised to Candin® received MVA85A/AERAS-485 
j. 
The subjects, the bronchoscopist and immunologists were blinded to treatment assignment; the investigator administering the vaccinations was not blinded 
k.  
One subject withdrew post first vaccination but prior to boost vaccination, and was replaced 
l. 
Starter group not blinded. For groups A and B the subjects, the bronchoscopist, and immunologists are blinded to treatment assignment; the investigator administering the vaccinations is not blinded. 
 
 
 
 
2.5 x 1010 vp ChAdOx1 85, (Day 0), 1 x 108 pfu MVA85A (Day 56) 
2.5 x 1010 vp ChAdOx1 85A (Day 0 and 28), 1 x 108 pfu MVA85A 
(Day 119) 
12 
12 
TB035 
Phase I open-label 
randomised trial 
Healthy BCG-vaccinated 
adults, UK 
5 x 107 pfu MVA85A (aerosol inhaled); placebo (ID) (Day 0), 5 x 107 
pfu MVA85A (ID); placebo (aerosol inhaled) (Day 28)e 
5 x 107 pfu MVA85A (ID), placebo (aerosol inhaled) (Day 0), 5 x 107 
pfu MVA85A (aerosol inhaled), placebo (ID), (Day 28)e 
5 x 107 pfu MVA85A (ID), placebo (aerosol inhaled) (Day 0), 5 x 107 
pfu MVA85A (ID), placebo (aerosol inhaled) (Day 28)e 
12 
 
13k 
 
12 
Completed 
TB036 
Phase II open label trial 
Healthy BCG-vaccinated 
adolescents, Uganda 
1 x 108 pfu MVA85A (IM); D0 
1 x 108 pfu MVA85A (IM); D0 
18 
18 
Completed 
TB040  
Phase  I randomised, 
partially blindedl 
Healthy adults with latent 
M.tb infection, UK  
1 x 107 pfu aerosol inhaled MVA85A; D0 
5 x 107 pfu aerosol inhaled MVA85A and IM saline placebo; D0 j 
5 x 107 pfu IM injection of MVA85A and aerosol inhaled saline 
placebo; D0 j 
3 
6 
6 
Enrolling 

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Safety profile 
No signs of any Koch reaction (i.e. exacerbation of tissue damage at a focus of TB infection) have been 
seen in volunteers infected with M.tb with this or any other candidate TB vaccine to date. One possible 
vaccine related SAE – early unmasking of pre-existing tuberculous meningitis - occurred in a patient 
with HIV in South Africa.   
Typical local and systemic reactions to IM injection, and the preliminary analysis of local and systemic 
reactions induced by the aerosol route that were reported in the completed Phase I safety trial are 
summarised in section 5.3 “Risks and Benefits”. 
Dosing 
Dose studies of MVA85A have been performed in a step-wise fashion to minimise the risk of a Koch 
reaction and the incidence of adverse events. The main systemic (as opposed to aerosol) dose-finding 
trial compared boosting doses of 1 x 107 pfu and 1 x 108 pfu to previous trials using boosting doses of 
5 x 107 pfu. An intradermal dose of 1 x 108 pfu was found to be significantly more immunogenic than 
the lower doses without concomitant worsening of adverse event profile, and has been adopted as 
the standard dose in all subsequent trials [46, 47].  
Immunogenicity 
When evaluated by various assays of cellular immunology including interferon gamma (IFN-γ) ELISpot 
and intracellular cytokine staining assays, MVA85A has induced a strong and sustained cell-mediated 
immune response which is known to be important for protective immunity [48]. As the phase IIb 
efficacy trial of MVA85A in BCG-vaccinated infants in South Africa did not show protection against TB 
disease or M.tb infection above that of BCG alone, work to identify correlates of protection from this 
trial’s samples is now underway.  So far there is evidence that T cell activation prior to MVA85A was 
associated with increased risk for subsequent TB disease, whereas BCG-specific T cells (as assessed by 
IFN- ELIspot) and antigen 85A specific antibodies are associated with protection [49]. 
Route 
No significant difference in adverse events or immunogenicity has been seen when comparing IM and 
ID delivery of MVA85A [50]. 
5.1.4. Description and pre-clinical experience of ChAdOx1 and ChAdOx1 85A 
ChAdOx1 85A is an adenoviral vaccine based on a vector that is a chimpanzee adenovirus isolate Y25 
expressing the M.tb antigen 85A [51]. Adenoviruses are attractive candidates for use as viral vectors 
and have been used as vaccine vectors for a number of conditions; however, the use has been limited 
by the high level of anti-vector immunity present in humans in whom adenovirus is a ubiquitous 
infection. This has led to the consideration of simian adenoviruses, which are not known to cause 
pathology or illness in humans and to which the prevalence of anti-vector antibodies is low. The 
ChAdOx1 vector has been developed by the University of Oxford and been used with different inserts 
for vaccination, for example the vaccine ChAdOx1 NP+M1 has demonstrated an excellent safety 
profile in the Influenza trial FLU004. A BCG – ChAdOx1 85A – MVA85A prime boost regime is more 
protective than BCG alone in mice [22].  
5.1.5. Clinical studies with ChAdOx1 85A 
ChAdOx1 85A has been used in one human clinical trial. TB034 was a phase 1 randomised trial to 
evaluate the safety and immunogenicity of ChAdOx1 85A with and without heterologous boosting by 
MVA85A in BCG-vaccinated UK adults, 42 healthy volunteers aged 18 to 55 years. 42 volunteers 
received ChAdOx1 85A. The study was completed on 20/04/2016 with no safety concerns. 
 

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Protocol 
Phase 
Population 
Treatment groupsa 
Nb 
Study Status 
TB034 
Phase 
I 
open 
label 
non-
randomi
sed 
Healthy 
BCG-
vaccinated 
UK 
adults 
Starter: 5 x 109 vp ChAdOx1 85A at D0  
A: 2.5 x 1010 vp ChAdOx1 85A at D0 
B: 2.5 x 1010 vp ChAdOx1 85A at D0 followed by 1 x 
108 pfu MVA85A at D56 
C: 2.5 x 1010 vp ChAdOx1 85A at D0 followed by 2.5 
x 1010 vp ChAdOx1 85A at D28 and 1 x 108 pfu 
MVA85A at D119 
6 
12 
12 
 
12 
Completed 
a. 
Intramuscular route of administration unless otherwise stated 
 
 
b. 
Number of subjects is actual number enrolled  
Table 3.  TB034 trial design 
 
Safety profile 
There have been no SAEs to date with ChAdOx1 85A.  In TB034 the majority of local AE’s were mild to 
moderate in nature in all 4 groups. Two volunteers in Group B reported severe pain at vaccination site 
however this was following MVA85A vaccination at D56. Local redness and swelling across all 
vaccinations were comparable with no significant difference seen using one-way Anova with Tukey’s 
test for multiple comparisons (p>0.05). The majority of systemic, solicited AE’s, were also 
mild/moderate in nature. Those who reported a severe AE included 1 volunteer in Group A and 1 in 
Group B (following D0 ChAdOx1 85A) with severe feverishness and fatigue, and 1 Group A volunteer 
who reported a severe headache. One Group B volunteer reported severe feverishness and headache 
following D56 MVA85A vaccination. Of unsolicited AE’s considered to be possibly, probably or 
definitely related to vaccination, of note 1 volunteer in Group A reported axillary lymphadenopathy 
which was transient. There were 12 haematological laboratory AE’s considered to be possibly, 
probably or definitely related to vaccination. Of those with a temporal relationship to ChAdOx1 85A 
vaccination, there were 3 lymphopenias, 2 neutropenias, 1 leukopenia, 2 eosinophilias (both in same 
volunteer) and 1 thrombocytopenia. All fully resolved. There was 1 Group C volunteer with a 
lymphopenia possibly related to MVA85A D119 vaccination which was ongoing at the end of the study. 
All others were transient. 
Dosing 
As TB034 was a first in man trial for ChAdOx1 85A a lower dose of 5 x 109 vp was administered initially, 
with dose escalation post safety review as follows. The first six volunteers in the study received 5 x 109 
vp of ChAdOx1 85A. Their data was deemed to have an acceptable AE profile at review, and so the 
dose was escalated to 2.5 x 1010 vp ChAdOx1 85A. 
Immunogenicity 
A single dose of 2.5x1010 vp of ChAdOx1 85A induced significant Ag85A-specific IFN-γ responses 
following vaccination in the three study groups, these responses peaked 14 days post-vaccination 
(Wilcoxon test, p=0.0005 for Groups A (ChAdOx1 85A alone), B (ChAdOx1 85A – MVA85A) and C 
(ChAdOx1 85A – ChAdOx1 85A – MVA85A), and remained significantly higher than baseline at the end 
of follow-up (D168) in Group A (p=0.003). A second dose of ChAdOx1 85A did not boost these IFN-γ 
responses in Group C, however they were significantly boosted with MVA85A vaccination at D56 
(Group B) and D119 (Group C) (p=0.0005 at D63 (Group B) and D126 (Group C), IFN-γ responses 
remained significantly higher than at baseline at the end of the study (p=0.005 for Group B D224 and 
p=0.001 for Group C D287). No differences were detected in the magnitude of the MVA85A-boosted 
IFN-γ responses between Group B and Group C one week post-MVA85A (p=0.31). Polyfunctional CD4 
and CD8 + T cells are detectable after ChAdOx1 85A and MVA85A vaccinations.  
 

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5.2. Goal 
Our goal is to identify a TB vaccination regimen that will induce strong protective immune responses 
against tuberculosis in a tropical endemic setting. 
5.3. Hypothesis 
Our hypothesis is that a prime-boost regimen of ChAdOx1 85A – MVA85A will have greater 
immunogenicity than BCG revaccination among Ugandan adolescents who were BCG vaccinated at 
birth, and comparable immunogenicity to that observed in European adults. 
5.4. Risks and Benefits 
5.4.1. Potential risks  
The potential risks to volunteers in this trial include risks associated with: 
1. Venepuncture  
Localised bruising and discomfort can occur at the site of venepuncture. Infrequently fainting may 
occur. The total volume of blood drawn over a 6-month period will be 160mL, which should not 
compromise these otherwise healthy volunteers.  
2. Vaccination 
ChAdOx1 85A has been administered to 42 healthy UK adults with no SAEs or safety concerns. 
MVA85A has now been administered to over 2500 healthy human individuals with one possible 
serious adverse reaction (SAR). BCG is a licensed vaccine which has been administered to millions of 
people.  The potential known adverse events associated with vaccination are: 
Local reaction from IM vaccination 
The typical local reaction as a result of IM injection is temporary pain, redness and swelling at the site 
of the injection. 
Local reaction for intradermal (ID) vaccination 
BCG vaccination or revaccination usually causes local scarring and occasionally an abscess and regional 
lymphadenopathy [52]. 
Systemic reactions 
Constitutional influenza-like symptoms such as fatigue, headache, malaise, feverishness, and muscle 
aches can occur with any vaccination and last for 2-3 days. In the case of MVA85A, and ChAdOx1 85A 
these are usually mild to moderate in severity, and transient. Following ChAdOx1 85A vaccination in 
TB034, transient lymphopenia and neutropenia was seen in some volunteers; all spontaneously 
resolved. Similar mild to moderate transient abnormalities of leukocyte parameters have been previously 
noted in other adenovectored vaccine studies [24, 53].  
Presyncopal and syncopal episodes may occur at the time of vaccination which rapidly resolve. As with 
any other vaccine, immune mediated reactions that can lead to organ damage may occur. For 
influenza vaccines an excess of approximately 1 Guillain-Barré syndrome case per million persons 
immunised has been observed. No cases were observed in people under 45 years of age. However, 
this has never been seen with the ChAdOx1 85A or MVA85A vaccines or vaccines containing any of its 
components.  In immunocompromised people, BCG vaccination can cause disseminated disease [54, 
55]. 
Allergic reactions 

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Allergic reactions from mild to severe may occur in response to any constituent of a medicinal 
product’s preparation. Anaphylaxis is extremely rare (less than 1 in 1000 people) but can occur in 
response to any vaccine or medication.  
5.4.2. Potential benefits 
Volunteers are not expected to benefit directly from participation in this trial. Volunteers will gain 
some information about their general health as a result of the screening history, examination, blood 
tests, and urine tests. Volunteers found to have a previously undiagnosed condition thought to require 
further medical attention will be referred appropriately for further investigation and treatment, with 
their permission. 
It is hoped that their contribution will further the development of a safe and successful vaccine for TB 
and our knowledge about TB infection and protection.  
 
 

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6. OBJECTIVES AND OUTCOME MEASURES 
Table 4. Objectives and Outcome Measures 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation of this 
outcome measure  
Primary Objective 
To 
evaluate 
the 
safety 
and 
immunogenicity of ChAdOx1 85A – 
MVA85A prime-boost vaccination 
in Ugandan adolescents 
 
Actively and passively collected 
data on adverse events 
 
All Adverse Events (AEs) from day 
0-28 post vaccination 
Serious Adverse Events (SAEs) 
throughout follow up 
T-cell 
Interferon- 
ELIspot 
response to antigen 85A 
ELIspot spot-forming counts per 
1x106 
peripheral 
blood 
mononuclear cells (PBMCs) at day 
14 for groups 1-4 
ELIspot spot-forming counts per 
1x106 
peripheral 
blood 
mononuclear cells (PBMCs) at day 
63 for groups 5 and 6 
Area under the curve (AUC) 
analysis of immunogenicity (days 0-
168 for groups 1-4; days 0-168 for 
groups 5 and 6) 
Secondary Objective 
To 
further 
characterise 
immunogenicity of ChAdOx1 85A – 
MVA85A prime-boost vaccination 
in Ugandan adolescents 
 
 
Antibody response to antigen 
85A  
 
Exploratory 
immunology 
including ELIspot response to 
BCG, flow cytometry, gene 
expression, and mycobacterial 
killing assays 
 
 
Screening and follow up visits as 
shown in Schedule of Visits, section 
3  
Tertiary Objectives 
1.  To compare the response to 
ChAdOx1 85A – MVA85A prime-
boost vaccination with the response 
to BCG revaccination in Ugandan 
adolescents 
2.  To compare the response to 
ChAdOx1 85A – MVA85A prime-
boost 
vaccination 
in 
Ugandan 
adolescents with the response in 
Oxford adults 
3.  To investigate pre-immunisation 
epidemiological and immunological 
characteristics associated with the 
immune 
response 
induced 
by 
ChAdOx1 85A – MVA85A prime-
boost 
vaccination 
in 
Ugandan 
adolescents 
 
 
T-cell Interferon- ELIspot 
response to antigen 85A 
 
 
Antibody response to antigen 
85A, exploratory immunology 
including T cell ELIspots, flow 
cytometry, gene expression, and 
mycobacterial killing assays 
 
 
Primary 
outcomes 
for 
these 
analyses will be antigen 85A 
specific 
ELIspot 
spot-forming 
counts per 1x106 peripheral blood 
mononuclear cells (PBMCs) at day 
63 from the first vaccination and 
ELIspot AUC analysis 
Additional outcomes using data 
from follow up visits as shown in 
Schedule of Visits, section 3  
Screening and follow up visits as 
shown in Schedule of Visits, section 
3 

TB042 Clinical Trial Protocol v4.1   21st October 2020       CONFIDENTIAL 
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7. TRIAL DESIGN  
We will commence with a dose-escalation and age de-escalation study in healthy adults and 
adolescents in Uganda, focussing on ChAdOx1 85A, to provide safety data for ChAdOx1 85A in this 
population. These measures are not required for MVA85A since this vaccine has been more widely 
used, including among adolescents in Uganda, and the dose has been standardised (as described 
above).  
ChAdOx1 85A dose escalation and age de-escalation will be followed by a Phase IIa randomised trial 
comparing the immunogenicity of ChAdOx1 85A and MVA85A with the immunogenicity of BCG 
revaccination. ChAdOx1 85A and MVA85A will be administered via the intramuscular route. The target 
dose for the Phase IIa trial is 2.5x1010 vp because the lower dose is expected to have lower 
immunogenicity, based on the Oxford study, TB034 (Table 3, above).  Data from the Oxford study 
suggest that this dose will be well tolerated.  However, if this dose is not tolerated then the lower dose 
will be used.  The dose of MVA85A will be 1 x 108 pfu in the groups in which it is given. 
There will be 6 study groups with 3 to 30 volunteers in each group (Table 5).  
Dose escalation for ChAdOx1 85A in adults 
Group 1.  The first three adults will receive ChAdOx1 85A at 5 x109 vp. 
Group 2.  The next three adults will be enrolled after safety data has been reviewed by the trial 
management team to one week after ChAdOx1 85A vaccination in group 1. These adults will receive 
ChAdOx1 85A at 2.5 x1010 vp. 
Age de-escalation and dose escalation for ChAdOx1 85A in adolescents 
Group 3. The first three adolescents will be enrolled after safety data has been reviewed to one week 
after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 5 x109 
vp  
Group 4.  The next three adolescents will be enrolled after safety data has been reviewed to one week 
after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 2.5 
x1010 vp  
Randomised comparison of ChAdOx1 85A-MVA85A versus BCG revaccination 
Once safety data has been reviewed for groups 1 to 4 to one week post ChAdOx1.85A vaccination, 
recruitment to the randomised trial will commence. Sixty adolescents will be randomised, 30 (group 
5) to receive ChAdOx1 85A at 2.5 x1010 vp followed by MVA85A boost and 30 (group 6) to receive BCG 
revaccination. 
BCG will be obtained from the Serum Institute of India, an approved provider for Uganda, and used at 
the standard dose of 0.1mL. BCG will be given intradermally. 
7.1. Trial Numbers and Groups 
Group  
Sample size 
Intervention 
1 
3 adults 
ChAdOx1 85A at 5 x109 vp  
2 
3 adults 
ChAdOx1 85A at 2.5 x1010 vp  
3 
3 adolescents 
ChAdOx1 85A at 5 x109 vp  
4 
3 adolescents 
ChAdOx1 85A at 2.5 x1010 vp  
5 
30 adolescents 
ChAdOx1 85A at 2.5 x1010 vp followed by MVA85A 1 x 108 pfu 
6 
30 adolescents 
BCG revaccination, Serum Institute of India, 0.1 mL intradermally 

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Table 5. Trial groups 
7.2. Recruitment  
The Entebbe Mother and Baby Study. 
This project will be undertaken within the Entebbe Mother and Baby Study (EMaBS) cohort [56].  
Between 2003 and 2005, 2,507 pregnant women were recruited to the cohort at the antenatal clinic 
of Entebbe General Hospital, Uganda. The study area was Entebbe Municipality and the neighbouring 
Katabi sub-county. The original objective was to investigate the effects of prenatal exposure to 
helminth infection on the infant response to vaccines, and on infant susceptibility to infectious 
diseases [56]. Children were born between April 2003 and April 2006.  In 2018, they will be aged 12 to 
17 years. The cohort has unique value for this study because extensive data are available on factors 
relevant to this trial including date of birth, date and strain of infant BCG immunisation, immune 
responses to TB antigens at age one and five years, and exposure to infectious diseases including TB, 
malaria, helminths and viral infections. Genetic data are also available for this cohort. Field workers 
regularly visit the participants at home and record the location of the home by global positioning 
systems (GPS) in order to facilitate follow up, and to allow adjustment for potential confounding 
related to location of residence in the analysis of results. The EMaBS archived data will contribute to 
investigation of factors that impact vaccine immunogenicity (tertiary aim 3). 
Stakeholder engagement. 
Before initiating the study, we will hold a series of meetings to engage relevant stakeholders, including 
vaccine and tuberculosis programmes at the Ministry of Health, district health officials, local council 
leaders and hospital staff. Also, we will hold meetings for community representatives, and for EMaBS 
participants and their families. The proposed work will be explained, and questions about it will be 
addressed. A consultative group of selected parents will be set up; this group will advise us on issues 
such as the timing of activities in relation to the school year. 
Recruitment of volunteers 
Using the EMaBS databases, we will identify participants who have no known chronic illness (such as 
HIV infection or sickle cell disease), who are either still resident in the original study catchment area 
or participants with documented good attendance who are willing to attend as required and who 
received immunisation within two weeks of birth with BCG Russia (BCG-I strain from Moscow, Serum 
Institute of India, India; the strain used for most EMaBS infants). A randomised list of these 
participants will be generated and they will be approached sequentially until the enrolment is 
complete.   
Potential adolescent volunteers and their parents or guardians will be invited to attend the clinic for 
the screening processes. 
To recruit the six adults, parents or guardians of EMaBS children will be approached until the target 
number have been enrolled.  Only one parent or guardian will be enrolled from each family.   
7.3. Informed Consent 
All volunteers will sign and date the informed assent form before any study specific procedures are 
performed, and a parent or guardian will sign a consent form (except in the case of adult volunteers, 
when only a consent form will be signed). The information sheet will be made available to the 
volunteer and their parents/ guardians at least 24 hours prior to the screening visit. At the screening 
visit, the volunteer and their parent/guardian will be fully informed of all aspects of the trial, the 
potential risks and their obligations. The following general principles will be emphasised: 
• 
Participation in the study is entirely voluntary 
• 
Refusal to participate involves no penalty or loss of medical benefits 

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• 
The volunteer may withdraw from the study at any time 
• 
The volunteer is free to ask questions at any time to allow him or her to understand the 
purpose of the study and the procedures involved 
• 
The study involves research of investigational vaccines 
• 
There is no direct benefit from participating 
• 
The volunteer’s EMaBS clinic file will be reviewed to corroborate their medical history 
• 
The volunteer’s blood samples taken as part of the study will be stored indefinitely and 
samples may be sent outside of Uganda to collaborating laboratories in the UK. These will be 
anonymised. 
The aims of the study and all tests to be carried out will be explained. The volunteer will be given the 
opportunity to ask about details of the trial, and will then have time to consider whether or not to 
participate. If they do decide to participate, they will sign and date two copies of the assent and 
consent forms, one for them to take away and keep, and one to be stored in the case report form 
(CRF). Separate information and consent forms will be provided for consent for storage of samples for 
future studies, and for anonymous sharing of data from this study. These forms will also be signed and 
dated by the Investigator. 
7.4. Inclusion Criteria 
Volunteers must meet all of the following criteria to enter the trial: 
• 
Resident within the study area and planning to be resident in the study area for the duration of 
the study or participants with documented good attendance who are willing to attend as required 
• 
Participant in the Entebbe Mother and Baby Study; healthy; aged 12 to 17 [or, for adults, a parent 
or guardian of a participant; healthy; aged 18 to 49] 
• 
Documented immunisation within two weeks of birth with BCG Russia (BCG-I strain from Moscow, 
Serum Institute of India, India) [adolescents only] 
• 
BCG scar or documented previous BCG immunisation [adults only] 
• 
No relevant findings in medical history or on physical examination 
• 
Written informed consent by parent or guardian [or by the volunteer themselves, for adults] 
• 
Written informed assent by subject [for adolescents] 
• 
Agreed to refrain from blood donation during the trial [adults only; adolescents under age 18 are 
not eligible to give blood] 
• 
Agree to avoid pregnancy for the duration of the trial (female only) 
• 
Able and willing (in the Investigator's opinion) to comply with all the study requirements  
7.5. Exclusion Criteria 
Volunteers must meet none of the following criteria to enter the trial: 
• 
Clinical, radiological, or laboratory evidence of current active TB diseasea 
• 
Laboratory evidence at screening of latent M.tb infection as indicated by a positive ELISPOT 
response to ESAT6 or CFP10 antigensb 
• 
Previous treatment for active or latent tuberculosis infection 
• 
Shared a residence with an individual who has started on anti-tuberculosis treatment, or been 
diagnosed with culture or smear-positive pulmonary tuberculosis, within six months prior to day 
0  
• 
Received a TST within 90 days prior to day 0 

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• 
Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer, 
cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder 
and neurological illness, drug or alcohol abuse 
• 
History of serious psychiatric condition or disorder 
• 
Concurrent oral or systemic steroid medication or the concurrent use of other 
immunosuppressive agents within 2 months prior to enrolment 
• 
History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of 
the study vaccine, including eggs 
• 
Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that 
may compromise the safety of the volunteer in the studya 
• 
Positive HBsAg, HCV or HIV antibodiesa 
• 
Use of an investigational medicinal product or non-registered drug, live vaccine, or medical device 
other than the study vaccine for 30 days prior to dosing with the study vaccine, or planned use 
during the study period 
• 
Administration of immunoglobulins and/or any blood products within the three months preceding 
the planned trial vaccination date 
• 
Female currently lactating, confirmed pregnancy or intention to become pregnant during the trial 
period 
• 
Screening blood sample positive for malaria by microscopy  
aSubjects who are excluded from the trial because they have been discovered during screening 
procedures to be suffering from a previously undiagnosed condition thought to require further 
medical attention will be referred appropriately for further investigation and treatment. 
bSubjects discovered to have evidence of latent M.tb infection as defined by a positive ELISPOT test 
will be referred for a plain chest X-ray and reviewed by a physician and considered for 
chemoprophylaxis. If there is any evidence of active TB disease either on clinical or radiological 
grounds, further investigation and treatment will be offered in collaboration with the National 
Tuberculosis Control Programme. 
Effective contraception for female volunteers 
Adolescent female volunteers will need to agree not to become pregnant during the course of the 
trial.  The introduction of formal methods of contraception in the young adolescent age group to be 
enrolled in this study would not be appropriate in Uganda. 
Adult female volunteers will be required to use an effective form of contraception during the course 
of the trial. There is no information about the effect of ChAdOx1 85A on a fetus. Previous 
investigations looking at excretion of viral vectors after vaccination in urine for males, demonstrated 
no detectable virus; therefore males are not required to use barrier contraception whilst taking part 
in this study as the risk of excretion of the virus is very low. 
Acceptable forms of contraception for female volunteers include: 
• 
Established use of oral, injected or implanted hormonal methods of contraception 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
• 
Permanent sterilisation or bilateral tubal occlusion 
• 
Barrier methods of contraception (condom; or occlusive cap with spermicide) 
• 
Male sterilisation, if the vasectomised partner is the sole partner for the subject 
• 
True abstinence, when this is in line with the preferred and usual lifestyle of the subject 
(periodic abstinence and withdrawal are not acceptable methods of contraception) 

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7.6. Screening and Eligibility Assessment 
Once the informed consent process has been completed, and consent (and assent) given, a baseline 
medical history (including concomitant medication) and history relating to risk of prior TB exposure 
will be collected. Vital signs will be checked and a physical examination will be performed. Inclusion 
and exclusion criteria will be checked using a tabulated format.  
Subjects will undergo pre- and post-test counselling for HIV, hepatitis B and C testing and (for girls) 
pregnancy testing by a trained and experienced nurse- or clinician-counsellor. Blood, urine and stool 
samples will be obtained, for tests as specified in the schedule of procedures. These tests are planned 
in order to exclude major, immunomodulating co-infections (HIV, malaria) or conditions that might 
impact safety, or the assessment of safety-related parameters (hepatitis, pregnancy). The total 
duration of the screening visit will be approximately one and a half hours. 
Subjects with abnormal findings on screening will be counselled, managed and referred as 
appropriate.   
• 
Any volunteers found to be HIV positive will be offered a CD4 T cell count and treated with 
antiretroviral therapy under the auspices of the EMaBS clinic, or referred to another provider, 
if preferred. 
• 
Any volunteers with evidence of hepatitis C infection, or of active hepatitis B infection (surface 
antigen positive) will be supported to undergo further serology and viral load testing 
(available, for example, at MBN laboratory, Nakasero, Kampala) and abdominal ultrasound. 
They will then be referred to Mulago Hospital (the national referral hospital) for further follow 
up and care. 
• 
Volunteers found to have a positive ELISPOT for M. tuberculosis–specific antigens (suggesting 
M.tb infection) will be examined by a physician, have a sputum examination (if they have a 
productive cough) and will be offered a chest x-ray. If there is evidence of active tuberculosis 
they will be referred to the nearest treatment centre of the National Tuberculosis Control 
Programme for further management. 
• 
Volunteers found to be positive for malaria will be treated. 
• 
Asymptomatic helminth infection (with normal full blood count, biochemistry and liver 
function tests) will not be an exclusion criterion.  These will be treated after data on the 
primary outcomes have been collected since it is possible that helminth co-infection 
contributes to the “normal” baseline immunological status in African populations, and 
treatment of helminths can result in sudden changes in immunological parameters [57]. 
Volunteers with asymptomatic helminth infection will be treated according to the schedules 
in section 3. 
• 
Volunteers found to have helminth infections that require immediate treatment (hookworm 
and haemoglobin level below 8 g/dl; Schistosoma mansoni with egg counts >2000 per gram (a 
level at which intensity is associated with hepatosplenic morbidity [58]) will be treated 
immediately.   
• 
Volunteers found to be pregnant will be counselled and referred to the most convenient 
antenatal care clinic of their choice. 
7.7. Enrolment 
Subjects who complete the screening processes, satisfy all the inclusion criteria, and meet none of the 
exclusion criteria will be enrolled into the trial and their visits scheduled in the calendar. The ongoing 
eligibility of the subject will be reviewed on the day of enrolment and any new events, medications, 
or changes to the screening documents recorded. Subjects will be enrolled on the vaccination visit 
(day 0). The vaccination visit will last approximately two hours, which includes a 60 minute follow up 
period in the clinic for observation after vaccination.  

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7.8. Randomisation and blinding 
After completion of the dose escalation and age de-escalation components, enrolment to the 
randomised trial of ChAdOx1 85A-MVA85A versus BCG revaccination will commence. This will be an 
open label trial as it will not be possible to blind either volunteers or clinic staff to the allocation.  
However, laboratory staff will be blinded to the allocation of the volunteers as they undertake the 
immunological assays.   
The randomisation code will be generated by an independent statistician. Eligible volunteers will be 
sequentially allocated to a randomisation number by the screening interviewer. Sealed envelopes, 
labelled with the code, will contain instructions on which vaccines should be given. 
7.9. Timepoints 
Screening – trial enrolment time window 
Enrolment should take place no longer than 90 days following the date of screening appointment. If 
more than 90 days elapse, the screening visit should be repeated in full prior to enrolment in order to 
minimise the risk to volunteers of any new unidentified health problems having arisen during that 
period. 
Vaccination of first volunteer – subsequent vaccination time window 
The first volunteer, who will be allocated to Group 1, will be vaccinated with ChAdOx1 85A by the 
intramuscular route at least 7 days before any subsequent volunteers in this group. After safety review 
by the clinical team and the Chief Investigator of the three Group 1 volunteers, the first volunteer in 
Group 2 will be vaccinated at least 7 days prior to further volunteer enrolment into Group 2. After 
similar safety review of the three Group 2 volunteers, the first volunteer in Group 3 will be vaccinated 
at least 7 days prior to further enrolment into Group 3.  After similar safety review of the three Group 
3 volunteers, the first volunteer in Group 4 will be vaccinated at least 7 days prior to further enrolment 
into Group 4.  After review by the clinical team and the Chief Investigator of the safety data from 
groups 1-4, enrolment into the randomised trial will commence. The data and safety monitoring board 
(DSMB) will be consulted if there are any issues of concern. 
Follow up period 
The follow up period for those enrolled after the COVID 19 lockdown will be 24 weeks after first 
vaccination and 24 weeks after booster vaccination for those enrolled before the lockdown in 
accordance with findings from previous studies in which adequate safety data and reliable markers of 
immunogenicity have been obtained in this time interval. Due to the nearly three months COVID-19 
lockdown and halting of trial activities, participants who had already been enrolled in the trial by that 
time will have a later MVA85A vaccination boost ranging up to 52 weeks (instead of 8 weeks) after 
initial vaccination with ChAdox1 85A. Their subsequent follow up visits will be at day 7, day 28, 3 
months and 6 months post boost vaccination. Their follow up visits will therefore fall within the 
following ranges of 63-372, 84-393, 140-449 and 224-533 days.  Newly enrolled participants into 
Group 5 will follow the original schedule of the MVA85A boost at day 56 and subsequent follow up 
visits on days 63, 84, 140 and 224. All follow up visits will last approximately 15 to 30 minutes. Most 
of the participants are currently in secondary school which are either day or boarding. For logistical 
and time management purposes as well as to minimize disruption of their studies, participants in 
boarding schools will be offered the option of having follow up visits done at the school premises. A 
qualified clinician and nurse will visit the school with the necessary supplies and equipment for the 
visit on the said date. The clinician will examine and assess the participant while the nurse will draw 
blood and collect the relevant samples for that visit. The trial team will seek permission and a formal 
introductory letter from the district education officials to the school management for access to the 
schools. The team will secure suitable space for these activities. The team will ensure the participant 

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is in a good health condition before departing from the school. The study contact phone number will 
be availed to the school to follow up on any concerns.        
7.10. 
Sample handling 
Details regarding samples, volume and frequency of sampling are listed in the Schedule of Trial Visits 
and Procedures (section 3.2). Blood and other samples will be processed according to local laboratory 
SOPs. All samples will be in anonymised form.  
Volunteers will be informed that there may be leftover samples of their blood. With the volunteers’ 
informed consent, any leftover cells and serum, or plasma samples will be frozen for future analysis 
of M.tb and/or BCG-related responses. This may include human DNA and RNA analysis to search for 
correlates of TB risk and/or protection. Samples may be shipped to other parties involved in our 
research in anonymised form for immunological analysis. Volunteers will be able to decide if they will 
permit such future use of any leftover samples. If they elect not to permit this, all of those leftover 
samples will be discarded after the required period of storage to meet GCP and regulatory 
requirements.  
7.11. 
Vaccination Postponement Criteria 
The following adverse events constitute contraindications to administration of vaccine at that point in 
time; if any one of these adverse events occurs at the time scheduled for vaccination, the subject may 
be vaccinated at a later date, or withdrawn at the discretion of the Investigator. The subject must be 
followed until resolution of the event as with any adverse event: 
• 
Acute disease at the time of vaccination. (Acute disease is defined as the presence of a 
moderate or severe illness with or without fever). All vaccines can be administered to persons 
with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-
grade febrile illness, i.e. temperature of ≤37.5°C/99.5°F. 
• 
Temperature of >37.5°C (99.5°F) at the time of vaccination. 
7.12. 
Discontinuation / Withdrawal Criteria 
In accordance with the principles of the current revision of the Declaration of Helsinki and any other 
applicable regulations, a volunteer has the right to withdraw from the study at any time and for any 
reason, and is not obliged to give his or her reasons for doing so. The Investigator may withdraw the 
volunteer at any time in the interests of the volunteer’s health and well-being. In addition the 
volunteer may withdraw/be withdrawn for any of the following reasons: 
• 
Administrative decision by the Investigator. 
• 
Ineligibility (either arising during the study or retrospectively, having been overlooked at 
screening). 
• 
Significant protocol deviation. 
• 
Volunteer non-compliance with study requirements. 
• 
An AE, which requires discontinuation of the study involvement or results in inability to 
continue to comply with study procedures. 
Any volunteer who becomes pregnant during the trial will be followed up as per the protocol and until 
the end of the pregnancy. The babies will also be followed up and examined for any adverse effects.  
We will not routinely perform venepuncture in a pregnant volunteer. 
The reason for withdrawal will be recorded in the CRF. If withdrawal is due to an AE, appropriate 
follow-up visits or medical care will be arranged, with the agreement of the volunteer, until the AE has 

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resolved, stabilised or a non-trial related causality has been assigned. Any volunteer who is withdrawn 
from the study may be replaced, if that is possible within the specified time frame. Any volunteer who 
fails to attend for two or more follow-up visits during the study will be deemed to have withdrawn 
from the study. 
If a volunteer withdraws from the study, blood samples collected before their withdrawal from the 
trial will be used/ stored unless the volunteer specifically requests otherwise.  
In all cases of subject withdrawal, excepting those of complete consent withdrawal, long-term safety 
data collection, including some procedures such as safety bloods, will continue as appropriate if 
subjects have received one or more vaccine doses.  
7.13. 
Discontinuation of the trial 
The trial will be discontinued in the event of any of the following: 
• 
New scientific information is published to indicate that volunteers in the trial are being exposed 
to undue risks as a result of administration of the IMPs, or as a result of the trial procedures or 
follow-up schedule. 
• 
Serious concerns about the safety of either of the IMPs arise as a result of one or more IMP-
related SAE(s) occurring in the volunteers enrolled in this or any other ongoing trial of these 
IMPs. 
• 
For any other reason at the discretion of the Investigator. 
7.14. 
End of Study Definition 
The trial will be completed when the last volunteer enrolled into the trial has completed their final 
follow up visit. 
8. CLINICAL PROCEDURES 
This section describes the clinical procedures for evaluating study volunteers and follow-up after 
administration of study vaccine.  
8.1. Schedule of Attendance 
All volunteers will have the same schedule of clinic attendances and procedures as indicated in the 
Schedules of Visits and Procedures (section 3). The total volume of blood donated during the study 
will be 160mL. Additional visits or procedures may be performed at the discretion of the investigators, 
e.g., further medical history and physical examination, or urine microscopy in the event of positive 
urinalysis. Participants will be given the option of having follow up visits done at school as detailed in 
section 7.9.  
8.2. Observations 
Pulse, blood pressure and temperature will be measured at the time-points indicated in the Schedule 
of Visits and Procedures (section 3) and may also be measured as part of a physical examination if 
indicated at other time-points. 
8.3. Blood tests, urine and stool analysis 
Blood will be drawn for the following laboratory tests and processed at the EMaBS clinic laboratory, 
or in laboratories at the Uganda Virus Research Institute (UVRI), using standard procedures: 
• 
Haematology and haemoparasitology: full blood count, malaria slide, Mansonella perstans (using 
modified Knott’s method [59]); malaria PCR will be conducted for sub-microscopic parasitaemia. 

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• 
Biochemistry: Sodium, Potassium, Urea, Creatinine, Albumin, Liver Function Tests (ALT, ALP, GGT) 
• 
Diagnostic serology: HBsAg, HCV antibodies, HIV antibodies (specific consent will be gained prior 
to testing blood for these blood-borne viruses) 
• 
Exploratory Immunology: Immunogenicity will be assessed by a variety of immunological assays. 
This includes ex vivo ELISpot assays for interferon gamma and flow cytometry assay. Other 
exploratory immunological assays including cytokine analysis and gene expression studies 
amongst others may be performed at the discretion of the Investigators.  Immunological assays 
will be conducted according to local SOPs. 
• 
Urinalysis: Urine will be tested for protein, blood and glucose at screening. For female volunteers 
only, urine will be tested for beta-human chorionic gonadotropin (β-HCG) at screening and 
immediately prior to vaccination. Urine will also be examined for circulating cathodic antigen of 
Schistosoma species. 
• 
Stool:  stool samples will be examined for helminths by the Kato Katz method, and by PCR [60].  A 
sample will be stored for possible analysis of the microbiome in future. 
Genetic studies, including a genome wide association analysis and work on HLA typing, have already 
been undertaken among EMaBS participants, based on prior ethical approval and consent. Genetic 
analyses relevant to vaccine responses were the primary motivation for the work.  This will provide 
the opportunity for genetic analyses using immunological data generated under this new protocol 
also.     
Collaboration with other specialist laboratories in the UK, Europe and outside of Europe for further 
exploratory tests may occur. This would involve the transfer of serum, urine or plasma and/or PBMC 
to these laboratories, but these would remain anonymised. Informed consent for this will be gained 
from volunteers.  A Material Transfer Agreement will be submitted for review and approval before 
any samples are sent to collaborating institutions. 
8.4. Study visits  
The study visits and procedures will be undertaken by one of the clinical trials team. The procedures 
to be included in each visit are documented in the Schedule of Visits and Procedures (Section 3). Each 
visit is assigned a time-point and a window period, within which the visit will be conducted. 
8.4.1. Screening visit 
All potential volunteers will have a screening visit, which may take place up to 120 days prior to 
vaccination. Informed consent will be taken before screening, as described in section 7. If consent is 
obtained, the procedures indicated in the Schedule of Visits and Procedures (section 3) will be 
undertaken including a medical history, physical examination and blood tests.  
The subject’s EMaBS study file will be reviewed to ascertain any significant medical history.  Abnormal 
clinical findings from the urinalysis or blood tests at screening will be assessed according to normal 
ranges defined locally by Lugada and colleagues for haematology [61], and those provided by the ISO 
accredited Clinical Diagnostic Laboratory at UVRI for biochemistry. Any abnormal test result deemed 
clinically significant may be repeated to ensure it is not a single occurrence. If an abnormal finding is 
deemed to be clinically significant, the volunteer will be informed and appropriate medical care 
arranged with the permission of the volunteer.  
The eligibility of the volunteer will be reviewed at the end of the screening visit and again when all 
results from the screening visit have been considered. Decisions to exclude the volunteer from 
enrolling in the trial or to withdraw a volunteer from the trial will be at the discretion of the 
Investigator. If eligible, a day 0 visit will be scheduled for the volunteer to receive the vaccine. 

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8.4.2. Day 0: Enrolment and vaccination visit 
Volunteers will not be considered enrolled in the study until they have received a vaccine. Before 
vaccination, the eligibility of the volunteer will be reviewed. Pulse, blood pressure and temperature 
will be observed and if necessary, a medical history and physical examination may be undertaken to 
determine need to postpone vaccination depending on criteria listed in section 7.11. A pregnancy test 
will be repeated for female volunteers.  Vaccinations will be administered as described below.  
8.4.3. Vaccination (D0) 
Group 1 adults will be given ChAdOx1 85A at 5 x109 vp intramuscularly 
Group 2 adults will be given ChAdOx1 85A at 2.5 x1010 vp intramuscularly 
Group 3 adolescents will be given ChAdOx1 85A at 5 x109 vp intramuscularly 
Group 4 adolescents will be given ChAdOx1 85A at 2.5 x1010 vp intramuscularly 
Group 5 adolescents will be given ChAdOx1 85A at 2.5 x1010 vp intramuscularly followed by MVA85A 
boost at 1 x 108 pfu intramuscularly between day 56 and day 140  
Group 6 adolescents will be given BCG revaccination, Serum Institute of India, 0.1 mL intradermally 
Following vaccination the following procedures will be undertaken:  
In all groups, volunteers will be given a thermometer, tape measure and paper diary card, with 
instructions on use, along with the emergency 24 hour telephone number to contact the on-call study 
physician if needed. Volunteers will be instructed on how to self-assess the severity of these AEs. There 
will also be space on the diary card to self-document unsolicited AEs, and whether medication was 
taken to relieve the symptoms. Diary cards will collect information on the timing and severity of the 
following solicited AEs: 
Local solicited AEs 
Systemic solicited AEs 
Pain 
Fever 
Redness 
Feverishness/Chills 
Warmth 
Joint pains 
 Itch 
Muscle pains 
Blistering or ulceration 
Fatigue 
Swelling of local lymph nodes 
Headache 
 
Malaise 
 
Abdominal pain 
 
Chills 
Table 6. Solicited AEs as collected on post vaccination diary cards 
 
8.4.1. 
Subsequent visits 
All volunteers will be asked to attend as per the Schedule of Visits and Procedures in section 3.  On 
visits other than for vaccination the volunteers will be assessed for local and systemic adverse events, 
using paper diary cards, interim history, physical examination and blood tests at the time-points 
indicated in the Schedule of Visits and Procedures (Section 3). Blood will also be taken for assessments 
of immunogenicity and exploratory immunology analysis. These follow up visits may be done at school 
(see section 7.9).  

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8.4.2. MVA85A booster immunisation. 
Volunteers in group 5 will be asked to attend between day 56 and day 365 for booster immunisation 
with MVA85A [volunteers in group 6 will also be asked to attend on this date, but only to provide the 
samples indicated]. For participants who were enrolled in the trial prior to the COVID-19 lockdown, 
this boost visit will fall between day 56 and day 365 after enrolment into the trial while for newly 
enrolled participants, the boost will be done on day 56.    
For group 5, before the MVA85A vaccination, the health of the volunteer will be reviewed. Pulse, blood 
pressure and temperature will be observed and if necessary, a medical history and physical 
examination may be undertaken to determine need to postpone booster vaccination. For girls, a 
pregnancy test will be repeated.  If the volunteer is well and the pregnancy test is negative MVA 
vaccination will be administered at 1 x 108 pfu. 
Group 5 volunteers will be provided with a diary card and instructed in its use as described above. 
Diary cards will be collected two weeks after ChAdOx1 85A and one week after MVA85A as these 
intervals correspond to the optimal time points for assessing the initial response to the two vaccines. 
9. INVESTIGATIONAL PRODUCTS 
9.1. ChAdOx1 85A 
9.1.1. ChAdOx1 85A Description 
ChAdOx1 85A is a new adenoviral vaccine vector (ChAdOx1) based on a chimpanzee adenovirus isolate 
Y25 expressing M. tb antigen 85A. ChAdOx1 85A is a replication defective adenovirus where the E1 
locus, required for viral replication has been deleted. This virus can therefore be propagated easily 
with good yields in cell lines expressing E1 from AdHu5 such as human embryonic kidney cells 293 
(HEK 293). ChAdOx1 85A also encodes almost the complete M. tb gene for Ag85A. 
9.1.2. Supply and Storage of ChAdOx1 85A 
ChAdOx1 85A is manufactured under Good Manufacturing Practice conditions at the Clinical 
Biomanufacturing Facility (CBF), University of Oxford. The vaccine is supplied as a liquid in glass vials 
for intramuscular administration and is stored at -80oC, in a locked, alarmed, temperature monitored 
freezer at the CCVTM, University of Oxford.  
ChAdOx 85A will be shipped from CBF directly to the UVRI on dry ice and in the presence of a 
temperature logger. The vaccine will be certified and labelled for use in trial TB042 by a qualified 
person (QP) at CBF.  
The vaccine will be stored at -80°C (nominal temperature) in a secure, temperature-monitored freezer 
at UVRI.  
All movements of the study vaccine between the CBF and UVRI will be documented. Vaccine 
accountability, storage, shipment and handling will be in accordance with our vaccine related SOPs 
and associated forms. 
9.1.3. Formulation of ChAdOx1 85A 
The ChAdOx1 85A vaccine is formulated in formulation buffer at a concentration of 1.74 x 1011 vp/ mL. 
The formulation buffer consists of 10mM Histidine, 7.5% sucrose, 35mM NaCI, 1mM MgCl2, 0.1% 
PS80, 0.1mM EDTA, 0.5% EtOH, pH 6.6. The fill volume is 0.5 mL. 

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9.1.4. Dispensing and administration of ChAdOx1 85A 
All movements of vials of the trial vaccine between the CBF and UVRI, and in or out of the locked 
freezers, will be documented. On vaccination day, vaccines will be allowed to thaw to room 
temperature and will be administered within 1 hour. The vaccine will be administered intramuscularly 
over the deltoid region of the non-dominant upper arm, according to the standardized SOP. Subjects 
will stay in the unit for 60 minutes (±10 minutes) after vaccination. During the administration of the 
vaccine, monitoring equipment, oxygen, medicines including bronchodilators and resuscitation 
equipment will be immediately available for the management of anaphylaxis and bronchospasm. 
In order to minimise dissemination of the recombinant vectored vaccine virus into the environment, 
a number of measures will be instituted during and following vaccination: 
• 
The intramuscular injection site will be covered with a dressing after vaccination to absorb 
any virus that may leak out through the needle track. The dressing will be removed from the 
injection site after 30 minutes. 
• 
The dilution process will be carried out in a sealed vial in accordance with the standardized 
SOP. 
• 
All disposable items including needles, vials, dressings, and protective clothing will be 
disposed of as GMO waste by autoclaving, in accordance with the current approved SOPs and 
standard practice. 
9.2. MVA85A 
9.2.1. MVA85A Description 
The MVA85A vaccine consists of the attenuated vaccinia virus MVA vector with a 1176 base-pair 
insert, which is almost the complete M.tb gene for Ag85A, with the tissue plasminogen activator (TPA) 
signal sequence preceding the N terminus and a monoclonal antibody tag (pk) at the C terminus. 
Expression of the antigen 85A DNA sequence is regulated by the vaccinia P7.5 early/late promoter. 
MVA85A is manufactured under Good Manufacturing Practice conditions by IDT Biologika GmbH (IDT), 
Germany. 
9.2.2. Formulation of MVA85A 
MVA85A is supplied as a sterile liquid in glass vials. Each vial of lot 0050811 contains 400 µL of vaccine 
at a concentration of 8.4 x 108 pfu/mL in 10mM Tris buffer 140 mM NaCl; pH 7.7. The dose of MVA85A 
to be used is 1 x 108pfu.  
9.2.3. Storage of MVA85A 
MVA85A will be shipped from IDT directly to the UVRI on dry ice and in the presence of a temperature 
logger. The vaccine will be certified and labelled for use in trial TB042 by a qualified person (QP) at 
IDT.  
The vaccine will be stored at -80°C (nominal temperature) in a secure, temperature-monitored freezer 
at UVRI.  
All movements of the study vaccine between IDT and UVRI will be documented. Vaccine 
accountability, storage, shipment and handling will be in accordance with our vaccine related SOPs 
and associated forms. 

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9.2.4. Dispensing and administration of MVA85A 
All movements of vials of the trial vaccine between IDT/CBF and UVRI and in or out of the locked 
freezer will be documented. Vaccine accountability, storage, shipment and handling will be in 
accordance with local SOPs and other relevant local forms. 
On vaccination day, vaccines will be allowed to thaw to room temperature and will be administered 
within 1 hour. The vaccine will be administered IM over the deltoid region of the non-dominant upper 
arm, according to the site-specific SOP. Volunteers will stay in the unit for 60 minutes (±10 minutes) 
after vaccination. During the administration of the vaccine, monitoring equipment, oxygen, medicines 
including bronchodilators and resuscitation equipment will be immediately available for the 
management of anaphylaxis and bronchospasm according to the site-specific SOP.  
In order to minimise dissemination of the recombinant vectored vaccine virus into the environment, 
a number of measures will be instituted during and following vaccination: 
• 
The dilution process will be carried out in a sealed vial in accordance with the vaccine dilution 
SOP.  
• 
The IM injection site will be covered with a dressing after vaccination to absorb any virus that 
may leak out through the needle track. The dressing will be removed from the injection site 
after 30 minutes and will be disposed as GMO waste by autoclaving. 
• 
All disposable items including nebuliser parts, needles, vials, dressings, and protective clothing 
will be disposed of as GMO waste by autoclaving, in accordance with the current approved 
SOP and standard practice. 
9.3. Vaccine accountability and disposal 
On completion of the trial and of close-out monitoring visits to check vaccine accountability, at the 
request of the CI, any remaining vials of investigational vaccines held in Uganda will either be shipped 
back to the Sponsor or will be destroyed by the National Drug Authority, and a certificate of shipment 
or destruction will be obtained as applicable. 
10. ASSESSMENT OF SAFETY   
Safety will be assessed by the frequency, incidence and nature of adverse events and serious adverse 
events arising during the trial.  
10.1. 
Interim Safety Review 
Prior to dose escalation of the IMP or age de-escalation, the clinical team and Chief Investigator will 
review the safety data and adverse events in volunteers before proceeding to the next group. 
Dose escalation or age de-escalation will not take place in the event of any of the holding criteria being 
met.  In addition, the Phase IIa randomised trial will be held, and the DSMB will be consulted, if any of 
the following holding criteria occurs. 
10.1.1. Holding criteria 
Safety holding rules would be activated by any of the following: 
• 
A serious adverse event considered possibly, probably or definitely related to vaccination occurs 
• 
Death occurs 
• 
A life-threatening reaction occurs 
• 
Solicited systemic adverse events:  

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If 2 or more vaccinations in group 1, 2, 3 or 4; or more than 25% of doses of the vaccine in group 
5; is followed by the same Grade 3 solicited systemic adverse event beginning within 2 days after 
vaccination (day of vaccination and one subsequent day) and persisting at Grade 3 for >48hrs.  
• 
Unsolicited adverse events: 
If 2 or more vaccinations in group 1, 2, 3 or 4; or more than 25% of doses of the vaccine in group 
5; develop the same Grade 3 unsolicited adverse event beginning within 7 days after vaccination 
that is considered related to vaccination and persists at Grade 3 for > 48 hours.  
• 
Laboratory adverse event: 
If 2 or more vaccinations in group 1, 2, 3 or 4; or more than 25% of doses of the vaccine in group 
5; develop the same Grade 3 laboratory adverse event beginning within 7 days after vaccination 
and persists at Grade 3 for > 48 hours.  
If a holding rule has been met, the internal safety review will consider:  
• 
The relationship of the AE or SAE to the vaccine. 
• 
The relationship of the AE or SAE to the vaccine dose, or other possible causes of the event. 
• 
If appropriate, additional screening or laboratory testing for other volunteers to identify those 
who may develop similar symptoms and alterations to the current Volunteer Information Sheet 
(PIS). 
• 
New, relevant safety information from ongoing research programs on the various components of 
the vaccine. 
The local ethics committee and vaccine manufacturers will also be notified if a holding rule is activated 
or released.  
All vaccinated volunteers will be followed for safety until the end of their planned participation in the 
study or until resolution or stabilisation (if determined to be chronic sequelae) of their AEs, providing 
they consent to this. 
In addition to these pre-defined criteria, the study can be put on hold upon advice of the Chief 
Investigator, Principal Investigator, Study Sponsor, Regulatory Authority, Ethical Committee(s) or 
DSMB, for any single event or combination of multiple events which, in their professional opinion, 
jeopardise the safety of the volunteers or the reliability of the data. 
10.2. 
Definitions 
10.2.1. Adverse Event (AE)  
An AE is any untoward medical occurrence in a volunteer, which may occur during or after 
administration of an Investigational Medicinal Product (IMP) and does not necessarily have a causal 
relationship with the intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the study 
intervention, whether or not considered related to the study intervention. 
10.2.2. Adverse Reaction (AR)  
An AR is any untoward or unintended response to an IMP. This means that a causal relationship 
between the IMP and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out. All cases judged by the reporting medical Investigator as having a reasonable suspected causal 
relationship to an IMP (i.e. possibly, probably or definitely related to an IMP) will qualify as adverse 
reactions. 

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10.2.3. Unexpected Adverse Reaction  
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information in the Investigator Brochure (IB).  
10.2.4. Serious Adverse Event (SAE)  
An SAE is an AE that results in any of the following outcomes, whether or not considered related to 
the study intervention. 
• 
Death  
• 
Life-threatening event (i.e., the volunteer was, in the view of the Investigator, at immediate 
risk of death from the event that occurred). This does not include an AE that, if it occurred in 
a more severe form, might have caused death. 
• 
Persistent or significant disability or incapacity (i.e., substantial disruption of one’s ability to 
carry out normal life functions). 
• 
Hospitalisation, regardless of length of stay, even if it is a precautionary measure for continued 
observation. Hospitalisation (including inpatient or outpatient hospitalisation for an elective 
procedure) for a pre-existing condition that has not worsened unexpectedly does not 
constitute a serious AE. 
• 
An important medical event (that may not cause death, be life threatening, or require 
hospitalisation) that may, based upon appropriate medical judgment, jeopardise the 
volunteer and/or require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic reaction requiring intensive 
treatment in an emergency room or clinic, blood dyscrasias, or convulsions that do not result 
in inpatient hospitalisation. 
• 
Congenital anomaly or birth defect. 
10.2.5. Serious Adverse Reaction (SAR)  
An adverse event (expected or unexpected) that is both serious and, in the opinion of the reporting 
Investigator or Sponsors, believed to be possibly, probably or definitely due to an IMP or any other 
study treatments, based on the information provided. 
10.2.6. Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A serious adverse reaction, the nature and severity of which is not consistent with the information 
about the medicinal product in question set out in the IB.   
NB: To avoid confusion or misunderstanding the following note of clarification is provided: “Severe” 
is often used to describe intensity of a specific event, which may be of relatively minor medical 
significance. “Seriousness” is the regulatory definition supplied above. 
10.3. 
Expected Serious Adverse Events 
No serious adverse events are expected in this trial. 
10.4. 
 Causality Assessment 
For every AE, an assessment of the relationship of the event to the administration of the vaccine will 
be undertaken by the CI-delegated clinician. An intervention-related AE refers to an AE for which there 
is a probable or definite relationship to administration of a vaccine. An interpretation of the causal 
relationship of the intervention to the AE in question will be made, based on the type of event; the 
relationship of the event to the time of vaccine administration; and the known biology of the vaccine 
therapy (Table 7). Alternative causes of the AE, such as the natural history of pre-existing medical 
conditions, concomitant therapy, other risk factors and the temporal relationship of the event to 

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vaccination will be considered and investigated. Causality assessment will take place during planned 
safety reviews, interim analyses (e.g. if a holding or stopping rule is activated) and at the final safety 
analysis, except for SAEs, which should be assigned by the reporting investigator. 
0 
No Relationship 
No temporal relationship to study product and 
Alternate aetiology (clinical state, environmental or other interventions); and 
Does not follow known pattern of response to study product 
1 
Unlikely 
Unlikely temporal relationship to study product and 
Alternate aetiology likely (clinical state, environmental or other interventions) and 
Does not follow known typical or plausible pattern of response to study product. 
2 
Possible 
 
Reasonable temporal relationship to study product; or 
Event not readily produced by clinical state, environmental or other interventions; 
or 
Similar pattern of response to that seen with other vaccines 
3 
Probable 
 
Reasonable temporal relationship to study product; and 
Event not readily produced by clinical state, environment, or other interventions or  
Known pattern of response seen with other vaccines 
4 
Definite 
 
Reasonable temporal relationship to study product; and 
Event not readily produced by clinical state, environment, or other interventions; 
and  
Known pattern of response seen with other vaccines 
Table 7. Guidelines for assessing the relationship of vaccine administration to an AE 
10.5. 
Reporting Procedures for All Adverse Events 
All local and systemic AEs occurring in the 28 days following each vaccination observed by the 
Investigator or reported by the volunteer, whether or not attributed to study medication, will be 
recorded. Recording and reporting of all AEs will take place as detailed in the study’s SOP.  All AEs that 
result in a volunteer’s withdrawal from the study will be followed up until a satisfactory resolution 
occurs, or until a non-study related causality is assigned (if the volunteer consents to this). Serious 
adverse events (SAEs) will be collected throughout the entire trial period.  
Table 8. Routinely solicited adverse events 
 
Adverse event 
Local  
 
Pain/tenderness at the injection site 
Swelling at injection site 
Warmth at the injection site 
Itch at the injection site 
Scaling/pustules at the injection site 
Systemic 
 
Documented fever (temperature > 37.5° C) 
Myalgia 
Arthralgia 
Feverishness 
Headache 
Fatigue 
Nausea 
Malaise 

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10.5.1. Reporting Procedures for Serious AEs  
In order to comply with current regulations on serious adverse event reporting to regulatory 
authorities, the event will be documented accurately and notification deadlines respected. SAEs will 
be reported on the SAE forms to members of the study team immediately the Investigators become 
aware of their occurrence, as described in the study’s SOP. Copies of all reports will be forwarded for 
review to the Chief Investigator (as the Sponsor’s representative) within 24 hours of the Investigator 
being aware of the suspected SAE. The data and safety monitoring board (DSMB) will be notified of 
SAEs that are deemed possibly, probably or definitely related to study interventions; the DSMB will be 
notified immediately (within 24 hours) of the Investigators’ being aware of their occurrence. SAEs will 
be reported to the Research Ethics Committee (REC) at UVRI within 7 calendar days of the Investigator 
becoming aware of them, and a full report (if the initial report is not complete) will be made within 7 
calendar days of the initial report. SAEs will not normally be reported immediately to the Oxford or 
LSHTM ethical committee(s) unless there is a clinically important increase in occurrence rate, an 
unexpected outcome, or a new event that is likely to affect safety of trial volunteers, at the discretion 
of the Chief Investigator and/or DSMB. In addition to the expedited reporting above, the Investigator 
shall include all SAEs in the annual Development Safety Update Report (DSUR) report. 
10.5.2. Reporting Procedures for SARs 
These will be reported as per any SAE. 
10.5.3. Reporting Procedures for SUSARs  
The Principal Investigator will report all SUSARs to the UVRI REC within 7 calendar days of the 
Investigator becoming aware of them, and a full report (if the initial report is not complete) will be 
made within 7 calendar days of the initial report. The Chief Investigator will report all SUSARs to the 
MHRA and Oxford and LSHTM ethical committee(s) within required timelines (15 days for all SUSARs, 
unless life threatening in which case 7 days, with a final report within a further 8 days (total 15)). The 
Chief Investigator will also inform all Investigators concerned of relevant information about SUSARs 
that could adversely affect the safety of volunteers. All SUSARs and deaths occurring during the study 
will be reported to the Sponsor. For all deaths, available autopsy reports and relevant medical reports 
will be made available for reporting to the relevant authorities. 
10.5.4. Development Safety Update Report 
A Development Safety Update Report (DSUR) will be submitted by the Sponsor to the UK competent 
authority and ethical committee on the anniversary of the first approval date from the regulatory 
authority for each IMP, in accordance with UK regulatory requirements. 
10.6. 
Assessment of Severity 
The severity of clinical and clinical laboratory adverse events will be assessed according to the scales 
in Table 9-11.  Clinical laboratory adverse events will be assessed as grade 1 if 1.1 to 2.4 times the limit 
of normal, grade 2 if 2.5 to 4.9 times, and 3 if greater than 5 times the limit of normal, in accordance 
with FDA guidance for toxicity grading.  Normal ranges will be based on those defined locally by Lugada 
and colleagues for haematology [61], and those provided by the ISO accredited Clinical Diagnostic 
Laboratory at UVRI for biochemistry. 
Adverse Event  
Grade  
Intensity  
Pain at injection site 
1 
Pain that is easily tolerated 
 
2 
Pain that interferes with daily activity 
 
3 
Pain that prevents daily activity 
Erythema at injection site* 
1 
>3 - ≤50 mm 
 
2 
>50 - ≤100 mm 

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3 
>100 mm 
Swelling at injection site 
1 
>1 - ≤20 mm 
 
2 
>20 - ≤50 mm 
 
3 
>50 mm 
Table 9. Severity grading criteria for local adverse events  
*erythema ≤3mm is an expected consequence of skin puncture and will therefore not be considered 
an adverse event 
 
Grade 1 
(mild) 
Grade 2 
(moderate) 
Grade 3 
(severe) 
Fever  
37.6°C - 38.0°C 
38.1°C – 39.0°C 
>39.0°C 
Tachycardia (bpm)* 
101 - 115 
116 – 130 
>130 
Bradycardia (bpm)** 
50 – 54 
40 – 49 
<40 
Systolic hypertension (mmHg) 
141 - 159 
160 – 179 
≥180 
Diastolic hypertension (mmHg) 
91 - 99 
100 – 109 
≥110 
Systolic hypotension (mmHg)*** 
85 - 89 
80 – 84 
<80 
 
Table 10. Severity grading criteria for physical observations [appropriate adjustments will be made for 
age, gender and height percentiles] 
*Taken after ≥10 minutes at rest; **When resting heart rate is between 60 – 100 beats per minute. 
Use clinical judgement when characterising bradycardia among some healthy volunteer populations, 
for example, conditioned athletes; ***Only if symptomatic (e.g. dizzy/ light-headed) 
 
GRADE 0 
None 
GRADE 1 
Mild: Transient or mild discomfort (< 48 hours); no medical intervention/therapy 
required 
GRADE 2 
Moderate: Mild to moderate limitation in activity – some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalisation possible 
Table 11. Severity grading criteria for respiratory and systemic AEs 
10.7. 
Procedures to be followed in the event of abnormal findings 
Eligibility for enrolment in the trial in terms of laboratory findings will be assessed as detailed in 
Section 7. Abnormal clinical findings from medical history, examination or blood tests will be assessed 
as to their clinical significance throughout the trial. Laboratory adverse events will be assessed using 
the normal ranges based on those defined locally by Lugada and colleagues for haematology [61], and 
those provided by the ISO accredited Clinical Diagnostic Laboratory at UVRI for biochemistry. If a test 
is deemed clinically significant, it may be repeated, to ensure it is not a single occurrence. If a test 
remains clinically significant, the volunteer will be informed and appropriate medical care arranged as 
appropriate and with the permission of the volunteer. Specific details regarding findings, discussion 
with volunteers and resulting actions will be recorded in the CRF. Decisions to exclude the volunteer 
from enrolling in the trial or to withdraw a volunteer from the trial will be at the discretion of the 
Investigator. 

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10.8. 
Data and Safety Monitoring Board (DSMB) 
A data and safety monitoring board (DSMB) will be appointed to provide real-time safety oversight. 
The DSMB will be notified within 24 hours of the Investigators’ being aware of the occurrence of SAEs. 
The DSMB has the power to place the trial on hold if deemed necessary following a trial intervention-
related SAE. The DSMB will be chaired by clinician experienced in early-phase clinical trials. There will 
be a minimum of two other appropriately qualified committee members.  Membership will include a 
statistician, and at least one Ugandan member.  All correspondence between Investigator and DSMB 
will be conveyed by the Chief Investigator to the trial Sponsor. The Chair of the DSMB will be contacted 
for advice and independent review by the Investigator or trial Sponsor in the following situations: 
• 
Following any SAE deemed to be possibly, probably, or definitely related to the trial challenge 
agent. 
• 
Any other situation where the Investigator or trial Sponsor feels independent advice or review 
is important. 
Reports will be provided to the DSMB on completion of recruitment to groups 1 and 2 (adult dose 
escalation) before proceeding to group 3; and on completion of recruitment to groups 3 and 4 
(adolescent dose escalation), before proceeding to the randomised trial (groups 5 and 6). 
11. STATISTICS  
This is primarily an exploratory immunogenicity and safety trial with descriptive endpoints.   
Adverse events will be listed and summarised by type of AE, frequency, severity and trial group. 
The sample size (12 participants for dose escalation and age de-escalation, 60 participants [30 in each 
arm] for the randomised trial) has been determined by the number of doses of ChAdOx1 85A available 
for this study.  The following are the considerations regarding sample size for the randomised 
component of the trial.  The primary outcome is the IFN- ELIspot response to antigen 85A at week 9 
which is measured in spot forming counts per 1x106 peripheral blood mononuclear cells (PBMCs).  
Assuming a standard deviation of 0.4 log10 sfc/1x106PBMC (spot forming counts/1x106 peripheral 
blood mononuclear cells) in the peak Ag85A response, our study will have over 80% power to detect 
a difference of 0.29 log10 in sfc/106 PBMC with p<0.05. This is comparable to the difference that was 
observed between the response to human adenovirus vectored TB vaccine candidate Aeras 402 alone 
(Day 14 post Aeras) and Aeras 402 with MVA85A boost (Day 7 post MVA boost) [21], or between BCG 
(Day 28) and MVA85A alone (Day 7) in UK subjects [62], and hence a reasonable difference to expect 
between BCG and ChAdOx1 85A-MVA85A (aim 2).  
For outcomes that are approximately normally distributed or normalised by log-transformation, 
differences in means will be presented together with 95% confidence intervals and p-values from 
unpaired t-tests. For non-normally distributed outcomes, the difference in medians between the two 
groups will be presented along with its 95% confidence intervals, and p-values from Wilcoxon ranksum 
tests.  
12. DATA MANAGEMENT 
12.1. 
Source Data 
Source documents are where data are first recorded, and from which volunteers’ CRF data are 
obtained. These include the CRF itself (history and examination), the volunteer consent form, blood 
and microbiology results, and any further correspondence relating to the volunteer regarding 
medical/clinical issues. The CRF will be electronic and/or paper together with paper diary cards. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is 
no other written or electronic record of data). All documents will be stored safely in confidential 

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conditions. On all trial-specific documents, other than the signed consent, the volunteer will be 
referred to by the trial volunteer number/code, not by name. 
12.2. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. All information 
relating to the trial and its volunteers will be held in strict confidence, and in accordance with GCP and 
institutional requirements. 
12.3. 
Data Recording and Record Keeping 
The PI will be responsible for collecting, recording, analysing, and storing all the data accruing from 
the trial. These tasks may be delegated to other Investigators. Paper CRFs will be stored in a key-locked 
cabinet at the EMaBS clinic and MRC/UVRI and LSHTM Uganda Research Unit archives, and electronic 
CRFs on the OpenClinica™ database, which is stored electronically on secure servers that are 
outsourced by OpenClinicaTM. Data from paper CRFs will be transcribed onto the OpenClinicaTM 
database. Lab data will be transferred into Stata datasets and then stored on the secure servers at the 
MRC/UVRI and LSHTM Uganda Research Unit. 
Trial records will be held by the Investigator for as long as required by legislation as a minimum 
(currently until at least 2 years after the last marketing authorisation for the product) and in order to 
enable dissemination of trial results after publication, and to enable decoding and destruction of 
anonymised samples if subsequently requested by a volunteer. Data will subsequently be transferred 
to a secure archive in accordance with the UK Data Protection Act. Volunteers will be assigned 
individual unique trial numbers for identification on all trial records, except where the use of 
identifiable information is unavoidable (including on registration documents and consent forms).  
Documents with identifying information will be stored securely and separately from the other 
participant data. 
13. QUALITY ASSURANCE PROCEDURES 
13.1. 
Quality Assurance 
Investigator procedures 
Approved site-specific SOPs will be used. 
Modification to protocol 
No substantial amendments to this protocol will be made without consultation with, and agreement 
of, the Sponsor. Any substantial amendments to the trial that appear necessary during the course of 
the trial must be discussed by the Investigator and Sponsor concurrently. If agreement is reached 
concerning the need for an amendment, it will be produced in writing by the CI and will be made a 
formal part of the protocol following ethical and regulatory approval. 
An administrative change to the protocol is one that modifies administrative and logistical aspects of 
a protocol but does not affect the volunteers’ safety, the scientific value of the trial, the conduct of 
the trial or safety of the challenge agent. An administrative change is a non-substantial amendment 
and does not require REC approval. The CI is responsible for ensuring that changes to an approved 
trial, during the period for which REC approval has already been given, are not initiated without REC 
review and approval except to eliminate apparent immediate hazards to the volunteer. 
Protocol deviation 
All deviations from the protocol will be documented in a protocol deviation form and filed in the trial 
master file and site file accordingly.  

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13.2. 
Monitoring 
Data will be evaluated for compliance with the protocol and accuracy in relation to source documents. 
The trial will be conducted in accordance with procedures identified in the protocol. Regular 
monitoring will be performed according to ICH GCP. According to applicable SOPs, the Monitors will 
verify that the clinical trial is initiated, conducted and completed, and data are generated, 
documented and reported in compliance with the protocol, GCP and the applicable regulatory 
requirements. 
14. SERIOUS BREACHES AND PROTOCOL VIOLATIONS 
In Uganda, protocol violations will be reported to the UVRI REC within 14 calendar days of the 
Investigator recognising them.  A protocol violation is a deviation from the IRB approved protocol that 
may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and reliability 
of the study data. 
 
In the UK, the Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the 
notification of "serious breaches" to the MHRA within 7 days of the Sponsor becoming aware of the 
breach. A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to 
a significant degree:  
 
• the safety or physical or mental integrity of the volunteers of the trial  
• the scientific value of the trial”  
 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. 
In collaboration with the CI, the serious breach will be reviewed by the Sponsor and, if appropriate, 
the Sponsor will report it to the REC committee, Regulatory Authority and the NHS host organisation 
within 7 calendar days. 
15. ETHICAL AND REGULATORY CONSIDERATIONS 
15.1. 
Declaration of Helsinki 
The Chief and Principal Investigators will ensure that this trial is conducted in accordance with the 
principles of the Declaration of Helsinki as agreed by the World Medical Association General Assembly 
(Washington 2002). 
15.2. 
Good Clinical Practice 
The Investigator will ensure that this trial is conducted in accordance with ICH Good Clinical Practice 
(GCP), and local regulatory requirements. 
15.3. 
Approvals 
A copy of the protocol, proposed informed consent form, other written volunteer information and the 
proposed advertising material will be submitted to an independent REC for written approval. The 
Investigators will submit and, where necessary, obtain approval from the REC for all subsequent 
substantial amendments to the protocol and informed consent document. The Investigators will notify 
deviations from the protocol or SAEs occurring at the site to the Sponsor and will notify the REC of 
these in accordance with local procedures. 
The Ethics Committees and Regulatory Authorities for this trial comprise the Research Ethics 
Committee of the UVRI, the Oxford Tropical Research Ethics Committee, the Ethics Committee of the 

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London School of Hygiene & Tropical Medicine, the Uganda National Council for Science and 
Technology and the Uganda National Drug Authority. 
15.4. 
Reporting 
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report 
to the REC, host organisation and Sponsor. In addition, an End of Study notification and final report 
will be submitted to the MHRA, the REC, host organisation and Sponsor. An annual DSUR will be 
submitted to the Regulatory Authority, if required by the MHRA. 
15.5. 
Volunteer Confidentiality 
All data will be anonymised: volunteer data will be identified by a unique study number in the CRF and 
database. A separate confidential file containing identifiable information will be stored in a secured 
location in accordance with the UK Data Protection Act 1998. Only the Sponsor representative, 
Investigators, the clinical monitor, the REC and the Regulatory Agency will have access to the records.  
15.6. 
Expenses and Benefits 
Volunteers will be compensated pro rata for their time, travel and for trial procedures while 
participating in the trial, amounting to a total of approximately £70 (30,000 UGX per visit), depending 
on the exact number of visits, site of recruitment and whether any repeat or additional visits are 
necessary. 
16. FINANCE AND INSURANCE 
16.1. 
Funding 
This trial will be financed by a research grant from Medical Research Council, held by Professor 
Pontiano Kaleebu (as director of the MRC/UVRI and LSHTM Uganda Research Unit) and by Professor 
Alison Elliott (as head of the Immunomodulation and Vaccines Programme). 
16.2. 
Indemnity 
If any volunteer is harmed as a result of this trial, medical care will be provided by Entebbe Hospital, 
or a referral hospital in Uganda if required. The sponsor should provide care until complete cure or 
stabilization of a research related injury. The injured research participant shall be given the best care 
available within the country for the research related injury. Research participants shall not be required 
to waive their legal rights for redress in courts of law.  
 
Negligent Harm 
Indemnity and/or compensation for negligent harm arising specifically from an accidental injury for 
which the University is legally liable as the Research Sponsor will be covered by the University of 
Oxford.  
Non-Negligent Harm 
Indemnity and/or compensation for harm arising specifically from an accidental injury, and occurring 
as a consequence of the Research volunteers' participation in the trial for which the University is the 
Research Sponsor will be covered by the University of Oxford. 

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16.3. 
Insurance 
The University of Oxford has a specialist insurance policy in place which would operate in the event of 
any volunteer suffering harm as a result of their involvement in the research (Newline Underwriting 
Management Ltd, at Lloyd’s of London and a local insurance company, Jubilee Insurance Ltd. 
17. PUBLICATION POLICY 
When the trial is complete, a manuscript describing the primary trial results will be written and 
published in a peer-reviewed, open access journal. International guidelines will be followed regarding 
authorship. There may also be secondary publications on more exploratory results. 

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