Phase 2, Double-blind, Randomized, Placebo-Controlled Study to Evaluate Safety and Efficacy of H56:IC31 in Reducing the Rate of TB Disease Recurrence in HIV Negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Sponsor: International AIDS Vaccine Initiative



Page 1 of 74 
H56:IC31 
Protocol A-055 
Statens Serum Institut 
IAVI SA 
CONFIDENTIAL 
19/May/2021; Final Version 5.0 
Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
PROTOCOL 
A Phase 2, Double-blind, Randomized, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of H56:IC31 in Reducing the rate of TB Disease 
Recurrence in HIV Negative Adults Successfully Treated for Drug-Susceptible 
Pulmonary Tuberculosis 
Investigational Product: 
H56:IC31 
Protocol Number: 
A-055
Co-sponsor: 
Statens Serum Institut (SSI) 
5 Artillerivej 
2300 Copenhagen S, Denmark 
Co-sponsor: 
IAVI South Africa, NPC  
 (Formerly Aeras Global TB Vaccine Foundation) 
Black River Park 
Observatory, 7925 
Cape Town, South Africa 
Sponsor's Authorized Representatives: 
  
Interim Director of Vaccine Development, SSI 
 
Clinical Director, IAVI 

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H56:IC31 
 
Protocol A-055  
Statens Serum Institut 
IAVI SA 
CONFIDENTIAL 
19/May/2021; Final Version 5.0 
 
 
Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
 TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
STUDY ABSTRACT .................................................................................................................... 8 
1 
INTRODUCTION........................................................................................................... 10 
1.1 
Background ............................................................................................................. 10 
1.2 
Description of the H56:IC31 Vaccine ..................................................................... 11 
1.3 
Non-clinical Experience with the H56:IC31 Vaccine ............................................. 12 
1.4 
Clinical Experience with the H56:IC31 Vaccine .................................................... 12 
1.5 
Clinical Experience with Vaccines Related to H56:IC31 ....................................... 13 
1.6 
Rationale for Study .................................................................................................. 14 
2 
STUDY OBJECTIVES AND DESIGN ......................................................................... 15 
2.1 
Objectives ................................................................................................................ 15 
2.1.1 
Primary Objective ..................................................................................... 15 
2.1.1.1 
Primary Endpoint ..................................................................... 15 
2.1.2 
Key Secondary Objective ......................................................................... 16 
2.1.2.1 
Key Secondary Endpoints ........................................................ 16 
2.1.3 
Other Secondary Objectives ..................................................................... 16 
2.1.3.1 
Other Secondary Endpoints...................................................... 16 
2.1.4 
Exploratory Objectives ............................................................................. 17 
2.1.4.1 
Exploratory Endpoints ............................................................. 17 
2.2 
Design ...................................................................................................................... 18 
3 
STUDY PROCEDURES ................................................................................................ 22 
3.1 
Schedule of Participant Evaluations ........................................................................ 22 
3.2 
Study Participants .................................................................................................... 26 
3.2.1 
Recruitment and Informed Consent .......................................................... 26 
3.2.2 
Assignment of Participant Identification Numbers ................................... 26 
3.2.3 
Inclusion Criteria ...................................................................................... 27 
3.2.4 
Exclusion Criteria ..................................................................................... 27 
3.2.5 
Screening Clinical Assessments and Laboratory Tests ............................ 28 
3.3 
Study Randomization/Entry .................................................................................... 29 
3.4 
Blinding ................................................................................................................... 29 
3.4.1 
Unblinding for Clinical Emergencies ....................................................... 30 
3.5 
Investigational Product Administration .................................................................. 30 
3.6 
Study Evaluations .................................................................................................... 31 
3.6.1 
Efficacy Evaluations ................................................................................. 31 
3.6.2 
Immunogenicity and Immunology Laboratory Evaluations ..................... 32 
3.6.3 
Safety Evaluations .................................................................................... 33 
3.6.3.1 
Pre-vaccination and Post-Vaccination Monitoring 
of Participants........................................................................... 33 
3.6.3.2 
Clinical Assessments and Laboratory Tests ............................. 34 
3.6.3.3 
Adverse Events ........................................................................ 34 
3.6.3.4 
Site of Injection Examination................................................... 35 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
3.6.3.5 
Concomitant Medications ........................................................ 35 
3.6.4 
Participant Follow-up and Contact ........................................................... 35 
3.6.5 
Lost to Follow-up ...................................................................................... 36 
4 
INVESTIGATIONAL PRODUCT................................................................................ 36 
4.1 
Description of Investigational Product .................................................................... 36 
4.2 
Receipt, Storage and Accountability ....................................................................... 37 
4.3 
Preparation .............................................................................................................. 37 
4.4 
Disposal of Unused Investigational Product ........................................................... 37 
5 
SAFETY ........................................................................................................................... 37 
5.1 
Responsibilities for Ensuring the Safety of the Study Participants ......................... 37 
5.1.1 
Principal Investigator ................................................................................ 38 
5.1.2 
Study Sponsor ........................................................................................... 38 
5.1.3 
Medically Responsible Person .................................................................. 38 
5.1.4 
Internal Data Review Committee and Independent Data 
Safety Monitoring Board .......................................................................... 38 
5.1.5 
Institutional Review Boards and Independent Ethics 
Committees ............................................................................................... 39 
5.1.6 
National Regulatory Authority ................................................................. 39 
5.2 
Definition of Adverse Event ................................................................................... 39 
5.3 
Assessing Intensity of an Adverse Event ................................................................ 40 
5.4 
Assessing Causal Relationship “Relatedness” of an Adverse Event ...................... 41 
5.5 
Definition of Adverse Reaction ............................................................................... 41 
5.6 
Assessing "Outcome" of an Adverse Event ............................................................ 41 
5.7 
Assessing "Seriousness" of an Adverse Event ........................................................ 42 
5.8 
Assessing “Expectedness” of Serious Adverse Reactions ...................................... 42 
5.9 
Definition of Suspected Unexpected Serious Adverse Reaction 
(SUSAR) ................................................................................................................. 43 
5.10 Reporting of Serious Adverse Events ..................................................................... 43 
5.11 Other Events Requiring Immediate Reporting ........................................................ 45 
5.12 Adverse Event Treatment and Follow-up ............................................................... 46 
5.13 Participant Diary ..................................................................................................... 46 
5.14 Follow-up of Participants Who Become Pregnant .................................................. 47 
6 
PAUSING AND STOPPING RULES ........................................................................... 48 
6.1 
Rules for Discontinuing Investigational Product in an Individual 
Participant ................................................................................................................ 48 
6.2 
Rules for Pausing the Study .................................................................................... 48 
7 
STATISTICAL CONSIDERATIONS .......................................................................... 49 
7.1 
Analysis Sets ........................................................................................................... 49 
7.2 
Demographics and Protocol Compliance ................................................................ 50 
7.3 
Efficacy Analyses .................................................................................................... 50 
7.3.1 
Analysis of Primary Efficacy Endpoint .................................................... 50 
7.3.2 
Analyses of Secondary Efficacy Endpoints .............................................. 51 
7.4 
Immunogenicity and Immunology Analyses .......................................................... 51 
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H56:IC31 
 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
7.4.1 
Intracellular Cytokine Staining (WB ICS) Using Whole 
Blood ......................................................................................................... 51 
7.4.2 
Antigen-specific IgG ELISA Assay Using Plasma .................................. 52 
7.4.3 
RNA Analysis and Blood Subset Counts Supporting RNA 
Analysis Using Whole Blood.................................................................... 52 
7.4.4 
Intracellular Cytokine Staining (ICS) Using PBMCs ............................... 53 
7.4.5 
Exploratory Immunology at TB Recurrence - Control 
Samples ..................................................................................................... 53 
7.4.6 
Adverse Events ......................................................................................... 53 
7.4.7 
Injection Site Reactions ............................................................................ 53 
7.4.8 
Clinical Laboratory and Vital Sign Parameters ........................................ 53 
7.5 
Sample Size Considerations .................................................................................... 54 
7.6 
Plan for Statistical Summaries and Analyses .......................................................... 54 
7.6.1 
Preliminary Data Reviews ........................................................................ 54 
7.6.2 
Exploratory Analysis of Immunogenicity Cohort ..................................... 54 
7.6.3 
Final Study Report .................................................................................... 55 
7.7 
Computer Methods .................................................................................................. 55 
8 
DATA COLLECTION, MONITORING, AND RECORD 
RETENTION................................................................................................................... 55 
9 
ETHICS AND REGULATORY .................................................................................... 56 
9.1 
Ethical and Regulatory Considerations ................................................................... 56 
9.2 
Informed Consent .................................................................................................... 57 
10 
STUDY COMPLETION ................................................................................................ 58 
11 
PUBLICATIONS ............................................................................................................ 58 
12 
CHANGES IN THE PROTOCOL ................................................................................ 58 
12.1 Amendment 1 (Protocol v2.0) ................................................................................. 59 
12.2 Amendment 2 (Protocol v3.0) ................................................................................. 64 
12.3 Amendment 3 (Protocol  v4.0) ................................................................................ 64 
12.4 Amendment 4 (Protocol v5.0) ................................................................................. 66 
13 
REFERENCES ................................................................................................................ 70 
14 
ADVERSE EVENTS OF SPECIAL INTEREST ........................................................ 73 
 
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H56:IC31 
 
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IAVI SA 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
LIST OF ABBREVIATIONS 
AE 
 
adverse event 
AFB 
 
acid fast bacilli (on sputum smear microscopy - the Auramine 
 
technique) 
ALP 
 
alkaline phosphatase 
ALT 
 
alanine aminotransferase 
anti-TNF 
 
anti-tumor necrosis factor  
AST 
 
aspartate aminotransferase 
 
 
 
ßHCG 
 
beta human chorionic gonadotropin 
BCG 
 
bacille Calmette-Guérin 
BMI 
 
body mass index 
BUN 
 
blood urea nitrogen 
CBC 
 
complete blood count 
CM 
 
concomitant medication 
CFR 
 
Code of Federal Regulations 
CPK 
 
creatinine phosphokinase 
CRO 
 
contract research organisation 
CT 
 
computed tomography 
DSMB 
 
data safety monitoring board 
ECG 
 
electrocardiogram 
eCRF 
 
electronic case report form 
EDC 
 
electronic data capture 
EDCTP 
 
The European & Developing Countries Clinical Trial Partnership 
ELISA 
 
enzyme linked immunosorbent assay 
ELISpot 
 
enzyme linked immunospot 
ESR 
 
erythrocyte sedimentation rate 
ET Visit 
 
early termination visit 
GCP 
 
good clinical practice 
GMP 
 
good manufacturing practice 
GGT 
 
gamma glutamyl transferase 
HIV 
 
human immunodeficiency virus 
HLA 
 
human leukocyte antigen 
IB 
 
investigator’s brochure 
ICH 
 
 
International Council for Harmonisation of Technical Requirements 
 
 
 
for Pharmaceuticals for Human Use 
ICS  
 
intracellular cytokine staining 
IgG ELISA 
 
immunoglobulin G enzyme linked immunosorbent assay 
IMP 
 
investigational medicinal product 
IEC 
 
Independent Ethics Committee 
IP 
 
investigational product 
IRB 
 
Institutional Review Board 
ITT 
 
intention to treat 
IXRS 
 
interactive voice/web response system 
LTBI 
 
latent tuberculosis infection 
LLN 
 
lower limit of normal 
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IAVI SA 
CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
MDR 
 
multi-drug-resistant 
mITT 
 
modified intention to treat 
 
 
 
Mtb 
 
Mycobacterium tuberculosis 
NHP 
 
non-human-primate 
 
 
 
 
 
 
PBMC 
 
peripheral blood mononuclear cell 
PI 
 
principal investigator 
POI 
 
prevention of infection 
POR 
 
prevention of recurrence 
PP 
 
per-protocol 
PT 
 
prothrombin time 
PTT 
 
partial thromboplastin time 
QFT 
 
QuantiFERON-TB 
SAHPRA 
 
South African Health Products Regulatory Authority 
SAE 
 
serious adverse event 
 
 
 
SOP 
 
standard operating procedure 
SSA 
 
Sub-Saharan Africa 
SSI 
 
Statens serum institute, Denmark 
STB Visit 
 
suspected TB visit 
SUSAR 
 
suspected unexpected serious adverse reaction 
 
 
 
TB 
 
tuberculosis 
TST 
 
tuberculin skin test 
TZ 
 
Tanzania 
 
 
 
ULN 
 
upper limit of normal 
UN 
 
United Nations 
WB 
 
whole blood 
WB ICS 
 
whole blood intracellular cytokine staining 
WGS 
 
whole genome sequencing 
WHO 
 
World Health Organization 
Xpert MTB/RIF 
Cartridge based nucleic acid amplification test (NAAT), automated  
(Ultra) 
diagnostic test  that can identify Mycobacterium tuberculosis (MTB) 
DNA and resistance to rifampicin (RIF) 
ZA 
 
South Africa 
 
 
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H56:IC31 
 
Protocol A-055  
Statens Serum Institut 
IAVI SA 
CONFIDENTIAL 
19/May/2021; Final Version 5.0 
 
 
Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
1 
INTRODUCTION 
The World Health Organization (WHO) has set the goal of ending the tuberculosis (TB) 
epidemic by 2035 (WHO core team within global TB programme, 2015) and the United 
Nations (UN) has set a similar target within the Sustainable Development Goals of ending TB 
by 2030 (UN General Assembly, 2014). The WHO has noted that without new drugs, 
diagnostics, and vaccines these targets will not be met (WHO core team within global TB 
programme, 2015). 
 
The European & Developing Countries Clinical Trial Partnership (EDCTP) has decided to 
fund this project where the primary objective is to unite African and European research 
institutions, clinical study sites and vaccine developers in a consortium to conduct an 
innovative and cost-effective TB vaccine phase 2 efficacy study. As TB vaccines target 
antigens are not implicated in the generation of resistance they are expected to be equally 
effective against both drug-resistant and drug-sensitive strains of TB. Therefore TB vaccines 
will be a critical tool for managing the spread of resistant strains, and also, through 
prevention of TB disease and hence transmission, will decrease the need for antibiotics. The 
prevention of recurrence (POR) Consortium consists of African and European partners. The 
African partners are; 
, 
, 
 (South Africa), 
, (South 
Africa), 
South Africa), 
 
South Africa) and 
 under the 
 (Tanzania). The European partners are; 
 (Denmark) and 
 
 (Italy). 
 
1.1 
Background 
Over the last 2 centuries, TB is estimated to have killed one billion people, remains the 
world’s most lethal infectious disease, and was South Africa’s leading cause of death in 2015 
(Statistics South Africa, 2017). The TB epidemic is responsible for economic devastation 
and a cycle of poverty and illness that entraps families, communities and even entire 
countries. Adults are the main transmitters of TB and a vaccine that is efficacious in 
preventing TB disease in adults will have the biggest and most immediate impact on the TB 
epidemic (Knight G et al, 2014). The burden of TB is largely borne by just 30 countries, 16 
of which are in Sub-Saharan Africa (SSA). The highest incidences of TB infection and 
disease in the world are encountered in SSA. South Africa reports one of the highest 
incidences in the world with 781 incident cases per 100.000 in 2016 (WHO, Geneva, 2017). 
 
There is growing bacterial resistance to available drugs, which means the disease is becoming 
more difficult to treat. There were an estimated 480,000 cases of multi-drug-resistant (MDR-) 
TB in 2015. The current tools for controlling TB are clearly insufficient, and without new 
efficacious TB vaccines, the 2035 World Health Organization’s End TB strategic goals of a 
reduction of TB deaths and cases of TB disease will not be met, nor will the target within the 
UN Sustainable Development Goals of ending TB by 2030 (UN General Assembly, 2014). 
 
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H56:IC31 
 
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IAVI SA 
CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
Recurrence of TB disease following successful treatment is a significant issue with rates of 
recurrence varying between 2% and 8% (Gillespie SH et al, 2014; Friedrich SO et al, 2013; 
Merle CS et al, 2014; Imperial et al, 2018) as a result of either relapse, i.e. due to the same 
Mtb strain that the patient was initially treated for, or reinfection, i.e. due to a new infection 
with a different strain. The majority of recurrences occur within the first year following the 
end of treatment (Gillespie SH et al, 2014; Friedrich SO et al, 2013; Merle CS et al, 2014, 
Imperial et al, 2018). The availability of an efficacious TB vaccine preventing recurrence will 
be a significant advance in the control of TB disease. 
 
1.2 
Description of the H56:IC31 Vaccine 
H56:IC31 is being developed by SSI and IAVI South Africa NPC and was the first multi-
stage TB subunit vaccine candidate to enter clinical studies. H56:IC31 is specifically 
designed to mediate protection both as a preventive vaccine and as a therapeutic vaccine, 
making it the ideal investigational vaccine for the present POR clinical study (A-055). 
 
The H56:IC31 vaccine candidate consists of a fusion protein of 3 antigens expressed at 
different stages of Mycobacterium tuberculosis (Mtb) infection (Wiker et al, 1992; Belisle et 
al, 1997; Horwitz et al, 2000; Ravn et al, 1999; Ulrichs et al, 1998; Pollock and Anderson, 
1997; Brandt et al, 1996; Brandt et al, 2000; Rustad et al, 2009; Betts et al 2002; 
Muttucumaru et al, 2004; Govender et al, 2010) and a T helper type 1 cell (Th1)-stimulating 
adjuvant, IC31® developed by Valneva (Kochenderfer et al, 2006). 
 
H56 fusion protein: 
 
- 
Ag85B: An immunodominant antigen secreted in the acute phase of infection 
- 
ESAT-6: The premier virulence-associated antigen highly expressed throughout all 
 
stages of infection 
- 
Rv2660c: A stress-induced antigen, the expression of which is strongly associated 
 
with latent TB infection 
 
IC31 adjuvant: 
IC31 is a 2-component adjuvant comprised of an oligodeoxynucleotide ODN1a and a 
polypeptide KLK. The first component, ODN1a, contains alternating sequences of the 
unusual bases inosine and cytidine: oligo-d(IC)13. This motif is similar to CpG motifs that 
act as T-cell adjuvants. The second component, KLK, is a synthetic cationic antimicrobial 
peptide composed of lysine (K) and leucine (L) in the sequence KLKLLLLLKLK. KLK is 
thought to enhance peptide specific immune responses by increasing uptake of the complexed 
antigen into antigen presenting cells. The negatively charged ODN1a and the positively 
charged KLK complex electrostatically. When IC31 is combined with H56, the adjuvant 
further complexes with the antigen to form H56:IC31. 
 
The two components of IC31 may be combined in various ratios but a 25:1 molar ratio of 
KLK to ODN1a is the ratio used for H56:IC31. Since the ratio of ODN1a and KLK is 
constant in H56:IC31, adjuvant amounts will be expressed in this document only as nmol of 
KLK for ease of presentation. 
 
H56:IC31 vaccine: 
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H56:IC31 
 
Protocol A-055  
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CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
The H56 fusion protein is formulated with IC31 in a good manufacturing practice (GMP) 
compliant environment in a ready to use final formulated vaccine.  
 
H56:IC31 is administered twice with a 56 days (+/-10) interval, 
with 
IC31 consisting of 500 nmol KLK and 20 nmol ODN1a, in a total volume of 0.5mL by the 
intramuscular route in the deltoid area using standard aseptic technique. 
 
Please refer to the H56:IC31 Investigator’s Brochure (IB) for further information. 
 
1.3 
Non-clinical Experience with the H56:IC31 Vaccine 
H56:IC31 was immunogenic and showed protective efficacy in mice, rats, guinea pigs 
(Aagaard et al, 2011) and non-human-primates (NHPs) (Lin et al, 2012, Billeskov et al, 
2016), although the effect varied in both guinea pigs and NHPs.  
 
In guinea pigs the efficacy was dependent on whether the vaccine was administered as a 
stand-alone vaccine (demonstrating protective efficacy) or as a BCG booster (non-
protective). In mice, the H56 antigen also protected against TB when given post-exposure to 
Mtb, which was not the case in guinea pigs (one experiment).  
 
In 3 independent NHP experiments, the H56 antigen and IC31 adjuvant were administered at 
the dose of 50 g of H56 in 500 nmol IC31. There was no evidence of systemic toxicity and 
no apparent local reactions at the injection sites. Vaccination with H56:IC31 significantly 
delayed and reduced TB associated inflammation measured by erythrocyte sedimentation rate 
(ESR). Boosting with H56:IC31 after BCG vaccination also delayed and reduced clinical 
disease and pathology and increased survival, compared to no vaccination and vaccination 
with BCG alone. In one experiment, the animals with developed LTBI were treated with anti-
TNF drug to reactivate TB disease, and the BCG/H56:IC31 vaccinated animals had minimal 
reactivation relative to the BCG vaccinated group. In a fourth NHP study, the H56 antigen 
and IC31 adjuvant were administered to animals at the dose of 15 g of H56 in 500 nmol 
IC31. In this study, the BCG vaccinated group performed better than expected, and 
BCG/H56:IC31 did not perform significantly better than BCG.  
 
No Koch-like reactions were seen in animals vaccinated up to 8 times with H56:IC31 (mice). 
There was no evidence of a broader toxic effect of H56:IC31 administered to rabbits in a 
more intensive regimen (4 doses; 100 µg H56 with or without 500 nmol IC31) than 
anticipated in the clinical program. The non-clinical information overall supports the 
suitability of H56:IC31 as a safe, immunogenic, and possibly effective vaccine to augment 
the immunity induced by a previous Mtb infection and/or BCG vaccination, and induce 
immunity in Mtb-uninfected individuals as well as in BCG-primed individuals. 
 
Please refer to the H56:IC31 IB for further information. 
 
1.4 
Clinical Experience with the H56:IC31 Vaccine 
Five H56:IC31 studies have been completed. In these studies a total of 248 participants have 
been vaccinated, 165 of whom have received H56:IC31, 24 of whom have received protocol-
specified BCG, 35 of whom have received placebo, and 24 of whom have received H4:IC31 
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H56:IC31 
 
Protocol A-055  
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CONFIDENTIAL 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
(a protein adjuvant candidate TB vaccine – see Section 1.5 - included in an arm of a phase 1b 
study (A-042) to evaluate immune responses to H56:IC31, H4:IC31 or BCG revaccination). 
The dose of H56:IC31 in these studies ranges from 5 to 50 g H56 with 500 nmol IC31, 
administered 2 or 3 times 2 months apart. 
 
Two of the studies, C-032-456 (Luabeya et al, 2015) and C-035-456 (Suliman et al, 2019), 
investigated the safety and immunogenicity of increasing intramuscular doses of H56:IC31 
initially in humans with no evidence of Mtb infection, followed by individuals with latent 
tuberculosis infection (LTBI)
clinical development based on data from these studies. 
 
In preparation for the present POR study, the safety and immunogenicity of H56:IC31 were 
investigated in a third study (C-037-456) in 22 participants recently successfully treated for 
TB disease (16 H56:IC31 and 6 placebo) in South Africa. H56:IC31 was demonstrated to be 
safe and immunogenic in this population. 
 
A fourth open label phase I study investigated H56:IC31 in participants undergoing TB 
treatment in Norway. In one of the study groups, 19 adults who had received TB treatment 
for 3 months at the time of the first dose, were vaccinated with 2 doses of H56:IC31 with 56 
days interval. Preliminary clinical data indicates acceptable safety profile and 
immunogenicity was observed when H56:IC31 is administered during ongoing TB treatment. 
 
H56:IC31 was associated with an acceptable safety profile in participants with and without 
LTBI, and in participants recently successfully treated for pulmonary TB. No vaccine-related 
SAEs were reported. Vaccination with H56:IC31 was associated mos
participants with a related adverse event (AE) with mild to moderate injection site reactions 
of pain, warmth, and swelling; and mild to moderate systemic AEs of fatigue, myalgia, and 
nausea. 
 
H56:IC31 induced a dominant CD4+ T cell response in both QFT (+) and QFT (-) 
participants, and in participants recently successfully treated for pulmonary TB. These 
responses were more pronounced in participants with prior TB exposure. 
 
Please refer to the H56:IC31 IB for further information. 
1.5 
Clinical Experience with Vaccines Related to H56:IC31 
Two other, closely related vaccine candidates consisting of fusion proteins of Mtb antigens 
combined with the IC31 adjuvant have been studied in humans: H1:IC31 and H4:IC31. 
H1:IC31 contains the H1 fusion protein, which includes antigens Ag85B and ESAT-6 and 
H4:IC31 contains the H4 fusion protein, which includes antigens Ag85B and TB10.4. 
 
A total of 3 phase I clinical studies of H1:IC31 have been completed (THYB-01, THYB-02, 
and THYB-03), in which 95 healthy adult participants were vaccinated with H1 at a dose of 
50 g. The dose of IC31 in these studies ranged from 0 to 500 nmol. Clinical manifestations 
related to H1:IC31 include mild injection site reactions, constitutional symptoms (such as 
fatigue, malaise, and feeling cold) that were typically mild, and erythema and itching at 
previously administered tuberculin skin test (TST) site. Two SAEs possibly related to 
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Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
 
vaccination have been reported (increased AST/ALT with fever, chills, generalized body 
weakness, and erythema at previous PPD injection site 12 hours post-vaccination in 1 
participant; and elevated CPK 24 and 48 hours post-vaccination in 1 participant who is a 
heavy weight lifter), both of which resolved within 72 hours. Two participants were 
withdrawn after experiencing mild AEs that were considered to be possibly related to the 
vaccine: 1 participant had progressively increasing eosinophilia, and 1 participant had 
erythema and itching at his previous PPD injection site. Two phase II studies with H1:IC31 
have also been completed: a dose finding study in 240 adolescents (THYB-04) and a study in 
48 HIV-infected adults, 40% Mtb infected with no evidence of TB disease (THYB-05). There 
have been no major safety signals in either of these phase II studies, and no vaccine-related 
SAEs were reported. 
 
A total of 4 phase I clinical studies of H4:IC31 have been completed and have unblinded data 
available, in which 234 healthy adult participants (previously vaccinated with BCG) were 
vaccinated (C-005-404, C-006-404, C-011-404, C-013-404). Of these participants, 198 
received H4:IC31 and 36 received placebo. The doses of H4:IC31 in these studies range from 
5 to 150 g H4 with 0 to 500 nmol IC31. No related SAEs were reported in these studies. 
Clinical manifestations related to H4:IC31 include mild to moderate injection site reactions, 
and mild to severe hypersensitivity reactions at previously administered TST test site when 
study vaccine was administered even when the original TST was non-reactive. The most 
common AEs (occurring in 10% of participants) considered related to H4:IC31, other than 
injection site reactions, were mild to moderate fatigue, myalgia, headache, arthralgia, and 
mild to severe pyrexia. A phase II study (C-040-404) including 990 HIV-negative, healthy 
adolescents (12 to 17 years of age) who had been vaccinated as infants with BCG has been 
completed. All participants were randomized evenly into 3 study arms: placebo, H4:IC31 (15 
g), or BCG revaccination. The data showed that both H4:IC31 and BCG appeared to be safe 
and produced an immune response in the adolescents studied. No vaccine-related serious 
adverse events were reported in the study, and the most common vaccine-related adverse 
event was injection site swelling in BCG revaccinated participants, typical for BCG 
vaccination. Safety was assessed in all participants who received at least one injection. 550 
participants experienced at least one AE. H4:IC31 and placebo had similar AE profiles 
(Nemes et al, 2018). 
1.6 
Rationale for Study 
The clinical development of H56:IC31 is aimed towards the development of a vaccine to 
induce protective immunity in Mtb-uninfected individuals and to augment the immunity in 
already Mtb sensitized or infected individuals who have previously been vaccinated with 
BCG. Completed H56:IC31 phase I studies have evaluated the safety and immunogenicity of 
increasing intramuscular doses of H56:IC31 initially in uninfected humans followed by 
individuals with LTBI, previously vaccinated with BCG. A dose (5 g H56/500 nmol IC31) 
has been selected for further development in QFT+ individuals. This dose was also 
determined to be safe and immunogenic in patients vaccinated as they approached the end of 
a 6-months course of TB treatment or who had very recently completed treatment for active 
pulmonary TB and who were, by the WHO definition, deemed to be cured (data on file). 
 
As demonstration of protective efficacy against TB disease in the target population will 
require a large (many thousands of participants) and lengthy (3 or more years) field study, 
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shorter and smaller proof of concept phase II studies, investigating sub-populations at greater 
risk of TB infection and/or disease than those in the general population, have been proposed 
by leading experts in the TB vaccine field (Ellis RD et al, 2015). These studies will determine 
the impact of vaccination with investigational TB vaccines on POR TB disease in recently 
successfully treated TB patients (Imperial et al, 2018) and prevention of sustained infection 
(POI) in adolescents at high risk of infection with Mtb. Recurrent TB disease is ~4-fold more 
frequent than incident TB disease in the general population, and infection in high risk groups, 
such as adolescents living in areas where there is a high force of infection, can occur up to 
~8-fold more frequently than incident TB disease (Nemes et al, 2018). Therefore, these 
studies can be completed more rapidly and more cost-effectively using smaller group sizes 
than could a proof of concept study with TB disease as an endpoint in the general population.. 
The outcomes of these proof of concept studies may then be used as Go/ No Go criteria to 
inform future investment and development, including large-scale manufacture and efficacy 
studies in a broader population.  
 
Preclinical data suggest H56:IC31 may be more efficacious if administered while patients are 
still on treatment (Aagaard et al, 2011; Hoang T et al, 2013). Following the national 
guidelines for TB treatment in South Africa (ZA) and Tanzania (TZ) we will obtain sputum 
samples from patients after at least 5 months (22 weeks) of treatment, at the same time they 
are obtained within the national TB control programmes, and if the sputum is smear negative, 
the criterion for successful treatment within TB programmes, the individual will be eligible 
for randomization and vaccination if the duration of their treatment period is not expected to 
exceed 28 weeks. 
 
As this is a proof of concept TB vaccine study, HIV positive individuals have been excluded 
as it is not yet known what effect HIV infection may have on the immune response to the 
vaccine. However, HIV positive individuals are an important population to include in future 
studies should efficacy be demonstrated. 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Objectives 
2.1.1 
Primary Objective 
To evaluate the following in HIV-negative participants who have completed at least 5 months 
(22 weeks) treatment for drug-susceptible pulmonary TB and who test negative for acid fast 
bacilli (AFB) on sputum smear microscopy prior to vaccination (participants unable to 
produce sputum, and considered asymptomatic by the investigator, may be considered Mtb 
negative): 
 
 Efficacy of H56:IC31 compared to placebo in reducing the rate of recurrent TB 
disease (relapse or reinfection) 
2.1.1.1 Primary Endpoint 
 Rate of TB disease recurrence (relapse or reinfection), defined as TB diagnosed by 
confirmation of Mtb by culture of sputum, during the period starting 14 days after the 
2nd vaccination (V6= Day 70) and ending 12 months after the 2nd vaccination  
(V8= Day 421) 
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2.1.2 
Key Secondary Objective 
To evaluate the following in HIV-negative participants who have completed at least 5 months 
(22 weeks) treatment for drug-susceptible pulmonary TB and who test negative for AFB on 
sputum smear microscopy prior to vaccination (participants unable to produce sputum, and 
considered asymptomatic by the investigator, may be considered Mtb negative): 
 
 Safety of H56:IC31 compared to placebo 
 
2.1.2.1 Key Secondary Endpoints 
 Solicited adverse events and all adverse events occurring the first 14 days after each 
of the 1st and 2nd vaccinations 
 Serious adverse events including medically important events occurring after the 1st 
vaccination through the end of the study 
 
2.1.3 
Other Secondary Objectives 
To evaluate the following in HIV-negative participants who have completed at least 5 months 
(22 weeks) treatment for drug-susceptible pulmonary TB and who test negative for AFB on 
sputum smear microscopy prior to vaccination (participants unable to produce sputum, and 
considered asymptomatic by the investigator, may be considered Mtb negative): 
 
 Trends towards efficacy of H56:IC31 compared to placebo in reducing the rate of TB 
disease relapse 
 Trends towards efficacy of H56:IC31 compared to placebo in reducing the rate of TB 
disease reinfection 
 Antigen-specific cell-mediated immune responses to H56:IC31 
 Humoral immune responses to H56:IC31  
 
2.1.3.1 Other Secondary Endpoints 
 Rate of TB disease relapse, defined as participants meeting the primary endpoint of 
TB disease recurrence, AND determined by whole genome sequencing (WGS) of the 
Mtb isolate to be the same strain of Mtb as in the participant’s original isolate from the 
time of diagnosis 
 
 Rate of TB disease reinfection, defined as participants meeting the primary endpoint 
of TB disease recurrence, AND determined by WGS of the Mtb isolate to be a 
different strain than in the participant’s original isolate from the time of diagnosis 
 
 Antigen-specific cell-mediated immune responses by whole blood intracellular 
cytokine staining (WB ICS) at baseline (V3= Day 0), and 14 days after the 2nd 
vaccination (V6= Day 70) in the immunogenicity cohort 
 
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 Humoral immune responses by IgG ELISA of plasma samples taken from the 
immunogenicity cohort at baseline (V3= Day 0) and 14 days after the 2nd vaccination 
(V6= Day 70)  
2.1.4 
Exploratory Objectives 
To evaluate the following in HIV-negative participants who have completed at least 5 months 
(22 weeks) treatment for drug-susceptible pulmonary TB and who test negative for AFB on 
sputum smear microscopy prior to vaccination (participants unable to produce sputum, and 
considered asymptomatic by the investigator, may be considered Mtb negative): 
 
 Trends towards efficacy of H56:IC31 compared to placebo in reducing the rate of 
recurrent TB disease by exploratory efficacy endpoint definitions (Section 2.1.4.1) 
 Transcriptomic signatures of inflammation or associated with TB disease recurrence 
 
Immunological correlates of risk and correlates of protection for TB disease 
recurrence 
 
Humoral immune responses to H56:IC31in participants with TB recurrence diagnosis 
compared to the participants in the control cohort  
 
2.1.4.1 Exploratory Endpoints 
 Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence AND participants who started TB 
treatment without confirmation of Mtb by culture of sputum 
 
Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence based on confirmation of Mtb by Xpert 
MTB/RIF Ultra or culture of sputum 
 
 Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence AND participants diagnosed between 
30 days after the 1st vaccination and 14 days after the 2nd vaccination, based on 
confirmation of Mtb by culture of sputum 
 
 Transcriptomic signatures (RNA analysis) and cellular composition (flow cytometry) 
of whole blood etc. at baseline (V3= Day 0) and at TB recurrence diagnosis 
 
 Blood subset counts of whole blood (supports the RNA analysis) at baseline (V3= 
Day 0) and at TB recurrence diagnosis 
 
 Antigen-specific cell-mediated immune responses by peripheral blood mononuclear 
cells (PBMC) ICS at baseline (V3= Day 0) and 14 days after the 2nd vaccination (V6= 
Day 70) and at TB recurrence diagnosis 
 
 Humoral immune responses by IgG ELISA of plasma samples at baseline (V3= Day 
0) and 14 days after the 2nd vaccination (V6= Day 70) and at TB recurrence diagnosis 
 
 
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recurrent isolates by WGS at OSR, Italy. During the 5-month period between V1 and V2, the 
study staff will regularly liaise with screened participants, staff from the TB clinics and 
community health care workers to monitor TB treatment compliance and continued eligibility 
for study participation. 
 
In- and exclusion criteria will be assessed  at V2, by review of medical history, physical 
examination (complete), vital signs, pregnancy testing (all females) and HIV testing. For 
eligible participants, 2 separate sputum samples will be obtained, and safety laboratory tests 
(blood) and urinalysis (dipsticks) will be performed. One AFB smear for microscopy using 
the Auramine technique will be created from each of the sputum samples.  
 
Upon written approval from the sponsors and relevant approvals for protocol amendment 
v5.0,the activities scheduled for the 1st screening visit (V1) will be performed on the same 
day as (or together with) the 2nd screening visit (V2). At a combined screening visit (V1 and 
V2) the participant must have completed at least 5 months (22 weeks) of TB treatment and 
while TB treatment must be ongoing. 
 
 
Randomisation and follow-up 
The TB treatment must still be ongoing at V3= Day 0, and it must be verified that the 
participant is tested Mtb negative, i.e. both sputum samples from V2 must be negative by 
smear AFB microscopy. Participants unable to produce sputum, but considered asymptomatic 
by the investigator, may be considered Mtb negative and eligible for inclusion. All inclusion 
and exclusion criteria will be assessed or re-assessed, by review of medical history, physical 
examination (symptom directed), weight, vital signs, pregnancy testing (all females ) and 
confirmation of negative HIV status from V2. 
 
Eligible participants, after verification of vaccination eligibility criteria, see Section 3.5, will 
be randomized (1:1) to receive either H56:IC31 or placebo, and the 1st vaccination will be 
administered. 
 
Before administering the 2nd vaccination on V5= Day 56, physical examination (symptom 
directed), weight, vital signs, pregnancy testing (all females), TB symptoms screen, and 
vaccination eligibility criteria will be assessed, see Section 3.5 and 6.1. 
 
After each vaccination, it will be assessed if immediate AEs occurred within 60 minutes (for 
details see Section 3.6.3.1), TB signs and symptoms training will be performed, and diary 
cards will be handed out to the participants. 
 
There will be short-term follow-up visits after each vaccination on V4= Day 14 and V6= Day 
70, with weight, vital signs, TB symptoms screen and review of diary cards. Solicited AEs 
including injection site reactions and concomitant medications (CM), and spontaneously 
reported AEs, including serious AEs and AEs of special interest, will be assessed and 
recorded. If there is suspicion of TB disease, 2 separate sputum samples will be obtained, and 
the case verification procedure (see details below) for recurrent TB disease will be initiated. 
 
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For the safety cohort (= the first 150 randomized participants across all sites), see Table 2-1, 
there will also be safety laboratory testing on V4= Day 14 and V6= Day 70. For the 
remaining participants, there will only be laboratory safety testing at screening (V2), or at the 
ET Visit, if within 14 days after the investigational medicinal product (IMP) administration. 
 
At the long-term follow-up visit on V7= Day 238, there will be a TB symptoms screen 
including weight and recording of serious adverse events (SAEs) and AEs of special interest. 
If there is suspicion of TB disease, 2 separate sputum samples will be obtained, and the case 
verification procedure (see details below) for recurrent TB disease will be initiated. 
 
At the last study visit, V8= Day 421, whether or not there is suspicion of TB disease, 2 
separate sputum samples will be obtained from all participants to identify missed cases, see 
Section 3.6.1. At this visit a negative Xpert MTB/RIF Ultra does not need to be verified by 
culture for participants with no clinical TB symptoms. Furthermore, SAEs and AEs of special 
interest will be assessed and recorded, if any. 
 
Immunogenicity / immunology laboratory samples: PBMCs and plasma for ICS and IgG 
ELISA will be collected from all participants on V3= Day 0, V6= Day 70 and at suspicion of 
TB recurrence, as defined for the STB Visit, ET Visit or V8.Whole blood for RNA analysis 
and blood subset counts (to support the RNA analysis) will be collected from all participants 
at V3= Day 0 and at suspicion of TB recurrence, as defined for the STB Visit, ET Visit or 
V8, see Table 3-2. 
 
For the immunogenicity cohort at the 
 TZ sites only (= first 50 
randomized participants at 
and first 50 randomized participants at 
 = in total 
100 participants), see Table 2-1, whole blood will be collected and stimulated for WB ICS on 
V3= Day 0 and V6= Day 70, see Table 3-2. For the remaining participants and sites, there 
will be no collection of whole blood for WB ICS. 
 
The immunogenicity cohort at the 
, TZ sites also serves as control 
cohort, see Section 7.4.5 and Table 2-1. Therefore there will be collection on V8= Day 421, 
of PBMCs and plasma for ICS and IgG ELISA and whole blood for RNA analysis and blood 
subset counts. These samples will be control samples for the corresponding immunology 
samples taken from participants under diagnosis of recurrent TB during the study, see Table 
3-2. 
 
TB signs and symptoms training will take place at all visits and telephone calls (TCs) from 
V3= Day 0 and onwards, and TB symptom screening at all visits and TCs from V4= Day 14 
and onwards. The TC1 to TC5 will take place on the following days: Day 154, 196, 280, 322 
and 364. If there is suspicion of TB at any of these occasions, based on the TB symptoms 
screening, 2 separate sputum samples will be obtained, and the case verification procedure 
(see details below) for recurrent TB disease will be initiated at a Suspected TB (STB) visit. 
 
Participants who are withdrawn from the study within 6 months after the last product 
administration, will be contacted at least 6 months after the last product administration for 
recording of SAEs and AEs of special interest. 
 
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Referral for diagnosis and management of recurrent TB is triggered by the investigator based 
on clinical suspicion of recurrent TB. Participants will not be withdrawn from the study based 
on this referral but will be withdrawn if Mtb positive by culture in the study or if the referral 
clinic diagnoses recurrent TB and starts TB treatment. The case verification procedure is 
initiated at a STB Visit. 
 
Case verification procedure for recurrent TB disease: 
 2 separate sputum samples are obtained: 
o 1 sputum sample is tested by Xpert MTB/RIF Ultra 
o The same sputum sample and the second sputum sample are both sent for 
culture  
o The remainder of the 2 separate sputum samples is stored (frozen) as 2 
separate samples for later analysis by WGS if recurrent TB is confirmed 
 
 The participant is HIV tested (including CD4 count for participants who test HIV 
positive) and immunology samples are taken, see Table 3-2. 
 
 If Mtb positive by culture in the study, the participant is informed of TB test results, 
referred to TB treatment management as per national programme guidelines (if not 
previously done), and is withdrawn (at the ET Visit) due to verified recurrent TB. 
 
 If Mtb negative by culture in the study the participant is informed of TB test results, 
continues in the study and no ET Visit is completed. 
 
 If Mtb negative by culture or the study culture result is pending, but the referral clinic 
diagnosed recurrent TB and started TB treatment, 2 additional sputum samples must 
be collected as soon as possible for repeat Mtb testing by culture, and the participant 
is withdrawn from the study. 
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Figure 2-1 
Study Flow Diagram 
 
Upon written approval of the Sponsors and relevant approvals for the Protocol Amendment v5.0, participants 
may be screened at a combined V1 and V2. This visit will be scheduled when the participant has completed at 
least 5 months (22 weeks) of TB treatment and TB treatment must be ongoing.  
  
An internal data review committee, consisting of the coordinating principal investigator (PI), 
the site PIs and the medically responsible person from each of the co-sponsors, will convene 
during the study to review the blinded reported SAEs, AEs including AEs of special interest, 
injection site reactions and laboratory safety test results to identify any possible safety issues 
when: 
 
 The first 150 participants across all sites have received their 1st vaccination and the 14 
days safety follow-up data is available 
 The first 150 participants across all sites have received their 2nd vaccination and the 
14 days safety follow-up data is available 
 
An independent data safety monitoring board (DSMB) will be established, consisting of a 
panel of independent experts, who will operate according to a DSMB charter. The DSMB 
will be convened if: 
 
 A stopping rule is triggered 
 The internal data review committee requests a DSMB meeting based on their review 
of the safety data 
 
For more details on the internal data review committee review of safety data and the DSMB 
procedures, please see sections 5.1.4 and 6.2. 
 
3 
 STUDY PROCEDURES 
3.1 
Schedule of Participant Evaluations 
Written informed consent must be obtained before any screening procedures are performed. 
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A Summary Schedule of Evaluations depicting all visit-specific procedures is provided in 
Table 3-1. 
 
Upon written approval from the sponsors and relevant approvals for protocol amendment 
v5.0, the activities scheduled for the 1st screening visit (V1) will be performed on the same 
day as (or together with) the 2nd screening visit (V2). At this combined screening visit (V1 
and V2) the participant must have completed at least 5 months (22 weeks) of TB treatment 
and TB treatment must be ongoing. Activities scheduled for both V1 and V2 do not need to 
be repeated.  
 
 
 
 
 
 
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3.2 
Study Participants 
3.2.1 
Recruitment and Informed Consent 
Various methods of recruitment will be used such as advertising, referrals, or proposition. All 
recruitment materials must be approved by the sponsor and Institutional Review Board (IRB) 
and/or Independent Ethics Committee (IEC). Interested TB patients will be invited to 
participate in the informed consent process. Informed consent will be obtained by the use of a 
written consent form approved by the IRB and/or IEC and signed and dated by the TB patient 
at the time of consent. 
 
Potential participants will be interviewed to ensure they meet all entry criteria relating to age, 
diagnosis, TB treatment status and history etc. The clinical investigator or medically qualified 
designee (e.g. nurse or physician’s assistant) will conduct the consent discussion on an 
individual basis in an appropriate private space (which does not have to be at the study site) 
with each potential participant, and will allow adequate time for all questions to be addressed. 
The potential participant will be encouraged to take the informed consent form home to 
discuss with family and friends before deciding whether or not to participate in the study. 
Written informed consent will be obtained prior to conducting any screening procedures. A 
copy of the signed consent form shall be given to the participant. Further details regarding 
informed consent are presented in Section 9.2. 
 
3.2.2 
Assignment of Participant Identification Numbers 
The site PI is responsible for keeping the participant identification log(s). After informed 
consent is obtained, the participants will be screened to assess for eligibility for entry into the 
study. 
 
For identification purposes, each participant for whom informed consent has been obtained 
will be assigned a unique participant identification number which will be listed in the 
participant identification log(s). 
 
For screening failures, the reason for exclusion must be listed. Participants who are 
randomized in the study will also receive a unique randomization number. 
 
The confidential participant identification log will identify the participants by full name, date 
of birth, participant screening number, address and contact number and will be stored in a 
secure location. The participant screening and enrollment log will identify participants by 
participant screening number, date of informed consent, date of randomization, 
randomization number, and date and reason for exclusion, if applicable. 
 
Eligibility for entry into the study will be based on the inclusion and exclusion criteria 
defined in Sections 3.2.3 and 3.2.4. The investigator must document confirmation of 
eligibility prior to randomization. 
 
The eCRF is used for allocating a randomization number to the participants that are eligible 
for inclusion. The unblinded site staff will, by use of the randomization number and their 
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exclusive access to the unblinded eCRF module, be able to identify if a given participant is to 
be vaccinated with H56:IC31 (investigational vaccine) or placebo. 
 
In the eCRF, personal details, such as, the full name, address and contact number will not be 
recorded. In the eCRF, the participants may be identified by the use of: unique participant 
identification number(s), age on date of V3= Day 0 and sex. It is however, possible to trace 
back any eCRF to the participant identification log(s) in case needed. 
 
At the end of the study, normally at the site close-out monitoring visit, the site PI must sign of 
the participant identification log(s) for correctness and completeness. 
 
3.2.3 
Inclusion Criteria 
Participants must meet all inclusion criteria at the time of randomization and 
vaccination: 
 
1. Completed the written informed consent process. 
2. Agrees to give access to medical records for study-related purposes. 
3. HIV-negative (self-reported) with a diagnosis of drug-susceptible pulmonary TB at the 
start of the TB treatment. 
4. 
. 
Participants are not expected to provide sputum samples prior to starting TB treatment if 
their 1st screening visit (V1) is performed on the same day as their 2nd screening visit 
(V2). 
5. Tested Mtb negative by smear AFB microscopy of 2 separate sputum samples taken on 
V2. Participants unable to produce sputum, but considered asymptomatic by the 
investigator, may be considered Mtb negative and eligible for inclusion. 
6. Confirmed HIV negative on V2. 
7. Completed  5 months (22 weeks) of TB treatment with treatment still ongoing at the 
time of the 1st vaccination on V3= Day 0, and total treatment time not extended beyond 
28 weeks. 
8. 
on the date of V1 
= Day 0. 
9. Agrees to stay in contact with the study site for the duration of the study, provide updated 
contact information as necessary, and has no current plans to move from the area for the 
duration of the study. 
 
3.2.4 
Exclusion Criteria 
Participants must meet none of the exclusion criteria at the time of randomization and 
vaccination: 
 
1. Diagnosis or co-diagnosis of extra pulmonary TB.  
2. Hospitalized for the current episode of drug-susceptible pulmonary TB disease. 
3. History of receipt of treatment against active TB, prior to the current treatment episode, 
within the last 5 years.  
4. History of or ongoing severe disease that in the opinion of the investigator might affect 
the safety of the participant or the immunogenicity of the investigational product. 
5. Insulin dependent diabetes. 
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6. History of allergic disease or reactions likely to be exacerbated by any component of the 
investigational product. 
7. History or laboratory evidence of immunodeficiency, autoimmune disease or 
immunosuppression. 
8. History of chronic hepatitis. 
9. Severe anemia, defined as hemoglobin less than 10 g/dL or a hematocrit less than 30 % 
based on most recent hematology obtained before randomization. 
10. Receipt of any investigational TB vaccine previously. 
11. Receipt or planned receipt of any investigational drug or investigational vaccine from V1 
through V8= Day 421. 
12. Receipt or planned receipt of any licensed vaccine from V1 through V6= Day 70, except 
for SARS-Cov-2 vaccines recommended by national vaccination programs which will be 
allowed if given > 28 days before and from the time of administration of clinical trial 
product. 
13. Receipt of treatment likely to modify the immune response (e.g. blood products, 
immunoglobulins, immunosuppressive treatment) within 42 days before V3= Day 0 
through V6= Day 70. Inhaled and topical corticosteroids are permitted. 
14. Has a body mass index (BMI) < 13 (weight, kg / height, m2) on the date of V1. 
15. Female participants of childbearing potential (not sterilized, menstruating or within 1 year 
of last menses, if post-menopausal): if not willing to use an acceptable method to avoid 
pregnancy (sterile sexual partner, sexual abstinence, hormonal contraceptives (oral, 
injection, transdermal patch, or implant) or intrauterine device from 28 days before V3= 
Day 0 until 2 months after the 2nd vaccination. 
16. Female participants: if lactating / nursing, or pregnant as per positive pregnancy test on 
V2. 
17. Not suitable for inclusion in the opinion of the investigator. 
 
3.2.5 
Screening Clinical Assessments and Laboratory Tests 
Adults not known to be HIV positive with a diagnosis of drug-susceptible pulmonary TB per 
national guidelines (confirmed by Xpert MTB/RIF or AFB smear), and who started their TB 
treatment not more than 7 days before the 1st screening visit (V1) will, if eligible for 
inclusion, be asked to produce 2 separate sputum samples at V1, which will be stored 
(frozen) for later comparison to recurrent isolates by WGS, for differentiation between 
relapse (=identical strains) and reinfection (=different strains). Participants with a combined 
V1 and V2 will not provide V1 sputum samples.   
 
Participants may also be eligible for inclusion at V1, if the Xpert rifampicin susceptibility test 
was unsuccessful at the local clinic, but the participant was started on a drug-susceptible 
treatment regimen according to national guidelines. The participant will then be screen failed 
prior to randomization (V3), if the site cannot confirm drug-susceptible TB by a test or a 
clinical response to treatment.  
 
The time period between V1 and the 2nd screening visit (V2) is approximately 5 months 
(approximately 22 weeks). Site staff will remain in contact with participants, TB clinic staff 
and community health care workers during this period to monitor TB treatment compliance 
and continued eligibility for study participation. The completion of a standard TB treatment 
regimen is 6 months (24 weeks) which can be extended up to 28 weeks. Participants with a 
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combined V1 and V2 may only be screened for the trial after at least 22 weeks of TB 
treatment and TB treatment must be ongoing. 
 
At V2 the samples for HIV screening and safety laboratory analysis are collected (for 
participants who are still eligible for inclusion) and subsequently evaluated. Furthermore, 2 
sputum samples will be collected, both samples need to test negative for Mtb by smear AFB 
microscopy using the Auramine method. The remainder of both Mtb negative sputum 
samples will be stored (frozen) for culture, if verified recurrent TB, and for exploratory use at 
the end of the study. Any left-over sputum samples will be destroyed. The screening 
samples/evaluations may be taken/performed over more than one visit. If a combined V1 and 
V2 is performed, participants will only provide a sputum sample once at V2. These samples 
serve to verify that the participant is Mtb negative and would still be stored for exploratory 
analysis.  
 
Participants unable to produce sputum, and considered asymptomatic by the investigator, 
may be considered Mtb negative and eligible for inclusion. 
 
3.3 
Study Randomization/Entry 
Participants will be randomized to the study based on a randomly-generated sequence of 
numbers (randomization list) managed by a validated module in the eCRF. The 
randomization list will be prepared by a statistician who will not be involved in the analysis 
of the study in order to maintain the blind of the study team. The day of randomization for 
each participant will be Study Day 0.  
 
Discontinued participants (for any reason) after randomization will not be replaced. 
 
3.4 
Blinding 
The unblinded persons in the study are the study vaccine manager (and designee) who 
manages the participant inventory log(s) at the study site, the unblinded site staff, and the 
unblinded study monitor(s) responsible for monitoring the investigational product at the study 
site. All unblinded persons must take care to not reveal individual participant treatment 
assignments to any other member of the study team. There will be an unblinded contact 
person at the sponsor’s site in order to manage queries from the unblinded site staff or the 
unblinded monitors in the study. 
 
The study vaccine manager (and designee) should be a designated site team member, such as 
the study pharmacist. Unblinded site staff must not participate in the administration of 
vaccine and evaluation of adverse events. 
 
A delegation of responsibility log will be maintained by the study site and will identify the 
individual(s) such as the study vaccine manager (and designee) and other unblinded site staff, 
i.e., individuals with access to unblinded data. 
 
The randomization list will be prepared by the unblinded statistician and will be implemented 
as a module in the eCRF. Access (through the eCRF) to information which links a 
randomization number to treatment assignment, will only be given to the study vaccine 
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manager (and designee) and to the unblinded study monitor(s) responsible for monitoring the 
investigational product at the study site.  
 
All pharmacy source documents and dose preparation records that can link a randomization 
number with a treatment assignment must remain secure (e.g., in the pharmacy with access 
limited to only unblinded persons) until notification from the sponsor that the study has been 
unblinded. 
 
Labels accompanying the syringes of prepared investigational product doses will not indicate 
which investigational product is in the syringe. Identical syringes, needles and labels will be 
used for preparation and administration of investigational vaccine and placebo. 
 
3.4.1 
Unblinding for Clinical Emergencies  
If there is an urgent clinical requirement to know a participant’s treatment assignment, the 
site PI will request the urgent unblinding of a participant’s treatment through use of the eCRF 
unblinding module, followed by immediate notification of the unblinding to the sponsor. 
 
The sponsor must be notified within 24 hours of any clinically required break of the study 
blind. The notification of the unblinding to the sponsor must include the participant 
identification number, the date, a brief justification of the clinical requirement for unblinding, 
and the site PI’s signature. The notification of the unblinding will be kept in the study file. 
 
It is recommended that the site PI consults with the sponsor’s medically responsible person 
prior to unblinding of a participant. However, in urgent circumstances, the study site can 
proceed with the unblinding of a participant at the site PI’s discretion, without prior 
consultation with the sponsor’s medically responsible person. 
 
3.5 
Investigational Product Administration 
On Study Day 0, the participants must receive their first dose of investigational product as 
soon as possible after randomization. At the time of vaccination on Study Day 0, participants 
C (axillary temperature), evidence of acute illness or take 
antipyretics; in such cases, randomization and vaccination will be deferred until the fever or 
acute illness has subsided. 
 
If randomization and vaccination cannot be done on the same day, the participant must come 
back as soon as possible for a subsequent visit for randomization and vaccination. If 
randomization and vaccination do not occur on the same day, then the day of vaccination will 
be considered Study Day 0.  
 
On Study Day 56, randomized participants who have not met any of the criteria for 
discontinuation of investigational product administration (see Section 6.1), and do not have a 
C (axillary temperature), evidence of a new acute illness or take antipyretics, will 
receive a second dose of investigational product. In case of fever or acute illness, the second 
dose of investigational product should be deferred until the fever or acute illness has 
subsided. The allowed window period for deferral of the second dose is a maximum of 10 
days. 
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The study vaccine manager will send the investigational product to the study site as a unit-
dose syringe, which will be identified with a participant identification number, date 
dispensed, and time taken from fridge/shelf, and the volume prepared. The syringe will 
contain 0.5 mL of investigational vaccine or placebo. An investigator must be present at the 
study site at the time of all investigational product administrations. 
 
Before administering the injection, the blinded study team member at the study site who will 
be administering the injection must inspect the syringe and investigational product volume, 
check that the syringe is identified with the correct patient identification number and verify 
the date dispensed and time  taken from fridge / shelf. A vaccine placed outside the 
refrigerator can only be stored at room temperature (maximum 25 °C) for a maximum of 2 
hours. 
 
The investigational product will be administered by intramuscular injection into the deltoid 
area using standard aseptic technique and alternating arms for each vaccination. 
Administration of the investigational product must be documented (including date, time and 
which arm was injected) in the participant’s study records by the blinded study team member 
who administered the investigational product. 
 
3.6 
Study Evaluations 
3.6.1 
Efficacy Evaluations 
After randomization and vaccination on Study Day 0, the participants will be questioned 
about TB signs and symptoms at every study visit and contact, and will be instructed to come 
to the study site if TB signs or symptoms occur between study visits or contacts. 
 
When there is clinical suspicion of TB disease, 2 separate sputum samples for Mtb testing 
will be obtained. 1 sputum sample will be tested by Xpert MTB/RIF Ultra. The same sputum 
sample will be sent for culture together with the second sputum sample for verification. The 
remainder of the 2 separate sputum samples is stored (frozen) as 2 separate samples for later 
analysis by WGS if recurrent TB is verified. 
 
Referral for diagnosis and management of recurrent TB is triggered by the investigator based 
on clinical suspicion of recurrent TB. Participants will not be withdrawn from the study based 
on this referral but will be withdrawn if Mtb positive by culture in the study or if the referral 
clinic diagnoses recurrent TB and starts TB treatment. 
 
In cases where the Mtb culture result in the study was negative or is pending, but the referral 
clinic diagnosed recurrent TB and started TB treatment, 2 additional sputum samples should 
be collected as soon as possible for repeat Mtb testing by culture, and the participant is 
withdrawn from the study. 
 
If Mtb negative by Xpert MTB/RIF Ultra and subsequent verification by culture, the 
participant continues in the study. For further details on the case verification procedure for 
recurrent TB disease, see Section 2.2. 
 
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At the final study visit (V8=Day 421) or at the ET Visit, if discontinuation is not due to 
verified recurrent TB, 2 separate sputum samples for Mtb testing will be obtained from all 
participants (capable of producing sputum), even if there is no clinical suspicion of TB 
disease, in order to ensure that no cases of recurrent TB disease are missed during the study 
and to detect subclinical cases in this population at high risk for recurrence of TB disease. If 
there is clinical suspicion of TB at V8, all V8 activities will be conducted and not a STB visit 
since at V8 two separate sputum samples for Mtb testing will be obtained from all 
participants even if there is no clinical suspicion of TB. This is to ensure that no cases of 
recurrent TB disease are missed during the trial. One sputum sample will be tested by Xpert 
MTB/RIF ultra. If Mtb negative by Xpert MTB/RIF ultra but there are clinical TB signs or 
symptoms, verification by culture testing will be requested from the laboratory and both of 
the sputum samples will then be processed for culture. In this instance HIV testing and 
immunology sample collection should also be performed at V8. 
 
Participants will be contacted to be given their Xpert MTB/RIF Ultra and culture result once 
available (whether positive or negative) and symptomatic participants will be referred as 
appropriate for management irrespective of the Xpert MTB/RIF Ultra and culture result. 
Asymptomatic participants not capable of producing sputum will be considered negative for 
TB disease recurrence. 
 
Confirmation of Mtb by one positive sputum culture result is required for a participant to 
meet the primary efficacy endpoint of TB disease recurrence. For the secondary efficacy 
endpoints of TB disease relapse and TB disease reinfection, WGS will be performed on Mtb 
isolates to distinguish relapse from reinfection. Participants with a combined V1 and V2 will 
not provide sputum samples prior to starting TB treatment because their 1st screening visit 
(V1) would be performed on the same day as V2. For these participants, it will therefore not 
be possible to determine if their TB recurrence was due to relapse or reinfection. 
 
For the exploratory efficacy endpoints, participants who started TB treatment without 
confirmation of Mtb by culture or participants with TB disease recurrence between 30 days 
after the 1st vaccination and 14 days after the 2nd vaccination will also be included. All 
efficacy endpoint definitions are given in Section 2.1. 
 
The HIV status (i.e., to assess if seroconversion occurred since HIV test at V2) will be 
determined at time of diagnosis of TB disease recurrence, and the CD4 count will be 
determined if the participant is HIV positive. 
 
A participant is considered to have clinical suspicion of TB when he/she presents with one or 
more of the following TB signs and symptoms: unexplained cough for longer than 2 weeks 
duration, fever, night sweats, loss of weight, hemoptysis, or other TB signs or symptoms. 
 
3.6.2 
Immunogenicity and Immunology Laboratory Evaluations 
A summary of immunogenicity and immunology assays to be performed on blood specimens 
is shown in Table 3-2.  
 
For the immunogenicity cohort at the 
 sites only (= first 50 
randomized participants at 
and first 50 randomized participants at 
 = in total 
=-
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 Systemic adverse events 
Fever, Arthralgia, Myalgia, Fatigue, Headache, Rash, Chills, Nausea 
Solicited injection site reactions will be considered causally related to the investigational 
product. 
 
Adverse events of special interest represent a subset of AEs that include autoimmune diseases 
and other systemic disorders of interest that could potentially have an immune etiology. AEs 
of special interest are listed in Appendix A. The PI should use clinical and scientific 
judgment in deciding whether other AEs (i.e., events not listed in Appendix A) could have an 
autoimmune origin. The investigator will report AEs of special interest in the eCRF, hereby 
informing the sponsor’s medically responsible persons. 
 
All participants will be provided a diary card, a thermometer to record axillary temperature, a 
ruler to measure injection site redness and swelling, and instructions on how to use the diary 
for AE and CM recording, for the first 7 days after each vaccination. 
 
In the period from 8 days after the vaccinations and until the diary card review at 14 days 
after each vaccination the participants are instructed to fill in the diary only in case they 
experience an AE or CM intake. 
 
3.6.3.4 Site of Injection Examination 
The injection sites will be examined immediately after the vaccinations, see section 3.6.3.1. 
After this, examinations for injection site reactions and loco-regional reactions such as 
axillary lymphadenopathy will be performed at the visits V4= Day 14 and V6= Day 70, see 
Table 3.1. The following will be assessed at these examinations: 
 
 Redness, swelling, tenderness/pain and axillary lymphadenopathy 
 
3.6.3.5 Concomitant Medications 
The collection of information on CMs used by participants following vaccination will 
coincide with the collection period of AEs. In addition, information on all CMs associated 
with the treatment of AEs, SAEs and AEs of special interest, will be collected throughout the 
study. 
 
CM includes prescription and non-prescription drugs or other treatments, and any vaccines 
other than the investigational product. The name of the medication, treatment start and stop 
dates (or ‘ongoing’), and indication must be recorded on the CM page in the electronic case 
report form (eCRF). The indication recorded on the CM eCRF page must correspond to a 
medical term/diagnosis recorded on the AE eCRF page, or to a pre-existing condition noted 
in the participant’s medical history, or be noted as prophylaxis. 
 
3.6.4 
Participant Follow-up and Contact 
All participants who are assigned a randomization number and receive the first vaccination 
will be followed according to the protocol unless consent is withdrawn.  
 
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The participants will be instructed to contact a study team member to report new signs and 
symptoms or new or worsened AEs and will be referred for medical attention as applicable. 
For emergencies and other unscheduled visits to a medical facility other than the study site, 
medical records will, to the extent possible, be obtained by the investigator. 
 
During each scheduled study visit or contact, the participants will be reminded to notify a 
study team member of the following: 
 
 
The occurrence of AEs and SAEs during the respective reporting periods. 
 
Receipt of any CMs during the applicable reporting period. 
 
Plans to move or if contact information changes.  
 
If participant has decided to withdraw from the study. 
 
Change in general health status including TB symptoms screen. 
 
Any other change in status that may affect the participant’s participation (e.g., pregnancy, 
plan to participate in another investigational study). 
 
Participant-level deviations from protocol procedures, evaluations, and/or visits must be 
documented. When possible, missed visits and procedures must be rescheduled and 
performed at the nearest possible time point to the original schedule. Deviations will be 
reported to the IRB/IEC and applicable national regulatory authorities per their guidelines. 
 
3.6.5 
Lost to Follow-up 
If the study site’s study team members are unable to establish contact with a participant who 
misses a scheduled study visit, the study site must make every possible effort to re-establish 
contact and document such efforts. If contact is re-established, then the participant will 
resume participation in the study. If contact with the participant cannot be re-established by 
the participant’s calculated V8= Day 421 visit date, then a determination of “lost to follow-
up” should be made on the date of the last contact. 
4 
INVESTIGATIONAL PRODUCT 
4.1 
Description of Investigational Product 
The administered volume is 0.5 mL for all doses of investigational product. Please refer to 
the most recent version of the Vaccine Management Manual and IB, for further details 
regarding the investigational product. 
 
H56:IC31 
The H56:IC31 vaccine is manufactured, filled into vials and labelled at SSI according to 
GMP. The inner labels are study specific while the labels for the outer packaging (i.e. the 
cardboard boxes) are study and site specific. Both are produced at SSI. H56:IC31 will be 
supplied in single dose vials by SSI at a concentration of 5 µg/0.5 mL with IC31 at a 
concentration of 500 nmol KLK and 20 nmol ODN1a/0.5 mL. 
 
Placebo: 
A 0.9 % saline placebo will be purchased commercially and used as a comparator in the 
study. A label should be placed on the external carton stating the protocol number and that 
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the saline is for clinical use only. 
 
4.2 
Receipt, Storage and Accountability 
Upon receipt of investigational product, the study vaccine manager must immediately inspect 
all vials for damage. Investigational product will be shipped with a continuous temperature-
monitoring device. Any damage or discrepancies from the packing list must be documented 
and promptly discussed with the sponsor and the study monitor to determine the appropriate 
action.  
 
H56:IC3 must be stored between +2°C and +8°C in a secured location with no access for 
unauthorized and blinded personnel. The normal saline placebo will be stored according to 
manufacturer’s requirements in the study pharmacy. 
 
Refer to the most recent version of the Vaccine Management Manual for detailed instructions 
regarding investigational product storage. 
 
It is the site PI’s responsibility that all unused and used vials are accounted for during the 
study and documented in the relevant study documents/logs. The study vaccine manager is 
delegated to maintain accurate investigational product accountability records. Instructions 
and forms to be completed and kept for accountability will be provided by the sponsor to the 
study vaccine manager. Upon completion of the study, all investigational product 
management records will be copied and the copies returned to the sponsor. The originals 
must be maintained at the study site with the rest of the study records. During the study an 
unblinded monitor will check that drug accountability is maintained. 
 
4.3 
Preparation 
Refer to the most recent version of the Vaccine Management Manual for detailed 
instructions. 
 
4.4 
Disposal of Unused Investigational Product 
After completion of the study the destruction of all used and unused vials is to be performed 
according to local regulatory and sponsor requirements. The destruction of investigational 
product may not be performed before the sponsor’s acceptance has been given in written 
form. Any disposal of investigational product conducted at the clinical study site must be 
documented in the site study file. 
 
5 
SAFETY 
5.1 
Responsibilities for Ensuring the Safety of the Study Participants 
The national regulatory authority, IRB/IEC, the study sponsor, the institution through which 
the research is performed and all members of the site PI’s clinical team share the 
responsibility for ensuring that participants in this study are exposed to the least possible risk 
of adverse events that may result from participation in the study. 
 
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5.1.1 
Principal Investigator 
The site PI from each study site has a personal responsibility to closely monitor participants 
and an inherent authority to take whatever measures necessary to ensure the safety of the 
participants. The site PI has the authority to terminate, suspend or require changes to a 
clinical study for safety concerns and may delay an individual’s investigational product 
administration. The site PI is responsible for determination of intensity, seriousness and 
causality with respect to the investigational product for each adverse event.  
 
The site PI may delegate specific tasks to a designee who is a medically qualified team 
member (who must be a sub-investigator in the case of assessment of adverse events). 
 
5.1.2 
Study Sponsor 
For this study SSI and IAVI are sharing sponsor responsibilities as co-sponsors. The sponsor 
has an institutional responsibility to ensure the safety of all participants in the study.  
 
5.1.3 
Medically Responsible Person 
The medically responsible person in the study is a physician from the sponsor. The medically 
responsible person will review the safety of the product during the study and will assess the 
causality of the reported SAEs and provide the expectedness of related SAEs. The medically 
responsible person is like the site PI, blinded in this study. 
 
Each co-sponsor has a medically responsible person who contributes to performing these 
tasks. 
 
The site PI can, in case of an emergency, unblind a participant’s treatment through a 
restricted access module in the eCRF (see Section 3.4.1). 
 
5.1.4 
Internal Data Review Committee and Independent Data Safety 
Monitoring Board 
An internal data review committee, consisting of the coordinating PI, the site PIs and the 
medically responsible person from each of the co-sponsors, will convene during the study to 
review the blinded reported SAEs, AEs including AEs of special interest, injection site 
reactions and laboratory safety test results to identify any possible safety issues when: 
 
 The first 150 participants across all sites have received their 1st vaccination and the 14 
days safety follow-up data is available 
 The first 150 participants across all sites have received their 2nd vaccination and the 
14 days safety follow-up data is available 
 
Randomization and vaccination will continue unless a stopping rule is triggered. 
 
In case a stopping rule is triggered at any time by the site PIs and/or sponsor’s medically 
responsible person, the study will be paused. Please see Section 6 for further details. 
 
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An independent DSMB will be established, consisting of a panel of independent experts, who 
will operate according to a DSMB charter. The DSMB will be convened if: 
 
 A stopping rule is triggered 
 The internal data review committee requests a DSMB meeting based on their review 
of the safety data 
 
Based on the DSMB review, the DSMB will make recommendations to the sponsor regarding 
further conduct of the study and further administration of the investigational product.  
 
The DSMB may require unblinding of any amount of safety information needed to conduct 
their assessment. All procedures associated with their review, including objectives, data 
handling, and elements to be included for review will be documented in the DSMB minutes.  
 
The DSMB may recommend suspension or resumption of enrollment and investigational 
product administration after review of the safety data. However, the sponsor will make the 
final decision to suspend or resume study activities. The recommendations of the DSMB, 
along with the sponsor’s decision, will be communicated to the site PIs, IRB/IEC, and the 
national regulatory authorities. The sponsor agrees to abide by any directives issued by the 
national regulatory authorities or the IRB/IEC. 
 
5.1.5 
Institutional Review Boards and Independent Ethics Committees 
The IRB/IEC has institutional responsibility for the rights, safety, and welfare of participants 
in clinical studies. The IRB/IEC has the authority to terminate, suspend or require changes to 
a clinical study. 
 
5.1.6 
National Regulatory Authority 
Each national regulatory authority receives all SUSARs and periodic safety reports 
summarizing the SAEs in the study and has the authority to terminate, suspend or require 
changes to the clinical study. 
  
5.2 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a product 
in humans, whether or not considered product related, if deemed clinically significant by the 
investigator. An AE can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product, and 
does not imply any judgment about causality. An AE can arise with any use of the product 
(e.g., off-label use, use in combination with another product) and with any route of 
administration, formulation, or dose, including an overdose. 
 
Medical conditions that exist prior to administration of the investigational product (pre-
existing conditions) will be recorded in the eCRF on the participant’s medical history page to 
establish baseline. Day-to-day fluctuations in pre-existing conditions that do not represent a 
clinically significant change in the participant’s status will not necessarily be reported as 
AEs. 
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Any adverse change from the participant’s baseline condition (determined from screening 
evaluations conducted to confirm study eligibility) that occurs following the administration of 
the investigational product will be considered an AE. This includes the occurrence of a new 
AE or the worsening of a baseline condition, whether or not considered related to the 
investigational product. Intermittent conditions such as headaches may be present on Study 
Day 0 but may represent an AE if the intensity or duration of the event is worse than usual 
following receipt of the investigational product. AEs include but are not limited to: adverse 
changes in the general condition of the participant, signs and symptoms noted by the 
participant, concomitant disease with onset or increased intensity after investigational product 
administration, and changes in laboratory and vital sign safety parameters considered 
clinically significant by the investigator occurring after investigational product 
administration. 
 
AEs will be reported using a recognized medical term or diagnosis that accurately reflects the 
event. AE evaluations will be reviewed by the site PI or sub-investigator. AE information is 
to be completed by members of the study team designated by the site PI. The onset and 
resolution dates of the event and action taken in response to the event will be documented. 
 
5.3 
Assessing Intensity of an Adverse Event 
The safety concepts of “intensity” and “seriousness” are distinct concepts (see Section 5.7). 
Intensity refers to a degree of clinical manifestation. “Seriousness” refers to defined 
outcomes of an AE. A severe AE is not always serious and a serious AE is not always severe.  
 
For all AEs, the investigator is responsible for assessing the intensity of the event, the 
seriousness and the causal relationship of the event to the investigational product. 
 
The intensity of all AEs, will be classified as one of the following grades: 
 
1. Mild 
2. Moderate  
3. Severe 
 
 
“Mild” events are generally regarded as noticeable but have no impact on normal 
activities; they may or may not require over-the-counter treatment managed by the 
participant. 
 
“Moderate” events generally have some impact on an individual’s normal activities and 
may require general symptomatic medical intervention by a healthcare professional or by 
the participant. 
 
“Severe” adverse events may be incapacitating, leading to suspension of normal daily 
activities, and would generally require more immediate medical evaluation and 
intervention by a healthcare professional. 
 
A change in intensity of an AE will not be recorded as a new AE. Only the highest intensity 
level that occurs during the entire period of the AE will be recorded in the eCRF with the 
onset and resolution dates encompassing the entire duration of the event.  
 
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5.4 
Assessing Causal Relationship “Relatedness” of an Adverse Event 
For all AEs, the investigator and, for SAEs, also the sponsor’s medically responsible person 
will determine if there is a causal relationship to the investigational product without 
knowledge of whether active vaccine or placebo was administered. A number of factors will 
be considered in making this assessment, including: 1) the temporal relationship of the event 
to the administration of the investigational product 2) whether an alternative etiology has 
been identified and 3) biological plausibility. Causality of all AEs should be assessed by the 
investigator using the following question: 
 
“Is there a reasonable possibility that the AE may have been caused by the investigational 
product?” 
 
• 
YES (related): There is a reasonable possibility that the investigational product 
contributed to the AE. This includes AEs that are considered possibly, probably or 
certainly related. 
• 
NO (not related): There is no reasonable possibility that the AE is causally related to the 
administration of the investigational product. There are other, more likely causes and 
administration of the investigational product is not suspected to have contributed to the 
AE. 
 
The site PI and sponsor’s medically responsible person will both determine the causality of a 
SAE and it is expected that communication and consultation may occur in this assessment. 
 
Every effort should be made by the investigator to determine the existence of any pre-existing 
conditions (e.g., headaches on Study Day 0 with onset prior to study vaccination) which must 
be taken into consideration when assessing the causal relationship of an AE. Pre-existing 
conditions should be recorded in the eCRF as baseline history and substantiated by 
appropriate source documentation. Intermittent conditions such as headaches may not be 
present on Study Day 0 but may represent an AE if the intensity or duration of the event is 
worse than usual following administration of the investigational product. 
 
5.5 
Definition of Adverse Reaction 
An adverse reaction is an AE assessed to be related to the investigational product. 
 
5.6 
Assessing "Outcome" of an Adverse Event 
The outcome of an AE must be assessed by the investigator using the following terms: 
 Fatal 
 Not yet recovered 
 Recovered with sequelae 
 Recovered without sequelae 
 Unknown 
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5.7 
Assessing "Seriousness" of an Adverse Event 
The “seriousness” of an AE must be assessed by the investigator by answering the following 
questions: 
 
 
Did the event result in death (i.e., the AE caused or led to the fatality)? Serious does not 
describe an event which hypothetically might have caused death if it were more severe. 
 
Has the event been or is the event life-threatening (i.e., the AE placed the participant at 
immediate risk of dying. It does not refer to an event which hypothetically may have led 
to death if it were more severe).  
 
Has the event required hospitalization or prolonged hospitalization beyond the expected 
length of stay? Hospitalizations for scheduled treatments and elective medical/surgical 
procedures related to a pre-existing condition that did not increase in intensity or 
frequency following receipt of investigational product, are not serious by this criterion. 
 
Has the event resulted in significant or persistent disability/incapacity (i.e., substantial 
reduction of the participant’s ability to carry out activities of daily living)? 
 
Has the event resulted in a congenital anomaly or birth defect (i.e., an adverse finding 
in a child or fetus of a participant exposed to the investigational product prior to 
conception or during pregnancy)? 
 
Was the event another medically important condition that may not have resulted in 
death, threatened life or required hospitalization but may have jeopardized the participant 
or required intervention to prevent one of the serious outcomes listed in these criteria? 
Based on medical and scientific judgment such events may also be considered serious. 
Example: allergic bronchospasm requiring intensive treatment in an emergency room or 
at home; blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. 
 
A serious adverse event is an AE meeting the criteria for “seriousness” regardless of 
relationship to the administered product. 
 
A serious adverse reaction is meeting the criteria for “seriousness” and was assessed to be 
related to the investigational product. 
 
5.8 
Assessing “Expectedness” of Serious Adverse Reactions 
The expectedness of related SAEs i.e. serious adverse reactions, is assessed by the sponsor’s 
medically responsible person only. The expectedness is assessed against the IB. If the 
outcome of the assessment is that the reaction is unexpected, then the reaction may represent 
a suspected, unexpected, serious adverse reaction (SUSAR) and the blind should be broken 
for this specific participant by the 
 through the restricted 
access module in the eCRF. 
 
Only, if the participant has received the investigational product (NOT placebo) AND the 
related SAE (i.e. serious adverse reaction) is unexpected (i.e. unlisted in the IB), the case 
represents a SUSAR. 
 
Expected related SAEs (i.e. serious adverse reactions) are consistent with the IB for the 
investigational product. 
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5.9 
Definition of Suspected Unexpected Serious Adverse Reaction 
(SUSAR) 
When an AE is judged to be related to an investigational product, and judged to be serious 
and unexpected in a participant who received the active vaccine, it is a SUSAR and is subject 
to expedited reporting. 
 
5.10 
Reporting of Serious Adverse Events 
All SAEs are reported by the clinical study site through the eCRF to the sponsor’s medically 
responsible person and to the 
 for the entire study period. The 
clinical study site will be provided with the specific reporting procedures before study start. 
 
All AEs will be assessed for seriousness, intensity and causal relationship to the 
investigational product by the investigator. If serious (SAEs), the sponsor’s medically 
responsible person will give a second assessment on causal relationship. Both assessments 
will be documented, but the highest degree of causal relationship will determine the ultimate 
classification of the event as related or unrelated SAE. 
 
For related SAEs i.e. serious adverse reactions, the sponsor’s medically responsible person 
will subsequently assess the expectedness and, if unexpected, report to the 
 
 within one business day.  
 
The SAE form for the event must be completed by the investigator within one business day of 
the clinical study site becoming aware of the event. Investigators must not wait to collect 
additional information to fully document the SAE before notifying the sponsor’s medically 
responsible person and the 
 
 
Fatal or life-threatening SAEs that the investigator suspects are related to the investigational 
product should be telephoned to sponsor’s medically responsible person immediately upon 
the investigator’s awareness of the event. If the investigator or sponsors medically 
responsible person is required by the protocol or chooses to suspend enrollment s/he shall 
immediately create a written memorandum for record to the study file.  
 
Fatal or life-threatening SAEs or SUSARs that occur in Tanzania must be telephoned, faxed 
or e-mailed to TFDA by the investigator within 24 hours of awareness. 
 
Please refer to below flowchart for the reporting of SAEs: 
 
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5.12 
Adverse Event Treatment and Follow-up 
Treatment of any AEs will be determined by the investigator using his/her best medical 
judgment and according to current clinical practice guidelines. All applied measures and 
follow-up will be recorded in the appropriate eCRF.  
 
The investigator will continue follow-up on AEs, including laboratory abnormalities until the 
event has resolved. AEs will be considered resolved when the condition returns to normal or 
returns to the participant’s baseline status as established on Study Day 0, or when the 
condition has stabilized with the expectation that it will remain chronic.  
The resolution date will be recorded in the eCRF as the last date on which the participant 
experienced the AE. If an AE resolution date is uncertain the investigator should estimate the 
completion date based on medical judgment and interview of the participant. Approximate 
dates of resolution from interviews may be taken as AE resolution dates. 
 
AEs that are still present at the end of the study (last visit) should be recorded as ongoing in 
the eCRF. Information recorded in the eCRF must be substantiated in the source documents 
and followed up until resolution or stabilization. If an AE evolves into a condition that 
becomes “serious,” it will be designated as serious on the AE form in the eCRF and a 
supplemental SAE form will be completed as specified in Section 5.10. 
  
Follow-up on SAEs must continue until resolution or stabilized, even if this extends beyond 
the SAE reporting period (i.e., after the final study visit). For analysis purposes, the outcome 
for SAEs will be determined on the final study visit. 
 
If at any time after completion of the SAE reporting period (the final study visit) the 
investigator becomes aware of a SAE that is suspected by the investigator to be related to the 
investigational product, the event must be reported to sponsor. 
 
5.13 
Participant Diary  
Day 0-7 after each study vaccination: 
All participants will be asked to fill in a diary daily for 7 days after each vaccination. In the 
diary the participants are asked to measure and report on the day of vaccination and the 
following 7 days details of the following AEs: 
 
 Solicited: 
- Injection site reactions (Redness, Swelling, Tenderness/Pain) 
- Systemic AEs (Fever, Arthralgia, Myalgia, Fatigue, Headache, Rash, Chills, 
Nausea)  
 
 Any other symptoms 
 
Solicited injection site reactions will be considered causally related to the investigational 
product. 
 
All participants will receive and be instructed in completing the diary. A ruler (for 
measurement of injection site reactions) and a thermometer (for axillary use) to be used 
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during the specified post-vaccination diary period after each study vaccination will be 
provided. The diary is a tool to aid the investigator to engage in a conversation with the 
participant about any AEs and/or CM intake that may have occurred between visits.  
 
If a diary is lost, the investigator will discuss the occurrence of any AEs and/or CM with the 
participant and document the discussion. The diary will be considered source documentation 
and information assessed to be an AE by the investigator will be recorded in the eCRF. 
Source should document the clinical significance assessment.  
 
Any change to an observation or event recorded by the participant in the diary based on the 
investigator’s evaluation of the event, must be explained by notation in source documentation 
by the investigator. 
 
Day 8-14 after each study vaccination: 
From day 8-14 after each study vaccination the participants are instructed to fill in the diary 
only in case they experience an adverse event(s) (or concomitant medication intake). The 
participant will on day 14 after each vaccination be interviewed by the investigator, if any 
signs or symptoms have been observed by the participant.  
 
5.14 
Follow-up of Participants Who Become Pregnant  
If a participant becomes pregnant during the study, she will not receive any further doses of 
investigational product, but she should be encouraged to continue in the study for safety, 
efficacy and immunogenicity follow-up. Follow-up should continue for pregnancy outcome 
including premature terminations, and data are to be included in the safety reports.  
 
A pregnancy eCRF page must be completed by the investigator, within one business day of 
the clinical study site becoming aware of the event. Following entry into the eCRF, sponsor’s 
medically responsible person and the 
 must be notified of the 
pregnancy. At a minimum, the estimated date of conception, the estimated due date, and the 
date the participant received the investigational product should be provided. The clinical 
study site will be provided with specific reporting procedures before study start. 
 
The health status of the mother and child, the date of delivery, and the child’s sex, birth 
weight and multiparity should be reported by completing the applicable pregnancy eCRF 
page. If delivery occurs before the final study visit, the participant should continue to be 
followed for SAEs through the final study visit unless withdrawal of consent has occurred. If 
delivery occurs after the final study visit, the investigator should attempt to maintain contact 
with the participant to obtain information after delivery. The outcome will also be reported to 
the sponsor’s medically responsible person and to the 
. 
 
Pregnancy will not be recorded as an AE. However, pregnancy outcomes will be recorded in 
the 
. If the pregnancy results in a miscarriage or a planned 
termination, the event (spontaneous abortion or elective abortion) will be reported as an AE 
or serious AE per the investigator's judgment (e.g., if it was a medically important or life-
threatening event that meets the definition of a SAE). 
 
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A congenital anomaly or birth defect (i.e., an adverse finding in a child or fetus of a 
participant exposed to the investigational product before conception or during pregnancy) 
must be reported as a SAE. 
 
If it is determined after completion of the study that a participant became pregnant during the 
study, the participant should notify the investigator. The pregnancy must be reported to 
sponsor’s medically responsible person and to the 
 
 
6 
PAUSING AND STOPPING RULES 
These rules govern the pausing and stopping of investigational product administration at any 
time during the study. 
 
6.1 
Rules for Discontinuing Investigational Product in an Individual 
Participant 
Administration of additional investigational product will be discontinued for an individual 
participant if he/she has any of the following: 
 
1. An objective clinical or laboratory parameter change which by the investigator is assessed 
as severe in intensity AND is judged to be related to the investigational product. 
2. AE thought to be an allergic reaction to the investigational product, including anaphylaxis 
or bronchospasm. 
3. Any extensive rash (>40% body surface) on the thorax, abdomen, or limbs, including but 
not limited to urticaria, generalized petechiae, or erythema multiforme judged to be 
related to the investigational product. 
4. Development of active TB. 
5. Development of severe disease, immunodeficiency, autoimmune disease, 
immunosuppression or reported HIV seroconversion. 
6. Receipt of investigational drug therapy or investigational vaccine (other than 
investigational product received as part of this study) between 1st and 2nd vaccination or 
any other vaccine as described in Exclusion Criteria #12. 
7. Any event that in the opinion of the site PI precludes administration of any further 
investigational product. 
8. Pregnancy. 
 
Participants who are withdrawn from the study within 6 months after the last product 
administration, will be contacted at least 6 months after the last product administration for 
recording of SAEs and AEs of special interest. 
 
6.2 
Rules for Pausing the Study 
The following rules will trigger pausing by the sponsor’s medically responsible person for 
enrollment, and investigational product administration: 
 
1. One or more SUSARs occur. 
 
OR 
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2. Anaphylaxis or bronchospasm within 4 hours of injection, indicative of an immediate 
hypersensitivity reaction to the study injection. 
 
OR 
 
3. An AE pattern of concern occur in a group of participants or for an individual. 
 
If the study is paused, the decision will be recorded in a memorandum to the study file and 
will trigger a DSMB review. If a recommendation to resume study enrollment and 
investigational product administration is made, the DSMB will record their judgment in a 
memorandum to the study file and notify the sponsor. The DSMB memorandum will be 
forwarded to the sponsor’s medically responsible person and site PIs. The DSMB may 
recommend resumption of enrollment with changes to the protocol if it judges that such 
changes will reduce safety risks. However, the final decision to resume study activities, 
amend the protocol, or terminate the study will be made by sponsor.  
 
The clinical study site will be allowed to resume activities only upon receipt of written 
notification from sponsor. Decisions regarding pausing and resumption of the study will be 
communicated to the IRB/IEC by the site PI and to the applicable national regulatory 
authorities by the sponsor. 
 
In addition, the study may be discontinued at any time by the applicable national regulatory 
authorities, the IRBs/IECs, sponsor or other governmental agencies as part of their duties to 
ensure that research participants are protected. 
 
7 
STATISTICAL CONSIDERATIONS 
The planned statistical analyses for this study are outlined below. A detailed statistical 
analysis plan will be created and finalized prior to database lock. 
 
7.1 
Analysis Sets 
The safety analysis set will consist of all participants who received at least one dose of 
investigational product. The primary analysis set for efficacy (modified intent-to-treat [mITT] 
analysis set) will include all randomized participants except those with TB disease recurrence 
before V6=Day 70 (or 14 days after dose 2 for those who received both vaccinations). The 
second mITT [mITT2] analysis set will include all randomized participants except those with 
TB disease recurrence prior to 30 days post 1st dose. The per-protocol [PP] analysis set will 
consist of all participants who received both doses of H56:IC31 or placebo within the 
specified dose intervals, who entered the evaluation period for efficacy 14 days after receipt 
of the second dose of H56:IC31 or placebo with no HIV seroconversion, and who had no 
major protocol deviations (to be defined in the statistical analysis plan). 
The immunogenicity analysis set will consist of participants from the mITT population who 
received both doses of H56:IC31 or placebo and who are included in the immunogenicity 
cohort (refer to Section 2.2). The ITT analysis set will consist of all randomized participants. 
 
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7.2 
Demographics and Protocol Compliance 
Demographic parameters (age, sex, and race/ethnicity) and other baseline characteristics will 
be summarized by treatment group for all participants in the safety analysis set, and may be 
summarized for participants in the mITT and PP analysis sets depending upon the numbers of 
participants in these analysis sets. 
 
Listings of randomized participants who missed any dose of investigational product and of 
participants with protocol deviations will be provided. 
 
7.3 
Efficacy Analyses 
7.3.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint in this study will be the detection of TB disease recurrence at 
any time greater than or equal to 14 days after receipt of the second dose of H56:IC31 or 
placebo through Study Day 421 (i.e. Study Day 70 through Study Day 421) (mITT analysis): 
 
 Rate of TB disease recurrence (relapse or reinfection), defined as TB diagnosed by 
confirmation of Mtb by culture of sputum, during the period starting 14 days after the 
2nd vaccination (V6= Day 70) and ending 12 months after the 2nd vaccination  
(V8= Day 421) 
 
The number (percentage) of participants meeting this endpoint will be summarized by 
treatment group and study site/country. The primary analysis set for efficacy will be the 
mITT analysis set (defined in Section 7.1). 
 
Summaries of median time to initial diagnosis of TB disease recurrence, person-time at risk, 
and associated 95% confidence intervals will be presented by treatment group and study site, 
for participants in the mITT analysis set. The log-rank statistic will be used to test the null 
hypothesis of no difference in the rates of TB Disease Recurrence over the follow-up period 
in the H56:IC31 compared to the placebo group. Additional analyses of the primary efficacy 
endpoint will include a Cox proportional hazards regression model to examine additional 
covariates such as study site, body mass index, age, and smoking. 
 
The cumulative person-years incidence of TB disease recurrence and associated 95% 
confidence intervals during study follow-up will be summarized by treatment group and 
study site. Person-time observation will be used to estimate the time at risk of TB disease 
recurrence and will be calculated based on participant’s date of last contact with the study or 
date of TB disease recurrence (whichever is earlier) minus the date at 14 days after receipt of 
the second dose of H56:IC31 or placebo. The incidence of TB disease recurrence will be 
calculated as the number of cases of TB disease recurrence diagnosed during study follow-up, 
divided by the total person-time of observation.  
Comparison of the incidence of TB disease recurrence in each treatment group will be 
performed using relative risk summaries and corresponding 95% confidence intervals, as 
appropriate. 
 
Supportive robustness and consistency analysis will be performed using the PP and ITT 
populations (defined in Section 7.1). 
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7.3.2 
Analyses of Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed using the same methods as 
described for the primary efficacy endpoint of TB disease recurrence (see Section 6.3.1).  
 
Methods for comparison of WGS of paired Mtb isolates in participants with TB disease 
recurrence will be described in the statistical analysis plan. 
 
 Rate of TB disease relapse, defined as participants meeting the primary endpoint of 
TB disease recurrence, AND determined by WGS of the Mtb isolate to be the same 
strain of Mtb as in the participant’s original isolate from the time of diagnosis 
 
 Rate of TB disease reinfection, defined as participants meeting the primary endpoint 
of TB disease recurrence, AND determined by WGS of the Mtb isolate to be a 
different strain than in the participant’s original isolate from the time of diagnosis 
 
.Analyses of Exploratory Efficacy Endpoints  
The following exploratory efficacy endpoints will be analyzed using the same methods as 
described for the primary efficacy endpoint of TB disease recurrence (see Section 7.3.1): 
 
 Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence AND participants who started TB 
treatment without confirmation of Mtb by culture of sputum 
 
 Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence based on confirmation of Mtb by Xpert 
MTB/RIF Ultra or culture of sputum 
 
 Rate of TB disease recurrence (relapse or reinfection), defined as participants meeting 
the primary endpoint of TB disease recurrence AND participants diagnosed between 
30 days after the 1st vaccination and 14 days after the 2nd vaccination, based on 
confirmation of Mtb by culture of sputum 
 
7.4 
Immunogenicity and Immunology Analyses 
Immunogenicity and immunology analysis will be summarized for all time points as collected 
and as available. The immunogenicity endpoint analysis will be based on participants in the 
immunogenicity analysis set (defined in Section 7.1). No imputation for missing data will be 
performed. Data will be transformed as appropriate prior to analysis. 
 
7.4.1 
Intracellular Cytokine Staining (WB ICS) Using Whole Blood 
This is a secondary endpoint in the study, see Section 2.1.3.1 and Table 3-2, and it is the 
primary immunogenicity endpoint. This endpoint will be measured in the immunogenicity 
cohort (see Table 2-1) at V3= Day 0 and V6= Day 70. 
 
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Responses will be measured by flow cytometry (up to 15 parameters) with the whole blood 
based ICS assay. The variables of interest for assessment of antigen-specific cell-medicated 
immune response to vaccination will be the percentage of CD4+ and CD8+ T cells that 
express selected cytokines and phenotypic markers alone or in combination in response to 
stimulation with peptide pools representing the entire amino acid sequence of the vaccine 
antigens. 
 
Frequencies of background (unstimulated control) subtracted cytokine responses will be 
expressed as medians and associated 95% confidence intervals or other descriptive statistics 
as appropriate will be used to summarize percentage T cell responses. Summaries of T cell 
responses will be presented by T cell type (CD4+ and CD8+) and by stimulation antigen. 
Summaries will include immune response at all available pre- and post-vaccination 
immunology time points, and change from pre-vaccination to post-vaccination time points. 
 
Analytic approaches for these endpoints will be informed by best practice and the most recent 
advances in vaccinology and systems biology. 
 
7.4.2 
Antigen-specific IgG ELISA Assay Using Plasma 
This is a secondary endpoint in the study, see Section 2.1.3.1 and Table 3-2, and is the 
secondary immunogenicity endpoint. This endpoint will be measured in the immunogenicity 
cohort (see Table 2-1) at V3= Day 0 and V6= Day 70. For remaining participants, it is an 
exploratory endpoint at V3= Day 0, V6= Day 70 or at suspicion of a diagnosis of recurrent 
TB at the time of evaluation of TB recurrence. Antigen-specific antibody will be assessed in 
plasma by enzyme linked immunosorbent assay (ELISA). Summaries will include immune 
response at all available pre- and post-vaccination immunology time points, and change from 
pre-vaccination to post-vaccination time points. 
 
7.4.3 
RNA Analysis and Blood Subset Counts Supporting RNA Analysis 
Using Whole Blood 
These are exploratory endpoints in the study, see Section 2.1.4.1 and Table 3-2. These 
endpoints will be measured in all participants at V3= Day 0 and in participants with suspicion 
of a diagnosis of recurrent TB at the time of evaluation of TB recurrence. Whole blood gene 
expression profiles will be measured by RNA sequencing and microfluidic qRT-PCR on 
PAXgene samples in a subset of participants: those who developed TB recurrence and a 
selected group of controls. 
 
Cellular composition of whole blood leukocytes will be characterized by flow cytometry in 
order to deconvolve transcriptomic patterns to account for changes in peripheral blood cell 
numbers. 
 
Transcriptomic signatures of inflammation and gene expression pathways as well as 
transcriptomic signatures associated with risk of TB recurrence and prediction of adaptive 
responses will also be investigated. 
 
The determination of absolute blood subset counts will support the RNA analysis. 
 
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Analytic approaches for these endpoints will be informed by best practice and the most recent 
advances in vaccinology and systems biology. 
 
7.4.4 
Intracellular Cytokine Staining (ICS) Using PBMCs 
This is an exploratory endpoint in the study, see Section 2.1.4.1 and Table 3-2. This endpoint 
will be measured in all participants at V3= Day 0 and V6= Day 70 and in participants with 
suspicion of a diagnosis of recurrent TB at the time of evaluation of TB recurrence. 
 
Analysis of cells stimulated with relevant antigens (ESAT-6, Ag85B, Rv2660c, as well as 
negative and positive controls) will include T, B and other lymphocyte lineages (such as NK 
and MAIT cells), expression of differentiation and activation markers as well as cell 
functions (such as cytokine production and cytotoxic potential). Responses will be measured 
by flow cytometry (up to 28 parameters) using a PBMC based ICS assay. 
 
7.4.5 
Exploratory Immunology at TB Recurrence - Control Samples 
The exploratory immunology samples to be taken at the time of evaluation of TB recurrence, 
from participants with a suspected diagnosis of recurrent TB disease will be: PBMC and 
plasma for ICS and IgG ELISA and whole blood for RNA analysis and Blood subset counts 
(that support the RNA analysis), see Table 3-2. 
 
For the analysis of these samples, “control samples” from a “control cohort” are needed. 
 
The immunology samples taken at V8= Day 421 from the participants in the immunogenicity 
cohort (excluding participants with recurrent TB, if any), see Table 2-1, will be these “control 
samples”. See Table 3.1. 
 
7.4.6 
Adverse Events 
The primary variable for evaluation of the safety profile will be the number and percentage of 
adverse events recorded after the first administration of vaccine on Study Day 0. The number 
of events and number (percentage) of participants with unsolicited adverse events and 
solicited adverse events will be summarized by MedDRA system organ class and preferred 
term. Additional summaries will present the number of events and number (percentage) of 
participants with adverse events by severity and by relationship to investigational product; 
Listings will be provided for participants with serious adverse events.  
 
7.4.7 
Injection Site Reactions 
The number (percentage) of participants recording injection site reactions (redness, swelling 
and tenderness/pain) and axillary lymphadenopathy will be summarized by treatment group 
and post-vaccination time point. In addition, measurements (recorded in mm) of redness and 
swelling will be summarized as continuous parameters by treatment group. 
 
7.4.8 
Clinical Laboratory and Vital Sign Parameters 
For each clinical laboratory and vital sign parameter pre-specified in the protocol, summary 
statistics for continuous parameters will be presented by treatment group for all pre- and post- 
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vaccination assessments and for change from pre-vaccination to post-vaccination 
assessments. 
 
The number (percentage) of participants with post-vaccination clinical laboratory values or 
vital sign values recorded as newly abnormal following study vaccination will be tabulated at 
each post-vaccination time point and overall. Clinical laboratory and vital sign abnormalities 
will also be reported as adverse events and included in the summaries of adverse events. 
 
7.5 
Sample Size Considerations 
The sample size for this study is based on the following assumptions: 
 
1. Estimated TB Disease Recurrence rate in placebo group: 4%/year. 
2. Follow-up period for each participant: 12 Months post Study Day 70.  
3. Drop-out/loss to follow-up rate: 10%. 
4. Vaccine Efficacy (VE): 60%. 
5. Type I error rate: 20% (2-sided). 
 
Based on the aforementioned assumptions, a sample size of 900 participants (N=450 in each 
treatment arm [1:1] per active versus placebo comparison) is expected to provide the 23 TB 
Disease Recurrence endpoints per active versus placebo comparison required to detect with 
80% power a VE of 60%, assuming a 10% drop-out rate and 12-month post Study Day 70 
follow-up period for each participant.  
 
7.6 
Plan for Statistical Summaries and Analyses 
7.6.1 
Preliminary Data Reviews 
An internal data review committee will review the unblinded safety data when 150 
participants have received the 1st vaccination and when 150 participants have received the 2nd 
vaccination. 
 
An independent DSMB with independent experts will be established. The DSMB will only be 
convened if, a stopping rule is triggered, or if the internal data review committee’s safety 
review triggers a DSMB meeting. Please refer to Section 5.1.4 for details of the procedures of 
the internal data review committee and the DSMB. 
 
 
7.6.2 
Exploratory Analysis of Immunogenicity Cohort 
Whole blood ICS assays are to be performed and analyzed by 
(Table 3-2) prior to 
unblinding of the trial. The blinded biostatistician will provide a list of unique, randomly 
assigned dummy participant identification (ID) numbers to a designated technologist who 
will not be involved in the conduct or analyses of the data. Two designated scientists who are 
not involved in any operational activities of the trial will analyze the data. They will receive a 
list linking each dummy ID with the participant’s treatment (H56:IC31 or placebo) to 
compare responses in participants receiving active vs. placebo; they will not be able to link 
the treatment with the real participant ID. A SOP will detail the transfer of samples to the 
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processing technologists and the transfer of data for analysis. Only after database lock will 
the staff be unblinded to the real participant IDs to enable linking of clinical outcomes to 
immunological responses. 
7.6.3 
Final Study Report 
The final study report will include all available data related to participant disposition; 
demography and baseline characteristics; vaccine administration; protocol deviations; 
efficacy, immunogenicity (excluding exploratory analyses), and safety analyses; clinical 
assessments; and concomitant medications through the final study visit. The database will be 
locked prior to preparation of the final study report when all of the above data have been 
entered, reviewed, and all queries related to the data have been addressed. 
 
Modifications or additions to the analyses described above will be included in the relevant 
statistical analysis plan(s). Any decisions to deviate from the planned analyses described in 
the protocol and in the statistical analysis plan will be described in detail in the final study 
report. 
 
7.7 
Computer Methods 
Statistical analyses will be performed using SAS®. 
8 
DATA COLLECTION, MONITORING, AND RECORD RETENTION 
For the purpose of monitoring and auditing the study, source data will consist of original 
records and certified copies of original records contained in source documents (e.g. existing 
medical records and/or study records developed and maintained by the investigator). 
 
At the investigational site, a document identifying all (expected) source documents should be 
prepared and signed by the site PI before the initiation of the study. 
 
Data recorded on source documents and required to be captured in the database will be 
entered in electronic case report forms (eCRFs) using an electronic data capture (EDC) 
system provided and approved by sponsor.  
 
The study will be monitored regularly, according to the protocol-specific monitoring plan. On 
site monitoring will be performed by a clinical CRO, sub-contracted by the sponsor, 
throughout the study period.  
 
Data management and statistical analysis will be sub-contracted by sponsor to a CRO. Before 
releasing the database for statistical analysis and clinical study reporting, the data manager 
will ensure that all quality control procedures in connection with data capture, cleaning and 
reconciliation of data have been finalized and documented. 
 
All study records (source documents, signed informed consent forms, IRB/IEC 
correspondence and approval letters, investigational product management records, and other 
essential documents) will be kept secured for a minimum of 15 years after the last 
participant’s last visit. Additional storage will be according to the guidance of the applicable 
national regulatory authority. The investigator will ensure that study records are not disposed 
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or removed from the clinical site without prior written notification and approval from 
sponsor. 
9 
ETHICS AND REGULATORY 
9.1 
Ethical and Regulatory Considerations 
The study will be conducted according to the ethical principles set forth in the Declaration of 
Helsinki, ICH-GCP, South African GCPs and local regulatory requirements, as applicable. 
The clinical study site(s) should have written operating procedures and recruitment and 
retention guidelines appropriate for the specific age group and health status (e.g., HIV-
positive, active TB disease) of the study population. 
 
The protocol (and protocol amendments if applicable) and informed consent forms will be 
reviewed and approved (as applicable) by the IRB/IEC of each participating clinical study 
site and the regulatory authorities in South Africa and Tanzania, prior to any protocol-
specified procedures being conducted.  
 
All the documents the IRB/IEC may need to fulfill its responsibilities, such as the protocol, 
protocol amendments, information concerning participant recruitment, payment or 
compensation procedures, etc., will be submitted to the IRB/IEC by the investigator. The 
IRB’s/IEC’s written, unconditional approval of the study protocol and the informed consent 
form will be in the possession of the investigator/clinical site staff prior to the conduct of any 
protocol-specified procedures.  
 
Modifications to the protocol may not be implemented without prior written IRB/IEC and 
regulatory authority approval except when necessary to eliminate immediate hazards to the 
participants or when the modification involves only logistical or administrative aspects of the 
study. Such logistical or administrative modifications will be submitted to the IRB/IEC in 
writing by the investigator and to the regulatory authorities by the sponsor. A copy of the 
correspondence to verify the submission will be maintained.  
 
The investigator must inform the IRB/IEC of modifications to the informed consent form or 
any other documents previously submitted for review/approval, of any new information that 
may adversely affect the safety of the participants or the conduct of the study, provide an 
annual update and/or request for re-approval, and advise the IRB/IEC when the study has 
been completed. The sponsor will inform the regulatory authorities of such information as 
required. 
 
Any site-generated documents or forms to be provided to the participant (e.g., information 
cards, form letters from the investigator), and all forms of study advertising (flyers, 
brochures, print advertisements, radio or television scripts, etc.) must be approved by sponsor 
prior to the clinical site submitting them to the IRB/IEC. Approval from the IRB/IEC must be 
obtained prior to providing the documents or forms to the participant. 
 
Written informed consent will be obtained from each participant prior to any protocol-
specified procedures being conducted.  HIV testing will be performed with appropriate pre- 
and post-test counseling. 
 
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To maintain confidentiality, participant identification number(s) will be used to identify the 
participant’s laboratory specimens, source documents, eCRF, study reports, etc. All study 
records will be maintained in a secured location. Clinical information will not be released 
without written permission from the participant except as necessary for monitoring or 
auditing of the study by sponsor or applicable regulatory authorities. 
 
After the study has been unblinded, the participant should be informed by the study staff on 
which treatment (H56:IC31 or placebo) the participant received and the results of the study. 
Participants who receive placebo will not be offered H56:IC31 at the end of the study even if 
prevention of recurrence is demonstrated. 
  
9.2 
Informed Consent  
The principles of informed consent in the current edition of the Declaration of Helsinki and 
ICH-GCP, and any other applicable GCPs, should be implemented prior to any protocol-
specified procedures being conducted. The written consent document will embody the 
elements of informed consent as described in the Declaration of Helsinki and will also 
comply with local regulations. Informed consent will be documented in writing on a version-
controlled consent form approved by the IRB/IEC.  
 
The informed consent process will be conducted in a private space to maintain 
confidentiality. The consent process will be conducted in the participant’s language of choice. 
All relevant information should be provided in both oral and written form in a way that is 
understandable to the participant. Ample time and opportunity must be given for the 
participant to inquire about details of the study. The potential participant should be 
encouraged to take the informed consent form home to discuss with family and friends before 
deciding whether or not to participate in the study. 
 
The investigator or the investigator’s qualified designee will explain the nature of the study 
and inform the participant that participation is voluntary and that the participant can leave the 
study at any time, without penalty or loss of benefits to which they are otherwise entitled. The 
participant must be informed about the study’s purpose including why the participant was 
selected to participate, study goals, expected benefits and risks, potential risks, and that some 
potential risks are unforeseeable. The participant must be provided with a description of the 
procedures and the estimated duration of time required for participation in the study, as well 
as alternative interventions or courses of treatment, if applicable.  
 
The participant must receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs and, if so, what they are, where further information 
may be obtained, and who to contact in the event of a study-related injury. IVIA carries an 
insurance programme including cover for clinical studies. The policy covers claims arising 
from injury/injuries caused by the investigational products used in this clinical study, if used 
in accordance with the instructions given in the protocol. Participants must be told who to 
contact for answers to any questions related to the study. The extent of the confidentiality of 
participant’s records must be defined and the participant must be informed that applicable 
data protection legislation applies. 
 
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The participant must be informed that the monitor(s), auditor(s), IRB/IEC members, and the 
applicable regulatory authorities will be granted direct access to the participant’s original 
study medical records for verification of protocol-specified procedures and/or data, without 
violating the confidentiality of the participant to the extent permitted by the applicable laws 
and regulations. The participant must be informed that his/her signature on the informed 
consent form indicates that he/she has decided to participate in the study, having read and 
discussed the information presented.  
 
The assessment of a participant’s understanding of the key study concepts (e.g., procedures, 
risks) prior to signing the consent form and the final consenting should be conducted by the 
investigator or medically qualified personnel. The investigator or medically qualified 
personnel should be aware of situations in which partners, family, or community members 
may be exerting undue influence on an individual to participate in the study.  
Modifications made by the investigator to an informed consent form template provided to the 
investigator by sponsor will be reviewed and approved by sponsor prior to being submitted to 
the IRB/IEC.  
 
The original, signed informed consent form for each participant will be maintained by the 
investigator as part of the participant’s study records. A copy of the signed informed consent 
form will be provided to each participant. 
 
Informed consent is an ongoing process. At every clinic visit it will be verbally reconfirmed 
that the participant is voluntarily consenting to the study and understands the significant 
aspects of the study (e.g., purpose, risks, duration). 
 
10 
STUDY COMPLETION 
The site PI or designated study site staff will notify the IRB/IEC when the study has been 
completed. Sponsor will notify the regulatory authorities in both South Africa and Tanzania. 
 
11 
PUBLICATIONS 
The final clinical study report will be made available to the site PIs for purposes of 
publications. The site PIs and study staff must send all manuscripts, abstracts, and 
presentations using data from this study to the sponsor for review prior to their submission. 
The sponsor reserves the right to delete any part or parts of such materials deemed to be 
confidential or proprietary. 
 
12 
CHANGES IN THE PROTOCOL 
The protocol may not be modified without written approval from the sponsor except where 
necessary to eliminate an immediate hazard(s) to study participants or when the change(s) 
involves only logistical or administrative aspects of the study. All substantial changes to the 
protocol must be submitted and approved by the IRB/IEC and applicable national regulatory 
authorities prior to their implementation. 
 
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12.2 
Amendment 2 (Protocol v3.0) 
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What's new in Protocol Final Version 3.0, excludes fo1matting, organizational, typographical 
and minor edito1ial changes. 
Section No., Paragraph 
No., Page No. in Final 
version 2.0 
2 .1.3 .1, 3rd bullet, page 
17 
2.1.3.1, 4th bullet, page 
17 
Text in Final 
Version 2.0 
Antigen-specific cell-
mediated immune 
responses by whole 
blood intracellular 
cytokine staining 
(WB ICS) at baseline 
(V3= Day 0), and 14 
days after the 2nd 
vaccination (V6= 
Day 70) 
Humoral immune 
responses by IgG 
ELISA of plaSllla 
samples taken at 
baseline (V3= Day 0) 
and 14 days after the 
2nd vaccination (V6= 
Day 70) and at TB 
recun-ence diagnosis 
12.3 
Amendment 3 (Protocol v4.0) 
Reason for change 
Text in Final Version 3.0 
Clarify specific population 
Antigen-specific cell-
to be analyzed 
mediated immune 
responses by whole blood 
intracellular cytokine 
staining (WB ICS) at 
baseline (V3= Day 0), and 
14 days after the 2nd 
vaccination (V6= Day 70) 
in the immunogenicity 
cohort 
Clarify specific population 
Hmnoral immune responses 
to be analyzed and data time 
by IgG ELISA of plasma 
point to exclude TB 
samples taken from the 
recurrence diagnosis. This 
immunogenicity cohort at 
change reconciles the 
baseline (V3= Day 0) and 
discrepancy between Section 
14 days after the 2nd 
2.1.3 and Section 7.4.2 of 
vaccination (V6= Day 70) 
version 2.0 
What's new in Protocol Final Version 4.0, excludes fo1matting, organizational, typographical 
and minor edit01ial changes. 
Section No., 
Text in Final Version 
Reason for change 
Text in Final Version 4.0 
Paragraph No., 
3.0 
Page No. in Final 
version 3.0 
3.2.4, page 27 
12. Receipt or planned
In anticipation of the 
12. Receipt or planned
receipt of any licensed
implementation of national 
receipt of any licensed
vaccine from Vl through
SARS-Cov-2 vaccines 
vaccine from Vl through
V6=Day 70
programs. 
V6= Day 70, except for
SARS-Cov-2 vaccines
recommended by national
vaccination programs
which will be allowed if
given > 28 days before and
from the time of
administration of clinical
trial product.
6.1, page 48 
6. Receipt of
In anticipation of the 
6. Receipt of investigational
investigational dmg
implementation of national 
dmg therapy or
therapy, investigational
SARS-Cov-2 vaccines 
investigational vaccine
vaccine ( other than
programs. 
(other than investigational
Aeras Clinical Protocol Template Edition 03.1; Reference SOP CLD-136 rev. 03, ATT-CLD136-A 
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Statens Serum lnstitut 
IAVI 
Section No., 
Paragraph No., 
Page No. in Final 
version 3.0 
None 
Text in Final Version 
3.0 
investigational product 
received as prut of this 
study) and/or any other 
vaccine between 1st and 
2nd vaccination. 
None 
CONFIDENTIAL 
Reason for change 
For operational reasons 
study terun and Pis decided 
to allow partial unblinding 
of the immunogenicity 
coho1t in order to conduct 
exploratory whole blood ICS 
while the tiial is pending 
completion. 
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Page 65 of 74 
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Text in Final Version 4.0 
product received as prut of 
this study) between 1st and 
2nd vaccination or any 
other vaccine as described 
in Exclusion C1iteria #12. 
7.6.2 Exploratory Analysis 
oflmmunogenicity Cohort 
Whole blood ICS assays are 
to be perfonned and 
analyzed by-(Table 
3-2) prior to unblinding of
the ti·ial. The blinded
biostatistician will provide
a list of unique, randomly
assigned dummy participant
identification (ID) numbers
to a designated technologist
who will not be involved in
the conduct or analyses of
the data. Two designated
scientists who are not
involved in any operational
activities of the tiial will
analyze the data. T11ey will
receive a list linking each
dummy ID with the
participant's treatinent
(H56:IC31 or placebo) to
compare responses in
participants receiving active
vs. placebo; they will not be
able to link the treatinent
with the real participant ID.
A SOP will detail the
transfer of samples to the
processing technologists
and the ti·ansfer of data for
analysis. Only after
database lock will the staff
be unblinded to the real
participant IDs to enable
linking of clinical outcomes
to immunological
responses.
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13 
REFERENCES 
Aagaard C, Hoang T, Dietrich J, et al. A multistage tuberculosis vaccine that confers efficient 
protection before and after exposure. Nat Med. 2011;17:189-194. 
Belisle JT, Vissa VD, et al. Role of the major antigen of Mycobacterium tuberculosis in cell 
wall biogenesis. Science. 1997;276(5317):1420-2. 
 
Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. Evaluation of a nutrient starvation 
model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. 
Mol Microbiol. 2002;43:717-731. 
Billeskov R, Esterlina V, Andersen P, et al. testing the H56 vaccine delivered in 4 different 
adjuvants as a BCG-booster in a non-human primate model of tuberculosis. PlosONE. Aug 
15 2016: DOI:10.1371. 
Brandt L, Oettinger T, Holm A, Andersen P. Key epitopes on the ESAT-6 antigen recognized 
in mice during the recall of protective immunity to Mycobacterium tuberculosis. J Immunol. 
1996;157:3527-3533. 
Brandt L, Elhay M, Rosenkrands I, Lindblad E, Andersen P. ESAT-6 subunit vaccination 
against Mycobacterium tuberculosis. Infect Immun. 2000;68:791-795. 
Ellis RD, Hatherill M, Tait D, Snowden M, Churchyard G, Hanekom W, et al. Innovative 
clinical trial designs to rationalize TB vaccine development. Tuberculosis 2015;95:352–7. 
doi:10.1016/j.tube.2015.02.036. 
Friedrich SO, Rachow A, Saathoff E, Singh K, Mangu CD, Dawson R, et al. Assessment of 
the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of 
response to tuberculosis treatment. Lancet Respir Med 2013;1:462–70.doi:10.1016/S2213-
2600(13)70119-X. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-
Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis. N Engl J Med 
2014;371:1577–87. doi:10.1056/NEJMoa1407426. 
 
Govender L, Abel B, Hughes EJ, et al. Higher human CD4 T cell response to novel 
Mycobacterium tuberculosis latency associated antigens Rv2660 and Rv2659 in latent 
infection compared with tuberculosis disease. Vaccine. 2010;29:51-57. 
Hoang T, Aagaard C, Dietrich J, et al. ESAT-6 (EsxA) and TB10.4 (EsxH) based vaccines 
for pre- and post-exposure tuberculosis vaccination. PlosONE. Dec 12 2013: DOI:10.1371. 
Horwitz MA, Harth G, et al. Recombinant bacillus calmette-guerin (BCG) vaccines 
expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater 
protective immunity against tuberculosis than conventional BCG vaccines in a highly 
susceptible animal model. Proc Natl Acad Sci USA. 2000;97(25):13853-8. 
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Imperial MZ, Nahid P., Phillips P.P.J et al. A patient-level pooled analysis of treatment-
shortening regimens for drug-susceptible pulmonary tuberculosis. Nature Medicine Vol 24, 
1708-1715, November 2018, DOI 10.1038. 
Knight G, Griffiths U, Sumner T et al. Impact and cost-effectiveness of new tuberculosis 
vaccines in low- and middle-income countries. PNAS;2014;111(43):15520-15525. 
Kochenderfer JN, Chien CD, Simpson JL, Gress RE. Synergism between CpG-containing 
oligodeoxynucleotides and IL-2 causes dramatic enhancement of vaccine-elicited CD8+ T 
cell responses. J Immunol. 2006;177(12):8860-73. 
Lin PL, Dietrich J, Tan E, et al. The multistage vaccine H56 boosts the effects of BCG to 
protect cynomolgus macaques against active tuberculosis and reactivation of latent 
Mycobacterium tuberculosis infection. J Clin Invest. 2012;122:303-314. 
 
Luabeya A, Kagina B, Tameris M, et al. First-in-human trial of the post-exposure 
tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected 
healthy adults. Vaccine. 2015; 33:4130-4140. 
 
Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al. A Four-Month 
Gatifloxacin-Containing Regimen for Treating Tuberculosis. N Engl J Med 2014;371:1588–
98. doi:10.1056/NEJMoa1315817. 
 
Muttucumaru DG, Roberts G, Hinds J, Stabler RA, Parish T. Gene expression profile of 
Mycobacterium tuberculosis in a non-replicating state. Tuberc. 2004;84:239-246. 
Nemes E., Geldenhuys H., Hatherill M. et al. Prevention of M. tuberculosis infection with 
H4:IC31 vaccine or BCG revaccination. N. Engl. J Med. 2018. 379;2 138-49. 
Pollock JM, Andersen P. Predominant recognition of the ESAT-6 protein in the first phase of 
infection with Mycobacterium bovis in cattle. Infect Immun. 1997;65:2587-2592 
Ravn P, Demissie A, Eguale T, et al. Human T cell responses to the ESAT-6 antigen from 
Mycobacterium tuberculosis. J Infect Dis. 1999;179:637-645. 
Rustad TR, Sherrid AM, Minch KJ, Sherman DR. Hypoxia: a window into Mycobacterium 
tuberculosis latency. Cell Microbiol. 2009;11:1151-1159. 
Statistics South Africa. Mortality and causes of death in South Africa, 2015. Findings 
from death notification. 28 February 2017.www.statssa.gov.za. 
Suliman S., Luabeya A., Geldenhuys H., et al. Dose optimization of H56:IC31 
Vaccine for Tubeculosis-Endemic Populations – a double-blind, placebo-controlled, 
dose-selection trial. 2019; 199:220-231. 
 
Ulrichs T, Munk ME, Mollenkopf H, et al. Differential T cell responses to Mycobacterium 
tuberculosis ESAT-6 in tuberculosis patients and healthy donors. Eur J Immunol. 
1998;28:3949-3958. 
 
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UN General Assembly. Global strategy and targets for tuberculosis prevention, care and 
control after 2015. WHO, 2014. www.who.int/tb/strategy/en. 
 
WHO core team within global TB programme. Implementing the end TB strategy: the 
essentials. WHO, 2015. www.who.int./tb/publications/2015/The_essentials_to_End_TB/en. 
 
WHO, Geneva. Global tuberculosis report 2017. Licence: CC BY-NC-SA 3.0 IGO. 
 
Wiker HG, Nagai S, et al. A family of cross-reacting proteins secreted by Mycobacterium 
tuberculosis. Scand J Immunol. 1992;36(2):307-19.
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14 
ADVERSE EVENTS OF SPECIAL INTEREST
 
Adverse events of special interest represent a subset of AEs that include autoimmune diseases 
and other systemic disorders of interest which could potentially have an autoimmune etiology. 
Adverse events of special interest are listed below. The PI should use clinical and scientific 
judgment in deciding whether other adverse events (i.e., events not listed here) could have an 
autoimmune origin. 
 
Acute disseminated encephalomyelitis (ADEM) 
Addison's Disease 
Anti-neutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis 
Ankylosing Spondylitis 
Anti-phospholipid Syndrome
Autoimmune Bullous Skin Diseases
Autoimmune Hemolytic Anemia 
Autoimmune Hepatitis 
Basedow’s Disease 
Behcet’s Syndrome
Bell's Palsy 
Carditis 
Celiac Disease 
Crohn’s Disease 
Cutaneous Lupus 
Demyelinating Disease 
Dermatomyositis 
Diabetes Mellitus, Insulin Dependent (IDDM)
Erythema Nodosum 
Glomerulonephritis 
Guillain Barre Syndrome
Grave’s Disease 
Idiopathic Thrombocytopenic Purpura (ITP) 
Inflammatory Bowel Disease (non-specific) 
Juvenile Rheumatoid Arthritis 
Mixed Connective Tissue Disease 
Multiple Sclerosis 
Myasthenia Gravis 
Myelitis/Transverse Myelitis 
Myocarditis 
Nephritis 
Optic neuritis 
Pericarditis 
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Polymyalgia Rheumatica 
Polymyositis 
Primary Biliary Cirrhosis 
Primary Sclerosing Cholangitis 
Psoriasis 
Psoriatic Arthritis 
Raynaud's Phenomenon 
Rheumatoid Arthritis 
Sarcoidosis 
Scleroderma 
Sjogren’s Syndrome 
Spondylo-arthropathy 
Stevens-Johnson Syndrome 
Systemic Lupus Erythematosus 
Temporal Arteritis 
Thyroiditis 
Ulcerative Colitis 
Ulcerative Proctitis 
Uveitis 
Vasculitis 
Vitiligo 
Wegener’s Granulomatosis 
 
 
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