A Phase I Trial to Compare the Safety and Immunogenicity of Candidate TB Vaccine MVA85A Administered by the Aerosol Inhaled Route and the Intramuscular Route in Healthy Adult Volunteers Who Are Latently Infected With Mycobacterium Tuberculosis
Phase: PHASE1
Conditions: Tuberculosis
Sponsor: University of Oxford

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 1 of 56 
  
 
CLINICAL TRIAL PROTOCOL 
 
A phase I trial to evaluate the safety and immunogenicity of candidate TB vaccine MVA85A 
administered by the aerosol inhaled route in healthy adult volunteers who are latently 
infected with Mycobacterium tuberculosis 
 
Short title: MVA85A aerosol vaccination in adults with latent M.tb infection 
 
Trial Reference: 
 
 
 
TB040 
EudraCT number: 
 
 
 
2015-001826-41 
REC Reference: 
 
 
 
15/SC/0370 
IRAS Reference: 
 
 
 
181214 
 
Date and Version Number 
 
19 December 2017, V7.0 
Chief Investigator: 
Professor Helen McShane 
Sponsor: 
University of Oxford 
Local Safety Committee Chair: 
Professor Brian Angus 
Funding body: 
 
 
TBVI, Wellcome Trust 
Author: 
Dr Julia Marshall and Dr Rebecca Powell Doherty 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, and members of the Research Ethics Committee, unless authorised 
to do so. This information cannot be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of Professor Helen McShane. 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 2 of 56 
 
TABLE OF CONTENTS 
 
 
1 
STATEMENT OF COMPLIANCE ............................................................................ 5 
2 
AMENDMENT HISTORY ...................................................................................... 6 
3 
KEY TRIAL CONTACTS AND ROLES .................................................................... 16 
4 
SYNOPSIS ........................................................................................................ 19 
4.1 
Synopsis................................................................................................................................. 19 
4.2 
Schedule of visits and procedures ........................................................................................ 21 
5 
ABBREVIATIONS .............................................................................................. 22 
6 
BACKGROUND AND RATIONALE ....................................................................... 23 
6.1 
Context .................................................................................................................................. 23 
Basis for the aerosol inhaled route ................................................................................................ 23 
Description and pre-clinical experience of MVA and MVA85A ..................................................... 24 
Clinical studies with MVA85A ........................................................................................................ 25 
Aerosol delivery devices ................................................................................................................ 29 
Bronchoscopy and bronchoalveolar sampling .............................................................................. 30 
6.2 
Rationale ............................................................................................................................... 30 
Hypothesis ..................................................................................................................................... 30 
Vaccine dosage .............................................................................................................................. 30 
6.3 
Risks and Benefits ................................................................................................................. 31 
Potential risks ................................................................................................................................ 31 
Potential benefits .......................................................................................................................... 33 
7 
OBJECTIVES AND OUTCOME MEASURES........................................................... 33 
Primary Objective .......................................................................................................................... 33 
8 
PARTICIPANT IDENTIFICATION ......................................................................... 33 
8.1 
Trial Participants ................................................................................................................... 33 
8.2 
Inclusion Criteria ................................................................................................................... 33 
8.3 
Exclusion Criteria ................................................................................................................... 34 
9 
TRIAL DESIGN AND PROCEDURES ..................................................................... 35 
9.1 
Trial Numbers and Groups .................................................................................................... 35 
9.2 
Recruitment .......................................................................................................................... 36 
9.3 
Informed Consent ................................................................................................................. 36 
9.4 
Screening and Eligibility Assessment .................................................................................... 37 
9.5 
Randomisation and blinding .................................................... Error! Bookmark not defined. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 3 of 56 
9.6 
Follow up visits ...................................................................................................................... 37 
9.7 
Timepoints ............................................................................................................................ 38 
9.8 
Sample handling .................................................................................................................... 38 
9.9 
Vaccination Postponement Criteria ...................................................................................... 38 
9.10 
Bronchoscopy Postponement criteria .................................................................................. 39 
9.11 
Discontinuation / Withdrawal Criteria .................................................................................. 39 
9.12 
Safety .................................................................................................................................... 40 
9.13 
End of Trial Definition ........................................................................................................... 40 
10 
INVESTIGATIONAL MEDICINAL PRODUCT AND DEVICES ................................... 40 
10.1 
IMP Description ..................................................................................................................... 40 
10.2 
Storage of IMP ...................................................................................................................... 40 
10.3 
Dispensing and administration ............................................................................................. 41 
10.4 
Saline ..................................................................................................................................... 41 
10.5 
MicroAIR NE-U22 .................................................................................................................. 41 
10.6 
Sedative & anaesthetic agents for bronchoscopy ................................................................ 41 
11 
ASSESSMENT OF SAFETY .................................................................................. 42 
11.1 
Interim Safety Review ........................................................................................................... 42 
11.2 
Definitions ............................................................................................................................. 42 
11.3 
Foreseeable Adverse Reactions ............................................................................................ 43 
11.4 
Expected Serious Adverse Events ......................................................................................... 43 
11.5 
Causality Assessment ............................................................................................................ 43 
11.6 
Reporting Procedures for All Adverse Events ....................................................................... 44 
11.7 
Assessment of Severity ......................................................................................................... 45 
11.8 
Procedures to be followed in the event of abnormal findings ............................................. 46 
11.9 
Local Safety Committee ........................................................................................................ 46 
12 
STATISTICS ....................................................................................................... 46 
13 
DATA MANAGEMENT ...................................................................................... 47 
13.1 
Source Data ........................................................................................................................... 47 
13.2 
Access to Data ....................................................................................................................... 47 
13.3 
Data Recording and Record Keeping .................................................................................... 47 
14 
QUALITY ASSURANCE PROCEDURES ................................................................. 48 
14.1 
Quality Assurance ................................................................................................................. 48 
14.2 
Monitoring ............................................................................................................................ 48 
15 
SERIOUS BREACHES ......................................................................................... 48 
16 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................. 49 
16.1 
Declaration of Helsinki .......................................................................................................... 49 
16.2 
Good Clinical Practice ........................................................................................................... 49 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 4 of 56 
16.3 
Approvals .............................................................................................................................. 49 
16.4 
Reporting............................................................................................................................... 49 
16.5 
Volunteer Confidentiality ...................................................................................................... 49 
16.6 
Expenses and Benefits .......................................................................................................... 49 
17 
FINANCE AND INSURANCE ............................................................................... 49 
17.1 
Funding ................................................................................................................................. 49 
17.2 
Indemnity .............................................................................................................................. 49 
17.3 
Insurance ............................................................................................................................... 50 
18 
PUBLICATION POLICY ....................................................................................... 50 
19 
REFERENCES .................................................................................................... 51 
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 5 of 56 
1 STATEMENT OF COMPLIANCE 
Investigator Agreement 
 
“I have read this protocol and agree to abide by all provisions set forth therein. I agree to comply with 
the International Conference on Harmonisation Tripartite Guideline on Good Clinical Practice.”   
 
 
 
Professor Helen McShane 
 
 
 
 
 
 
 
 
 
   16.01.18  
Chief Investigator 
 
Professor Helen McShane 
 
Investigator Signature 
 
Date  
 
 
 
Conflict of Interest  
“According to the Declaration of Helsinki, 2008, I have read this protocol, and declare no conflict of 
interest with any Investigators” 
 
 
 
 
 
Professor Helen McShane 
 
 
 
 
 
 
 
16.01.18 
Chief Investigator 
 
Professor Helen McShane 
 
Investigator Signature 
 
Date  
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 6 of 56 
2 AMENDMENT HISTORY 
Protocol v7.0 Substantial amendment 
Section 
From 
Changed To 
Title 
A phase I trial to compare the safety 
and immunogenicity of candidate TB 
vaccine MVA85A administered by the 
aerosol inhaled route and the 
intramuscular route in healthy adult 
volunteers who are latently infected 
with Mycobacterium tuberculosis 
 
Short title: MVA85A aerosol vs 
intramuscular in adults with latent M.tb 
infection 
 
A phase I trial to evaluate the safety and 
immunogenicity of candidate TB vaccine 
MVA85A administered by the aerosol inhaled 
route in healthy adult volunteers who are 
latently infected with Mycobacterium 
tuberculosis 
 
Short title: MVA85A aerosol vaccination in 
adults with latent M.tb infection 
3.0 
 
PIC Addition: 
 
St George’s University Hospitals NHS 
Foundation Trust 
Queen Mary’s Hospital 
Tuberculosis Chest Clinic 
Roehampton Ln,  
London SW15 5PN 
 
Collaborator Addition: 
 
Dr Catherine Cosgrove 
Consultant Infectious Diseases Physician 
Adult Lead at the Vaccine Institute SGUL 
St George’s, University Hospitals NHS 
Foundation Trust 
Tel: +44 (0)208 725 5827 
Email: CCosgrov@sgul.ac.uk 
 
3.0 
Investigator Dr Morven Wilke 
Investigator Dr Julia Marshall 
3.0 
Project Manager Samantha Vermaak 
Project Manager Dr Rebecca Powell Doherty 
3.0 
Statistician Sharon Love 
Statistician Nicola Williams 
4.1 
15 subjects: 
Starter Group: the first 3 volunteers will 
receive 1 x 107 pfu aerosol inhaled 
MVA85A  
The next 12 subjects will be randomised 
to two trial arms: 
Group A: 6 volunteers receiving 5 x 107 
pfu aerosol inhaled MVA85A and IM 
saline placebo 
Group B: 6 volunteers receiving 5 x 107 
pfu IM injection of MVA85A and aerosol 
inhaled saline placebo 
6-9 subjects: 
Starter Group: the first 3 volunteers will 
receive 1 x 107 pfu aerosol inhaled MVA85A  
Group A: A minimum of 3 and a maximum of 
6 volunteers will receive the standard dose of 
5 x 107 pfu aerosol inhaled MVA85A 
4.1 
 
Trial interventions: Removal of IM route 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 7 of 56 
4.1 
To evaluate the systemic and mucosal 
cellular and humoral immunogenicity 
induced by MVA85A vaccination by the 
aerosol inhaled and IM route, in healthy 
volunteers who are latently infected 
with M.tb   
To evaluate other exploratory markers 
of cell-mediated and humoral 
immunogenicity induced by aerosol and 
IM MVA85A, including transcriptomic 
analysis 
To evaluate the systemic and mucosal 
cellular and humoral immunogenicity 
induced by MVA85A vaccination by the 
aerosol inhaled in healthy volunteers who 
are latently infected with M.tb  
  
To evaluate other exploratory markers of 
cell-mediated and humoral immunogenicity 
induced by aerosol MVA85A, including 
transcriptomic analysis 
4.1 
Route of IMP: Aerosol inhalation by 
nebuliser or IM needle injection in the 
deltoid region of the arm 
Allocation method: Variable block 
randomisation by sequentially 
numbered sealed envelopes 
Route of IMP: Aerosol inhalation by nebuliser 
Allocation method: Sequential allocation 
4.1 
15 subjects: 
Starter Group: the first 3 volunteers will 
receive 1 x 107 pfu aerosol inhaled 
MVA85A  
The next 12 subjects will be randomised 
to two trial arms: 
Group A: 6 volunteers receiving 5 x 107 
pfu aerosol inhaled MVA85A and IM 
saline placebo 
Group B: 6 volunteers receiving 5 x 107 
pfu IM injection of MVA85A and aerosol 
inhaled saline placebo 
 
Follow up duration: 24 weeks from 
vaccination day 
6-9 subjects: 
Starter Group: the first 3 volunteers will 
receive 1 x 107 pfu aerosol inhaled MVA85A  
Group A (Standard Dose) : 3-6 volunteers will 
receive 5 x 107 pfu aerosol inhaled MVA85A 
 
 
 
 
 
 
 
 
Follow up duration: Final visit 12 weeks from 
vaccination day with telephone call at 24 
weeks. 
4.2 Schedule of 
visits and 
procedures 
Bronchoscopy at 1 week +/- 2 days 
Bronchoscopy at 1 week +4 days,- 2 days 
4.2 
D168 scheduled visit with vital signs and 
phlebotomy with immunology  
D168 telephone call. No blood tests and no 
vital signs. Volunteers will be asked to come 
in for physical examination if deemed 
medically necessary. 
4.2 
“U&Es, LFTs (except day 2 when CRP 
only; if raised, to be repeated on day 7)” 
 
Clarification of wording around when CRP is 
taken 
“U&Es, LFTs, CRP (except day 2 when CRP 
only)” 
4.2 
“Cumulative blood volume 416ml” 
“Cumulative blood volume 356ml” 
Clarification of blood volume: “Blood 
volumes stated for Oxford. The exact 
volumes of blood taken will depend on the 
local site – cumulative blood volumes for 
volunteers outside Oxford may be slightly 
lower or higher than those of Oxford 
volunteers, due to the use of different 
volume vacutainers for biochemistry, 
haematology and serology samples as per 
local Trust standard procedures” 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 8 of 56 
5.0 
Abbreviations 
 
Addition of  
CRP: C-reactive protein 
GSTT: Guys and St. Thomas’ NHS Foundation 
Trust 
PFU: Particle forming unit 
SGUL: St George’s University of London 
 
Deletion of: 
ART: Anti-retroviral therapy 
CFU: Colony forming unit 
 
Throughout 
 
Minor updates to reflect the fact that TB035 
trial has now completed 
6.1 Context 
A second Phase I safety trial assessing 
anti-vector immunity with nebulised 
MVA85A was completed in 2016 
(TB035, Clinical Trials.gov reference 
number NCT01954563). An 
intermediate dose of 5 x 107 pfu was 
used in TB035. To our knowledge there 
have been no other clinical studies of 
viral vectored vaccines delivered by 
aerosol. 
A second Phase I safety trial assessing anti-
vector immunity with nebulised MVA85A 
was completed in 2016 (TB035, Clinical 
Trials.gov reference number NCT01954563). 
An intermediate dose of 5 x 107 pfu was used 
in TB035. No vaccine related SAEs were 
reported (unpublished data). To our 
knowledge there have been no other clinical 
studies of viral vectored vaccines delivered 
by aerosol. 
6.2 Hypothesis 
We postulate that the aerosol inhaled 
route is practical and feasible and has an 
acceptable safety profile, comparable to 
the systemic safety profile of the IM 
route of administration of MVA85A in 
volunteers latently infected with M.tb. 
We hypothesise that the aerosol inhaled 
route of administration will induce 
greater 
mucosal 
immunity 
and 
comparable systemic immunity when 
compared to the IM (systemic) route of 
administration in these volunteers. 
 
We postulate that the aerosol inhaled route is 
practical and feasible and has an acceptable 
safety profile, in volunteers latently infected 
with M.tb.  
We hypothesise that the aerosol inhaled 
route of administration will induce greater 
mucosal and comparable systemic immunity 
when compared to historical data of IM 
(systemic) route of administration in healthy 
volunteers. 
6.2 vaccine 
dosage 
Once the Starter Group is fully enrolled 
and the second safety review is 
completed, we will start randomisation 
to Groups A and B, with dose escalation 
to 5 x 107 pfu (the same dose as currently 
used in TB035). For safety reasons, the 
first volunteer will be assigned to Group 
A (aerosol MVA85A plus saline placebo) 
and there will be no further vaccinations 
until 48 hours has elapsed and the safety 
data reviewed. If the CI decides it is safe 
to proceed, the remaining volunteers 
will then be randomised.   
 
Once the Starter Group is fully enrolled and 
the second safety review is completed, we will 
start enrolment into Group A (Standard Dose), 
with dose escalation to 5 x 107 pfu (the same 
dose used in TB035). For safety reasons, the 
first volunteer in this group will be vaccinated 
ahead of other volunteers and no other 
volunteers will be vaccinated until at least 48 
hours has elapsed. If the CI decides it is safe to 
proceed, the remaining volunteers will then 
be enrolled. The target enrolment for this 
group is 6 volunteers. However, given the 
often reduced pace of recruitment from the 
latently infected population, we will accept a 
minimum of 3 volunteers if the target has not 
been reached by October 2018. 
6.3 Risks and 
benefits 
 
Local reactions to IM injection deleted 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 9 of 56 
Table 2 
TB034: 
 
Study Status: Enrolling 
 
TB035: 
 
Nb : 12, 2, 12 
 
Study Status: Enrolling 
 
e. 
Subjects blinded as to whether they 
received MVA85A via the ID or aerosol 
inhaled route. 
 
TB034: 
 
Study Status: Completed 
 
 
 
Nb : 12, 13, 12 
 
Study Status: Completed 
 
e. 
Subjects blinded as to whether they received 
MVA85A via the ID or aerosol inhaled route; 
Volunteers in group 2 who were due to receive 
their day 28 vaccination on or after 2nd 
September 2015 did not receive this boost 
vaccination due to a higher frequency of mild 
respiratory adverse events in this group. 
Volunteers 
received 
placebo 
by 
both 
intradermal and aerosol inhaled group to 
maintain blinding. 
 
7.0 Objectives 
and Outcome 
Measures 
At each visit, via diary card for 14 days 
after vaccination 
To evaluate the systemic and mucosal 
cellular and humoral immunogenicity 
induced by MVA85A vaccination by the 
aerosol inhaled and IM route, in healthy 
volunteers who are latently infected 
with M.tb. 
To evaluate other exploratory markers 
of 
cell-mediated 
and 
humoral 
immunogenicity induced by aerosol and 
IM MVA85A, including transcriptomic 
analysis 
At each visit, via diary card for 14 days after 
vaccination and at the 6 month phone call 
To evaluate the systemic and mucosal cellular 
and humoral immunogenicity induced by 
MVA85A vaccination by the aerosol inhaled 
route in healthy volunteers who are latently 
infected with M.tb. 
To evaluate other exploratory markers of cell-
mediated 
and 
humoral 
immunogenicity 
induced by aerosol MVA85A, including 
transcriptomic analysis  
 
8.0 Inclusion 
Exclusion criteria 
 
Ineligible for chemoprophylaxis 
for latent M.tb infection, declined 
prophylaxis or considered low 
risk due to distant contact history 
 
Considered low risk of reactivation of 
their latent infection due to distant 
contact history 
9.1 Trial design 
and procedures 
15 volunteers will be enrolled; the first 3 
to the starter group, then 12 randomly 
allocated to either group A or group B 
(1st volunteer in Group A is not 
randomised). 
 
9 volunteers will be enrolled; the first 3 to the 
starter group, then 6 volunteers into Group A. 
 
Table 4 
Starter group: 
3 
Aerosol inhaled MVA85A 1 x 107 pfu 
 
Group A: 
6 
Aerosol inhaled MVA85A 5 x 107 pfu and 
IM saline placebo 
 
Group B: 
6 
IM MVA85A 5 x 107 pfu and inhaled 
aerosol saline placebo 
Starter group: 
3 
Aerosol inhaled MVA85A 1 x 107 pfu 
 
Group A (Standard dose): 
3-6 
Aerosol inhaled MVA85A 5 x 107 pfu 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 10 of 56 
 
9.2 
Volunteers, either ineligible for or 
declining 
anti-tuberculous 
chemoprophylaxis, or considered to be 
at low risk of reactivation of their latent 
infection due to distant contact history, 
will be recruited from TB contact clinics 
at 
Oxford 
University 
Hospitals, 
Birmingham 
Heartlands 
Hospital, 
Birmingham Chest Clinic, Royal Free 
Hospital, King’s College Hospital, and St 
Thomas’ Hospital. 
Volunteers considered to be at low risk of 
reactivation of their latent infection due to 
distant contact history, will be recruited from 
TB contact clinics at Oxford University 
Hospitals, Birmingham Chest Clinic Heart of 
England, Royal Free Hospital, King’s College 
Hospital, Guy’s and St Thomas’ Hospital and St 
George’s University Hospital 
9.2 
Prospective anti-TB chemoprophylaxis, 
provided through the usual NHS routes 
and TB/chest clinics, would be delayed 
until after the trial D28 follow-up visit 
and CT, decision not to enrol, or early 
withdrawal; whichever occurs first. 
  Ideally, the volunteer will delay their 
prospective 
anti-tuberculous 
chemoprophylaxis, provided through the 
usual NHS routes and TB/chest clinics, until 
after the trial D28 follow-up visit and CT, 
decision not to enrol, or early withdrawal; 
whichever occurs first. The study team will 
keep each volunteer’s NHS TB/chest clinic 
team aware of when these timelines are 
reached. However, considering the challenges 
inherent in recruiting latently infected 
volunteers, if the volunteer does not want 
their prospective anti-TB chemoprophylaxis 
delayed they will still be eligible to be enrolled 
onto the study. 
9.5 
Randomisation 
and blinding 
 
Deletion of this section 
9.6 Follow up 
visit 
 
MVA85A vaccination will be performed 
by the aerosol or intramuscular route 
according to the site specific SOP. 
 
The bronchoscopy visit lasts several 
hours 
and 
takes 
place 
at 
the 
bronchoscopy suite in the OUH NHS 
Foundation Trust Hospitals by the 
specialist team there. Details of the 
procedure are outlined in section 6.1 
 
Now 9.5 Follow up visit 
MVA85A vaccination will be performed by the 
aerosol route according to the trial SOP.  
 
The bronchoscopy visit lasts several hours and 
takes place at the bronchoscopy suite in the 
OUH NHS Foundation Trust Hospitals by the 
specialist team there. Details of the procedure 
are outlined in section 6.1 
In 
exceptional 
circumstances 
where 
volunteers are absolutely unable to travel to 
Oxford, the bronchoscopy may be performed 
at the other NHS trust study sites (King’s 
College Hospital NHS Trust, University of 
Birmingham NHS Trust, Royal Free Hospital 
NHS Trust). The bronchoscopy will always be 
performed by a respiratory consultant trained 
in the procedure and following the trial 
specific SOP. 
10.3 
The vaccine will be administered IM over 
the deltoid region of the non-dominant 
The vaccine will be administered by aerosol 
inhalation, according to the trial-specific SOP. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 11 of 56 
upper arm, or by aerosol inhalation, 
according to the site-specific SOP. 
 
 
10.4 Saline 
Sterile saline will be used for dilution and 
placebo doses. The volume of saline 
used as placebo will be identical to the 
vaccine volume by the same route. For 
volunteers 
receiving 
the 
aerosol 
vaccination (Starter Group, Group A) we 
will administer the vaccine dose made 
up to 1ml with saline and at the same 
time a paired placebo (Group A only) of 
60µl of normal saline for IM injection. 
For volunteers receiving the vaccine IM 
(Group B) we will administer 60µl and at 
the same time a paired placebo of 1ml of 
saline inhaled.  
 
Sterile saline will be used for dilution of 
MVA85A as needed, to achieve the correct 
dose. Once prepared, the vaccine will then be 
made up to 1ml with saline for administration 
via the MicroAIR NE-U22 nebuliser.  
 
11.7 Assessment 
of severity 
 
Local injection site reactions table deleted 
12.0 Statistics 
Following the first three volunteers 
enrolled into the starter group, six 
volunteers will be recruited into each 
experimental arm of the trial (groups A 
and B). Our previous experience with 
clinical trials using MVA85A suggests 
that this sample size is a feasible number 
to recruit, screen, enroll, and follow up 
in practical terms, whilst also allowing 
the determination of any substantial 
differences in the outcome measures 
between the two groups. A twofold 
increase in the magnitude of the cellular 
immune response (as measured by 
ELISpot 
response 
to 
85A 
peptide 
stimulation) 
is 
considered 
immunologically 
meaningful. 
This 
sample size is appropriate for a proof-of-
concept Phase I safety study and takes 
into account the low number of 
potentially eligible healthy adults with 
latent M.tb infection in the UK and the 
impact of this on recruitment. The 
sample size has not been determined 
with the aim of achieving statistical 
significance. 
The one-week and six-month responses 
will be compared between the two 
groups using a t-test. If the resulting data 
are not normally distributed then 
medians and interquartile ranges will be 
used to summarise the data and the 
Mann Whitney U test will be used for 
statistical comparisons. An area-under-
curve analysis will be used to compare 
This is primarily a safety trial with descriptive 
endpoints. 
Following 
the 
first 
three 
volunteers enrolled into the starter group, 3-
6 volunteers will be recruited into Group A, to 
receive the target dose. Due to existing 
difficulties recruiting to this clinical trial we 
have decided to take out Group B (the 
comparator arm) to ensure that the numbers 
recruited will still be sufficient to allow for the 
primary objective, an assessment of safety. 
The one-week and three-month responses 
will be compared. Medians and interquartile 
ranges will be used to summarise the data and 
the Mann Whitney U test will be used for 
statistical comparisons. An area-under-curve 
analysis will be used to compare the overall 
responses over time comparing these aerosol 
data with historical data from previous trials. 
This analysis will make use of data collected at 
all time points.  
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 12 of 56 
the overall responses over time between 
the two groups. This analysis will make 
use of data collected at all time points. 
 
16.6 
Reimbursements 
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 £515-£635, 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 £505-£625, depending 
on the exact number of visits, site of 
recruitment and whether any repeat or 
additional visits are necessary. 
 
Protocol v6.0 Substantial amendment 
Section 
From 
Changed To 
9.2 
Patients who fulfil the inclusion criteria 
will be given a Volunteer Information 
Sheet at their clinic attendance and 
asked if they would like to participate. If 
interested, their details will be passed to 
the trial team to arrange a screening 
appointment. 
Patients who fulfil the inclusion criteria will be 
given a Volunteer Information Sheet Summary 
at their clinic attendance and asked if they 
would be interested in finding out more about 
the trial. If so, they will be given the full 
Volunteer Information Sheet to take with them 
to read in their own time. If still interested, 
and with their permission, the trial team will 
contact the patient to arrange a screening 
appointment. 
 
Protocol v5.0 Substantial amendment 
Section 
From 
Changed To 
Throughout 
 
Reduction of sample size for Starter Group, 
Group A and Group B 
Throughout  
 
Addition of three new sites 
Throughout 
 
Minor typographical corrections 
Synopsis 
Trial Duration estimated at 24 months 
Trial Duration estimated at 30 months 
 
Protocol v4.0 Substantial amendment 
Section 
From 
Changed To 
3.0 
 
Removal of Mike Riste as trial Investigator 
8.2  
 
Healthy adult aged 18-50 years 
 
Healthy adult aged 18-55 years 
9.2 
Prospective 
anti-tuberculous 
chemoprophylaxis would be delayed until 
the end of the trial, or early withdrawal; 
whichever occurs first.  
Prospective 
anti-tuberculous 
chemoprophylaxis, provided through the usual 
NHS routes and TB/chest clinics, would be 
delayed until after the trial D28 follow-up visit 
and CT, decision not to enroll, or early 
withdrawal; whichever occurs first. The study 
team will keep each volunteer’s NHS TB/chest 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 13 of 56 
clinic team aware of when these timelines are 
reached.  
11.9 
The LSM will perform independent 
external safety reviews prior to dose 
escalations. 
[deleted to match other safety sections (11.1) 
as dose escalation safety review will be 
performed by PI and team] 
 
Protocol v3.0 Substantial amendment 
Section 
From 
Changed To 
9.2 
 
 
We will also display posters in GP 
practices in the hope of attracting 
interest 
from 
latently 
infected 
individuals in the community who are 
no longer attending TB contact clinics. 
 
Protocol v2.2 Non-substantial amendment 
Section 
From 
Changed To 
Throughout 
 
Oxford University Hospitals NHS 
Trust 
 
 
Oxford 
University 
Hospitals 
NHS 
Foundation Trust 
 
 
Protocol v2.1 Non-substantial amendment 
Section 
From 
Changed To 
8.2 
 
Use effective contraception for 
the duration of the trial period 
(females only) 
 
 
Use effective contraception (see below) 
for the duration of the trial period 
(females only) 
 
8.3 
 
Explanation added of “Effective contraception 
for female volunteers”.  
11.2 
 
Hospitalisation, regardless of 
length of stay, even if it is a 
precautionary measure for 
continued observation.  
 
Hospitalisation or prolongation of 
existing hospitalisation, regardless of 
length of stay, even if it is a 
precautionary measure for continued 
observation.  
 
Protocol v2.0 Substantial amendment  
Section 
From 
Changed To 
Throughout 
 
Incorrect references to placebo for Starter Group 
removed 
Throughout 
 
Clarification that first volunteer in Group A will be 
assigned, not randomised 
3.0 
Principal Investigator:  
Principal Investigator:  

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 14 of 56 
Dr Martin Dedicoat 
Consultant Infectious Diseases Physician 
Department of Infection & Tropical 
Medicine 
 
 
 
Heart of England NHS Trust 
Birmingham, B9 5SS 
Tel: +44 (0)121 4242357 
Fax: +44 (0)121 4241309 
Email: 
martin.dedicoat@heartofengland.nhs.uk 
 
Prof Paul Moss  
NIHR-WTCRF 
Tel: +44 (0)121 414 2824 
Email: p.moss@bham.ac.uk 
 
3.0 
Collaborator: 
Dr Henry Bettinson 
Consultant Respiratory and Intensive Care 
Physician 
Oxford Centre for Respiratory Medicine 
Oxford University Hospitals NHS Trust 
Oxford, OX3 7LE 
Tel: +44 (0)1865 225234 
Fax: +44 (0)1865 225221 
Email: henry.bettinson@ouh.nhs.uk 
 
Collaborators: 
Dr Henry Bettinson 
Consultant Respiratory and Intensive Care 
Physician 
Oxford Centre for Respiratory Medicine 
Oxford University Hospitals NHS Trust 
Oxford, OX3 7LE 
Tel: +44 (0)1865 225234 
Fax: +44 (0)1865 225221 
Email: henry.bettinson@ouh.nhs.uk 
 
Dr Martin Dedicoat 
Consultant Infectious Diseases Physician 
Department of Infection & Tropical Medicine 
Heart of England NHS Trust 
Birmingham, B9 5SS 
Tel: +44 (0)121 4242357 
Fax: +44 (0)121 4241309 
Email: martin.dedicoat@heartofengland.nhs.uk 
 
4.1 
 
Trial interventions corrected to match Table 1 
Table 1 
Diary cards provided / collected 
 
E-diary setup / final review 
Addition of pulmonary function test at D14 
Addition of CRP at D2 
Details of biochemistry tests added 
Table 2 
 
Missing footnotes added, plus minor changes to  
match updated Investigator Brochure 
9.4 
 
Urinalysis and a pregnancy test will be 
performed 
Addition of clotting profile 
Deleted (duplication) 
9.8 
All samples will be in anonymised form 
All samples will be in anonymised form at the 
CCVTM; samples at the NIHR-WTCRF may contain 
patient numbers and details as per NHS procedures. 
11.6 
 
Ediary.  
Addition: All AEs starting after the diary card period, 
or persisting after this period, will be recorded in 
the AE line listing of the CRF.  
13.1 and 13.3 
 
Paper CRFs also at CCVTM  

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 15 of 56 
Secure encrypted University of Oxford 
server 
Secure encrypted servers that are outsourced by 
OpenClinicaTM. 
Throughout 
 
Minor typographical corrections 
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 16 of 56 
3 KEY TRIAL CONTACTS AND ROLES 
Clinical Trial Units: 
 
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)  
 
 
 
 
Churchill Hospital, 
 
 
 
 
Old Road 
 
 
 
 
Headington 
 
 
 
 
Oxford, OX3 7LE 
 
Oxford Centre for Respiratory Medicine, and John Warin Ward, 
Oxford University Hospital NHS Foundation Trust 
Headington 
Oxford, OX3 7LE 
 
National Institute for Health Research-Wellcome Trust Clinical 
Research Facility (NIHR-WTCRF) 
 
 
 
 
Queen Elizabeth Hospital, Edgbaston 
 
 
 
 
Birmingham, B15 2TH 
 
Royal Free London NHS Foundation Trust 
Royal Free Hospital 
Pond Street 
London, NW3 2QG 
 
King’s College Hospital NHS Foundation Trust 
Denmark Hill 
London, SE5 9PJ 
 
PICs: 
Heartlands Hospital 
 
Heart of England NHS Foundation Trust 
Bordesley Green East 
Birmingham, B9 5SS 
 
Guy’s and St Thomas’ NHS Foundation Trust 
St Thomas’ Hospital 
Westminster Bridge Road 
London, SE1 7EH 
 
 
 
 
             St George’s University Hospitals NHS Foundation Trust 
             Queen Mary’s Hospital 
             Tuberculosis Chest Clinic 
              Roehampton Ln,  
             London SW15 5PN 
 
Chief Investigator: 
 
Professor Helen McShane 
 
 
 
 
CCVTM 
 
 
 
 
Tel: +44 (0)1865 617606 
 
 
 
 
Fax: +44 (0)1865 857471 
 
 
 
 
Email: helen.mcshane@ndm.ox.ac.uk 
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 17 of 56 
Principal Investigators:  
Prof Paul Moss 
NIHR-WTCRF Birmingham 
Tel: +44 (0)121 414 2824 
Email: p.moss@bham.ac.uk 
 
Dr Marc Lipman 
Royal Free Hospital 
Tel: +44 (0)20 7317 7560 
Email: marclipman@nhs.net 
 
Dr Felicity Perrin 
King’s College Hospital NHS Foundation Trust 
Tel: +44 (0)20 3299 1729 
Email: felicity.perrin@nhs.net 
 
Investigators:  
 
Dr Julia Marshall 
 
 
 
 
TB Vaccine Trial Physician 
 
 
 
 
CCVTM 
 
Collaborators:  
 
Dr Henry Bettinson 
 
 
 
 
Consultant Respiratory and Intensive Care Physician 
 
 
 
 
Oxford Centre for Respiratory Medicine 
 
 
 
 
Oxford University Hospitals NHS Foundation Trust 
 
 
 
 
Oxford, OX3 7LE 
 
 
 
 
Tel: +44 (0)1865 225234 
 
 
 
 
Fax: +44 (0)1865 225221 
 
 
 
 
Email: henry.bettinson@ouh.nhs.uk 
 
Dr Martin Dedicoat 
 
 
 
 
Consultant Infectious Diseases Physician 
 
 
 
 
Department of Infection & Tropical Medicine 
 
 
 
 
Heart of England NHS Trust 
 
 
 
 
Birmingham, B9 5SS 
 
 
 
 
Tel: +44 (0)121 4242357 
 
 
 
 
Fax: +44 (0)121 4241309 
 
 
 
 
Email: martin.dedicoat@heartofengland.nhs.uk 
 
Dr Ronan Breen 
Consultant Respiratory Physician 
Guy’s and St Thomas’ NHS Foundation Trust 
Tel: +44 (0)7788 1714 966 
Email: Ronan.Breen@gstt.nhs.uk 
 
Dr Catherine Cosgrove 
Consultant Infectious Diseases Physician 
Adult Lead at the Vaccine Institute SGUL 
St George’s, University Hospitals NHS Foundation Trust 
Tel: +44 (0)208 725 5827 
Email: CCosgrov@sgul.ac.uk 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 18 of 56 
Project Managers: 
 
Dr Rebecca Powell Doherty & Dr Alison Lawrie 
 
 
 
 
CCVTM 
 
Local Safety Monitor:  
Professor Brian Angus 
Nuffield Department of Medicine, University of Oxford 
Old Road, Headington 
Oxford, OX3 7BN 
Tel: +44 (0)1865 220154 
Fax: +44 (0)1865 222962 
Email: brian.angus@ndm.ox.ac.uk 
 
Senior Immunologist:  
Dr Iman Satti 
 
 
 
 
The Jenner Institute 
 
 
 
 
Old Road Campus Research Building 
 
 
 
 
Roosevelt Drive, Headington  
 
 
 
 
Oxford, OX3 7DQ 
 
 
 
 
Tel: +44 (0)1865 617623 
 
 
 
 
Fax: +44 (0)1865 617608 
 
 
 
 
Email: iman.satti@ndm.ox.ac.uk 
 
Statistician: 
 
 
Nicola Williams 
Senior Trial Statistician 
Nuffield Department of Primary Care Health Sciences  
Radcliffe Observatory Quarter, University of Oxford 
Woodstock Road,  
Oxford. OX2 6GG. 
Tel: +44 (0) 1865 289300. 
 
Sponsor:  
 
 
Clinical Trials & Research Governance 
 
 
 
 
Joint Research Office, University of Oxford 
 
 
 
 
Block 60, Churchill Hospital 
 
 
 
 
Old Road, Headington 
 
 
 
 
Oxford, OX3 7LE 
 
Monitor: 
 
 
Clinical Trials & Research Governance 
 
 
 
 
Joint Research Office, University of Oxford 
 
 
 
 
Block 60, Churchill Hospital 
 
 
 
 
Old Road, Headington 
 
 
 
 
Oxford, OX3 7LE 
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 19 of 56 
4 SYNOPSIS 
4.1 Synopsis 
Trial Title 
A phase I trial to evaluate the safety and immunogenicity of candidate TB vaccine 
MVA85A administered by the aerosol inhaled route in healthy adult volunteers 
who are latently infected with Mycobacterium tuberculosis 
Trial Identifier 
TB040 
Clinical Phase  
I 
Chief Investigator 
Professor Helen McShane 
Trial Centres 
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Churchill Hospital, 
Old Road, Headington, Oxford, OX3 7LE 
 
John Warin Ward, Oxford University Hospital NHS Foundation Trust, Churchill 
Hospital, Old Road, Headington, Oxford, OX3 7LE 
 
NIHR-Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, 
Edgbaston, Birmingham, B15 2TH 
 
Royal Free London NHS Foundation Trust, Royal Free Hospital, Pond Street, 
London, NW3 2QG 
 
King’s College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9PJ 
 
Trial participants 
Healthy adult volunteers who are latently infected with M.tb 
Planned Sample Size 
6-9 subjects: 
Starter Group: the first 3 volunteers will receive 1 x 107 pfu aerosol inhaled 
MVA85A  
Group A (Standard Dose) : 3-6 volunteers will receive 5 x 107 pfu aerosol inhaled 
MVA85A 
Vaccination Schedule 
Single vaccination at day 0 
Follow-up Duration 
Final visit 12 weeks from vaccination day with telephone call at 24 weeks. 
Blood Sampling  
See visit schedule 
Trial Interventions 
CT thorax at screening and day 28 
Pulmonary function tests (as per table 1)  
Vaccination by aerosol inhaled route  
Venepuncture 
Bronchoscopy and BAL 
Trial Duration 
Estimated at 42 months 
Planned Trial Period 
Planned start date is July 2015 
 
Objectives 
Outcome Measures 
Primary 
To evaluate the safety of MVA85A 
vaccination by the aerosol inhaled route 
in healthy volunteers who are latently 
infected with M.tb  
Actively and passively collected data on 
adverse events 
Secondary 
To evaluate the systemic and mucosal 
cellular and humoral immunogenicity 
induced by MVA85A vaccination by the 
aerosol inhaled in healthy volunteers 
who are latently infected with M.tb   
Laboratory markers of cell mediated 
immunity, including ex-vivo ELISpot in 
blood and intracellular cytokine staining 
in blood and BAL samples 
Tertiary 
To evaluate other exploratory markers 
of cell-mediated and humoral 
immunogenicity induced by aerosol 
MVA85A, including transcriptomic 
analysis 
Laboratory markers of cell mediated 
and humoral immunity in blood and BAL 
samples 
IMP 
MVA85A 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 20 of 56 
Dose(s) 
1 x 107 pfu (Starter group). 5 x 107 pfu (Group A) 
Route of IMP 
Aerosol inhalation by nebuliser  
Allocation Method 
Sequential allocation 
 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 21 of 56 
4.2 Schedule of visits and procedures 
Table 1. Schedule of trial procedures 
Attendance number 
1 
2 
3 
4 
5 
6 
7 
8 
Timeline (days)* 
S 
0 
2 
7 
14 
28 
84 
168T 
Timeline (weeks)* 
S 
0 
 
1 
2 
4 
12 
24 
Time windows (days) 
 
 
1 
+4, -2 
4 
7 
14 
21 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Review contra-indications  
X 
X 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Physical examination 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
CT chest 
X 
 
 
 
 
X 
 
 
PFTs 
X 
X 
X 
X 
X 
 
 
 
β-HCG urine test 
X 
X 
 
X 
 
 
 
 
Vaccinations  
 
X 
 
 
 
 
 
 
Bronchoscopy 
 
 
 
X 
 
 
 
 
Local & systemic 
events/reactions 
 
X 
X 
X 
X 
X 
X 
X 
Ediary setup 
 
X 
 
 
 
 
 
 
Ediary final review 
 
 
 
 
X 
 
 
 
Biochemistry (4mL)** 
X 
 
X 
X 
 
X 
 
 
Haematology (2mL) 
X 
 
 
X 
 
X 
 
 
Coagulation (4mL) 
X 
 
 
 
 
 
 
 
HBV, HCV, HIV (10mL) 
X 
 
 
 
 
 
 
 
HLA typing (4mL) 
 
X 
 
 
 
 
 
 
Exploratory immunology incl 
ELISpot (16-60mL***) 
X 
X 
X 
X 
X 
X 
X 
 
Blood vol (mL) 
30 
64 
20 
56 
60 
66 
60 
 
Cumulative blood vol 
(mL)**** 
30 
94 
114 
170 
230 
296 
356 
 
S 
Screening  
X  
Event scheduled to occur 
(X) 
If considered necessary, emphasising any complaint or change in medications 
T 
Telephone call. Final visit is deemed to be at D84 with follow up phone call at D168  
* 
Timeline is approximate only, as exact timings ( windows periods) of visits relate to the actual (not intended) 
date of the previous visit 
** 
U&Es, LFTs (except day 2 when CRP only;) 
*** 
60ml at all visits except screening (10ml, T spot), visit 3 (16ml, no ELISpot) and visit 4 (50ml) 
**** 
Blood volumes stated for Oxford. The exact volumes of blood taken will depend on the local site – cumulative 
blood volumes for volunteers outside Oxford may be slightly lower or higher than those of Oxford volunteers, 
due to the use of different volume vacutainers for biochemistry, haematology and serology samples as per local 
Trust standard procedures 
Grey  
Highlights vaccination day 
 
 Blue 
Highlights bronchoscopy day 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 22 of 56 
5 ABBREVIATIONS 
AE 
Adverse Event 
 
AR 
 
Adverse Reaction 
BAL 
 
Bronchoalveolar Lavage 
BCC 
 
Basal cell carcinoma 
BCG 
 
Bacille Calmette-Guérin 
β-HCG 
 
Beta - Human Chorionic Gonadotrophin 
CCVTM 
 
Centre for Clinical Vaccinology and Tropical Medicine 
CIS 
 
Carcinoma in situ 
CRF 
 
Case Report Form 
CRP 
 
C-reactive protein 
CT 
 
Computed Tomography 
DNA 
 
Deoxyribonucleic Acid 
ELISpot 
 
Enzyme-linked Immunospot 
FBC 
 
Full Blood Count 
GCP 
 
Good Clinical Practice 
GMO 
 
Genetically Modified Organism 
GLP 
 
Good Laboratory Practice 
GMSC 
 
Genetic Modification Safety Committee 
GSTT 
 
Guy’s and St. Thomas’ NHS Foundation Trust 
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 
IMP 
 
Investigational Medicinal Product 
LFT 
 
Liver Function Test 
LSC 
 
Local Safety Committee 
MHRA 
 
Medicines & Healthcare Regulatory Authority 
M.tb 
 
Mycobacterium tuberculosis 
MVA 
 
Modified vaccinia Virus Ankara 
NIHR 
 
National Institute for Health Research 
PBMC 
 
Peripheral Blood Mononuclear Cells 
PFT 
 
Pulmonary Function Tests 
PFU 
 
Particle Forming Unit 
REC 
 
Research Ethics Committee 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SGUL 
 
St George’s University of London 
SmPC 
 
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
Tuberculosis 
TMF 
 
Trial Master File 
U&Es 
 
Urea & Electrolytes 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 23 of 56 
VP 
 
Viral Particles 
WTCRF  
 
Wellcome Trust Clinical Research Facility 
6 BACKGROUND AND RATIONALE 
6.1 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 (1). In 2013, there were 9 million new 
cases worldwide and 1.5 million people died of TB (2). Co-infection with human immunodeficiency 
virus (HIV) greatly increases risk of TB reactivation and death (3, 4). 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.  
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 (5). Although it does not protect 
against pulmonary TB in endemic areas, it is effective in preventing disseminated TB disease including 
tuberculous meningitis in childhood (4, 6, 7).  
Recently, heterologous “prime-boost” vaccination strategies, in which two 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 would therefore be an ideal priming vaccine. 
MVA85A (Modified Vaccinia virus Ankara expressing M.tb antigen 85A) has been shown to be 
immunogenic as a booster vaccine in BCG-primed subjects (8); however, a phase IIb efficacy trial in 
2797 BCG-vaccinated infants in South Africa reported no enhancement of BCG-induced protection (9). 
In this trial, the immunogenicity was 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 has also just reported and no efficacy was demonstrated. Immunogenicity in this 
trial was also lower than that seen in UK adults and innovative ways of enhancing immunogenicity are 
urgently needed (10).  
 
Basis for the aerosol inhaled route 
The route of M.tb infection is by inhalation of aerosolised infectious droplets containing tubercle 
bacilli, leading to the establishment of primary infection in the lung, which has a distinct mucosal 
immune system characterized by bronchus associated lymphoid tissue (BALT), which is well adapted 
to encounter and process such antigens. Immunising via the airway should therefore have the 
advantage, over other routes, of eliciting protective immune responses in the lung mucosa. 
There is data from preclinical animal models with MVA85A and other virally vectored vaccines to 
suggest that immunising the respiratory mucosa may give superior protection against respiratory 
diseases (11-15). Feasibility studies of aerosolised MVA delivery in non-human primates have 
demonstrated safe and consistent mucosal delivery to the respiratory tract, with potent and long-
lasting insert specific immune responses (16). We know that BCG, administered systemically, protects 
most effectively against systemic disease in childhood (6, 7). It may follow that airway vaccination is 
needed to induce effective protection from pulmonary disease. In addition, the aerosol inhaled route 
of MVA85A delivery could offer practical, tolerability and safety benefits over and above needle-based 
methods (see below). There is, therefore, considerable international interest in developing this route 
of administration of TB vaccines.  

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 24 of 56 
The inhaled route is a well-established route of drug delivery. Aerosolised droplets of bronchodilating, 
anti-inflammatory, and antimicrobial drugs are administered by inhalation to millions of patients each 
day. Clinical trials of aerosolised measles vaccines have shown that mass immunization by the 
respiratory mucosal route in a developing country is feasible and can induce strong and long lasting 
immune responses (17-23). There is also valuable experience with aerosol vaccines given to over 4 
million schoolchildren in Mexico, where public acceptance was high, costs were low, and fewer side 
effects were reported than with subcutaneous vaccination (24). A nasally administered influenza 
vaccine is licensed in North America (25-27) and others are in clinical trials (28-30). The principle of 
mucosal surface vaccination is well established, as shown by widely used and effective mucosal 
vaccines against polio, typhoid, cholera and rotavirus. 
There are numerous perceived advantages of aerosol inhaled vaccination: it is safe, needle-free, well-
tolerated, popular, less technically demanding, economically beneficial, and allows self-administration 
of vaccine or administration by less technically trained community health workers (24). Furthermore, 
use of non-injectable vaccines reduces the likelihood of unsafe disposal and reuse of syringes in 
immunisation programmes (31). 
Another important potential advantage of mucosal immunisation is that aerosol vaccination may 
minimise or avoid induction of systemic anti-vector immunity and allow homologous boosting with 
the same viral vector; thus minimising cost of vaccine development (32-34).  
The first clinical trial of a candidate TB vaccine being delivered by aerosol to humans was completed 
at Oxford in 2013. This Phase I trial (TB026) assessed the safety and feasibility of administering 
MVA85A by nebuliser direct into the airways (35). 12 volunteers received aerosolised MVA85A (10 
received the low dose (1 x 107 pfu) and 2 received the higher dose that we would normally give 
intradermally (1 x 108 pfu)) and saline intradermal placebo, while 12 volunteers received MVA85A as 
intradermal injection with inhaled saline placebo. No vaccine related SAEs were reported and aerosol 
immunisation was well tolerated (35).  Antigen-specific Th1 immunity was higher in the BAL fluid after 
aerosol administration than after intradermal administration. Antigen-specific Th1 immunity in the 
blood was comparable between routes of administration. Importantly, no reduction of systemic 
immunity was seen after aerosol administration. Interestingly no serum anti-MVA antibodies were 
detected after aerosol administration, in comparison with intradermal administration where anti-
MVA antibodies were induced. A second Phase I safety trial assessing anti-vector immunity with 
nebulised MVA85A was completed in 2016 (TB035, Clinical Trials.gov reference number 
NCT01954563). An intermediate dose of 5 x 107 pfu was used in TB035. No vaccine related SAEs were 
reported (unpublished data). To our knowledge there have been no other clinical studies of viral 
vectored vaccines delivered by aerosol. 
Aerosol delivery of a candidate TB vaccine, therefore, shows promise; however, before this potential 
route of vaccine administration can be evaluated in TB high burden countries, it is imperative that 
safety in subjects with latent M.tb infection be determined, because of the theoretical risk of 
immunopathology. This trial aims to assess safety and immunogenicity of aerosol MVA85A vaccination 
by repeating our previous phase I clinical trial of aerosol MVA85A vaccination in healthy adults (35) in 
UK adult human volunteers with latent M.tb infection. The essential safety and immunogenicity data 
that will be generated from this trial is a critical go/no-go criteria before this potentially promising 
route of vaccination can be evaluated in TB high burden countries, where an improved TB vaccine is 
most needed.  
 
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 and is therefore suitable for use as a 
viral vector 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 (36-39), and 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 25 of 56 
has since been used in numerous clinical trials of candidate vaccines against viral, mycobacterial and 
protozoal infections (40, 41). 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 (42).  
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 (43). Antigen 85A is highly immunodominant in both animal and human studies 
(44-46), and protects against M.tb challenge in mice, guinea pigs and non-human primates (47, 48). 
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 (11, 48-50). Animal toxicity studies using the intradermal route of administration revealed no 
differences from PBS-injected controls apart from irritation at the site of administration. 
 
Clinical studies with MVA85A 
Over 2500 volunteers have now received MVA85A, of which (in completed trials) 48 were by the 
intramuscular route, 12 by the aerosol route and the remainder intradermally. 22 phase I/II clinical 
studies of MVA85A have been completed, a further three are ongoing. These are summarised in table 
2. We have conducted one previous trial evaluating MVA85A in adults with latent M.tb infection 
(TB007). Volunteers were vaccinated intradermally and the vaccine was safe and immunogenic, with 
no serious adverse events. In addition, several previous studies (TB010, TB011, TB019 and TB021) have 
all included volunteers with latent M.tb infection. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 26 of 56 
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 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 27 of 56 
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 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 28 of 56 
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. Of 9 subjects who received aerosol boost vaccination 1 month after ID prime, 7 experienced transient mild to moderate 
respiratory AEs. All were self-limiting. This only occurred in subjects receiving an aerosol boost 1 month after an ID prime. The last 3 subjects in this group did not therefore receive an aerosol MVA85A boost.;.*1 
subject withdrawn post first vaccination but prior to boost vaccination so was replaced.  
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 
 
 
 
 
 
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 
 
13e* 
 
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 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 29 of 56 
Safety profile 
No signs of any Koch reaction in volunteers infected with M.tb have been seen with this or any other 
candidate vaccine to date. One possible vaccine related SAE – early unmasking of pre-existing 
tuberculous meningitis - occurred in a patient with HIV in South Africa.   
The analysis of local and systemic reactions induced by the aerosol route that were reported in the 
completed Phase I safety trials are summarised in section 6.3 “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 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 subsequently been adopted as the standard 
dose in all subsequent trials (51, 52). The aerosol dose administered in trial TB026, a Phase I safety 
trial assessing the safety and feasibility of administering MVA85A by the aerosol route, was 1 x 107 pfu 
and the dose used in TB035 was 5 x 107pfu. In TB035, 2 patients with a significant history of atopy 
experienced transient systemic reactions following their 2nd vaccine dose. These included Grade 3 
temperature, SOB, feverishness, fatigue, nausea and malaise, Grade 2 wheeze, cough and headache, 
and Grade 1 phlegm, myalgia, arthralgia and sore throat. These symptoms peaked at 24-48 hours and 
resolved fully by one week, excepting cough which resolved by day 14. There was a transient but 
significant reduction in exercise tolerance and PFTs; one volunteer had a 40% drop in FEV1 and FVC 
which normalized by 72 hours, the other a 15% drop (within normal parameters) which also resolved 
in this timeframe. As a result of this, volunteers with a significant history of atopy are now excluded 
from aerosol trials. 
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 (53). 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. 
 
Aerosol delivery devices 
Currently the World Health Organisation (WHO) is making a major investment in developing new 
aerosol devices for portable, low cost vaccine delivery (55). The WHO Measles Aerosol Project aims to 
develop and license respiratory delivery for measles vaccines currently given by injectable methods. 
The Edmonton-Zagreb strain of measles vaccine, a live virus vaccine, has been given by mesh nebuliser 
with excellent results. The most modern devices are small, lightweight, portable, and aerosolise 
through a mesh to provide small and consistent particle size which deliver vaccine to the distal airway 
mucosa more consistently and precisely than conventional jet mechanisms.  
One such mesh nebuliser is the MicroAIR NE-U22 (Omron® Healthcare Limited, Japan) which uses 
ultrasound to push liquid through a fine metal mesh. This generates an aerosol mist with a particle 
diameter of about 4 µm. It is in current use with licensed drugs such as bronchodilating and 
antimicrobial agents and achieves good bioavailability. MVA particles are typically around 400 nm in 
size and can therefore be aerosolised with minimal damage.  
We demonstrated adequate delivery of our vaccine, MVA85A, by this device in preliminary plaque 
assays. Using a nebuliser adapted for rodent administration, we performed GLP standard toxicology 
studies of aerosolised MVA85A (1 x 108 pfu) in BalbC mice, demonstrating satisfactory safety and 
systemic immunogenicity. We further administered aerosolised MVA85A (1 x 108 pfu) by the MicroAIR 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 30 of 56 
NE-U22 mesh nebuliser to eight macaques, showing a good safety profile and satisfactory delivery by 
inhaled route (unpublished data). We have subsequently used this Omron device in TB026 and TB035, 
with a good safety profile.   
 
Bronchoscopy and bronchoalveolar sampling 
Protection from TB induced by intra-pulmonary vaccination correlates with cellular immune responses 
detected in the BAL samples of immunised mice (56). In macaques receiving aerosolised MVA85A we 
detected significant levels of antigen-specific cellular immune responses in BAL samples (57). In TB026 
we detected significant levels of antigen-specific cellular immune responses in these BAL specimens, 
with higher frequencies in the aerosol group (35). Both CD4+ and CD8+ antigen specific T cells were 
detectable in the BAL. Clinical trials of intranasal vaccine candidates for other infectious diseases have 
analysed humoral immunity within nasal lavage, but a cellular immune response is essential for 
protective immunity against M.tb (58). Nasal mucosal samples are unlikely to provide adequate 
cellular samples as nasal lavage generally yields insufficient and variable numbers of cells (59). 
Furthermore as the vaccine is nebulised and inhaled orally we do not expect it to reach the nasal 
mucosa.  
BAL samples are obtained by performing a bronchoscopy, a widely and safely used procedure. The 
short procedure involves the insertion of a narrow flexible fibre-optic tube into the airway under light 
intravenous sedation and topical local anaesthesia. Under direct vision saline is delivered to a section 
of lung mucosa and then recollected by suction. In clinical trial TB026 bronchoscopies were well 
tolerated by volunteers. Bronchoscopy is an essential component of this clinical trial because BAL 
samples are the ideal method to analyse the lung mucosal cellular immune responses which we intend 
to induce by vaccination (63).   
6.2 Rationale 
 
Hypothesis 
We postulate that the aerosol inhaled route is practical and feasible and has an acceptable safety 
profile, in volunteers latently infected with M.tb. We hypothesise that the aerosol inhaled route of 
administration will induce greater mucosal immunity and comparable systemic immunity when 
compared to historical data of the IM (systemic) route of administration from previous studies in 
healthy volunteers. 
 
Vaccine dosage 
Trials of MVA85A to date have established 1 x 108 pfu as the optimal dose for intradermal injection in 
adults. Although the fractional delivered dose of aerosolised viral vectored vaccines to the mucosal 
surface may be considerably less than 25%, there is evidence that strong mucosal and systemic 
immune responses, comparable to the injectable route, are nevertheless achieved (16, 64). 
As this trial will be the first time that aerosolised MVA85A is given to individuals with latent M.tb 
infection, we plan to begin with a low dose Starter Group, who will receive 1 x 107 pfu MVA85A by 
aerosol inhalation. This is the dose used in trial TB026 in healthy adults. The first volunteer in this 
group will be vaccinated ahead of other volunteers and no other volunteers will be vaccinated until at 
least 48 hours has elapsed. The CI will perform a review of the 48 hour safety data and decide if it is 
safe to vaccinate the remaining volunteers. There will be a second review of safety data after 
vaccination of all volunteers in the Starter Group.   
Once the Starter Group is fully enrolled and the second safety review is completed, we will start 
enrolment into Group A (Standard Dose), with dose escalation to 5 x 107 pfu (the same dose used in 
TB035). For safety reasons, the first volunteer in this group will be vaccinated ahead of other 
volunteers and no other volunteers will be vaccinated until at least 48 hours has elapsed. If the CI 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 31 of 56 
decides it is safe to proceed, the remaining volunteers will then be enrolled. The target enrolment for 
this group is 6 volunteers. However, given the often reduced pace of recruitment from the latently 
infected population, we will accept a minimum of 3 volunteers if the target has not been reached by 
October 2018. 
6.3 Risks and Benefits 
 
Potential risks  
The potential risks to participants in this trial include risks associated with: 
1. Venepuncture and intravenous cannulation 
Localised bruising and discomfort can occur at the site of venepuncture. Infrequently fainting may 
occur. The total volume of blood drawn over a six month period will be 356mL, which should not 
compromise the health of these healthy individuals. 
An intravenous cannula is routinely inserted into a peripheral (usually forearm) vein prior to 
bronchoscopy to administer intravenous sedation and removed once the procedure is completed. The 
risks of cannulation are identical to those associated with venepuncture. Additionally cannulation 
carries a small risk of soft tissue infection which will be minimised by an aseptic insertion technique 
and is easily recognisable and treatable. The short duration of cannulation (a few hours) further 
minimises this risk. 
2. Vaccination 
MVA85A has undergone thorough pre-clinical testing and has now been administered to over 2500 
healthy human individuals with one possible SAR. The potential known adverse events associated with 
vaccination are: 
Local reaction from aerosol inhaled vaccination 
Expected reactions to inhaled vaccination include mild throat discomfort and coughing.  Transient 
bronchospasm (causing wheeze) is possible. In the completed aerosolised trials (TB026 and TB035) 
there was no significant difference between respiratory adverse events or pulmonary function tests 
between the group receiving a priming immunisation with aerosol MVA85A and the group receiving a 
priming immunisation with ID MVA85A. In both groups AEs were infrequent and mild.  In TB035, of 
the 9 subjects who received an aerosol boost vaccination 1 month after ID prime, 7 experienced 
transient mild to moderate respiratory AEs. All were self-limiting. This only occurred in subjects 
receiving an aerosol boost 1 month after an ID prime. The last 3 subjects in this group did not therefore 
receive an aerosol MVA85A boost. 
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, fatigue and 
headache are most common, occurring in 50-90% of volunteers, and these are nearly always mild. 
Presyncopal and syncopal episodes may occur at the time of vaccination which rapidly resolve. As with 
any other vaccine, temporary ascending paralysis (the Guillain-Barré syndrome, GBS) or immune 
mediated reactions that can lead to organ damage may occur. For influenza vaccines an excess of 
approximately 1 GBS 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 MVA85A vaccine or 
vaccines containing any of its components. 
TB specific risks 
There is a very small risk of a Koch reaction, or immunopathology at the site of infection occurring 
when volunteers latently infected with M.tb are vaccinated with MVA85A. No such reactions were 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 32 of 56 
seen in previous trial TB007, where MVA85A was administered systemically to volunteers with latent 
M.tb infection. All volunteers will be closely monitored and followed up both clinically and 
radiologically. 
Allergic reactions 
Allergic reactions from mild to severe may occur in response to any constituent of a vaccine 
preparation. Anaphylaxis is extremely rare but can occur in response to any vaccine.  
3. Bronchoscopy 
Bronchoscopy is a widely and safely used investigative procedure in clinical research studies involving 
both healthy volunteers and patients with respiratory conditions such as asthma and interstitial lung 
disease (60, 61). Clinical guidelines for performing investigative bronchoscopy in research studies are 
well established (62).  
The bronchoscopies will be carried out in a dedicated NHS bronchoscopy suite with an excellent safety 
record by highly skilled and experienced consultant respiratory physicians. Intravenous sedation and 
topical local anaesthesia are administered prior to bronchoscopy to reduce discomfort, facilitate the 
procedure, and remove memory of the event (In 98% of cases, subjects have no memory of the 
procedure). Trained, experienced staff and facilities for resuscitation and drugs for reversal of sedation 
will be available. No transbronchial or endobronchial biopsies will be taken. To further minimise risk, 
volunteers will be excluded if they have an abnormal CT chest, a significant smoking history, a history 
of atopy, or any evidence of lung disease, including asthma (as defined by: a clinical diagnosis of 
asthma; prescription of asthma medication; airflow obstruction on spirometry; history of nocturnal or 
exercise-induced wheeze). 
The risks of bronchoscopy are discussed at the time of consent and comprise: adverse reaction to 
sedation or local anaesthetic, sore throat, nose bleed (minimized as scope passed through mouth), 
laryngospasm, hypoxia, post-procedure flu-like symptoms (1-2 days) and risk of death (<1 in 100,000). 
 
Bronchoalveolar lavage is a routine procedure in investigative bronchoscopy and carries minimal 
bleeding risk. The risk of infection or febrile reactions will be minimised by full bronchoscope 
asepsis and superflush. 
 
Respiratory depression secondary to sedation is rare. No rescue medication for oversedation has 
been required for volunteers participating in trials TB026 and TB035 to date.  
 
Allergic reactions from mild to severe may occur in response to any constituent of the local 
anaesthetic or sedative agents. Anaphylaxis is extremely rare but can occur. 
The Summary of Product Characteristics (SmPC) for the local anaesthetic and sedative agents contain 
full details of the indications and side effects of these licensed medications. 
4. CT thorax 
A computed tomography scan of the thorax is a painless radiological investigation which exposes 
volunteers to approximately 2 milliSieverts of radiation, equivalent to around 9 months of natural 
background radiation. The additional risk of cancer due to one CT thorax is small, approximately 1 in 
9000. The total radiation exposure for this trial (two CT scans) will therefore be 4 milliSieverts, carrying 
an attributable cancer risk of 1 in 4500. 
5. Pulmonary Function Tests 
Vigorous respiratory manoeuvres such as forced expiration through the spirometer can occasionally 
lead to coughing or lightheadedness, but these symptoms are mild and rapidly self-limiting. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 33 of 56 
 
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, urine tests, CT thorax and pulmonary function tests. They may also gain health information from 
the bronchoscopy. Volunteers found to have a previously undiagnosed condition thought to require 
further medical attention will be referred appropriately to their GP or an NHS specialist service for 
further investigation and treatment. 
It is hoped that their contribution will enable the development of a safe and successful vaccine for TB 
and further our knowledge about mucosal vaccines.  
 
7 OBJECTIVES AND OUTCOME MEASURES 
Table 3. Objectives and Outcome Measures 
 
8 PARTICIPANT IDENTIFICATION 
8.1 Trial Participants 
Healthy UK adults who are latently infected with M.tb and have no evidence of active disease. 
8.2 Inclusion Criteria 
Volunteers must meet all of the following criteria to enter the trial: 
 
Healthy adult aged 18-55 years 
 
Resident in or near Oxford, Birmingham or London for the duration of the trial period 
Objectives 
Outcome Measures  
Timepoint(s) 
of 
evaluation of this 
outcome measure  
Primary Objective 
To evaluate the safety of MVA85A vaccination 
by the aerosol inhaled route in healthy adult 
volunteers who are latently infected with 
M.tb. 
Actively 
and 
passively 
collected data on adverse 
events 
At each visit, via 
diary card for 14 
days 
after 
vaccination and at 
the 6 month phone 
call 
Secondary Objectives 
To evaluate the systemic and mucosal cellular 
and humoral immunogenicity induced by 
MVA85A vaccination by the aerosol inhaled 
route, in healthy volunteers who are latently 
infected with M.tb.  
Laboratory markers of cell 
mediated 
and 
humoral  
immunity, including ex-vivo 
ELISpot 
in 
blood 
and 
intracellular 
cytokine 
staining in blood and BAL 
samples 
At each visit 
Tertiary Objectives 
To evaluate other exploratory markers of cell-
mediated 
and 
humoral 
immunogenicity 
induced 
by 
aerosol MVA85A, 
including 
transcriptomic analysis 
Laboratory markers of cell 
mediated 
and 
humoral 
immunity in blood and BAL 
samples 
At each visit 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 34 of 56 
 
Screening IGRA positive  
 
Considered low risk of reactivation of their latent infection due to distant contact history 
 
Chest CT normal; or abnormal with features consistent with primary M.tb infection but no 
features suggestive of active disease 
 
No relevant findings in medical history or on physical examination 
 
Allow the Investigators to discuss the individual’s medical history with their GP 
 
Use effective contraception (see below) for the duration of the trial period (females only) 
 
Refrain from blood donation during the trial. 
 
Give written informed consent 
 
Allow the Investigator to register volunteer details with a confidential database (The Over-
volunteering Protection Service) to prevent concurrent entry into clinical trials 
 
Able and willing (in the Investigator’s opinion) to comply with all the trial requirements 
8.3 Exclusion Criteria 
Volunteers must meet none of the following criteria to enter the trial: 
 
Participation in another research study involving receipt of an investigational product in the 30 
days preceding enrolment, or planned use during the trial periodd 
 
Prior vaccination with candidate vaccine MVA85A, candidate vaccine FP85A, any other 
recombinant MVA vaccine or any other candidate TB vaccine 
 
Administration of immunoglobulins and/or any blood products within the three months 
preceding the planned trial vaccination date 
 
Clinically significant history of skin disorder, allergy, atopy, immunodeficiency (including HIV), 
cancer (except BCC or CIS), cardiovascular disease, gastrointestinal disease, liver disease, renal 
disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse 
 
Concurrent oral or systemic steroid medication or the concurrent use of other 
immunosuppressive agents 
 
History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component 
of the trial vaccine, sedative drugs, or any local or general anaesthetic agents 
 
Pregnancy, lactation or intention to become pregnant during trial period 
 
Any respiratory disease, including asthma 
 
Current smoker   
 
Clinically significant abnormality on screening CT thoraxa, b 
 
Clinically significant abnormality of pulmonary function testsb 
 
Any nasal, pharyngeal, or laryngeal finding which precludes bronchoscopy 
 
Current use of any medication taken through the nasal or inhaled route including cocaine or 
other recreational drugs 
 
Clinical, radiological, or laboratory evidence of current active TB diseasec 
 
Past treatment for TB disease 
 
Any clinically significant abnormality of screening blood or urine testsb 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 35 of 56 
 
Positive HBsAg, HCV or HIV antibodiesb 
 
Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may 
either put the volunteer at risk, affect the volunteer’s ability to participate in the trial or impair 
interpretation of the trial data 
a Excepting findings felt to be consistent with latent TB infection only.   
b Volunteers 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 to their GP or an NHS specialist service for further 
investigation and treatment. 
c If there is any evidence of active TB disease either on clinical or radiological grounds, further 
investigation and treatment will be offered under the supervision of a consultant physician in 
respiratory or infectious diseases.  
d Volunteers will be excluded from the trial if they are concurrently involved in another study or trial 
that involves regular blood tests or an investigational medicinal product. In order to check this, 
volunteers will be asked to provide their National Insurance or Passport number (if they are not 
entitled to a NI number) and will be registered on a national database of participants in clinical trials 
(www.tops.org.uk). 
 
Effective contraception for female volunteers 
Female volunteers are required to use an effective form of contraception during the course of the 
trial. There is no information about the effect of these vaccines 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 on 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) 
9 TRIAL DESIGN AND PROCEDURES 
This is a phase I trial to evaluate the safety and immunogenicity of candidate TB vaccine MVA85A 
administered by the aerosol inhaled route in healthy volunteers who are latently infected with M.tb. 
9.1 Trial Numbers and Groups 
9 volunteers will be enrolled; the first 3 to the starter group, , then 3-6 volunteers into Group A. 
Table 4. Trial groups 
Arm of trial 
Sample size 
Intervention 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 36 of 56 
Starter group 
3 
Aerosol inhaled MVA85A 1 x 107 pfu  
Group A (Standard Dose) 
3-6 
Aerosol inhaled MVA85A 5 x 107 pfu  
9.2 Recruitment 
Volunteers considered to be at low risk of reactivation of their latent infection due to distant contact 
history, will be recruited from TB contact clinics at Oxford University Hospitals, Birmingham Chest 
Clinic Heart of England, Royal Free Hospital, King’s College Hospital, Guy’s and St Thomas’ Hospital 
and St George’s University Hospital. Patients who fulfil the inclusion criteria will be given a Volunteer 
Information Sheet Summary at their clinic attendance and asked if they would be interested in finding 
out more about the trial. If so, they will be given the full Volunteer Information Sheet to take with 
them to read in their own time. If still interested, and with their permission, the trial team will contact 
the patient to arrange a screening appointment. Ideally, the volunteer will  delay their prospective 
anti-tuberculous chemoprophylaxis, provided through the usual NHS routes and TB/chest clinics, until 
after the trial D28 follow-up visit and CT, decision not to enrol, or early withdrawal; whichever occurs 
first. The study team will keep each volunteer’s NHS TB/chest clinic team aware of when these 
timelines are reached. However, considering the challenges inherent in recruiting latently infected 
volunteers, if the volunteer does not want their prospective anti-TB chemoprophylaxis delayed they 
will still be eligible to be enrolled onto the study. 
Additionally, we will send a letter to patients seen at the clinic over the previous year with a diagnosis 
of latent M.tb infection who have not been given anti-tuberculous therapy, inviting them to 
participate in this trial. We will also display posters in GP practices in the hope of attracting interest 
from latently infected individuals in the community who are no longer attending TB contact clinics. 
9.3 Informed Consent 
Written informed consent will be obtained at screening by a GCP trained Investigator.  
The volunteer must sign and date the latest approved version of the consent form before any trial 
specific procedures are performed.  
The Volunteer Information Sheet will be made available to the volunteer no less than 24 hours prior 
to attending for screening. The details enclosed will be discussed with the volunteer, including: 
 
the aims and nature of the trial 
 
the vaccines used  
 
the schedule of visits and tests to be carried out 
 
the implications and constraints of the protocol 
 
compensation for the volunteer 
 
known side effects and risks of taking part in the trial 
The following general principles will be emphasised:   
 
Participation is entirely voluntary 
 
The volunteer may withdraw from the trial at any time for any reason 
 
Withdrawal or refusal to participate involves no penalty or loss of medical benefits 
 
The volunteer is free to ask questions at any time to allow him or her to understand the 
purpose of the trial and the procedures involved 
 
There is no direct benefit from participating 
 
The volunteer’s GP will be contacted to corroborate their medical history and confirm that the 
volunteer does not meet any of the exclusion criteria 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 37 of 56 
 
The volunteer will be registered on the TOPS database (The Over-Volunteering Protection 
System) 
 
The volunteer’s blood samples taken as part of the trial will be stored indefinitely for further 
research. The volunteer may elect to have their samples destroyed after the period required 
to meet Good Clinical Practice and regulatory requirements. 
The volunteer will then have time to consider whether or not to participate. If the volunteer decides 
to participate, they will sign and date two copies of the consent form, one for them to take away and 
keep, and one for the Investigator which will be retained at the trial site. These forms will also be 
signed and dated by the Investigator or Clinical Research Nurse. This will occur before any trial specific 
procedures are performed. 
9.4 Screening and Eligibility Assessment 
Once the volunteer has given their consent to undergo screening, a baseline medical history (including 
concomitant medication) and physical examination will be performed by a GCP trained doctor. 
Inclusion and exclusion criteria will be checked using a tabulated format. Demographic and 
occupational data relating to risk of prior M.tb exposure will be collected. Vital signs will be checked 
and bloods taken including FBC, clotting profile, U&Es, CRP, LFTs, HIV antibodies, HBsAg, HCV 
antibodies and IGRA. Volunteers will be counselled by one of the Investigators for HIV, Hepatitis B and 
Hepatitis C testing. Urine will be tested for the presence of clinically significant proteinuria, glycosuria 
or haematuria. A pregnancy test will be performed for female volunteers. Volunteers will then be 
scheduled to re-attend for a CT thorax provided no exclusion criteria have been met. 
Laboratory parameters for inclusion/exclusion in the trial will be considered on an individual basis, 
with Investigator discretion for interpretation of results and the need for repeated tests. In general, 
volunteers will be excluded if a result at screening constitutes what would qualify as a grade 1 (or 
higher) laboratory AE, according to the site-specific laboratory AE tables, filed in the TMF (Oxford), or 
Site Master File (Birmingham and London). 
The total duration of the screening visit will be around 2 hours. 
9.5 Follow up visits 
D0 - Vaccination 
Any new medical issues or symptoms that have arisen will be assessed. Venepuncture and other 
samples will be taken according to the Schedule of Trial Procedures in section 4.2. The inclusion and 
exclusion criteria for the trial will be reviewed; provided that the volunteer still satisfies all inclusion 
criteria (and no exclusion criteria) and their consent remains valid, the volunteer will be allocated to 
a group. MVA85A vaccination will be performed by the aerosol route according to the trial SOP. 
Volunteers will be kept under observation for around 60 minutes after vaccination. The vaccination 
visit will last approximately 2 hours. Volunteers will also have blood taken for HLA typing. 
D7 – Bronchoscopy 
The bronchoscopy visit lasts several hours and takes place at the bronchoscopy suite in the OUH NHS 
Foundation Trust Hospitals by the specialist team there. Details of the procedure are outlined in 
section 6.1. In exceptional circumstances where volunteers are absolutely unable to travel to Oxford, 
the bronchoscopy may be performed at the other NHS trust study sites (King’s College Hospital NHS 
Trust, University of Birmingham NHS Trust, Royal Free Hospital NHS Trust). The bronchoscopy will 
always be performed by a respiratory consultant trained in the procedure and following the trial 
specific SOP. 
D28 – CT thorax 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 38 of 56 
The volunteer will usually have a clinic assessment on the same day, prior to the scan. Any abnormality 
reported on the CT will be appropriately investigated and followed up. 
Other follow-up visits 
These will be performed as specified in the Schedule of Trial Procedures (section 4.2). Any new medical 
issues or symptoms that have arisen will be assessed. Additional procedures or laboratory tests may 
be carried out at the discretion of the Investigators if deemed clinically necessary. Follow-up visits will 
last approximately 15-30 minutes. The maximum trial duration will be around 24 weeks after the date 
of enrolment. 
9.6 Timepoints 
Screening – trial enrolment time window 
Enrolment should take place no longer than 120 days following the date of screening appointment. If 
more than 120 days elapse, the screening visit should be repeated in full prior to enrolment in order 
to minimise the risk to participants 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 the Starter Group, will be vaccinated with MVA85A by the 
aerosol inhaled route at least 48 hours before any subsequent volunteers in this group. After safety 
review, the first volunteer in Group A will be vaccinated at least 48 hours prior to further enrolment. 
Vaccination – bronchoscopy time window 
According to our clinical research (and in line with pre-clinical findings), the peak effector T cell 
response detected from PBMC in venous blood samples is around seven days after vaccination with 
MVA85A. In our previous trial of aerosolised MVA85A, high frequencies of Ag85A-specific cytokines 
were detected in BAL samples at one week post-vaccination, therefore bronchoscopy will be 
performed at seven days to match that trial.  
Follow up period 
The follow up period will be six months in accordance with findings from previous trials in which 
adequate safety data and reliable markers of immunogenicity have been obtained in this time interval. 
9.7 Sample handling 
Details regarding samples, volume and frequency of sampling are listed in the Schedule of Trial 
Procedures (section 4.2). Blood samples will be processed according to local laboratory standard 
operating procedures. All samples will be in anonymised form at the CCVTM; samples at Birmingham 
and London sites may contain patient numbers and details as per NHS procedures.  
Volunteers will be informed that there may be leftover samples of their blood. With the volunteers’ 
informed consent, any leftover cells and serum, plasma or BAL samples will be frozen for future 
analysis of M.tb and/or vaccine-related responses. This may include human DNA and RNA analysis to 
search for correlates of vaccine immunogenicity and efficacy. 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.  
9.8 Vaccination Postponement Criteria 
Vaccination will not proceed on the scheduled day in any of the following situations: 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 39 of 56 
 
The volunteer has a current or recent upper respiratory tract infection, unless they have been 
symptom-free for at least one week 
 
The volunteer has a positive pregnancy test 
 
The volunteer has a temperature > 37.5oC 
 
The Investigator judges the volunteer to have an acute moderate or severe illness (whether 
febrile or not) 
 
The volunteer has received a live non-trial vaccine within the preceding 28 days 
 
The Investigator has any other concern that vaccination may not be in the volunteer’s best 
interests 
In this case the volunteer may be vaccinated at a later date or withdrawn from the trial at the 
discretion of the Investigator. 
9.9 Bronchoscopy Postponement criteria 
Bronchoscopy will not proceed on the scheduled day in any of the following situations: 
 
The volunteer has a temperature > 37.5oC 
 
The volunteer has a positive pregnancy test 
 
The Investigator judges the volunteer to have an acute moderate or severe illness (whether 
febrile or not)  
 
The Investigator has any other concern that bronchoscopy may not be in the volunteer’s best 
interests 
In the event of postponement the bronchoscopy will be rescheduled when possible up to a 3 week 
window. 
9.10 
Discontinuation / Withdrawal Criteria 
Every reasonable effort will be made to maintain protocol compliance and participation in the trial. 
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 (including on the advice 
of the LSC). In addition the volunteer may withdraw/be withdrawn for any of the following reasons: 
 
Administrative decision by the Investigator 
 
Ineligibility (either arising during the trial or retrospectively, having been overlooked at 
screening) 
 
Significant protocol deviation 
 
Volunteer non-compliance with trial requirements (failure to attend two or more follow-up 
visits) 
 
Any AE which requires discontinuation of trial involvement or results in inability to comply with 
trial procedures 
 
Confirmed pregnancy during the trial 
Any volunteer who becomes pregnant during the trial will be followed up as per the protocol and until 
the end of the pregnancy. We will not routinely perform venepuncture in a pregnant volunteer. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 40 of 56 
The reason for withdrawal will be recorded in the CRF. Volunteers withdrawn from the trial may be 
replaced on the decision of the Investigator. If the volunteer is withdrawn due to an AE, the 
Investigator will arrange for appropriate specialist management or follow up visits or telephone calls 
until the AE has resolved or stabilised. The regulatory authorities will be informed in a timely manner. 
The extent of follow up after premature discontinuation will be determined by the Investigator but 
will be at least for the whole trial period, and if pregnant, until pregnancy outcome.   
If a volunteer withdraws from the trial, samples collected before their withdrawal from the trial will 
be used/stored unless the volunteer specifically requests otherwise. Long term safety data collection 
will continue as appropriate if a volunteer has received one or more vaccine doses.   
9.11 
Safety 
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 IMP, or as a result of the trial procedures or 
follow-up schedule. 
 
Serious concerns about the safety of the IMP arise as a result of one or more vaccine related 
SAE(s) occurring in the volunteers enrolled in this or any other ongoing trial of the MVA85A 
vaccine. 
 
For any other reason at the discretion of the Investigator. 
9.12 
End of Trial Definition 
The trial will be completed when the last volunteer enrolled into the trial has completed the final 
follow up telephone call. An end of trial letter will be sent to each volunteer’s GP and their TB clinician. 
 
10 INVESTIGATIONAL MEDICINAL PRODUCT AND DEVICES 
10.1 
IMP 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. 
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 in the starter group will be 1 x 107 pfu (120 μL of a 1:10 dilution, as per Vaccine Dilution 
SOP) diluted in saline and administered by aerosol inhalation. The dose of MVA85A to be used in 
Group A will be 5 x 107pfu (60µl) diluted in saline for aerosol inhalation. 
10.2 
Storage of IMP 
MVA85A will be shipped from IDT directly to the Clinical Biomanufacturing Facility (CBF) on dry ice and 
in the presence of a temperature logger. The vaccine will be certified and labelled for use in trial TB040 
by a qualified person (QP) at the University of Oxford.  

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 41 of 56 
The vaccine will be stored at -80°C (nominal temperature) in a secure, temperature-monitored freezer 
at the Centre for Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital.  
10.3 
Dispensing and administration 
All movements of vials of the trial vaccine between IDT and the University of Oxford 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 by aerosol inhalation, according to the trial-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 aerosol inhaled vaccination will take place in a closed clinic room and not opened until 10 
minutes after the end of nebulisation.  
 
During aerosol inhalation clinical staff will wear appropriate protective clothing as agreed with 
the GMSC.  
 
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 the contained use GMO regulations 2014. 
 
All hard surfaces within the clinic room where vaccination took place will be cleaned and 
disinfected in accordance with GMSC recommendations. 
 
Non-disposable parts of the MicroAIR NE-U22 nebuliser will be cleaned and disinfected in 
accordance with the device documentation and GMSC recommendations. 
10.4 
Saline 
Sterile saline will be used for dilution of MVA85A (as needed, to achieve the correct dose). Once 
prepared, the vaccine will then be made up to 1ml with saline for administration via the MicroAIR NE-
U22 nebuliser.  
10.5 
MicroAIR NE-U22 
This is an approved electromedical device, CE0197, EAN code 40 15672 10142 1. Information about 
the specifications, usage, and maintenance of the nebuliser device can be found in the device 
documentation (65). This is the same device used in studies TB026 and TB035. 
10.6 
Sedative & anaesthetic agents for bronchoscopy 
Fentanyl is a licensed opioid used routinely to provide analgesia and sedation during medical 
procedures. It will be stored, dispensed and administered in accordance with standard NHS 
procedures and the Summary of Product Characteristics (SmPC). 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 42 of 56 
Midazolam is a licensed benzodiazepine used routinely to provide sedation and amnesia during 
medical procedures. It will be stored, dispensed and administered in accordance with standard NHS 
procedures and the SmPC. 
Lignocaine is a licensed local anaesthetic used routinely during medical procedures. It will be stored, 
dispensed and administered in accordance with standard NHS procedures and the SmPC. 
Other licensed drugs may be used during bronchoscopy at the discretion of the Investigators. 
 
11 ASSESSMENT OF SAFETY   
Safety will be assessed by the frequency, incidence and nature of adverse events and serious adverse 
events arising during the study. 
11.1 
Interim Safety Review 
Prior to dose escalation of the vaccine, the clinical team and Chief Investigator will review the safety 
data and adverse events in volunteers before proceeding to the next vaccine dose. Interim safety data 
may also be made available to manufacturers (in coded format) as specified in the contract with the 
manufacturer(s).  
11.2 
Definitions 
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.  
Each adverse event will be graded by the participant according to the table for grading severity of 
adverse events (see Section 11.7). Severity gradings may be reviewed and discussed with the 
participants at the clinic visits.  
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.  
Unexpected Adverse Reaction  
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., IB for an unapproved IMP).  
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.  

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 43 of 56 
 
Persistent or significant disability or incapacity (i.e., substantial disruption of one’s ability to 
carry out normal life functions).  
 
Hospitalisation or prolongation of existing 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.  
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.  
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 or SmPC. 
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. 
11.3 
Foreseeable Adverse Reactions 
Foreseeable adverse reactions are listed in section 6.3. 
11.4 
Expected Serious Adverse Events 
No serious adverse events are expected in this study. 
11.5 
 Causality Assessment 
For every unsolicited AE, an assessment of the relationship of the event to the administration of the 
vaccine will be undertaken. 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 
5). Causality assessment will take place during interim analyses and at the final safety analysis.  
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 44 of 56 
Table 5. Guidelines for assessing the relationship of vaccine administration to an AE 
 
11.6 
 Reporting Procedures for All Adverse Events 
All AEs occurring in the 14 days following each vaccination observed by the Investigator or reported 
by the volunteer, whether or not attributed to study medication, will be recorded on electronic diary 
cards. Data from the diary cards will be extracted at each safety review and following the last volunteer 
last visit (LVLV). Outside the diary card periods, expected local and systemic AEs (listed in table 7 
below) will be specifically solicited at each visit, and graded by severity and causality (as detailed in 
sections 11.7 and 11.5). All AEs starting after the diary card period, or persisting after this period, will 
be recorded in the AE line listing of the CRF.  
The overall appearance of the lung mucosa will be assessed at the day 7 bronchoscopy. 
Any radiological changes to the lungs will be assessed at the day 28 CT thorax.  
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.  
Reporting Procedures for Serious AEs (see Safety Reporting SOP)  
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 site-specific SOP. Copies of all reports will be forwarded 
for review to the Chief Investigator and Principal Investigators (as the Sponsor’s representatives) 
within 24 hours of the Investigator being aware of the suspected SAE. The local safety committee (LSC) 
will be notified of SAEs which are deemed possibly, probably or definitely related to study 
interventions; the LSC will be notified immediately (within 24 hours) of the Investigators’ being aware 
of their occurrence. SAEs will not normally be reported immediately to the ethical committee(s) unless 
there is a clinically important increase in occurrence rate, an unexpected outcome, or a new event 
0 
No Relationship 
No temporal relationship to trial product; and 
Alternate aetiology (clinical state, environment or other interventions); 
and 
Does not follow known pattern of response to vaccine 
1 
Unlikely 
Unlikely temporal relationship to trial product; and 
Alternate aetiology likely (clinical state, environment or other 
interventions); and 
Does not follow known typical or plausible pattern of response to 
vaccine 
2 
Possible 
Reasonable temporal relationship to trial product; or 
Event not readily produced by clinical state, environment or other 
interventions; or 
Similar pattern of response to that seen with other vaccines 
3 
Probable 
Reasonable temporal relationship to trial product; and 
Event not readily produced by clinical state, environment or other 
interventions; and 
Known pattern of response seen with other vaccines 
4 
Definite 
Reasonable temporal relationship to vaccine; and 
Event not readily produced by clinical state, environment or other 
interventions; and 
Known pattern of response seen with the vaccine 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 45 of 56 
that is likely to affect safety of trial volunteers, at the discretion of the Chief Investigator and/or LSC. 
In addition to the expedited reporting above, the Investigator shall include all SAEs in the annual 
Development Safety Update Report (DSUR) report.  
 
Reporting Procedures for SUSARS  
The Chief Investigator will report all SUSARs to the MHRA and 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 participants.  
 
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.  
 
Development Safety Update Report  
A Development Safety Update Report (DSUR) will be submitted by the Sponsor to the competent 
authority and ethical committee on the anniversary of the first approval date from the regulatory 
authority for each IMP.    
11.7 
Assessment of Severity 
The severity of clinical AEs will be assessed according to the scale in Tables 6-7: 
 
Table 6. Severity grading criteria for physical observations. 
 
Grade 1  
(mild) 
Grade 2  
(moderate) 
Grade 3  
(severe) 
Fever (oral) 
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 
 
*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) 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 46 of 56 
Table 7. Severity grading criteria for local and systemic AEs399 
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 
11.8 
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 9.4. 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 site-specific tables in the Site Master File/TMF. 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. 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. 
11.9 
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 study on hold if deemed necessary following a study intervention-related SAE. 
At the time of writing the LSC will be chaired by Professor Brian Angus, Clinical Tutor in Medicine, 
Honorary Consultant Physician and Director of the Oxford Centre for Clinical Tropical Medicine at 
Oxford University. There will be a minimum of two other appropriately qualified committee members. 
All correspondence between Investigator and LSC will be conveyed by the 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: 
 
Following any SAE deemed to be possibly, probably, or definitely related to the trial vaccine. 
 
Any other situation where the Investigator or Trial Sponsor feels independent advice or review 
is important. 
Safety Profile Review 
The safety profile will be assessed on an on-going basis by the Investigators. The Chief Investigator, 
Principal Investigator, and relevant Investigators (as per the trial delegation log) will also review safety 
issues and SAEs as they arise.   
 
12 STATISTICS  
This is primarily a safety trial with descriptive endpoints. Following the first three volunteers enrolled 
into the starter group, 3-6 volunteers will be recruited into  Group A, to receive the target dose. Due 
to existing difficulties recruiting to this clinical trial we have decided to take out Group B (the 
comparator arm) to ensure that the numbers recruited will still be sufficient to allow for the primary 
objective, an assessment of safety. A twofold increase in the magnitude of the cellular immune 
response (as measured by ELISpot response to 85A peptide stimulation) is considered immunologically 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 47 of 56 
meaningful. This sample size is appropriate for a proof-of-concept Phase I safety study and takes into 
account the low number of potentially eligible healthy adults with latent M.tb infection in the UK and 
the impact of this on recruitment. The sample size has not been determined with the aim of achieving 
statistical significance.  
It is anticipated that the immunological endpoints will not follow a normal distribution. The one-week 
and three-month responses will be compared. Medians and interquartile ranges will be used to 
summarise the data and the Mann Whitney U test will be used for statistical comparisons. An area-
under-curve analysis will be used to compare the overall responses over time comparing these aerosol 
data with historical data from previous trials. This analysis will make use of data collected at all time 
points. 
13 DATA MANAGEMENT 
13.1 
Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include the CRF itself (history and examination), the volunteer consent form, blood 
and microbiology results, CT report, GP response letter, copy of bronchoscopy report and any further 
correspondence relating to the volunteer regarding medical/clinical issues. The CRF will be paper or 
electronic and paper together with electronic 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 
conditions. On all trial-specific documents, other than the signed consent, the participant will be 
referred to by the trial participant number/code, not by name. 
13.2 
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 ICH E6 
GCP and institutional requirements. 
13.3 
Data Recording and Record Keeping 
The Chief Investigator 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 each site, 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. Some data may be duplicated anonymously into an 
electronic Microsoft Excel™ file on the CCVTM secure server for clinical monitoring through the trial. 
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 or 2 years after 
discontinuation of clinical development of an investigational product) and in order to enable 
dissemination of study results after publication, and to enable decoding and destruction of 
anonymized samples if subsequently requested by a volunteer. Data will subsequently be transferred 
to a secure archive in accordance with the 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 GP correspondence, registration documents, and consent 
forms).   

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 48 of 56 
14 QUALITY ASSURANCE PROCEDURES 
14.1 
Quality Assurance 
Investigator procedures 
Approved site-specific SOPs will be used at all clinical and laboratory sites. 
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 study or safety of the IMP. An administrative change is a non-substantial amendment and does 
not require REC approval. However, the REC will be notified whenever an administrative change is 
made. 
The Chief Investigator 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.  
14.2 
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. 
15 SERIOUS BREACHES 
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. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 49 of 56 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Declaration of Helsinki 
The Investigator 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). 
16.2 
Good Clinical Practice 
The Investigator will ensure that this trial is conducted in accordance with ICH Good Clinical Practice 
(GCP), the requirements of the Medicines for Human Use (Clinical Trial) Regulations 2004, and local 
regulatory requirements. 
16.3 
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. 
16.4 
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 Trial notification and final report will 
be submitted to the MHRA, the REC, host organisation and Sponsor. 
16.5 
Volunteer Confidentiality 
The trial staff will ensure the volunteers’ anonymity is maintained. All documents will be stored 
securely and only accessible by trial staff and authorised personnel. No information concerning the 
trial or the data will be released to any unauthorised third party, without prior written approval of the 
sponsor. The trial will comply with the Data Protection Act, which requires data to be anonymised as 
soon as it is practical to do so. 
16.6 
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 £505-£625, depending on the exact 
number of visits, site of recruitment and whether any repeat or additional visits are necessary. 
17 FINANCE AND INSURANCE 
17.1 
Funding 
This trial will be financed by research grants from TBVI and The Wellcome Trust, held by Professor 
Helen McShane. 
17.2 
Indemnity 
If any volunteer is harmed as a result of this trial, medical care will be provided under the NHS. 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 50 of 56 
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. 
17.3 
Insurance 
The University has a specialist insurance policy in place - Newline Underwriting Management Ltd, at 
Lloyd’s of London - which would operate in the event of any volunteer suffering harm as a result of 
their involvement in the research. 
18 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. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 51 of 56 
19 REFERENCES 
1. 
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of 
tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and 
Monitoring Project. JAMA : the journal of the American Medical Association. 1999 Aug 18;282(7):677-
86. PubMed PMID: 10517722. Epub 1999/10/12. eng. 
2. 
WHO. 
Global 
tuberculosis 
report 
2014. 
http://apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng.pdf?ua=1 (accessed 03 
March 2015). 2014  Contract No.: WHO/HTM/TB/2014.08 
3. 
Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in sub-Saharan Africa: 
opportunities, challenges, and change in the era of antiretroviral treatment. Lancet. 2006 Mar 
18;367(9514):926-37. PubMed PMID: 16546541. Epub 2006/03/21. eng. 
4. 
Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG 
vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA : the journal 
of the American Medical Association. 1994 Mar 2;271(9):698-702. PubMed PMID: 8309034. Epub 
1994/03/02. eng. 
5. 
Fine PE. The BCG story: lessons from the past and implications for the future. Rev Infect Dis. 
1989 Mar-Apr;11 Suppl 2:S353-9. PubMed PMID: 2652252. Epub 1989/03/01. eng. 
6. 
Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and 
miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet. 2006 
Apr 8;367(9517):1173-80. PubMed PMID: 16616560. Epub 2006/04/18. eng. 
7. 
Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis 
and miliary tuberculosis: a meta-analysis. International journal of epidemiology. 1993 Dec;22(6):1154-
8. PubMed PMID: 8144299. Epub 1993/12/01. eng. 
8. 
McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, et al. Recombinant 
modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired 
antimycobacterial immunity in humans. Nat Med. 2004 Nov;10(11):1240-4. PubMed PMID: 15502839. 
Epub 2004/10/27. eng. 
9. 
Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and 
efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a 
randomised, placebo-controlled phase 2b trial. Lancet. 2013 Mar 23;381(9871):1021-8. PubMed 
PMID: 23391465. 
10. 
Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dieye S, et al. Safety, immunogenicity, 
and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a 
randomised, placebo-controlled, phase 2 trial. The Lancet Respiratory medicine. 2015 Mar;3(3):190-
200. PubMed PMID: 25726088. 
11. 
Goonetilleke NP, McShane H, Hannan CM, Anderson RJ, Brookes RH, Hill AV. Enhanced 
immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-
Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus 
Ankara. J Immunol. 2003 Aug 1;171(3):1602-9. PubMed PMID: 12874255. Epub 2003/07/23. eng. 
12. 
Santosuosso M, McCormick S, Zhang X, Zganiacz A, Xing Z. Intranasal boosting with an 
adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG 
immunization against pulmonary tuberculosis. Infect Immun. 2006 Aug;74(8):4634-43. PubMed PMID: 
16861651. Pubmed Central PMCID: 1539608. 
13. 
Xing Z, McFarland CT, Sallenave JM, Izzo A, Wang J, McMurray DN. Intranasal mucosal 
boosting with an adenovirus-vectored vaccine markedly enhances the protection of BCG-primed 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 52 of 56 
guinea pigs against pulmonary tuberculosis. PLoS One. 2009;4(6):e5856. PubMed PMID: 19516906. 
Pubmed Central PMCID: 2689939. 
14. 
Xing Z, Lichty BD. Use of recombinant virus-vectored tuberculosis vaccines for respiratory 
mucosal immunization. Tuberculosis (Edinb). 2006 May-Jul;86(3-4):211-7. PubMed PMID: 16504584. 
15. 
Wang J, Thorson L, Stokes RW, Santosuosso M, Huygen K, Zganiacz A, et al. Single mucosal, 
but not parenteral, immunization with recombinant adenoviral-based vaccine provides potent 
protection from pulmonary tuberculosis. J Immunol. 2004 Nov 15;173(10):6357-65. PubMed PMID: 
15528375. 
16. 
Corbett M, Bogers WM, Heeney JL, Gerber S, Genin C, Didierlaurent A, et al. Aerosol 
immunization with NYVAC and MVA vectored vaccines is safe, simple, and immunogenic. Proc Natl 
Acad Sci U S A. 2008 Feb 12;105(6):2046-51. PubMed PMID: 18270165. Pubmed Central PMCID: 
2538878. Epub 2008/02/14. eng. 
17. 
Sabin AB. Immunization against measles by aerosol. Rev Infect Dis. 1983 May-Jun;5(3):514-
23. PubMed PMID: 6348918. Epub 1983/05/01. eng. 
18. 
Sabin AB, Flores Arechiga A, Fernandez de Castro J, Sever JL, Madden DL, Shekarchi I, et al. 
Successful immunization of children with and without maternal antibody by aerosolized measles 
vaccine. I. Different results with undiluted human diploid cell and chick embryo fibroblast vaccines. 
JAMA : the journal of the American Medical Association. 1983 May 20;249(19):2651-62. PubMed 
PMID: 6341638. Epub 1983/05/20. eng. 
19. 
Dilraj A, Cutts FT, de Castro JF, Wheeler JG, Brown D, Roth C, et al. Response to different 
measles vaccine strains given by aerosol and subcutaneous routes to schoolchildren: a randomised 
trial. Lancet. 2000 Mar 4;355(9206):798-803. PubMed PMID: 10711928. Epub 2000/03/11. eng. 
20. 
Dilraj A, Sukhoo R, Cutts FT, Bennett JV. Aerosol and subcutaneous measles vaccine: measles 
antibody responses 6 years after re-vaccination. Vaccine. 2007 May 22;25(21):4170-4. PubMed PMID: 
17408818. Epub 2007/04/06. eng. 
21. 
LiCalsi C, Maniaci MJ, Christensen T, Phillips E, Ward GH, Witham C. A powder formulation of 
measles vaccine for aerosol delivery. Vaccine. 2001 Mar 21;19(17-19):2629-36. PubMed PMID: 
11257402. Epub 2001/03/21. eng. 
22. 
Bellanti JA, Zeligs BJ, Mendez-Inocencio J, Garcia-Garcia ML, Islas-Romero R, Omidvar B, et al. 
Immunologic studies of specific mucosal and systemic immune responses in Mexican school children 
after booster aerosol or subcutaneous immunization with measles vaccine. Vaccine. 2004 Mar 
12;22(9-10):1214-20. PubMed PMID: 15003650. Epub 2004/03/09. eng. 
23. 
Hiremath GS, Omer SB. A meta-analysis of studies comparing the respiratory route with the 
subcutaneous route of measles vaccine administration. Hum Vaccin. 2005 Jan-Feb;1(1):30-6. PubMed 
PMID: 17038828. Epub 2006/10/14. eng. 
24. 
Cutts FT, Clements CJ, Bennett JV. Alternative routes of measles immunization: a review. 
Biologicals. 1997 Sep;25(3):323-38. PubMed PMID: 9325001. Epub 1997/11/05. eng. 
25. 
Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, et al. The efficacy of live 
attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. The New England 
journal of medicine. 1998 May 14;338(20):1405-12. PubMed PMID: 9580647. eng. 
26. 
Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M, et al. Live attenuated 
versus inactivated influenza vaccine in infants and young children. The New England journal of 
medicine. 2007 Feb 15;356(7):685-96. PubMed PMID: 17301299. eng. 
27. 
Gaglani MJ, Piedra PA, Herschler GB, Griffith ME, Kozinetz CA, Riggs MW, et al. Direct and total 
effectiveness of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine against 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 53 of 56 
the 2000-2001 influenza A(H1N1) and B epidemic in healthy children. Archives of pediatrics & 
adolescent medicine. 2004 Jan;158(1):65-73. PubMed PMID: 14706961. eng. 
28. 
Langley JM, Halperin SA, McNeil S, Smith B, Jones T, Burt D, et al. Safety and immunogenicity 
of a Proteosome -trivalent inactivated influenza vaccine, given nasally to healthy adults. Vaccine. 2006 
Mar 6;24(10):1601-8. PubMed PMID: 16303215. eng. 
29. 
Stephenson I, Zambon MC, Rudin A, Colegate A, Podda A, Bugarini R, et al. Phase I evaluation 
of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and 
novel biovector as mucosal adjuvants, using adult volunteers. Journal of virology. 2006 
May;80(10):4962-70. PubMed PMID: 16641287. eng. 
30. 
Langley JM, Aoki F, Ward BJ, McGeer A, Angel JB, Stiver G, et al. A nasally administered 
trivalent inactivated influenza vaccine is well tolerated, stimulates both mucosal and systemic 
immunity, and potentially protects against influenza illness. Vaccine. 2011 Feb 24;29(10):1921-8. 
PubMed PMID: 21219987. Epub 2011/01/12. eng. 
31. 
Omer SB, Hiremath GS, Halsey NA. Respiratory administration of measles vaccine. Lancet. Feb 
27;375(9716):706-8. PubMed PMID: 20189011. Epub 2010/03/02. eng. 
32. 
Song K, Bolton DL, Wei CJ, Wilson RL, Camp JV, Bao S, et al. Genetic immunization in the lung 
induces potent local and systemic immune responses. Proc Natl Acad Sci U S A. 2010 Dec 
21;107(51):22213-8. PubMed PMID: 21135247. Pubmed Central PMCID: 3009829. 
33. 
Tucker SN, Tingley DW, Scallan CD. Oral adenoviral-based vaccines: historical perspective and 
future opportunity. Expert Rev Vaccines. 2008 Feb;7(1):25-31. PubMed PMID: 18251691. 
34. 
Belyakov IM, Moss B, Strober W, Berzofsky JA. Mucosal vaccination overcomes the barrier to 
recombinant vaccinia immunization caused by preexisting poxvirus immunity. Proc Natl Acad Sci U S 
A. 1999 Apr 13;96(8):4512-7. PubMed PMID: 10200293. Pubmed Central PMCID: 16363. 
35. 
Satti I, Meyer J, Harris SA, Manjaly Thomas ZR, Griffiths K, Antrobus RD, et al. Safety and 
immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated 
healthy adults: a phase 1, double-blind, randomised controlled trial. The Lancet Infectious diseases. 
2014 Oct;14(10):939-46. PubMed PMID: 25151225. Pubmed Central PMCID: 4178237. 
36. 
Stickl H, Hochstein-Mintzel V, Mayr A, Huber HC, Schafer H, Holzner A. [MVA vaccination 
against smallpox: clinical tests with an attenuated live vaccinia virus strain (MVA) (author's transl)]. 
Dtsch Med Wochenschr. 1974 Nov 22;99(47):2386-92. PubMed PMID: 4426258. Epub 1974/11/22. 
MVA-Stufenimpfung gegen Pocken. Klinische Erprobung des attenuierten Pocken-Lebendimpfstoffes, 
Stamm MVA. ger. 
37. 
Mayr A, Stickl H, Muller HK, Danner K, Singer H. [The smallpox vaccination strain MVA: marker, 
genetic structure, experience gained with the parenteral vaccination and behavior in organisms with 
a debilitated defence mechanism (author's transl)]. Zentralbl Bakteriol B. 1978 Dec;167(5-6):375-90. 
PubMed PMID: 219640. Epub 1978/12/01. Der Pockenimpfstamm MVA: Marker, genetische Struktur, 
Erfahrungen mit der parenteralen Schutzimpfung und Verhalten im abwehrgeschwachten 
Organismus. ger. 
38. 
Hochstein-Mintzel V, Huber HC, Stickl H. [Virulence and immunogenicity of a modified vaccinia 
virus (strain MVA) (author's transl)]. Z Immunitatsforsch Exp Klin Immunol. 1972 Sep;144(2):104-56. 
PubMed PMID: 4282933. Epub 1972/09/01. Virulenz und Immunogenitat eines modifizierten 
Vaccinia-Virus (Stamm MVA). ger. 
39. 
Hochstein-Mintzel V, Hanichen T, Huber HC, Stickl H. [An attenuated strain of vaccinia virus 
(MVA). Successful intramuscular immunization against vaccinia and variola (author's transl)]. Zentralbl 
Bakteriol Orig A. 1975;230(3):283-97. PubMed PMID: 1146441. Epub 1975/01/01. Vaccinia- und 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 54 of 56 
variolaprotektive Wirkung des modifizierten Vaccinia-Stammes MVA bei intramuskularer 
Immunisierung. ger. 
40. 
Goonetilleke N, Moore S, Dally L, Winstone N, Cebere I, Mahmoud A, et al. Induction of 
multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation 
in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-
vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes. Journal of virology. 2006 
May;80(10):4717-28. PubMed PMID: 16641265. Pubmed Central PMCID: 1472051. Epub 2006/04/28. 
eng. 
41. 
Bejon P, Peshu N, Gilbert SC, Lowe BS, Molyneux CS, Forsdyke J, et al. Safety profile of the viral 
vectors of attenuated fowlpox strain FP9 and modified vaccinia virus Ankara recombinant for either 
of 2 preerythrocytic malaria antigens, ME-TRAP or the circumsporozoite protein, in children and adults 
in Kenya. Clin Infect Dis. 2006 Apr 15;42(8):1102-10. PubMed PMID: 16575727. Epub 2006/04/01. eng. 
42. 
Gherardi MM, Esteban M. Recombinant poxviruses as mucosal vaccine vectors. J Gen Virol. 
2005 Nov;86(Pt 11):2925-36. PubMed PMID: 16227213. Epub 2005/10/18. eng. 
43. 
Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS. Role of the major antigen of 
Mycobacterium tuberculosis in cell wall biogenesis. Science. 1997 May 30;276(5317):1420-2. PubMed 
PMID: 9162010. Epub 1997/05/30. eng. 
44. 
Denis O, Tanghe A, Palfliet K, Jurion F, van den Berg TP, Vanonckelen A, et al. Vaccination with 
plasmid DNA encoding mycobacterial antigen 85A stimulates a CD4+ and CD8+ T-cell epitopic 
repertoire broader than that stimulated by Mycobacterium tuberculosis H37Rv infection. Infect 
Immun. 1998 Apr;66(4):1527-33. PubMed PMID: 9529077. Pubmed Central PMCID: 108084. Epub 
1998/04/07. eng. 
45. 
McShane H, Brookes R, Gilbert SC, Hill AV. Enhanced immunogenicity of CD4(+) t-cell 
responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination 
regimen for murine tuberculosis. Infect Immun. 2001 Feb;69(2):681-6. PubMed PMID: 11159955. 
Pubmed Central PMCID: 97939. Epub 2001/02/13. eng. 
46. 
Vordermeier HM, Rhodes SG, Dean G, Goonetilleke N, Huygen K, Hill AV, et al. Cellular immune 
responses induced in cattle by heterologous prime-boost vaccination using recombinant viruses and 
bacille Calmette-Guerin. Immunology. 2004 Jul;112(3):461-70. PubMed PMID: 15196215. Pubmed 
Central PMCID: 1782509. Epub 2004/06/16. eng. 
47. 
Huygen K, Content J, Denis O, Montgomery DL, Yawman AM, Deck RR, et al. Immunogenicity 
and protective efficacy of a tuberculosis DNA vaccine. Nat Med. 1996 Aug;2(8):893-8. PubMed PMID: 
8705859. Epub 1996/08/01. eng. 
48. 
Verreck FA, Vervenne RA, Kondova I, van Kralingen KW, Remarque EJ, Braskamp G, et al. 
MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show 
protective efficacy against tuberculosis in rhesus macaques. PLoS One. 2009;4(4):e5264. PubMed 
PMID: 19367339. Pubmed Central PMCID: 2666807. Epub 2009/04/16. eng. 
49. 
Williams A, Hatch GJ, Clark SO, Gooch KE, Hatch KA, Hall GA, et al. Evaluation of vaccines in 
the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis. Tuberculosis 
(Edinb). 2005 Jan-Mar;85(1-2):29-38. PubMed PMID: 15687025. Epub 2005/02/03. eng. 
50. 
Vordermeier HM, Dean GS, Rosenkrands I, Agger EM, Andersen P, Kaveh DA, et al. Adjuvants 
induce distinct immunological phenotypes in a cattle tuberculosis vaccine model. Clin Vaccine 
Immunol. 2009 Jul 29. PubMed PMID: 19641101. Epub 2009/07/31. Eng. 
51. 
Scriba TJ, Tameris M, Mansoor N, Smit E, van der Merwe L, Mauff K, et al. Dose-finding study 
of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants. J Infect Dis. 
2011;203(21606542):1832-43. 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 55 of 56 
52. 
Pathan AA, Minassian AM, Sander CR, Rowland R, Porter DW, Poulton ID, et al. Effect of 
vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated 
UK adults. Vaccine. 2012 Aug 17;30(38):5616-24. PubMed PMID: 22789508. Pubmed Central PMCID: 
3424417. 
53. 
McShane H. Developing an improved vaccine against tuberculosis. Expert Rev Vaccines. 2004 
Jun;3(3):299-306. PubMed PMID: 15176946. Epub 2004/06/05. eng. 
54. 
Meyer J, Harris SA, Satti I, Poulton ID, Poyntz HC, Tanner R, et al. Comparing the safety and 
immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal 
delivery. Vaccine. 2013 Feb 4;31(7):1026-33. PubMed PMID: 23266342. 
55. 
WHO. 
IVR 
strategic 
plan 
2010 
- 
2020. 
http://whqlibdoc.who.int/hq/2010/WHO_IVB_10.02_eng.pdf?ua=1 (accessed 02 March 2015) 2010. 
56. 
Santosuosso M, McCormick S, Roediger E, Zhang X, Zganiacz A, Lichty BD, et al. Mucosal 
luminal manipulation of T cell geography switches on protective efficacy by otherwise ineffective 
parenteral genetic immunization. J Immunol. 2007 Feb 15;178(4):2387-95. PubMed PMID: 17277145. 
Epub 2007/02/06. eng. 
57. 
White AD, Sibley L, Dennis MJ, Gooch K, Betts G, Edwards N, et al. Evaluation of the safety and 
immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of 
macaques. Clin Vaccine Immunol. 2013 May;20(5):663-72. PubMed PMID: 23446219. Pubmed Central 
PMCID: PMC3647747. Epub 2013/03/01. eng. 
58. 
Flynn JL, Chan J. Immunology of tuberculosis. Annual review of immunology. 2001;19:93-129. 
PubMed PMID: 11244032. eng. 
59. 
Kongerud J, Madden MC, Hazucha M, Peden D. Nasal responses in asthmatic and 
nonasthmatic subjects following exposure to diesel exhaust particles. Inhalation toxicology. 2006 
Aug;18(9):589-94. PubMed PMID: 16864550. eng. 
60. 
Kariyawasam HH, Aizen M, Kay AB, Robinson DS. Safety and tolerability of three consecutive 
bronchoscopies after allergen challenge in volunteers with mild asthma. Thorax. 2007 Jun;62(6):557-
8. PubMed PMID: 17536034. eng. 
61. 
Elston WJ, Whittaker AJ, Khan LN, Flood-Page P, Ramsay C, Jeffery PK, et al. Safety of research 
bronchoscopy, biopsy and bronchoalveolar lavage in asthma. Eur Respir J. 2004 Sep;24(3):375-7. 
PubMed PMID: 15358694. eng. 
62. 
Busse WW, Wanner A, Adams K, Reynolds HY, Castro M, Chowdhury B, et al. Investigative 
bronchoprovocation and bronchoscopy in airway diseases. Am J Respir Crit Care Med. 2005 Oct 
1;172(7):807-16. PubMed PMID: 16020805. Pubmed Central PMCID: 2718402. Epub 2005/07/16. eng. 
63. 
Ho LP, Davis M, Denison A, Wood FT, Greening AP. Reduced interleukin-18 levels in BAL 
specimens from patients with asthma compared to patients with sarcoidosis and healthy control 
subjects. Chest. 2002 May;121(5):1421-6. PubMed PMID: 12006423. eng. 
64. 
Wong-Chew RM, Islas-Romero R, Garcia-Garcia Mde L, Beeler JA, Audet S, Santos-Preciado JI, 
et al. Immunogenicity of aerosol measles vaccine given as the primary measles immunization to nine-
month-old Mexican children. Vaccine. 2006 Jan 30;24(5):683-90. PubMed PMID: 16154241. Epub 
2005/09/13. eng. 
65. 
OMRON. OMRON Microair U22 website http://www.omron-healthcare.com/eu/en/our-
products/respiratory-therapy/microair-u22 (accessed  02 March 2015). 2015. 
 
 

TB040 Clinical Trial Protocol v7.0, 19 December, 2017, © University of Oxford       CONFIDENTIAL Page 56 of 56