Phase 2b Placebo-Controlled Randomized Study of BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children to Assess Immunological Response and Safety of a Single Dose BPZE1 With/Without Coadministration of Tdap (Boostrix™)
Phase: PHASE2
Conditions: Bordetella Pertussis, Whooping Cough
Sponsor: ILiAD Biotechnologies

CLINICAL STUDY PROTOCOL 
 
A Phase 2b, Multi-Center, Placebo-Controlled, Randomized Study of 
BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children to 
Assess the Immunological Response and Safety Profile of a Single Dose 
BPZE1 With and Without Co-Administration of Tetanus, Diphtheria, and 
Acellular Pertussis (Boostrix™) 
IB-201P 
Sponsor: 
ILiAD Biotechnologies 
4581 Weston Road, Suite 260 
Weston, FL 33331 
Sponsor Contacts: 
Medical Monitor: 
Date of Amendment 6 (v7.0) 
30 March 2023 
Date of Previous Versions:  
03 February 2021 (Version 1.0) 
02 April 2021 (Version 2.0) 
09 June 2021 (Version 3.0) 
07 July 2021 (Version 4.0) 
16 August 2021 (Version 5.0) 
30 May 2022 (Version 6.0) 
 
CONFIDENTIAL 
All financial and non-financial support for this study will be provided by ILiAD 
Biotechnologies. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of ILiAD Biotechnologies. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6 (current version): Good Clinical Practice. 

ILiAD Biotechnologies 
BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
Confidential 
Page 2 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2b, Multi-Center, Placebo-Controlled, Randomized Study of 
BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children 
to Assess the Immunological Response and Safety Profile of a Single 
Dose BPZE1 With and Without Co-Administration of Tetanus, 
Diphtheria, and Acellular Pertussis (Boostrix™) 
Protocol Number IB-201P 
Protocol Date 
and Version 
30 March 2023 (Amendment 6, v7.0) 
 
Protocol accepted and approved by: 
Chief Medical Officer 
ILiAD Biotechnologies 
4581 Weston Road, Suite 260 
Weston, FL 33331 

ILiAD Biotechnologies 
BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
Confidential 
Page 3 
Protocol Approval – Principal/Coordinating Investigator 
Study Title 
A Phase 2b, Multi-Center, Placebo-Controlled, Randomized Study of 
BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children 
to Assess the Immunological Response and Safety Profile of a Single 
Dose BPZE1 With and Without Co-Administration of Tetanus, 
Diphtheria, and Acellular Pertussis (Boostrix™) 
Protocol Number IB-201P 
Protocol Date 
and Version 
30 March 2023 (Amendment 6, v7.0) 
 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
 

ILiAD Biotechnologies 
BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
Confidential 
Page 4 
Protocol Approval – Lead Statistician 
Study Title 
A Phase 2b, Multi-Center, Placebo-Controlled, Randomized Study of 
BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children 
to Assess the Immunological Response and Safety Profile of a Single 
Dose BPZE1 With and Without Co-Administration of Tetanus, 
Diphtheria, and Acellular Pertussis (Boostrix™) 
Protocol Number IB-201P 
Protocol Date 
and Version 
30 March 2023 (Amendment 6, v7.0) 
 
Protocol accepted and approved by: 
Lead Statistician 

ILiAD Biotechnologies 
BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
Confidential 
Page 5 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2b, Multi-Center, 
Placebo-Controlled, Randomized Study of BPZE1 Intranasal Pertussis Vaccine in Healthy 
School-Age Children to Assess the Immunological Response and Safety Profile of a Single 
Dose BPZE1 With and Without Co-Administration of Tetanus, Diphtheria, and Acellular 
Pertussis (Boostrix™)” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Original Protocol, the International Council for Harmonisation 
harmonised tripartite guideline E6 (current version): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with ILiAD Biotechnologies or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to subjects. I agree to administer 
study treatment only to subjects under my personal supervision or the supervision of a 
sub-investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from ILiAD Biotechnologies. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 

ILiAD Biotechnologies 
BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
Confidential 
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Table of Contents 
Table of Contents .................................................................................................................. 6 
List of Tables ......................................................................................................................... 9 
Protocol Synopsis ................................................................................................................ 10 
List of Abbreviations ........................................................................................................... 32 
1 
Introduction ................................................................................................................. 34 
1.1 
Background Information ..................................................................................... 34 
1.2 
Rationale............................................................................................................. 36 
1.3 
Potential Risks and Benefits ................................................................................ 38 
1.3.1 
Potential Risks ...................................................................................... 38 
1.3.2 
Known Potential Benefits ..................................................................... 45 
2 
Study Objectives and Endpoints ................................................................................... 46 
2.1 
Primary Objectives and Endpoints ...................................................................... 46 
2.2 
Secondary Objectives and Endpoints ................................................................... 47 
2.3 
Other Exploratory Objectives and Endpoints ....................................................... 52 
3 
Investigational Plan ...................................................................................................... 53 
3.1 
Study Design ...................................................................................................... 53 
3.1.1 
Substudy: Attenuated Challenge With BPZE1 Following Prior 
Vaccination with BPZE1, BPZE1 + Boostrix, or Boostrix Alone .......... 55 
4 
Subject Selection and Withdrawal Criteria ................................................................... 58 
4.1 
Selection of Study Population ............................................................................. 58 
4.1.1 
Inclusion Criteria .................................................................................. 58 
4.1.2 
Exclusion Criteria ................................................................................. 59 
4.1.3 
Other Considerations for Temporarily Holding Vaccination (Days 1 or 
Substudy Day 85) ................................................................................. 62 
4.2 
Withdrawal of Subjects From Study Treatment and/or the Study ......................... 62 
4.2.1 
Reasons for Withdrawal/Discontinuation .............................................. 62 
4.2.2 
Handling of Withdrawals ...................................................................... 63 
4.2.3 
Replacements ....................................................................................... 64 
5 
Study Treatments ......................................................................................................... 64 

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Clinical Study Protocol 
 
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5.1 
Method of Assigning Subjects to Treatment Groups ............................................ 64 
5.2 
Treatments Administered .................................................................................... 65 
5.3 
Identity of Investigational Product ...................................................................... 66 
5.3.1 
Investigational Product Packaging and Storage ..................................... 67 
5.3.2 
Investigational Product Accountability ................................................. 67 
5.3.3 
Other Supplies ...................................................................................... 68 
5.4 
Overdose Management........................................................................................ 68 
5.4.1 
Treatment of Overdose ......................................................................... 68 
5.5 
Blinding .............................................................................................................. 69 
5.5.1 
Breaking the Blind Due to Medical Emergency .................................... 69 
5.6 
Treatment Compliance ........................................................................................ 69 
5.7 
Prior and Concomitant Medications, Therapies, or Vaccines ................................ 70 
6 
Study Assessments and Procedures .............................................................................. 71 
6.1 
Demographic and Baseline Data ......................................................................... 71 
6.2 
Medical History .................................................................................................. 71 
6.3 
Safety Assessments ............................................................................................. 71 
6.3.1 
Vital Sign Measurements ...................................................................... 71 
6.3.2 
Post-Vaccination Evaluation ................................................................. 72 
6.3.3 
Physical Examination ........................................................................... 73 
6.3.4 
Clinical Safety Laboratory Assessments ............................................... 73 
6.3.5 
Adverse Events..................................................................................... 73 
6.4 
Immunogenicity and Colonization Assessments .................................................. 79 
6.5 
Vaccination Pause Rules...................................................................................... 80 
6.6 
Pregnancy ........................................................................................................... 80 
7 
Statistical and Analytical Plan ...................................................................................... 82 
7.1 
Sample Size Calculations .................................................................................... 82 
7.2 
Blinded Sample Size Recalculation ..................................................................... 83 
7.3 
Analysis Sets ...................................................................................................... 83 
7.4 
Statistical Analysis Methodology ........................................................................ 85 
7.4.1 
Analyses of Primary Endpoints ............................................................. 86 
7.4.2 
Analyses of Key Secondary Serum Immunogenicity (IgG) Endpoints .. 87 

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Clinical Study Protocol 
 
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7.4.3 
Analyses of Secondary Endpoints ......................................................... 87 
7.4.4 
Analyses of Endpoints for the Optional Substudy ................................. 90 
7.4.5 
Other Analyses ..................................................................................... 91 
7.4.6 
Interim Database Lock.......................................................................... 91 
8 
Data Quality Assurance ................................................................................................ 92 
8.1 
Data Management ............................................................................................... 92 
9 
Ethics ........................................................................................................................... 93 
9.1 
Independent Ethics Committee ............................................................................ 93 
9.2 
Ethical Conduct of the Study ............................................................................... 93 
9.3 
Subject Information and Consent ........................................................................ 93 
10 Investigator’s Obligations ............................................................................................ 95 
10.1 Confidentiality .................................................................................................... 95 
10.2 Financial Disclosure and Obligations .................................................................. 95 
10.3 Investigator Documentation ................................................................................ 95 
10.4 Study Conduct .................................................................................................... 95 
10.5 Adverse Events and Study Report Requirements ................................................. 96 
10.6 Investigator’s Final Report .................................................................................. 96 
10.7 Records Retention ............................................................................................... 96 
10.8 Publications ........................................................................................................ 96 
11 Study Management ...................................................................................................... 98 
11.1 Monitoring .......................................................................................................... 98 
11.1.1 
External Data Monitoring Committee ................................................... 98 
11.1.2 
Monitoring of the Study ....................................................................... 99 
11.1.3 
Inspection of Records ........................................................................... 99 
11.2 Management of Protocol Amendments and Deviations ........................................ 99 
11.2.1 
Modification of the Protocol ................................................................. 99 
11.2.2 
Protocol Deviations .............................................................................. 99 
11.3 Study Termination ............................................................................................. 100 
11.4 Final Report ...................................................................................................... 100 
12 Reference List ............................................................................................................ 102 

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Clinical Study Protocol 
 
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13 Appendices ................................................................................................................ 105 
13.1 Appendix: Schedule of Events .......................................................................... 105 
13.2 Appendix: Toxicity Grading Scales ................................................................... 110 
13.3 Appendix: Expected Normal Ranges in School-Age Children and Adolescents . 113 
 
List of Tables 
Table 1-1 
Adverse Reactions Reported in Clinical Trials with Boostrix ........................ 42 
Table 1-2  
Adverse Reactions Reported with Boostrix During Post-Marketing 
Surveillance ................................................................................................. 43 
Table 3-1 
Dosing Scheme ............................................................................................ 53 
Table 13-1 
Schedule of Events ..................................................................................... 106 
Table 13-2 
Local Reactogenicity Grading Scale ........................................................... 110 
Table 13-3 
Nasal/Respiratory Reactogenicity Grading Scale ........................................ 111 
Table 13-4 
Systemic Reactogenicity Grading Scale ...................................................... 112 
Table 13-5 
Expected Normal Ranges for Heart Rate and Respiratory Rate in School-Age 
Children and Adolescents ........................................................................... 113 
 

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BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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Protocol Synopsis 
Protocol 
Number: 
IB-201P 
Title: 
A Phase 2b, Multi-Center, Placebo-Controlled, Randomized Study of 
BPZE1 Intranasal Pertussis Vaccine in Healthy School-Age Children 
to Assess the Immunological Response and Safety Profile of a Single 
Dose BPZE1 With and Without Co-Administration of Tetanus, 
Diphtheria, and Acellular Pertussis (Boostrix™) 
Sponsor: 
ILiAD Biotechnologies 
4581 Weston Road, Suite 260 
Weston, FL 33331 
Study Phase: 
2b 
Study Sites: 
Approximately 30 centres in the United Kingdom, 
European/Commonwealth countries, and/or Costa Rica 
Indication: 
Pertussis booster in adults and school-age children 
Rationale: 
Acellular pertussis (aP) vaccines were introduced into most developed 
countries in the late 1990’s and early 2000’s, and for 2 decades, 
children in these countries have received only aP vaccinations. The 
resurgence of Bordetella pertussis (B. pertussis) in these countries, 
despite high vaccination rates, is hypothesized to be linked to the sole 
use of aP vaccines, which do not alter B. pertussis acquisition and have 
limited durability. The availability of a cost-effective pertussis vaccine 
that provides improved efficacy and prolonged protection with the 
potential to reduce or eliminate transmission would present a 
breakthrough in the prevention of colonizing B. pertussis infections. 
The current pertussis vaccine strategies do not provide mucosal 
immunity or alter B. pertussis acquisition and therefore have not been 
successful in halting human-to-human transmission. As humans are the 
only known reservoir for B. pertussis, targeting colonization would 
provide a novel approach through mucosal-induced immunity to 
reduce the B. pertussis reservoir in the population and thereby reduce 
transmission. The timing of aP vaccine introduction has resulted in a 
school-age population who could benefit from a broader immune 
response achievable with a live attenuated pertussis vaccine such as 
BPZE1. 
The intranasally administered BPZE1 live attenuated vaccine provides 
an opportunity to generate a locally effective mucosal antibody 
response at the site of potential exposure, mimic the route of entry of 
the wild-type pathogen, and induce a broader immune response as 
measured by cellular, mucosal, and serum indices. Inducing mucosal 

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BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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immunity with an attenuated live vaccine delivered through intranasal 
vaccination could halt progression from upper airway to lower airway 
disease in BPZE1-vaccinated individuals as well as strengthen herd 
immunity by reducing upper airway person-to-person transmission. 
The overall effect would be improved protection of even the most 
vulnerable from B. pertussis through a robust booster vaccination 
strategy with the best potential to disrupt B. pertussis epidemics. 
Acellular pertussis vaccines are currently recommended as both 
primary and booster vaccinations and usually given in a combination 
vaccine containing diphtheria (D/d), tetanus (T), and pertussis (P/p) 
with the level of antigen content dictated by standard nomenclature of 
DTaP (higher antigen content overall) or Tdap (lower antigen content 
for diphtheria and pertussis). The current recommendation in the 
United Kingdom includes the childhood booster of Tdap at 3 years of 
age with no adolescent booster of aP-containing vaccine, whereas 
some other European/Commonwealth countries and the US have a 
similar early childhood DTaP vaccination schedule but have added a 
Tdap booster during the school-age period (up to and including 
adolescence). This study will investigate BPZE1-induced immune 
responses in a background of DTaP or Tdap, with the last 
pertussis-containing booster occurring more than 3 years prior. BPZE1 
alone as well as coadministration with Boostrix will be investigated to 
test safety and whether augmenting/broadening mucosal immune 
responses are possible in an aP primed-only population. Furthermore, 
the testing of interference of BPZE1 with all components found in 
Boostrix will be investigated as a key secondary objective. In addition, 
demonstrating protection against subsequent colonization using the 
attenuated challenge model (re-vaccination/attenuated challenge with 
BPZE1) will be investigated at 3 months following initial vaccination 
(optional substudy) as a secondary objective. As this population has 
never received a whole cell pertussis (wP) vaccination, this will be the 
first time that a broader immunization against B. pertussis is provided; 
therefore, additional hypotheses include that a single intranasal 
vaccination with BPZE1 will be sufficient to induce a differential 
immune response compared to Boostrix (eg mucosal immunity 
induction and reduction in B. pertussis acquisition), and a differential 
cellular-mediated response will be investigated following vaccination 
with either BPZE1, BPZE1 + Boostrix, or Boostrix. 
 
 

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BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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Objectives and 
Endpoints 
Immunogenicity 
Primary objectives 
Primary endpoints 
 
• 
To demonstrate BPZE1 
induction of broad pertussis 
mucosal secretory 
immunoglobulin A (S-IgA) 
immunity is measurable at Day 
29 by geometric mean fold rise 
(GMFR) by antibodies to whole 
cell extract (WCE) (BPZE1, 
BPZE1 + Boostrix). 
• 
GMFR of BPZE1 induction of 
mucosal S-IgA against WCE at 
Day 29 by treatment group 
(BPZE1, BPZE1 + Boostrix).  
 
Safety 
 
Primary objective 
Primary endpoint 
 
• 
To assess reactogenicity by 
toxicity scoring through 7 days 
following first study vaccination 
with any combination of 
pertussis-containing vaccines 
(BPZE1, BPZE1 + Boostrix, 
Boostrix). 
• 
Occurrence of solicited adverse 
events (AEs) including local, 
nasal/respiratory, and systemic 
reactogenicity events through 
7 days following first study 
vaccination with any 
combination of 
pertussis-containing vaccines. 
 
Immunogenicity 
 
Key secondary objectives  
Key secondary endpoints  
 
• 
To demonstrate non-
interference of immunoglobulin 
G (IgG) serum responses for all 
Boostrix-containing antigens 
(diphtheria, tetanus, pertussis 
toxin [PT], filamentous 
hemagglutinin [FHA], pertactin 
[PRN]) at Day 29 when BPZE1 
is co-administered with 
Boostrix (BPZE1 + Boostrix vs 
Boostrix). 
• 
BPZE1 + Boostrix induction of 
serum IgG against diphtheria, 
tetanus, and all aP antigens (PT, 
FHA, PRN) compared with 
Boostrix at Day 29 (criteria to 
be assessed for diphtheria and 
tetanus responses per WHO 
guidelines).  
 
 

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BPZE1 
Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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Colonization (optional substudy only) 
 
Secondary objectives  
Secondary endpoints  
 
• 
To describe colonization in each 
of the groups: BPZE1, 
BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix 
control. 
• 
Proportion of subjects with 
colonization at either Day 92 or 
99 (B. pertussis culture or 
polymerase chain reaction 
[PCR]) with prior BPZE1 
immunization following 
re-vaccination/attenuated 
challenge at Day 85 (BPZE1, 
BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix 
control). Expressed as absolute 
proportion (Yes/No). 
 
Mucosal secretory immunogenicity (S-IgA): WCE, PT, FHA, PRN, and any 
additional anti-pertussis mucosal antibodies identified during assay 
development using GMT and geometric mean fold rise (GMFR) unless 
otherwise stated. 
NOTE: To also be tested separately in subjects who participate in the optional 
substudy as exploratory endpoints, to assess response following re-
vaccination/attenuated challenge.  
 
Secondary objectives  
Secondary endpoints  
 
• 
To demonstrate BPZE1 
induction of mucosal S-IgA 
immunity is non-inferior to 
Boostrix at Day 29 as measured 
by antibodies to WCE (BPZE1 
vs Boostrix). 
• 
BPZE1 induction of mucosal S-
IgA against WCE compared 
with Boostrix at Day 29. 
 
• 
To demonstrate BPZE1 
induction of mucosal S-IgA 
immunity is greater than 
baseline at Day 29 (BPZE1, 
BPZE1 + Boostrix). 
• 
BPZE1 induction of mucosal 
S-IgA at Day 29 compared to 
baseline. 
 
• 
To demonstrate BPZE1 
induction of mucosal S-IgA 
immunity remains greater than 
baseline over the study period 
and at Day 169/ end of study 
(EOS) (BPZE1, 
BPZE1 + Boostrix).  
• 
BPZE1 and BPZE1 + Boostrix 
induction of mucosal S-IgA 
compared with baseline at 
Days 85 and 169/EOS (tested 
independently). 
 
• 
To demonstrate BPZE1 + 
Boostrix induction of mucosal 
S-IgA immunity is non-inferior 
to BPZE1 at Day 29 and 
Day 169/EOS (BPZE1 + 
Boostrix vs BPZE1).  
• 
BPZE1 + Boostrix induction of 
mucosal S-IgA compared with 
BPZE1 at Days 29 and 
169/EOS (tested 
independently). 

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Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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• 
To assess if age, time since last 
aP vaccination (prior to study 
entry), or other baseline 
demographics have a 
differential response to 
induction of mucosal S-IgA 
immunity (BPZE1, 
BPZE1 + Boostrix) at Day 29. 
• 
BPZE1 and BPZE1 + Boostrix 
induction of mucosal S-IgA in 
covariate analysis by age, time 
since last aP vaccination (prior 
to study entry), or other baseline 
demographics at Day 29. 
 
• 
To assess if baseline antibody 
values, by baseline quantile, 
have variable responses at 
Day 29 to induction of S-IgA 
immunity when BPZE1 is given 
alone or with Boostrix (BPZE1, 
BPZE1 + Boostrix). 
• 
BPZE1 and BPZE1 + Boostrix 
induction of mucosal S-IgA by 
baseline quantile at Day 29. 
 
• 
To assess seroconversion for 
each of the anti-pertussis S-IgA 
antibodies at Day 29 (BPZE1, 
BPZE1 + Boostrix, Boostrix). 
Additional combinations of 
antibody response (WCE, PT, 
FHA, PRN, and any additional 
anti-pertussis antibodies) may 
also be tested.  
• 
Seroconversion rate (2-fold 
increase over baseline value or a 
4-fold increase over the lower 
limit of assay detection 
[whenever the baseline value 
falls below the lower limit of 
assay detection]) for mucosal 
S-IgA at Day 29 by treatment 
group.  
 
• 
To assess reverse cumulative 
distribution curves for immune 
response (S-IgA) at Day 29. 
• 
Reverse cumulative distribution 
curves of each anti-pertussis 
mucosal antibodies S-IgA GMT 
at Day 29 by treatment group. 
 
Serum immunogenicity (IgA and IgG): WCE, PT, FHA, PRN, and any 
additional anti-pertussis antibodies identified during assay development using 
GMT and GMFR unless otherwise stated. 
NOTE: To also be tested separately in subjects who participate in the optional 
substudy as exploratory endpoints, to assess response following re-
vaccination/attenuated challenge. 
 
Secondary objectives  
Secondary endpoints  
 
• 
To demonstrate that BPZE1 
(BPZE1, BPZE1 + Boostrix) 
induction of serum immunity is 
significantly greater than 
baseline at Day 29. 
• 
BPZE1 and BPZE1 + Boostrix 
induction of serum immunity 
(IgA, IgG) at Day 29 compared 
with baseline (tested 
independently by treatment 
group). 
 
• 
To demonstrate that BPZE1 + 
Boostrix induction of serum 
immunity is non-inferior 
compared to Boostrix at Day 29 
(BPZE1 + Boostrix vs 
Boostrix). 
• 
BPZE1 + Boostrix induction of 
serum immunity (IgA, IgG) 
compared with Boostrix at 
Day 29. 

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Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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• 
To demonstrate that BPZE1 
(BPZE1, BPZE1 + Boostrix) 
induction of serum immunity 
remains significantly greater 
than baseline over the course of 
the study and at Day 169/EOS 
and to assess antibody decay 
curves for BPZE1, 
BPZE1 + Boostrix and 
Boostrix. 
• 
BPZE1 and BPZE1 + Boostrix 
induction of serum immunity 
(IgA, IgG) at Day 85 and 
Day 169/EOS compared with 
baseline (tested independently 
by treatment group and day). 
• 
Antibody decays (IgA, IgG) 
over the course of the study 
(tested independently by 
treatment group). 
 
• 
To demonstrate that BPZE1 
induction of serum 
immunoglobulin A (IgA) is 
non-inferior to Boostrix at 
Day 169/EOS (BPZE1 vs 
Boostrix; BPZE1 + Boostrix vs 
Boostrix). 
• 
BPZE1 induction of serum IgA 
compared with Boostrix at 
Day 169/EOS. 
• 
BPZE1 + Boostrix induction of 
serum IgA compared with 
Boostrix at Day 169/EOS. 
 
• 
To assess if age, time since last 
aP vaccination (prior to study 
entry), or other baseline 
demographics have a 
differential response to BPZE1 
or Boostrix at Day 29 (BPZE1, 
BPZE1 + Boostrix, Boostrix). 
• 
BPZE1, BPZE1 + Boostrix, and 
Boostrix induction of serum 
immunity (IgA, IgG) by age, 
time since last aP vaccination 
(prior to study entry), or other 
baseline demographics at Day 
29 (tested independently by 
treatment group). 
 
• 
To assess if baseline antibody 
values, by baseline quantile, 
have variable serum immunity 
responses at Day 29 when 
BPZE1 is given alone or with 
Boostrix or with Boostrix alone 
(BPZE1, BPZE1 + Boostrix, 
Boostrix). 
• 
BPZE1, BPZE1 + Boostrix and 
Boostrix induction of serum 
immunity (IgA, IgG) at Day 29 
by baseline quantile (tested 
independently by treatment 
group). 
 
• 
To demonstrate that BPZE1 
(BPZE1, BPZE1 + Boostrix) 
induces a measurable functional 
antibody response (subset of 
subjects) at Day 29; and to 
assess whether there is similar 
magnitude as that seen with 
Boostrix (BPZE1 vs BPZE1 + 
Boostrix vs Boostrix).  
• 
BPZE1 and BPZE1 + Boostrix 
induction of measurable 
functional antibody (subset of 
subjects) compared with 
Boostrix at Day 29 (tested 
independently by treatment 
group). 

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Protocol No. IB-201P Amendment 6 (v7.0) 
Clinical Study Protocol 
 
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• 
To assess for seroconversion at 
Days 29 and 85 (BPZE1, 
BPZE1 + Boostrix, Boostrix). 
Additional combinations of 
antibody response (WCE, PT, 
FHA, PRN, and any additional 
anti-pertussis antibodies) may 
also be tested. 
• 
Seroconversion rate for serum 
immunity (IgA, IgG) defined as 
a 2-fold increase over baseline 
value; or a 4-fold increase over 
the lower limit of assay 
detection (whenever the 
baseline value falls below the 
lower limit of assay detection) 
at Day 29 and Day 85 (tested 
independently by treatment 
group and day). 
 
• 
To assess reverse cumulative 
distribution curves for immune 
responses (IgA and IgG) at 
Day 29. 
• 
Reverse cumulative distribution 
curves of GMT at Day 29 by 
treatment group. 
 
Safety 
NOTE: Subjects participating in the substudy will be evaluated for safety 
endpoints in a separate evaluation after Day 85 re-vaccination/attenuated 
challenge. 
 
Secondary objectives  
Secondary endpoints  
 
• 
To describe reactogenicity 
events during the 7 days 
following any study 
vaccination. Primary and 
re-vaccination/attenuated 
challenge (substudy subjects) to 
be described separately, by 
treatment group. Reactogenicity 
will be classified by local, 
nasal/respiratory, and systemic. 
• 
Maximum daily severity during 
the 7 days following study 
vaccination (by treatment 
group). 
• 
Incidence by toxicity grade 
during the 7 days following 
study vaccination (by treatment 
group). 
• 
Mean response (for any 
measurements) and duration 
during the 7 days following 
study vaccination (by treatment 
group).  
 
• 
To describe (severity and 
relationship to study 
vaccination) all AEs through 
28 days following any study 
vaccination. Primary and 
re-vaccination/attenuated 
challenge (substudy subjects) to 
be described separately and by 
treatment group.  
• 
All AEs through 28 days 
following study vaccination by 
severity and relationship to 
study vaccination (by treatment 
group). 
 

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• 
To describe (severity and 
relationship to study 
vaccination) any medically 
attended AE (MAAE) through 
84 days following any study 
vaccination. Primary and 
re-vaccination/attenuated 
challenge to be described 
separately and by treatment 
group. 
• 
All MAAEs through 84 days 
following study vaccination by 
severity and relationship to 
study vaccination, and by time 
since study vaccination (by 
treatment group).  
 
• 
To describe any AE of special 
interest (AESI) and serious AE 
(SAE) through Day 169/EOS 
including relationship to study 
vaccination. 
• 
All AESIs and SAEs through 
Day 169/EOS by severity and 
relationship to study 
vaccination, and by time since 
study vaccination (by treatment 
group).  
 
• 
To describe any severe acute 
respiratory syndrome 
coronavirus 2 (SARS-CoV-2) 
infection or AESI associated 
with COVID-19 disease if the 
COVID-19 pandemic remains 
ongoing in the region or if there 
are mass vaccinations using a 
COVID-19 vaccine during 
study conduct. 
• 
Incidence of SARS-CoV-2 
infections or AESIs associated 
with COVID-19 disease by 
severity, and by time since 
study vaccination (by treatment 
group). 
 
• 
To assess proportion of subjects 
(subset of subjects) cleared from 
colonization (present/absent) 
through Day 85.  
• 
B. pertussis clearance following 
study vaccination (subset of 
subjects at varying time points 
through Day 85). 
 
Mucosal secretory immunogenicity (S-IgA) (optional substudy only) 
Note that S-IgA objectives and endpoints for the overall study (as noted above) 
will also be analysed for the optional substudy and will be considered 
exploratory.  
 
Exploratory objectives  
Exploratory endpoints  
 
• 
To evaluate mucosal immunity 
of individual and combinations 
of pertussis antibodies (eg, 
WCE, PT, FHA and PRN and 
other known anti-pertussis 
mucosal antibodies) are 
relational to protection against 
colonization (BPZE1, BPZE1 + 
Boostrix, BPZE1 and BPZE1 + 
Boostrix, Boostrix control). 
• 
Induction of mucosal S-IgA at 
Day 29 or 85 (tested 
independently) compared by 
protection against colonization 
(Colonizers/Non-colonizers) by 
treatment group (BPZE1, 
BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix 
control). 

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• 
To measure BPZE1 induction of 
mucosal immunity (S-IgA) at 
Day 113 by treatment group; 
and to assess if induction of a 
boost response (relative to 
Day 85 response) is observed 
for those subjects with prior 
BPZE1 vaccination (BPZE1, 
BPZE1 + Boostrix).  
• 
Induction of mucosal S-IgA 
(WCE, PT, FHA, PRN and any 
additional anti-pertussis 
mucosal antibodies identified 
during assay development) at 
Day 113 compared with Day 85 
following BPZE1 attenuated 
challenge by treatment group 
(BPZE1, BPZE1 + Boostrix). 
 
• 
To assess if Day 113 response 
and longer-term durability 
through Day 169/EOS (absolute 
GMT) is altered with 
re-vaccination/attenuated 
challenge when compared to 
those subjects who did not 
participate in the substudy, 
relative to each randomized 
treatment group (BPZE1, 
BPZE1 + Boostrix, Boostrix).  
• 
Induction of mucosal S-IgA at 
Days 113 and 169/EOS (tested 
independently) in subjects who 
participated in the substudy 
compared with subjects who did 
not participate in the substudy 
by treatment group. 
 
Serum immunogenicity (IgA and IgG) (optional substudy only): WCE, PT, 
FHA, PRN, and any additional anti-pertussis antibodies identified during assay 
development using GMT and GMFR unless otherwise stated. 
Note that serum IgA and IgG objectives and endpoints for the overall study (as 
noted above) will also be analysed for the optional substudy and will be 
considered exploratory. 
 
Exploratory objectives  
Exploratory endpoints  
 
• 
To measure BPZE1 induction of 
serum immunity at Day 113; 
and to assess if induction of a 
boost response (relative to 
Day 85 response) is observed 
for those subjects with prior 
BPZE1 vaccination (BPZE1, 
BPZE1 + Boostrix). 
• 
BPZE1, BPZE1 + Boostrix, and 
Boostrix induction of serum 
immunity (IgA, IgG) at 
Day 113 compared with 
baseline (by treatment group). 
• 
BPZE1, BPZE1 + Boostrix, and 
Boostrix induction of serum 
immunity (IgA, IgG) at 
Day 113 compared with Day 85 
(by treatment group). 

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• 
To assess if Day 113 response 
and longer-term immune 
durability through 
Day 169/EOS is altered with 
re-vaccination/attenuated 
challenge when compared to 
those subjects who did not 
participate in the substudy, 
relative to each randomized 
treatment group (BPZE1, 
BPZE1 + Boostrix, Boostrix). 
• 
BPZE1, BPZE1 + Boostrix, and 
Boostrix induction of serum 
immunity (IgA, IgG) at Day 
113 and Day 169/EOS in 
subjects who participated in the 
substudy compared with 
subjects who did not participate 
in the substudy (tested 
independently by treatment 
group and day). 
 
• 
To assess if serum immunity of 
individual and combinations of 
pertussis antibodies (eg, WCE, 
PT, FHA, PRN, and any 
additional anti-pertussis 
antibodies) at Day 29 or 85 is 
relational to protection against 
colonization by treatment group 
and overall (BPZE1, 
BPZE1 + Boostrix, Boostrix).  
• 
BPZE1, BPZE1 + Boostrix, 
BPZE1 and BPZE1 + Boostrix, 
Boostrix induction of serum 
immunity (IgA, IgG) at Day 29 
or Day 85 compared by 
protection against colonization 
(Colonized/Non-colonized) 
(tested independently by 
treatment group and overall). 
 
• 
To assess functional antibody 
response by treatment group at 
Day 113 compared to baseline 
and Day 29, as measured by an 
appropriate assay for 
bactericidal activity. 
• 
Proportion of subjects with 
≥50% killing (or equivalent) for 
functional antibody response at 
Day 113 compared to baseline 
and Day 29 (tested 
independently by treatment 
group and day).  
 
Colonization (optional substudy only) 
 
Exploratory objective 
Exploratory endpoints  
 
• 
To demonstrate prior 
vaccination with BPZE1 
substantially reduces 
colonization at Days 92 and 99.  
• 
B. pertussis colony counts at 
each of Days 92 and 99 by 
treatment group (mean counts, 
area under the curve [AUC] or 
similar total bacterial load 
assessments will also be 
calculated). 
• 
Subjects with colonization at 
each of Days 92 and 99 by 
treatment group. Expressed as 
absolute proportion (Yes/No) 
and percent reduction relative to 
control. 
 
 

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Other, including cellular-mediated response 
 
Exploratory objectives 
Exploratory endpoints 
 
• 
To assess cellular-mediated 
response (by ELISpot or 
flow cytometry) to BPZE1 
and Boostrix (Th1 and Th2) 
in a subset of subjects. 
• 
Cellular-mediated response at 
baseline and Day 8 (safety lead-in 
cohort) and Days 85 and 113 (subset 
of substudy subjects). 
 
• 
To further characterize 
mucosal and serum 
immunological responses 
over time, relative to 
baseline status and to 
vaccination response, with 
any future assays developed 
for BPZE1. 
• 
Immunologic response measurement 
by treatment group. 
Study 
Population: 
Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in this 
study: 
1. The subject is male or female 6 to 17 years of age, inclusive, on 
Day 1 (day of vaccination). 
2. The subject (and/or legal guardian) is capable of understanding 
the written informed consent, providing signed and witnessed 
written informed consent (or assent, depending on age), and 
understanding and complying with protocol requirements. 
3. Female subjects of reproductive age must be nonpregnant and 
nonlactating, and if of childbearing potential (defined as any 
female who has experienced menarche at any time prior to or 
during the study), must agree to be heterosexually inactive from 
at least 21 days prior to enrolment and through 90 days 
following any study vaccination or agrees to consistently use 
any of the following methods of birth control from at least 
21 days prior to enrolment and through 90 days following any 
study vaccination: 
a. Condoms (male or female) with or without spermicide* 
b. Diaphragm with or without spermicide* 
c. Cervical cap with or without spermicide* 
*NOTE: The highest level of protection is required, in 
accordance with local regulations. 
d. Intrauterine device 
e. Oral or patch contraceptives 

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f. Norplant®, Depo-Provera®, or other acceptable method 
of birth control that is designed to protect against 
pregnancy. 
NOTE: Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of birth control. 
4. The subject has a stable health status, as established by physical 
examination, vital sign measurements (body temperature and 
heart rate), and medical history. 
5. The subject (and/or legal guardian) has access to a consistent 
and reliable means of electronic or telephone contact, which 
may be in the home, workplace, school, or by personal mobile 
electronic device. 
6. The subject is willing to refrain from routine nasal sprays 
(including steroid sprays) or washes for at least 7 days 
following any study vaccination. 
7. The subject (and/or legal guardian) lives within a reasonable 
distance from the clinical site, is willing and able to travel to 
and from the clinical site for follow-up visits and agrees to 
medical evaluation in the event of an AE requiring acute 
assessment. 
8. The subject (and/or legal guardian) agrees to stay in contact 
with the clinical site for the duration of the study, has no current 
plans to move from the study area, and agrees to provide 
updated contact information, as necessary. 
Exclusion Criteria 
Subjects meeting any of the following criteria (by review of medical 
history and subject intake) will be excluded from the study: 
1. The subject has a history of pertussis-containing vaccination 
(inclusive of school vaccination programs) or documented 
B. pertussis infection within 3 years prior to Day 1 and/or a 
history of Td-containing vaccination (without pertussis vaccine 
component) within 1 month prior to Day 1. 
2. The subject has a chronic significant illness actively being 
treated or a history of recent intervention for worsening or 
fluctuating symptoms (at the discretion of the investigator). 
3. The subject has a history of cancer (malignancy). 

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4. The subject has a congenital, hereditary, or acquired disease or 
disorder classified as autoimmune, immunodeficient, 
coagulopathy, hepatic, renal, neurologic (including a history of 
Bell’s palsy), or moderate to severe cognitive. (Attention deficit 
hyperactivity disorder permitted.) 
5. The subject currently uses smoking products (including vaping 
and e-cigarettes) and is unwilling to refrain from use from 
Day 1 through Day 29 following any study vaccination. 
6. The subject has received immunoglobulin, blood-derived 
products, systemic corticosteroids (at a dose of >10 mg per day 
for more than 10 days in total), or other immunosuppressant 
drugs within 90 days prior to Day 1. 
7. The subject has any chronic pulmonary disease requiring active 
medication or pulmonary therapies, with the following 
exceptions: 
a. Subjects with exercise-induced bronchospasm, if 
currently well controlled, who are willing to refrain 
from intense exercise for 7 days following study 
vaccination or 
b. Subjects with Step 1 (intermittent) asthma classification 
who have not had an exacerbation requiring oral 
systemic corticosteroids in the past year; have an FEV1 
documented to be >80%; do not have restrictions in 
normal activity due to breathing issues; and have used a 
short-acting beta-agonist less than or equal to 2 days per 
week over the past 2 months. 
NOTE: Subjects in the safety lead-in cohort are not 
allowed to have these exceptions. 
8. The subject has a history of oro/nasopharynx surgery 
(eg, adenoidectomy, tonsillectomy) within 60 days prior to 
Day 1. 
9. The subject has a known hypersensitivity to latex or any 
component of any study vaccine. Specific to the prior use of 
Boostrix: the subject has known hypersensitivity to neomycin 
or polymyxin; hypersensitivity after previous administration of 
diphtheria, tetanus, or pertussis vaccines; or has experienced 
transient thrombocytopenia or neurological complications 
following an earlier immunisation against diphtheria and/or 
tetanus. 

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10. The subject has participated in any other clinical trial for the 
testing of an unlicensed product where such product was 
received within 6 months prior to Day 1 or is planning to 
participate in any other clinical trial during study conduct 
through Day 85 following last study vaccination. 
NOTE: Exceptions may be considered for an investigational 
COVID-19 vaccine if the product has entered into adult Phase 3 
efficacy trials or is part of a mass vaccination rollout in this age 
group of subjects within a country. Direct guidance will be 
provided by the sponsor prior to study initiation. 
11. The subject has routine and/or repeated contact with, or is 
currently living in a household with, an immunocompromised 
individual. 
12. The subject has any medical condition that, in the opinion of 
the investigator, might interfere with the evaluation of the study 
objectives or might affect the safety of the individual (eg, 
eating disorder, major depression or anxiety disorder, history of 
alcohol or drug use). 
13. The subject is a study team member or first-degree relative of a 
study team member. 
14. The subject resides in a residence during the vaccination period 
(defined as through Day 85 following any study vaccination) 
where an infant less than 6 months of age resides or may reside. 
Additional Exclusion Criteria for Substudy Subjects ONLY 
Subjects meeting any of the following criteria will be excluded from 
participation in the optional substudy. 
15. Has received a pertussis-containing vaccination outside of 
study conduct since enrolment. 
16. Has received any form of immunotherapy determined to 
potentially have an effect on immune response (as determined 
by medical consultation, when necessary). 
Other Considerations for Temporarily Holding Vaccination 
(Days 1 or Substudy Day 85) 
Subjects meeting any of the following criteria may have a planned 
study vaccination deferred to a later date, but these criteria are not 
exclusionary for study enrolment/participation. For Visit 1, Day 1, 
subjects may be enrolled on a return visit if they remain within 45 days 
of consenting. Otherwise, subjects must be reconsented and reassessed 
per the inclusion and exclusion criteria (ie, re-enrolled).  

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• The subject has or reports acute respiratory tract 
symptoms/infection or rhinorrhoea within the past 3 days. 
Subject may be vaccinated once all symptoms have been 
resolved for at least 3 days. 
• The subject has or reports a body temperature of 100.4°F 
(38°C) or higher within the past 3 days. The subject may be 
vaccinated once the fever resolves and body temperature 
(site-measured or subject-measured) remains below 100.4°F 
(38°C) for at least 3 days. 
• The subject used antibiotics within the past 10 days. 
• The subject received a licensed vaccine (including any 
vaccine under emergency use authorization) within the past 
14 days. 
• The subject has a positive SARS-CoV-2 test result (eg, 
infection is ongoing) within the 3 days preceding 
vaccination. For those subjects testing positive, they must 
have a subsequent SARS-CoV-2 test result that is negative 
prior to vaccination (visit window may be extended to 
accommodate retesting needs). 
Study Design: 
This is a multi-centre, randomized, observer-blinded, placebo- and 
active comparator-controlled trial with a 6-month safety follow-up 
after first study vaccination. After signing the informed consent form 
(ICF; or providing assent when necessary) and meeting all inclusion 
and none of the exclusion criteria, eligible subjects will receive an 
intranasal vaccination with either BPZE1 vaccine or formulation buffer 
(placebo) via the intranasal mucosal atomization device (MAD) and an 
intramuscular (IM) injection of either Tdap vaccine (ie, Boostrix) or 
sterile normal saline (placebo) on Day 1. To maintain the blind, 
placebo vaccination via intranasal and IM routes, using formulation 
buffer and normal saline, respectively, will be included, and an 
unblinded team will manage vaccine logistics, preparation, and 
administration (when needed to maintain blinding) but will not be 
involved in study-related assessments or have subject contact for data 
collection after study vaccination. 
Approximately 360 subjects will be enrolled and randomly assigned 
(1:1:1) to 1 of 3 treatment groups (refer to Table S1) to contribute to 
safety and efficacy assessments. Enrolment will be operationally 
managed at the study level to maintain a minimum number of subjects 
enrolled in 2 age groups: 6 to 10 years, inclusive; and 11 to 17 years, 

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inclusive. It is estimated that a 10% dropout rate will occur, allowing 
for approximately 108 evaluable subjects per treatment group. 
 
Table S1 Dosing Scheme 
Treatment 
Group 
n 
Intranasal Vaccinationa 
(Day 1) 
IM Vaccinationb 
(Day 1) 
BPZE1 
Placebo 
Boostrix 
Placebo 
A 
120 
X 
- 
- 
X 
B 
120 
X 
- 
X 
- 
C 
120 
- 
X 
X 
- 
a 
Intranasal application of ~0.4 mL per nostril (0.8 mL total volume delivered). 
Intranasal vaccination will occur prior to IM vaccination. 
b  
IM injection of 0.5 mL to the deltoid region. 
All subjects will be monitored for at least 30 minutes after final study 
vaccination. On Day 1, intranasal vaccination will occur prior to 
IM vaccination with a minimum of 10 minutes (minimum of 
30 minutes for subjects in the safety lead-in cohort of 11 to 17 year 
olds) between intranasal and IM vaccinations. Immediate 
reactogenicity will be assessed at 30 minutes (+30 minutes) after the 
last study vaccination of the Day (ie, after IM vaccination on Day 1, 
after nasal vaccination on Day 85), prior to release from clinical 
observation. 
All subjects will record maximum daily reactogenicity in a subject 
diary for 7 consecutive days starting the day following any study 
vaccination (retrospective of the highest value in the previous 
24 hours). Subject diaries will be age-adjusted as appropriate. Local 
(arm; after IM injection only), nasal/respiratory, and general systemic 
reactogenicity events will be recorded, including start and stop dates 
and including any actual measurements (ie, body temperature, redness 
and/or swelling at the injection site). Trained clinical staff will review 
the information from the subject diary with the subjects at the 
following visit and apply a standard toxicity grade to any 
reactogenicity event. Subjects will be instructed that should they have 
reactogenicity with a potential toxicity grade 3 at any time, they should 
contact the site on the same day and be seen or referred to a qualified 
medical facility within 24 hours. 
As this is the first study of BPZE1 in school-age children, a staggered 
enrolment is planned. The first 45 subjects enrolled will be in the older 
age group (11 to 17 years, inclusive) and designated the safety lead-in 
cohort. Reactogenicity will be reviewed with these subjects during a 

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supplemental visit 7 days following first study vaccination. After 
reactogenicity for the safety lead-in cohort is reviewed by the medical 
monitor, medical lead, and Safety Monitoring Committee (SMC) 
chairman (with appropriate consultation with investigators, if needed), 
the remainder of subjects will be enrolled.  
All AEs will be monitored through 28 days after any study vaccination; 
all MAAEs will be monitored through 84 days following any study 
vaccination; and all AESIs and SAEs will be monitored through 
Day 169/EOS. Due to the COVID-19 pandemic, a SARS-CoV-2 
infection (confirmed by testing within the public health system) and 
any associated symptoms will be collected on a unique COVID-19 
electronic case report form through Day 169/EOS if the COVID-19 
pandemic remains ongoing in the region or if there are mass 
vaccinations using a COVID-19 vaccine during study conduct. 
Vaccines received outside of the study will be specifically queried at 
each visit and recorded through Day 169/EOS. 
An informational card will be provided to all subjects indicating their 
participation in this vaccination study to prevent subjects from 
inadvertently receiving any scheduled/planned Boostrix-containing 
vaccines (tetanus, pertussis, diphtheria) during study conduct. Any 
enrolled subject who does not receive Boostrix during the study will be 
offered Boostrix at the conclusion of the study (following unblinding); 
this Boostrix ‘catch-up’ will be provided outside of the study schedule, 
at the discretion of the investigator, with vaccine provided by the 
sponsor. 
Nasal and blood samples for immunogenicity assessments will be 
collected before vaccination and at selected time points following 
study vaccination. Mid-turbinate/nasopharyngeal sample collections 
will occur at selected time points following study vaccination to assess 
initial colonization (safety lead-in cohort only, Day 8) and to assess for 
clearance (remainder of cohort, either Day 29 or Day 85). Subjects in 
the safety lead-in cohort and a subset of subjects in the optional 
substudy will also have the option to provide extra blood for 
cellular-mediated immunity assessments at selected time points. 
Due to the uncertainty with movement and/or isolation practices 
associated with the COVID-19 pandemic, telemedicine and remote 
sampling may be initiated with proper investigator and/or medical 
oversight. 
The primary database lock will occur after all data are clean and all 
planned study procedures through Day 169/EOS (6 months) are 
complete. An interim database lock may occur after all subjects have 

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completed Day 29 and sample testing for all primary and select 
secondary immune endpoints have been completed (mucosal and 
serum), but results will only be provided at treatment assignment level 
to maintain the blind. The site and those interacting directly with the 
site or subject data (eg, contract research organization [CRO], 
laboratories) will remain blinded to subject assignment until EOS or 
end of sample testing, depending on the activities of the associated 
entities. 
Vaccination pause rules will be in place with a review by the SMC 
initiated if any rule is met. In addition, the medical monitor and 
medical lead are empowered to request a review by the SMC at any 
time for any safety reason. 
 
Substudy: Attenuated Challenge With BPZE1 Following Prior 
Vaccination with BPZE1, BPZE1 + Boostrix, or Boostrix Alone 
This is an optional open-label substudy in which enrolled subjects may 
elect to participate at any time from the day of enrolment through 
Day 85. A separate signed ICF (and separate assent when necessary) 
will be obtained prior to participation in the substudy. Subjects will be 
excluded from participating in the substudy if they meet additional 
exclusion criteria. Temporary vaccination holding criteria are to be 
followed for the Day 85 vaccination. 
Up to 120 enrolled subjects may participate in the substudy. The 
duration of the entire study will not change; however, additional 
visits/procedures starting on Day 85 will include the following: 
• 3 additional visits (Days 92, 99, and 113) 
• 1 additional intranasal vaccination (Day 85) 
• Up to 3 additional nasal samples (Days 92, 99, and 113), 
including 2 needed for mid-turbinate/nasopharyngeal 
sample collection (Days 92 and Day 99) and 1 needed for 
leukosorb (Day 113). Subjects will contribute to all Day 85 
sampling (systemic and nasal) 
• Up to 2 additional blood samples (Day 85 [if not already 
assigned to provide] and Day 113, including blood for 
cellular-mediated and systemic immunity responses) 
• 1 additional subject diary (subjects to record maximum 
daily reactogenicity [nasal/respiratory, systemic] in a 
subject diary for 7 consecutive days starting the day 
following study vaccination) 

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• 1 additional test for SARS-CoV-2 within 72 hours prior to 
Day 85 vaccination (see exclusion criteria for a temporary 
hold on vaccination). All subjects participating in the open-
label substudy will receive an intranasal 
re-vaccination/attenuated challenge with BPZE1 on Day 85. 
Subjects may have the planned re-vaccination/attenuated 
challenge deferred to a later date (up to 20 days) if 
pre-defined temporary exclusion criteria are met or for other 
personal reasons (eg, holiday, school schedule). Subjects 
will be monitored for at least 30 minutes after 
re-vaccination/attenuated challenge, with a post-vaccination 
evaluation for reactogenicity (nasal/respiratory, and 
systemic) completed prior to release from clinical 
observation. 
Subjects will receive a subject diary on Day 85. All subjects (with 
assistance when needed) will record maximum daily reactogenicity in a 
subject diary for 7 consecutive days starting the day following 
re-vaccination/attenuated challenge (retrospective of the highest value 
in the previous 24 hours). Subject-reported symptom diaries will be 
age-adjusted as appropriate. Nasal/respiratory and general systemic 
reactogenicity events will be recorded, including measurements of 
body temperature. Trained clinical staff will review the information 
from the subject diary with the subjects at the following visit and apply 
a standard toxicity grade to any reactogenicity event. Subjects will be 
instructed that should they have reactogenicity with a potential toxicity 
grade 3 at any time, they should contact the site on the same day and be 
seen or referred to a qualified medical facility within 24 hours. 
Nasal and blood samples for immunogenicity assessments will be 
collected before re-vaccination/attenuated challenge and at selected 
time points thereafter. Mid-turbinate/nasopharyngeal sample 
collections will be performed at selected time points to assess BPZE1 
colonization (B. pertussis culture or PCR). Subjects in the substudy 
will also have the option to provide extra blood for cellular-mediated 
immunity assessments at Day 85 and Day 113 (a maximum of 
45 subjects). 
All AEs will be collected following re-vaccination/attenuated challenge 
on Day 85 through Day 113. Following Day 113, only MAAEs, AESIs, 
and SAEs will be collected though Day 169/EOS. 
Estimated 
Study Duration: 
Study duration is approximately 9 months and duration of subject 
participation is approximately 6 months. 

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Immunogenicity 
and 
Colonization 
Assessments: 
Immune measurements will be conducted on serum (IgG and IgA) and 
nasal mucosal secretion (S-IgA) samples for anti-pertussis antibodies 
of WCE, PT, FHA, and PRN, as well as any additional antigens 
included in assay development. Serum bactericidal activity (or other 
functional assays identified) will be measured in a subset of subjects. 
Cellular-mediated responses to BPZE1 and Boostrix (Th1/Th17 vs 
Th2) will be assessed by ELISpot or flow cytometry in subjects at 
baseline and Day 8 (safety lead-in cohort) and Day 85 and Day 113 
(subset of substudy subjects). Additional testing for antibodies specific 
to B. pertussis may be performed at a later date as BPZE1 induces 
broader immunity more similar to natural infection induced immunity 
and does not contain the purified antigen levels of PT, FHA, and PRN 
found in Boostrix. Mid-turbinate/nasopharyngeal samples will be 
evaluated by real-time PCR or by B. pertussis culture for colonization 
of B. pertussis. 
Subjects will consent for the use of samples for further anti-pertussis 
antibody testing or other assay development as part of the standard 
consenting process. Aliquots of collected samples from this study may 
be retained for additional testing of biological responses (eg, 
antibodies, T-cell responses, microbiome) specific to future 
development of BPZE1 and ILiAD Biotechnologies’ B-Tech program 
for a maximum of 15 years (starting from the date at which the last 
subject had the last study visit), unless local rules, regulations, or 
guidelines require different time frames or different procedures, and in 
accordance with subject consent.  
Safety 
Assessments: 
Safety assessments for all subjects will include the following: vital sign 
measurements (including body temperature and heart rate), targeted 
physical examinations, reactogenicity, and AEs (including MAAEs, 
AESIs, and SAEs). 
Investigational 
Products, 
Dosage, and 
Route of 
Administration: 
• BPZE1, reconstituted with sterile water to provide 
109 colony-forming units (CFU) per 0.8 mL; administered 
intranasally, with approximately 0.4 mL per nostril (0.8 mL total 
volume delivered), by syringe with MAD 
• Boostrix (Tetanus Toxoid, Reduced Diphtheria Toxoid and 
Acellular Pertussis Vaccine, Adsorbed) injectable suspension, for 
IM use; administered as a single 0.5 mL IM injection to the deltoid 
region 
• Intranasal placebo (lyophilized BPZE1 buffer reconstituted with 
sterile water); administered intranasally, with approximately 
0.4 mL per nostril (0.8 mL total volume delivered), by syringe with 
MAD 

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• IM placebo (sterile normal saline for injection); administered as a 
single 0.5 mL IM injection to the deltoid region 
Sample Size: 
The sample size is based on calculations to achieve adequate response 
on Day 29 over baseline of S-IgA for WCE assay in the BPZE1 and 
BPZE1 + Boostrix groups. Assuming the GMT follows a log-normal 
distribution, by applying a natural logarithmic transformation of the 
GMT, a paired t-test will be used to test the difference of mucosal 
S-IgA against WCE at Day 29 compared with baseline (equivalent to 
natural logarithmic transformation of the GMFR). With an effective 
sample size of N=108 subjects per group, the study provides 95% 
power for detecting an effect size of 0.35 for each of the two primary 
comparisons with a two-sided significance level of 0.05. By 
multiplying the power for each of the two comparisons, the study 
provides an overall power of 90% (=95%*95%) for testing the primary 
endpoint in each of the two groups. Factoring in an estimated 10% 
drop-out rate, each treatment group would include approximately 120 
subjects for a total of approximately 360 subjects in the study.  
Statistical 
Methods: 
Statistical analysis will be performed using SAS software Version 9.3 
or later. Continuous variables will be summarized using the mean, 
standard deviation, median, first quartile, third quartile, minimum 
value, and maximum value. Categorical variables will be summarized 
using frequency counts and percentages, as well as a two-sided 95% 
confidence interval (CI) for proportions computed using the 
Agresti-Coull method. 
 
Primary endpoints 
For mucosal S-IgA against WCE at Day 29, the two-sided 95% CI for 
change from baseline in GMFR will be calculated. Assuming the GMT 
follows a log-normal distribution, by applying natural logarithmic 
transformation of the GMT, a paired t-test will be used to test the 
difference of mucosal S-IgA against WCE at Day 29 compared with 
baseline (equivalent to natural logarithmic transformation of the 
GMFR). The superiority objective will be demonstrated if the lower 
limit of the 95% CI for the difference of mucosal S-IgA against WCE 
at Day 29 compared to baseline on natural log scale is greater than 0 
within the treatment group. The superiority hypothesis will be tested in 
treatment groups BPZE1 and BPZE1 + Boostrix separately. 
 
Key secondary endpoints 
For comparisons of two proportions between treatment groups, eg, 
comparison between BPZE1 + Boostrix and Boostrix for the 

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proportion with titer ≥ 0.1 IU/mL (for diphtheria, tetanus), a non-
inferiority test for the difference between two proportions will be used. 
If the lower limit of the 95% CI for the difference of two proportions 
(proportion for BPZE1 + Boostrix - proportion for Boostrix) is greater 
than the non-inferiority margin (eg, -0.1), then BPZE1 + Boostrix is 
considered to be non-inferior to Boostrix. For comparisons between 
two groups on GMT (eg, comparison between BPZE1 + Boostrix and 
Boostrix) to demonstrate non-interference of IgG serum responses for 
the Boostrix-containing antigens (PT, FHA, PRN) at Day 29 when 
BPZE1 is co-administered with Boostrix, a two-sample t-test will be 
used to test the significance of the difference between two natural 
logarithmic transformed GMTs. If the lower limit of the 95% CI for the 
difference in the natural logs of two GMTs [ln(GMT for BPZE1 + 
Boostrix) - ln(GMT for Boostrix)] is greater than the non-inferiority 
margin (eg, -0.693), then BPZE1 + Boostrix is considered to be non-
inferior to Boostrix. 
  
For the key secondary endpoints, the Holm method will be used to 
control for multiplicity.  
 
A blinded sample size recalculation may occur when Day 29 
immunogenicity data for approximately 40 to 60 subjects per group are 
available.  
 
Version and 
Date of 
Protocol: 
30 March 2023 (Amendment 6, v7.0) 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
aP 
acellular pertussis 
AUC 
area under the curve 
BMI 
body mass index 
CFU 
colony-forming units 
CI 
confidence interval 
CRO 
contract research organization 
CSR 
clinical study report 
DHHS 
Department of Health and Human Services 
DNT 
dermonecrotic toxin 
DTaP 
diphtheria-tetanus-acellular pertussis 
eCRF 
electronic case report form 
EOS 
end of study 
FHA 
filamentous hemagglutinin 
GCP 
Good Clinical Practice 
GMFR 
geometric mean fold rise 
GMT 
geometric mean titre 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IM 
intramuscular 
IPV 
inactivated poliovirus vaccine 
IRT 
interactive response technology 
IU 
international unit(s) 
MAAE 
medically attended adverse event 

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Abbreviation 
Definition 
MAD 
mucosal atomization device 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
over-the-counter 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PRN 
pertactin 
PT 
pertussis toxin 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
S-IgA 
secretory immunoglobulin A 
SMC 
safety monitoring committee 
SUSAR 
suspected unexpected serious adverse reaction 
TCT 
tracheal cytotoxin 
Td 
tetanus and diphtheria toxoids 
Tdap 
tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis 
US 
United States 
WCE 
whole cell extract 
WFI 
Water for Injection 
wP 
whole cell pertussis 

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1 
Introduction 
1.1 
Background Information 
Currently registered acellular pertussis (aP) vaccines protect against respiratory disease but 
not against colonizing Bordetella pertussis (B. pertussis) infection and transmission. 
Bordetella pertussis is a gram-negative bacterium and a causative agent of pertussis, more 
commonly known as whooping cough. In a nonhuman primate model, convalescence from a 
natural B. pertussis infection protected against colonizing infection and transmission caused 
by a subsequent virulent B. pertussis challenge (ie, a natural infection confers short-term 
sterilizing immunity); however, vaccination with aP vaccines did not protect against 
subsequent challenge or transmission in animals housed in proximity (Warfel et al 2014). In 
contrast, a single intranasal administration of the highly attenuated live B. pertussis vaccine 
BPZE1 has demonstrated the ability to reduce the bacterial burden of a substantial 
B. pertussis challenge by more than 99.8% when compared to prior studies in nonhuman 
primates immunized with 3 doses of aP vaccine (Locht et al 2017). ILiAD Biotechnologies 
has licensed BPZE1 from the Institut Pasteur de Lille and Inserm with worldwide rights, and 
the company is conducting further clinical and regulatory development with the goal of an 
indication for active booster immunization against B. pertussis in adults and school-age 
children (ie, those who have received their childhood aP vaccination series). 
Despite the dramatic decline in pertussis cases and deaths in industrialized nations during the 
20th century due to public health vaccine initiatives, the last 2 decades have witnessed an 
increase in epidemics, and it is generally agreed that the short durability of aP vaccines along 
with the lack of protection against B. pertussis acquisition and/or transmission has 
contributed significantly to this resurgence (WHO 2015). In a recent outbreak in the United 
States (US), 82% of children who acquired pertussis had received their full complement of 
diphtheria-tetanus-acellular pertussis (DTaP) vaccinations. The adjusted risk of pertussis 
3 or more years after vaccination was 5 times higher than the risk less than 1 year after 
vaccination; and among children aged 7 to 11 years, the adjusted risk of pertussis 
6 or more years after vaccination was twice as high as the risk less than 3 years after 
vaccination (Zerbo et al 2019). In addition, the emergence of pertactin-negative B. pertussis 
strains may contribute to the reduced-effectiveness of aP vaccines (Safarchi et al 2015; 
Xu et al 2019). There is now a critical need for new and more effective vaccines targeting 
B. pertussis. As a potential solution to this problem, the BPZE1 vaccine has been developed 

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to be given as a single intranasal administration. Unlike existing aP vaccines, BPZE1 has the 
potential to prevent transmission of B. pertussis, through its mechanism of mucosal action 
that mimics wild-type B. pertussis infection, reducing the circulating burden of B. pertussis, 
and thereby disrupting the cycle of transmission that is the basis for ongoing epidemics 
currently observed every 3 to 5 years. 
BPZE1 was engineered by genetically altering or removing three B. pertussis toxins: 
pertussis toxin (PT), tracheal cytotoxin (TCT), and dermonecrotic toxin (DNT). Genetic 
stability of liquid BPZE1 formulation was demonstrated in vitro and in vivo 
(Thalen et al 2020). The safety of liquid BPZE1 has been assessed in immunocompetent and 
immunosuppressed animals (Mielcarek et al 2006; Feunou et al 2008; Skerry et al 2009; 
Mielcarek et al 2010). These results contributed to downgrading BPZE1 from a 
Biosafety Level 2 to a Biosafety Level 1 organism in the US and France. Good Laboratory 
Practice toxicology studies have confirmed the safety of BPZE1 in 2 animal models: mouse 
and rabbit (data on file). 
BPZE1 in a liquid formulation has been studied at various doses from 
103 to 109 colony-forming units (CFU) in two Phase 1 clinical studies in Sweden with no 
vaccine-related serious adverse events (SAEs) and comparable general adverse events (AEs) 
to placebo controls. Most recently, in a Phase 2b study conducted in the US, BPZE1 (or 
Boostrix™) was given as a single vaccination supplied in a lyophilized vial for reconstitution 
prior to intranasal administration via the intranasal mucosal atomization device (MAD) and 
then a re-vaccination/attenuated challenge was given 3 months later with BPZE1 (or placebo) 
to 300 healthy adults aged 18 to 50 years. BPZE1 (but not Boostrix) was shown to induce 
mucosal secretory immunoglobulin A (S-IgA) as measured by whole cell extract (WCE), 
filamentous hemagglutinin (FHA), and pertactin (PRN) assays, and these antibodies were 
sustained through 9 months (end of study [EOS]). Unlike Boostrix, the BPZE1-induced 
mucosal immunity was associated with protection from B. pertussis acquisition 
(colonization) using an attenuated challenge with BPZE1 3 months later. In addition, BPZE1 
induced systemic immunoglobulin A (IgA) and immunoglobulin G (IgG) anti-pertussis 
antibodies (WCE, PT, FHA and PRN), which were sustained above baseline through the 
9 months of study. A single vaccination appeared sufficient to induce both mucosal and 
systemic responses in this population. In addition, systemic and nasal/respiratory 
reactogenicity was overall none to mild, similar to Boostrix/placebo in intensity, with average 

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duration of 3 days, and was not associated with severe events. Re-vaccination/attenuated 
challenge did not result in worsening reactogenicity. Overall, the AE profile was similar 
between treatment groups and no SAEs were attributed to vaccination. The Phase 2b study 
was conducted in adults, in which the majority (>90%) was estimated to have received a 
whole cell pertussis (wP) vaccination as their primary vaccination series during infancy. In 
the current study, subjects will all have received aP vaccinations containing (at a minimum) 
PT, FHA, and PRN as their primary series and will have never received a wP vaccination. 
Since wP vaccines and BPZE1 induce Th1/Th17 responses, which have been associated with 
polarizing Th1 long-term immunity, whereas aP vaccines preferentially stimulates a 
polarizing Th2 pathways, administration of BPZE1 in this school-age population may be the 
first stimulation of the Th1/Th17 pathway for preferential T-cell-associated immunity (Warfel 
et al 2014; Antunes et al 2018). 
1.2 
Rationale 
Acellular pertussis vaccines were introduced into most developed countries in the late 1990’s 
and early 2000’s, and for 2 decades, children in these countries have received only aP 
vaccinations. The resurgence of B. pertussis in these countries, despite high vaccination rates, 
is hypothesized to be linked to the sole use of aP vaccines, which do not alter B. pertussis 
acquisition and have limited durability (Althouse and Scarpino 2015; WHO 2015). The 
availability of a cost-effective pertussis vaccine that provides improved efficacy and 
prolonged protection with the potential to reduce or eliminate transmission would present a 
breakthrough in the prevention of colonizing B. pertussis infections. The current pertussis 
vaccine strategies do not provide mucosal immunity or alter B. pertussis acquisition and 
therefore have not been successful in halting human-to-human transmission. As humans are 
the only known reservoir for B. pertussis, targeting colonization would provide a novel 
approach through mucosal-induced immunity to reduce the B. pertussis reservoir in the 
population and thereby reduce transmission. The timing of aP vaccine introduction has 
resulted in a school-age population who could benefit from a broader immune response 
achievable with a live attenuated pertussis vaccine such as BPZE1. 
The intranasally administered BPZE1 live attenuated vaccine provides an opportunity to 
generate a locally effective mucosal antibody response at the site of potential exposure, 
mimic the route of entry of the wild-type pathogen, and induce a broader immune response as 
measured by cellular, mucosal, and serum indices. Inducing mucosal immunity with an 

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attenuated live vaccine delivered through intranasal vaccination could halt progression from 
upper airway to lower airway disease in BPZE1-vaccinated individuals as well as strengthen 
herd immunity by reducing upper airway person-to-person transmission. The overall effect 
would be improved protection of even the most vulnerable from B. pertussis through a robust 
booster vaccination strategy with the best potential to disrupt B. pertussis epidemics. 
Acellular pertussis vaccines are currently recommended as both primary and booster 
vaccinations and usually given in a combination vaccine containing diphtheria (D/d), tetanus 
(T), and pertussis (P/p), with the level of antigen content dictated by standard nomenclature 
of DTaP (higher antigen content overall) or Tdap (lower antigen content for diphtheria and 
pertussis). The current recommendation in the United Kingdom includes the childhood 
booster of Tdap at 3 years of age with no adolescent booster of aP-containing vaccine, 
whereas some other European/Commonwealth countries and the US have a similar early 
childhood DTaP vaccination schedule but have added a Tdap booster during the school-age 
period (up to and including adolescence). This study will investigate BPZE1-induced 
immune responses in a background of DTaP or Tdap, with the last pertussis-containing 
booster occurring more than 3 years prior. BPZE1 alone as well as coadministration with 
Boostrix will be investigated to test safety and whether augmenting/broadening mucosal 
immune responses are possible in an aP primed-only population. Furthermore, the testing of 
interference of BPZE1 with all components found in Boostrix will be investigated as a key 
secondary objective. In addition, demonstrating protection against subsequent colonization 
using the attenuated challenge model (re-vaccination/attenuated challenge with BPZE1) will 
be investigated at 3 months following initial vaccination (optional substudy) as a secondary 
objective. As this population has never received a wP vaccination, this will be the first time 
that a broader immunization against B. pertussis is provided; therefore, additional hypotheses 
include the following: a single intranasal vaccination with BPZE1 will be sufficient to induce 
a differential immune response compared to Boostrix (eg, mucosal immunity induction and 
reduction in B. pertussis acquisition), and immunological boosting with 
re-vaccination/attenuated challenge is not required to achieve mucosal immunity and 
protection. 

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1.3 
Potential Risks and Benefits 
1.3.1 Potential Risks 
1.3.1.1 Risks of Study Participation 
The risks of study participation include exposure to study vaccine, maintenance of 
confidentiality, and side effects of blood and nasal sample collections. All risks will be 
minimized to every extent possible. 
1.3.1.2 BPZE1 Risks to Study Subjects 
The risks of BPZE1 administration are expected to be minimal and clinically manageable. 
The attenuated BPZE1 bacteria colonize the upper respiratory tract similarly to wild-type 
B. pertussis and colonization is strictly limited to respiratory epithelium without 
dissemination of the bacteria outside the respiratory tract, which also excludes systemic 
bacteraemia of the BPZE1 strain. Clearance of BPZE1 follows kinetics of wild-type 
clearance over the course of 28 days with the majority of subjects clearing in the first 
2 weeks (data on file). In the recent Phase 2b study, systemic and nasal/respiratory 
reactogenicity events were mainly none to mild in severity with mean duration of 3 days and 
did not vary between BPZE1 and Boostrix. A second dose of BPZE1 did not induce greater 
reactogenicity events. No grade 3 reactogenicity events occurred without a secondary cause 
(unrelated to vaccination). Treatment-emergent AEs were mainly mild and of similar 
incidence between BPZE1 and Boostrix (first vaccination) and placebo (re-vaccination). 
There were no SAEs attributed to vaccination in any studies to date. 
B. pertussis is spread mainly by aerosol formed by coughing of infected persons. The 
coughing is induced by the TCT, which is more than 95% reduced in BPZE1. The BPZE1 
strain is not expected to induce significant coughing (as demonstrated in the Phase 2b study); 
therefore, transmission of the attenuated strain is highly unlikely. Furthermore, Bordetella 
species have fastidious growth requirements and have limited survival time outside the 
human body. 
B. pertussis has not been shown to be allergenic in any preclinical or clinical studies to date, 
nor have any of the excipients in the lyophilized formulation been shown to induce allergic 
reactions. In fact, using a classical murine asthma model, nasal inoculation of BPZE1 
10 days before ovalbumin sensitization reduced peri-bronchial inflammation upon ovalbumin 

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challenge, as compared with the nonvaccinated control group of sensitized mice 
(Kavanagh et al 2010). However, there remains a theoretical risk of immediate allergic 
reaction, as is present with any vaccine product and therefore subjects will remain in clinic 
for 30 minutes of observation following vaccinations. 
BPZE1 vaccine or the placebo will be administered intranasally via the MAD attached to a 
syringe while subjects partially recline or tilt their head with their neck in retraction. The 
MAD atomizes the liquid vaccine as it exits the syringe to provide a uniform spray to the 
mucosal surface. Atomization could induce local nasal reactogenicity such as sneezing, 
irritated nasal passage, cough, sore throat, or in very rare cases, epistaxis. These 
reactogenicity parameters will be assessed daily for 7 days following any study vaccination 
and will be attributed to the vaccine. 
Chronic carriage of B. pertussis has not been reported and BPZE1 has always been shown to 
clear in prior studies. Long-term BPZE1 colonization is therefore not expected. No 
cross-contamination between the subjects was observed in the previous clinical trials of 
BPZE1, nor has any risk to the family members of study subjects been reported; however, as 
a precaution, subjects who are in close (and repeated) contact with individuals with known 
immunodeficiency or on immunosuppressant therapy or who reside or may reside with an 
infant (<6 months of age) during the vaccination period will be excluded from participation 
in the study. In case of transmission to other humans or accidental exposure, an efficient 
treatment is a commercially available macrolide (BPZE1, similar to B. pertussis, has been 
shown to be sensitive to erythromycin/azithromycin). 
No reproductive toxicology studies have been performed with BPZE1 to date; however, 
when female mice were vaccinated with BPZE1 shortly before mating, no negative effect on 
either the pregnancy or their offspring was observed, and the offspring were protected against 
B. pertussis challenge (Feunou et al 2016). 
1.3.1.3 Boostrix Risks to Study Subjects 
The risks of Boostrix administration are expected to be minimal and clinically manageable. 
Local adverse reactions include pain, redness, swelling, and injected arm circumference 
increase. In rare cases, significant upper extremity swelling may occur after repeated 
vaccinations with aP vaccines. General adverse reactions include headache, fatigue, 
gastrointestinal symptoms, and fever. 

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If Guillain-Barré syndrome occurred within 6 weeks of receipt of a prior vaccine containing 
tetanus toxoid, the risk of Guillain-Barré syndrome may be increased following a subsequent 
dose of tetanus toxoid-containing vaccine, including Boostrix. 
The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic 
reactions. 
Syncope can occur in association with administration of injectable vaccines, including 
Boostrix. Syncope can be accompanied by transient neurological signs such as visual 
disturbance, paraesthesia, and tonic-clonic limb movements. Procedures for administration 
should be in place to avoid falling injury and to restore cerebral perfusion following syncope. 
Progressive or unstable neurologic conditions (eg, cerebrovascular events and acute 
encephalopathic conditions) are reasons to defer vaccination with a pertussis-containing 
vaccine, including Boostrix. It is not known whether administration of Boostrix to subjects 
with an unstable or progressive neurologic disorder might hasten manifestations of the 
disorder or affect the prognosis. Administration of Boostrix to subjects with an unstable or 
progressive neurologic disorder may result in diagnostic confusion between manifestations of 
the underlying illness and possible adverse effects of vaccination. For these reasons, subjects 
with congenital or acquired neurologic conditions will be excluded from this study. 
Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a 
tetanus toxoid-containing vaccine usually have a high serum tetanus antitoxin level and 
should not receive Boostrix or other tetanus toxoid-containing vaccines unless at least 
10 years have elapsed since the last dose of tetanus toxoid-containing vaccine. 
Note that the safety of Tdap-inactivated poliovirus vaccine (IPV) was similar when Tdap-IPV 
vaccine was administered 1 month after either Td-IPV or placebo in 500 subjects (Beytout et 
al 2009). At 7 days, 85.1% versus 93.4% of subjects reported at least one reaction at the 
injection site, mainly pain (82.6% versus 92.1%); 40.5% versus 45.0% reported at least one 
systemic AE (mainly headache: 26.4% versus 26.0%); fever concerned 1.7% of both groups. 
No serious vaccine-related AEs were reported. The pertussis immunization lead at the UK 
Health Security Agency has also confirmed the acceptability of the study approach (personal 
communication). 

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Prior to administration, the healthcare provider should review the immunization history for 
possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an 
assessment of benefits and risks. Epinephrine and other appropriate agents used for the 
control of immediate allergic reactions must be immediately available should an acute 
anaphylactic reaction occur. 
Investigators should refer to the product insert provided for Boostrix (BOOSTRIX 2020). 
The following section on the possible undesirable effects from Boostrix is provided verbatim 
from the SmPC (Boostrix 2021): 
“Summary of the Safety Profile 
The safety profile presented below is based on data from clinical trials where Boostrix was 
administered to 839 children (from 4 to 8 years of age) and 1931 adults, adolescents, and 
children (from 10 to 76 years of age) (Table 1-1). 
The most common events occurring after Boostrix administration in both groups were local 
injection site reactions (pain, redness, and swelling) reported by 23.7 – 80.6% of subjects in 
each trial. These usually had their onset within the first 48 hours after vaccination. All 
resolved without sequelae. 
Tabulated List of Adverse Reactions 
Adverse reactions reported are listed according to the following frequency: 
• Very common:  
(≥ 1/10) 
• Common: 
 
(≥ 1/100 to < 1/10) 
• Uncommon: 
 
(≥ 1/1,000 to < 1/100) 
• Rare:  
 
(≥ 1/10,000 to < 1/1,000) 
• Very rare: 
 
(< 1/10,000) 
Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. 

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Clinical Trials 
Table 1-1 
Adverse Reactions Reported in Clinical Trials with Boostrix 
System Organ Class 
Frequency 
Adverse Reactions 
Subjects Aged 4 – 8 years 
(N=839) 
Subjects Aged 10 – 76 years 
(N=1931) 
Infections and 
infestations 
Uncommon 
Upper respiratory tract infection 
Upper respiratory tract 
infection, pharyngitis 
Blood and lymphatic 
system disorders 
Uncommon 
 
Lymphadenopathy 
Metabolism and 
nutrition disorders 
Common 
Anorexia 
 
Psychiatric disorders 
Very 
common 
Irritability 
 
Nervous system 
disorders 
Very 
common 
Somnolence 
Headache 
Common 
Headache 
Dizziness 
Uncommon 
Disturbance in attention 
Syncope 
Eye disorders 
Uncommon 
Conjunctivitis 
 
Respiratory, thoracic 
and mediastinal 
disorders 
Uncommon 
 
Cough 
Gastrointestinal 
disorders 
Common 
Diarrhoea, vomiting, 
gastrointestinal disorders 
Nausea, gastrointestinal 
disorders 
Uncommon 
 
Diarrhoea, vomiting 
Skin and 
Subcutaneous tissue 
disorders 
Uncommon 
Rash 
Hyperhidrosis, pruritis, rash 
Musculoskeletal and 
connective tissue 
disorders 
Uncommon 
 
Arthralgia, myalgia, joint 
stiffness, musculoskeletal 
stiffness 
General Disorders 
and administration 
site conditions 
Very 
Common 
Injection site reactions (such as 
redness and/or swelling), 
injection site pain, fatigue 
Injection site reactions (such as 
redness and/or swelling), 
malaise, fatigue, injection site 
pain 
Common 
Pyrexia (fever ≥ 37.5°C including 
fever > 39.0°C), extensive 
swelling of vaccinated limb 
(sometimes involving the 
adjacent joint) 
Pyrexia (fever ≥ 37.5°C), 
injection site reactions (such as 
injection site mass and injection 
site abscess sterile) 
Uncommon 
Other injection site reactions 
(such as induration), pain 
Pyrexia (fever > 39.0°C), 
influenza like illness, pain 

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Reactogenicity After Repeat Dose 
Data on 146 subjects suggest that there might be a small increase in local reactogenicity 
(pain, redness, swelling) with repeated vaccination according to a 0, 1, 6 months schedule in 
adults (> 40 years of age). 
Data suggest that in subjects primed with DTP in childhood, a second booster dose might 
give an increase of local reactogenicity. 
Post-Marketing Surveillance 
Because these events were reported spontaneously, it is not possible to reliably estimate their 
frequency (Table 1-2). 
Table 1-2 
Adverse Reactions Reported with Boostrix During Post-Marketing 
Surveillance 
System Organ Class 
Frequency 
Adverse Reactions 
Immune system disorders 
Unknown 
Allergic reactions, including anaphylactic and 
anaphylactoid reactions 
Nervous system disorders 
Unknown 
Hypotonic-hyporesponsiveness episodes, 
convulsions (with or without fever) 
Skin and subcutaneous tissue 
disorders 
Unknown 
Urticaria, angioedema 
General disorders and 
administration site conditions 
Unknown 
Asthenia 
 
Following administration of tetanus toxoid-containing vaccines, there have been very rare 
reports of adverse reactions on the central or peripheral nervous systems, including 
ascending paralysis or even respiratory paralysis (eg Guillain-Barre syndrome).” 
1.3.1.4 Risks to the Environment or Potential for Interaction With 
Wild-Type B. Pertussis Strains 
To avoid accidental exposure, actions should be taken to minimize generation of aerosols 
beyond that given directly into the nasal cavity, since the bacterium is strictly a respiratory 

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tract organism. Clinical staff members should follow appropriate biological handling 
procedures. 
The attenuated strain of B. pertussis (BPZE1) was engineered by genetically altering or 
removing three B. pertussis toxins: PT, TCT, and DNT. The genetic modifications 
(replacement of the ampG gene, deletion of the DNT, and the mutations of the PT) are not 
expected to alter the host range of B. pertussis BPZE1 compared to the wild-type 
B. pertussis. The genetic modifications in BPZE1 strongly increase the in vivo and in vitro 
safety, as follows: 
• The double nucleotide mutation in the substrate binding and the active site of the PT 
results in a strong reduction of the enzyme activity. 
• The replacement of the B. pertussis ampG gene by the Escherichia coli ampG gene 
results in an over 95% reduction in release of the TCT in the medium. 
• The DNT is not expressed in the BPZE1 strain. 
• BPZE1 is not invasive and has no selective advantage in the environment. The 
potential for exchange of genetic material is highly improbable since B. pertussis 
does not harbour plasmids or conjugative transposons. In addition, B. pertussis 
Tohama I (origin of BPZE1) does not harbour intact prophage genomes and is 
therefore incapable of producing functional phage particles. 
Reversion to wild type has not been demonstrated in vivo or in vitro, including 20 continuous 
in vitro passages over a period of 20 weeks, as well as 9 in vivo passages through mice over a 
period of 27 weeks (Feunou et al 2008; Thalen et al 2020). 
Due to the robust preclinical safety data, BPZE1 has been classified as a Biosafety 
Level 1 organism by US and French authorities Republique Francaise Ministere de 
l’Enseignement Superieur et de la Recherche (French Ministry of Higher Education and 
Research). Germany, Belgium, Spain, the US, the Netherlands, and Sweden have accepted 
the Level 1 rating for the purpose of manufacturing and clinical studies. 
In summary, the preliminary risk assessment for this study suggests there is an extremely low 
risk for potential environmental impact associated with administering the BPZE1 to study 
subjects. 

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1.3.2 Known Potential Benefits 
The benefits of the study lie primarily in the opportunities to science and humanity. No direct 
personal benefit from participation in the study can be guaranteed, as the vaccine may or may 
not confer protection in humans. As Boostrix is an approved vaccine for boosting the 
immune response to pertussis, tetanus, and diphtheria, a clinical benefit of receiving this 
vaccine has been established. All subjects will have the benefit of receiving Boostrix either 
during the study (if randomized to receive Boostrix) or at study conclusion (at the discretion 
of the investigator). 

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2 
Study Objectives and Endpoints 
2.1 
Primary Objectives and Endpoints 
Immunogenicity 
Primary objectives 
Primary endpoints 
• 
To demonstrate BPZE1 induction of broad 
pertussis mucosal secretory 
immunoglobulin A (S-IgA) immunity is 
measurable at Day 29 by geometric mean 
fold rise (GMFR) by antibodies to whole 
cell extract (WCE) (BPZE1, 
BPZE1 + Boostrix). 
• 
GMFR of BPZE1 induction of mucosal 
S-IgA against WCE at Day 29 by treatment 
group (BPZE1, BPZE1 + Boostrix). 
Safety 
Primary objectives 
Primary endpoints 
• 
To assess reactogenicity by toxicity scoring 
through 7 days following first study 
vaccination with any combination of 
pertussis-containing vaccines (BPZE1, 
BPZE1 + Boostrix, Boostrix). 
• 
Occurrence of solicited AEs including local, 
nasal/respiratory, and systemic 
reactogenicity events through 7 days 
following first study vaccination with any 
combination of pertussis-containing 
vaccines. 
 

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2.2 
Secondary Objectives and Endpoints 
Immunogenicity 
Key secondary objectives 
Key secondary endpoints 
• 
To demonstrate non-interference of 
immunoglobulin G (IgG) serum responses for 
all Boostrix-containing antigens (diphtheria, 
tetanus, pertussis toxin [PT], filamentous 
hemagglutinin [FHA], pertactin [PRN]) at Day 
29 when BPZE1 is co-administered with 
Boostrix (BPZE1 + Boostrix vs Boostrix). 
• 
BPZE1 + Boostrix induction of serum 
IgG against diphtheria, tetanus, and all aP 
antigens (PT, FHA, PRN) compared with 
Boostrix at Day 29 (criteria to be 
assessed for diphtheria and tetanus 
responses per WHO guidelines). 
Colonization (optional substudy only) 
Secondary objective 
Secondary endpoints 
• 
To describe colonization in each of the groups: 
BPZE1, BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix control. 
• 
Proportion of subjects with colonization 
at either Day 92 or 99 (B. pertussis 
culture or polymerase chain reaction 
[PCR]) with prior BPZE1 immunization 
following re-vaccination/attenuated 
challenge at Day 85 (BPZE1, 
BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix control). 
Expressed as absolute proportion 
(Yes/No). 
Mucosal secretory immunogenicity (S-IgA): WCE, PT, FHA, PRN, and any additional anti-pertussis 
mucosal antibodies identified during assay development using geometric mean titre (GMT) and 
geometric mean fold rise (GMFR) unless otherwise stated. 
NOTE: To also be tested separately in subjects who participate in the optional substudy as exploratory 
endpoints, to assess response following re-vaccination/attenuated challenge.  
Secondary objectives 
Secondary endpoints 
• 
To demonstrate BPZE1 induction of mucosal 
S-IgA immunity is non-inferior to Boostrix at 
Day 29 as measured by antibodies to WCE 
(BPZE1 vs Boostrix). 
• 
BPZE1 induction of mucosal S-IgA 
against WCE compared with Boostrix at 
Day 29. 
• 
To demonstrate BPZE1 induction of mucosal 
S-IgA immunity is greater than baseline at 
Day 29 (BPZE1, BPZE1 + Boostrix). 
• 
BPZE1 induction of mucosal S-IgA at 
Day 29 compared to baseline. 
• 
To demonstrate BPZE1 induction of mucosal 
S-IgA immunity remains greater than baseline 
over the study period and at Day 169/EOS 
(BPZE1, BPZE1 + Boostrix).  
• 
BPZE1 and BPZE1 + Boostrix induction 
of mucosal S-IgA compared with 
baseline at Days 85 and 169/EOS (tested 
independently). 
• 
To demonstrate BPZE1 + Boostrix induction 
of mucosal S-IgA immunity is non-inferior to 
BPZE1 at Days 29 and 169/EOS (BPZE1 + 
Boostrix vs BPZE1).  
• 
BPZE1 + Boostrix induction of mucosal 
S-IgA compared with BPZE1 at Days 29 
and 169/EOS (tested independently). 

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• 
To assess if age, time since last aP vaccination 
(prior to study entry), or other baseline 
demographics have a differential response to 
induction of mucosal S-IgA immunity 
(BPZE1, BPZE1 + Boostrix) at Day 29. 
• 
BPZE1 and BPZE1 + Boostrix induction 
of mucosal S-IgA in covariate analysis 
by age, time since last aP vaccination 
(prior to study entry), or other baseline 
demographics at Day 29. 
• 
To assess if baseline antibody values, by 
baseline quantile, have variable responses at 
Day 29 to induction of S-IgA immunity when 
BPZE1 is given alone or with Boostrix 
(BPZE1, BPZE1 + Boostrix). 
• 
BPZE1 and BPZE1 + Boostrix induction 
of mucosal S-IgA by baseline quantile at 
Day 29. 
• 
To assess seroconversion for each of the 
anti-pertussis S-IgA antibodies at Day 29 
(BPZE1, BPZE1 + Boostrix, Boostrix). 
Additional combinations of antibody response 
(WCE, PT, FHA, PRN, and any additional 
anti-pertussis antibodies) may also be tested.  
• 
Seroconversion rate (2-fold increase over 
baseline value or a 4-fold increase over 
the lower limit of assay detection 
[whenever the baseline value falls below 
the lower limit of assay detection]) for 
mucosal S-IgA at Day 29 by treatment 
group.  
• 
To assess reverse cumulative distribution 
curves for immune response (S-IgA) at Day 
29. 
• 
Reverse cumulative distribution curves of 
each anti-pertussis mucosal antibodies 
S-IgA GMT at Day 29 by treatment 
group. 
Serum immunogenicity (IgA and IgG): WCE, PT, FHA, PRN, and any additional anti-pertussis 
antibodies identified during assay development using GMT and GMFR unless otherwise stated. 
NOTE: To also be tested separately in subjects who participate in the optional substudy as exploratory 
endpoints, to assess response following re-vaccination/attenuated challenge. 
Secondary objectives 
Secondary endpoints 
• 
To demonstrate that BPZE1 (BPZE1, 
BPZE1 + Boostrix) induction of serum 
immunity is significantly greater than baseline 
at Day 29. 
• 
BPZE1 and BPZE1 + Boostrix induction 
of serum immunity (IgA, IgG) at Day 29 
compared with baseline (tested 
independently by treatment group). 
• 
To demonstrate that BPZE1 + Boostrix 
induction of serum immunity is non-inferior 
compared to Boostrix at Day 29 
(BPZE1 + Boostrix vs Boostrix). 
• 
BPZE1 + Boostrix induction of serum 
immunity (IgA, IgG) compared with 
Boostrix at Day 29. 
• 
To demonstrate that BPZE1 (BPZE1, 
BPZE1 + Boostrix) induction of serum 
immunity remains significantly greater than 
baseline over the course of the study and at 
Day 169/EOS and to assess antibody decay 
curves for BPZE1, BPZE1 + Boostrix and 
Boostrix. 
• 
BPZE1 and BPZE1 + Boostrix induction 
of serum immunity (IgA, IgG) at Day 85 
and Day 169/EOS compared with 
baseline (tested independently by 
treatment group and day). 
• 
Antibody decays (IgA, IgG) over the 
course of the study (tested independently 
by treatment group). 

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• 
To demonstrate that BPZE1 induction of 
serum IgA is non-inferior to Boostrix at Day 
169/EOS (BPZE1 vs Boostrix; BPZE1 + 
Boostrix vs Boostrix) 
• 
BPZE1 induction of serum IgA 
compared with Boostrix at Day 169/EOS. 
• 
BPZE1 + Boostrix induction of serum 
IgA compared with Boostrix at Day 
169/EOS. 
• 
To assess if age, time since last aP vaccination 
(prior to study entry), or other baseline 
demographics have a differential response to 
BPZE1 or Boostrix at Day 29 (BPZE1, BPZE1 
+ Boostrix, Boostrix).  
• 
BPZE1, BPZE1 + Boostrix, and Boostrix 
induction of serum immunity (IgA, IgG) 
by age, time since last aP vaccination 
(prior to study entry), or other baseline 
demographics at Day 29 (tested 
independently by treatment group). 
• 
To assess if baseline antibody values, by 
baseline quantile, have variable serum 
immunity responses at Day 29 when BPZE1 is 
given alone or with Boostrix or Boostrix alone 
(BPZE1, BPZE1 + Boostrix, Boostrix). 
• 
BPZE1, BPZE1 + Boostrix and Boostrix 
induction of serum immunity (IgA, IgG) 
at Day 29 by baseline quantile (tested 
independently by treatment group). 
• 
To demonstrate that BPZE1 (BPZE1, 
BPZE1 + Boostrix) induces a measurable 
functional antibody response (subset of 
subjects) at Day 29; and to assess whether 
there is similar magnitude as that seen with 
Boostrix (BPZE1 vs BPZE1 + Boostrix vs 
Boostrix).  
• 
BPZE1 and BPZE1 + Boostrix induction 
of measurable functional antibody 
(subset of subjects) compared with 
Boostrix at Day 29 (tested independently 
by treatment group). 
• 
To assess for seroconversion at Days 29 and 
85 (BPZE1, BPZE1 + Boostrix, Boostrix). 
Additional combinations of antibody response 
(WCE, PT, FHA, PRN, and any additional 
anti-pertussis antibodies) may also be tested. 
• 
Seroconversion rate for serum immunity 
(IgA, IgG) defined as a 2-fold increase 
over baseline value; or a 4-fold increase 
over the lower limit of assay detection 
(whenever the baseline value falls below 
the lower limit of assay detection) at 
Days 29 and 85 (tested independently by 
treatment group and day). 
• 
To assess reverse cumulative distribution 
curves for immune responses (IgA and IgG) at 
Day 29. 
• 
Reverse cumulative distribution curves of 
GMT at Day 29 by treatment group. 
Safety 
NOTE: Subjects participating in the substudy will be evaluated for safety endpoints in a separate 
evaluation after Day 85 re-vaccination/attenuated challenge.  
Secondary objectives 
Secondary endpoints 

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• 
To describe reactogenicity events during the 
7 days following any study vaccination. 
Primary and re-vaccination/attenuated 
challenge (substudy subjects) to be described 
separately, by treatment group. Reactogenicity 
will be classified by local, nasal/respiratory, 
and systemic.  
• 
Maximum daily severity during the 
7 days following study vaccination (by 
treatment group). 
• 
Incidence by toxicity grade during the 
7 days following study vaccination (by 
treatment group). 
• 
Mean response (for any measurements) 
and duration during the 7 days following 
study vaccination (by treatment group).  
• 
To describe (severity and relationship to study 
vaccination) all AEs through 28 days 
following any study vaccination. Primary and 
re-vaccination/attenuated challenge (substudy 
subjects) to be described separately and by 
treatment group.  
• 
All AEs through 28 days following study 
vaccination by severity and relationship 
to study vaccination (by treatment 
group). 
 
• 
To describe (severity and relationship to study 
vaccination) any medically attended AE 
(MAAE) through 84 days following any study 
vaccination. Primary and 
re-vaccination/attenuated challenge to be 
described separately and by treatment group. 
• 
All MAAEs through 84 days following 
study vaccination by severity and 
relationship to study vaccination, and by 
time since study vaccination (by 
treatment group).  
• 
To describe any AE of special interest (AESI) 
and SAE through Day 169/EOS including 
relationship to study vaccination. 
• 
All AESIs and SAEs through 
Day 169/EOS by severity and 
relationship to study vaccination, and by 
time since study vaccination (by 
treatment group).  
• 
To describe any severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) 
infection or AESI associated with COVID-19 
disease if the COVID-19 pandemic remains 
ongoing in the region or if there are mass 
vaccinations using a COVID-19 vaccine 
during study conduct. 
• 
Incidence of SARS-CoV-2 infections or 
AESIs associated with COVID-19 
disease by severity, and by time since 
study vaccination (by treatment group). 
• 
To assess proportion of subjects (subset of 
subjects) cleared from colonization 
(present/absent) through Day 85.  
• 
B. pertussis clearance following study 
vaccination (subset of subjects at varying 
time points through Day 85). 
Mucosal secretory immunogenicity (S-IgA) (optional substudy only) 
Note that S-IgA objectives and endpoints for the overall study (as noted above) will also be analysed 
for the optional substudy and will be considered exploratory. 
Exploratory objectives 
Exploratory endpoints 

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• 
To evaluate mucosal immunity of individual 
and combinations of pertussis antibodies (eg, 
WCE, PT, FHA and PRN and other known 
anti-pertussis mucosal antibodies) are 
relational to protection against colonization 
(BPZE1, BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix control). 
• 
Induction of mucosal S-IgA at Day 29 
or 85 (tested independently) compared by 
protection against colonization 
(Colonizers/Non-colonizers) by treatment 
group (BPZE1, BPZE1 + Boostrix, 
BPZE1 and BPZE1 + Boostrix, Boostrix 
control). 
• 
To measure BPZE1 induction of mucosal 
immunity (S-IgA) at Day 113 by treatment 
group; and to assess if induction of a boost 
response (relative to Day 85 response) is 
observed for those subjects with prior BPZE1 
vaccination (BPZE1, BPZE1 + Boostrix).  
• 
Induction of mucosal S-IgA (WCE, PT, 
FHA, PRN and any additional 
anti-pertussis mucosal antibodies 
identified during assay development) at 
Day 113 compared with Day 85 
following BPZE1 attenuated challenge 
by treatment group (BPZE1, 
BPZE1 + Boostrix). 
• 
To assess if Day 113 response and longer-term 
durability through Day 169/EOS (absolute 
GMT) is altered with re-vaccination/attenuated 
challenge when compared to those subjects 
who did not participate in the substudy, 
relative to each randomized treatment group 
(BPZE1, BPZE1 + Boostrix, Boostrix).  
• 
Induction of mucosal S-IgA at Days 113 
and 169/EOS (tested independently) in 
subjects who participated in the substudy 
compared with subjects who did not 
participate in the substudy by treatment 
group. 
Serum immunogenicity (IgA and IgG) (optional substudy only): WCE, PT, FHA, PRN, and any 
additional anti-pertussis antibodies identified during assay development using GMT and GMFR unless 
otherwise stated. 
Note that serum IgA and IgG objectives and endpoints for the overall study (as noted above) will also 
be analysed for the optional substudy and will be considered exploratory. 
Exploratory objectives 
Exploratory endpoints 
• 
To measure BPZE1 induction of serum 
immunity at Day 113; and to assess if 
induction of a boost response (relative to 
Day 85 response) is observed for those 
subjects with prior BPZE1 vaccination 
(BPZE1, BPZE1 + Boostrix). 
• 
BPZE1, BPZE1 + Boostrix, and Boostrix 
induction of serum immunity (IgA, IgG) 
at Day 113 compared with baseline (by 
treatment group). 
• 
BPZE1, BPZE1 + Boostrix, and Boostrix 
induction of serum immunity (IgA, IgG) 
at Day 113 compared with Day 85 (by 
treatment group). 
• 
To assess if Day 113 response and longer-term 
immune durability through Day 169/EOS is 
altered with re-vaccination/attenuated 
challenge when compared to those subjects 
who did not participate in the substudy, 
relative to each randomized treatment group 
(BPZE1, BPZE1 + Boostrix, Boostrix). 
• 
BPZE1, BPZE1 + Boostrix, and Boostrix 
induction of serum immunity (IgA, IgG) 
at Days 113 and 169/EOS in subjects 
who participated in the substudy 
compared with subjects who did not 
participate in the substudy (tested 
independently by treatment group and 
day). 

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• 
To assess if serum immunity of individual and 
combinations of pertussis antibodies (eg, 
WCE, PT, FHA, PRN, and any additional 
anti-pertussis antibodies) at Day 29 or 85 is 
relational to protection against colonization by 
treatment group and overall (BPZE1, 
BPZE1 + Boostrix, Boostrix).  
• 
BPZE1, BPZE1 + Boostrix, BPZE1 and 
BPZE1 + Boostrix, Boostrix induction of 
serum immunity (IgA, IgG) at Day 29 or 
Day 85 compared by protection against 
colonization (Colonized/Non-Colonized) 
(tested independently by treatment group 
and overall). 
• 
To assess functional antibody response by 
treatment group at Day 113 compared to 
baseline and Day 29, as measured by an 
appropriate assay for bactericidal activity. 
• 
Proportion of subjects with ≥50% killing 
(or equivalent) for functional antibody 
response at Day 113 compared to 
baseline and Day 29 (tested 
independently by treatment group and 
day).  
Colonization (optional substudy only) 
Exploratory objective 
Exploratory endpoints 
• 
To demonstrate prior vaccination with BPZE1 
substantially reduces colonization at Day 92 
and Day 99.  
• 
B. pertussis colony counts at each of 
Days 92 and Day 99 by treatment group 
(mean counts, area under the curve 
[AUC] or similar total bacterial load 
assessments will also be calculated). 
• 
Subjects with colonization at each of 
Days 92 and 99 by treatment group. 
Expressed as absolute proportion 
(Yes/No) and percent reduction relative 
to control. 
 
2.3 
Other Exploratory Objectives and Endpoints 
Other Exploratory Objectives 
Other Exploratory Endpoint(s) 
• 
To assess cellular-mediated response (by 
ELISpot or flow cytometry) to BPZE1 
and Boostrix (Th1 and Th2) in a subset of 
subjects. 
• 
Cellular-mediated response at baseline and 
Day 8 (safety lead-in cohort) and Days 85 and 
113 (subset of substudy subjects). 
• 
To further characterize mucosal and 
serum immunological responses over 
time, relative to baseline status and to 
vaccination response, with any future 
assays developed for BPZE1. 
• 
Immunologic response measurement by 
treatment group. 
 

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3 
Investigational Plan 
3.1 
Study Design 
This is a multi-centre, randomized, observer-blinded, placebo- and active 
comparator-controlled trial with a 6-month safety follow-up after first study vaccination. 
After signing the informed consent form (ICF; or providing assent when necessary) and 
meeting all inclusion and none of the exclusion criteria, eligible subjects will receive an 
intranasal vaccination with either BPZE1 vaccine or formulation buffer (placebo) via the 
MAD and an intramuscular (IM) injection of either Tdap vaccine (i.e., Boostrix) or sterile 
normal saline (placebo) on Day 1. To maintain the blind, placebo vaccination via intranasal 
and IM routes, using formulation buffer and normal saline, respectively, will be included, and 
an unblinded team will manage vaccine logistics, preparation, and administration (when 
needed to maintain blinding) but will not be involved in study-related assessments or have 
subject contact for data collection after study vaccination. 
Approximately 360 subjects will be enrolled and randomly assigned (1:1:1) to 
1 of 3 treatment groups (refer to Table 3-1) to contribute to safety and efficacy assessments. 
Enrolment will be operationally managed at the study level to maintain a minimum number 
of subjects enrolled in 2 age groups: 6 to 10 years, inclusive; and 11 to 17 years, inclusive. It 
is estimated that a 10% dropout rate will occur, allowing for approximately 108 evaluable 
subjects per treatment group. 
Table 3-1 
Dosing Scheme 
Treatment 
Group 
n 
Intranasal Vaccinationa 
(Day 1) 
IM Vaccinationb 
(Day 1) 
BPZE1 
Placebo 
Boostrix 
Placebo 
A 
120 
X 
- 
- 
X 
B 
120 
X 
- 
X 
- 
C 
120 
- 
X 
X 
- 
a 
Intranasal application of ~0.4 mL per nostril (0.8 mL total volume delivered). Intranasal vaccination will 
occur prior to IM vaccination. 
b  
IM injection of 0.5 mL to the deltoid region. 
All subjects will be monitored for at least 30 minutes after final study vaccination. On Day 1, 
intranasal vaccination will occur prior to IM vaccination with a minimum of 10 minutes 
(minimum of 30 minutes for subjects in the safety lead-in cohort of 11 to 17 year olds) 

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between intranasal and IM vaccinations. Immediate reactogenicity will be assessed at 30 
minutes (+30 minutes) after the last study vaccination of the Day (ie, after IM vaccination on 
Day 1, after nasal vaccination on Day 85), prior to release from clinical observation. 
All subjects will record maximum daily reactogenicity in a subject diary for 7 consecutive 
days starting the day following any study vaccination (retrospective of the highest value in 
the previous 24 hours). Subject diaries will be age-adjusted as appropriate. Local (arm; after 
IM injection only), nasal/respiratory, and general systemic reactogenicity events will be 
recorded, including start and stop dates and including any actual measurements (ie, body 
temperature, redness and/or swelling at the injection site). Trained clinical staff will review 
the information from the subject diary with the subjects at the following visit and apply a 
standard toxicity grade to any reactogenicity event. Subjects will be instructed that should 
they have reactogenicity with a potential toxicity grade 3 at any time, they should contact the 
site on the same day and be seen or referred to a qualified medical facility within 24 hours. 
As this is the first study of BPZE1 in school-age children, a staggered enrolment is planned. 
The first 45 subjects enrolled will be in the older age group (11 to 17 years, inclusive) and 
designated the safety lead-in cohort. Reactogenicity will be reviewed with these subjects 
during a supplemental visit 7 days following first study vaccination. After reactogenicity for 
the safety lead-in cohort is reviewed by the medical monitor, medical lead, and Safety 
Monitoring Committee (SMC) chairman (with appropriate consultation with investigators, if 
needed), the remainder of subjects will be enrolled. 
All AEs will be monitored through 28 days after any study vaccination; all MAAEs will be 
monitored through 84 days following any study vaccination; and all AESIs and SAEs will be 
monitored through Day 169/EOS. Due to COVID-19 pandemic, a SARS-CoV-2 infection 
(confirmed by testing within the public health system) and any associated symptoms will be 
collected on a unique COVID-19 electronic case report form (eCRF) through Day 169/EOS 
if the COVID-19 pandemic remains ongoing in the region or if there are mass vaccinations 
using a COVID-19 vaccine during study conduct. Vaccines received outside of the study will 
be specifically queried at each visit and recorded through Day 169/EOS. 
An informational card will be provided to all subjects indicating their participation in this 
vaccination study to prevent subjects from inadvertently receiving any scheduled/planned 
Boostrix-containing vaccines (tetanus, pertussis, diphtheria) during study conduct. Any 

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enrolled subject who does not receive Boostrix during the study will be offered Boostrix at 
the conclusion of the study (following unblinding); this Boostrix ‘catch-up’ will be provided 
outside of the study schedule, at the discretion of the investigator, with vaccine provided by 
the sponsor. 
Nasal and blood samples for immunogenicity assessments will be collected before 
vaccination and at selected time points following study vaccination. Mid-
turbinate/nasopharyngeal sample collections will occur at selected time points following 
study vaccination to assess initial colonization (safety lead-in cohort only, Day 8) and to 
assess for clearance (remainder of cohort, either Day 29 or Day 85). A subset of subjects will 
also have the option to provide extra blood for cellular-mediated immunity assessments at 
baseline and Day 8 (safety lead-in cohort) and Days 85 and 113 (subgroup optional in 
substudy). 
Due to the uncertainty with movement and/or isolation practices associated with the 
COVID-19 pandemic, telemedicine and remote sampling may be initiated with proper 
investigator and/or medical oversight. 
The primary database lock will occur after all data are clean and all planned study procedures 
through Day 169/EOS (6 months) are complete. An interim database lock may occur after all 
subjects have completed Day 29 and sample testing for all primary and select secondary 
immune endpoints have been completed (mucosal and serum), but results will only be 
provided at treatment assignment level to maintain the blind. The site and those interacting 
directly with the site or subject data (eg, contract research organization [CRO], laboratories) 
will remain blinded to subject assignment until EOS or end of sample testing, depending on 
the activities of the associated entities. 
Vaccination pause rules (refer to Section 6.5) will be in place with a review by the SMC 
initiated if any rule is met. In addition, the medical monitor and medical lead are empowered 
to request a review by the SMC (refer to Section 11.1.1.1) at any time for any safety reason. 
3.1.1 Substudy: Attenuated Challenge With BPZE1 Following Prior 
Vaccination with BPZE1, BPZE1 + Boostrix, or Boostrix Alone 
This is an optional open-label substudy in which enrolled subjects may elect to participate at 
any time from the day of enrolment through Day 85. A separate signed ICF (and separate 

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assent when necessary) will be obtained prior to participation in the substudy. Subjects will 
be excluded from participating in the substudy if they meet additional exclusion criteria listed 
in Section 4.1.2.1. Temporary vaccination holding criteria are to be followed for the Day 85 
vaccination. 
Up to 120 enrolled subjects may participate in the substudy. The duration of the entire study 
will not change; however, additional visits/procedures starting on Day 85 will include the 
following: 
• 3 additional visits (Days 92, 99, and 113) 
• 1 additional intranasal vaccination (Day 85) 
• Up to 3 additional nasal samples, including 2 of those needed for mid-
turbinate/nasopharyngeal sample collection (Days 92 and 99) and 1 needed for 
leukosorb (Day 113). Subjects will contribute to all Day 85 sampling (systemic and 
nasal) 
• Up to 2 additional blood samples (Days 85 [if not already assigned to provide] and 113, 
including blood for cellular-mediated and systemic immunity responses) 
• 1 additional subject diary (subjects to record maximum daily reactogenicity 
[nasal/respiratory, systemic] in a subject diary for 7 consecutive days starting the day 
following study vaccination) 
• 1 additional test for SARS-CoV-2 within 72 hours prior to Day 85 vaccination  
All subjects participating in the open-label substudy will receive an intranasal 
re-vaccination/attenuated challenge with BPZE1 on Day 85. Subjects may have the planned 
re-vaccination/attenuated challenge deferred to a later date (up to 20 days) if pre-defined 
temporary exclusion criteria are met (Section 4.1.2.1) or for other personal reasons (eg, 
holiday, school schedule). Subjects will be monitored for at least 30 minutes after 
re-vaccination/attenuated challenge, with a post-vaccination evaluation for reactogenicity 
(nasal/respiratory, and systemic) completed prior to release from clinical observation. 
Subjects will receive a subject diary on Day 85. All subjects (with assistance when needed) 
will record maximum daily reactogenicity in a subject diary for 7 consecutive days starting 
the day following re-vaccination/attenuated challenge (retrospective of the highest value in 
the previous 24 hours). Subject-reported symptom diaries will be age-adjusted as appropriate. 

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Nasal/respiratory and general systemic reactogenicity events will be recorded, including 
measurements of body temperature. Trained clinical staff will review the information from 
the subject diary with the subjects at the following visit and apply a standard toxicity grade to 
any reactogenicity event. Subjects will be instructed that should they have reactogenicity 
with a potential toxicity grade 3 at any time, they should contact the site on the same day and 
be seen or referred to a qualified medical facility within 24 hours. 
Nasal and blood samples for immunogenicity assessments will be collected before 
re-vaccination/attenuated challenge and at selected time points thereafter. 
Mid-turbinate/nasopharyngeal sample collections will be performed at selected time points to 
assess BPZE1 colonization (B. pertussis culture or PCR). Some subjects participating in the 
substudy may also provide extra blood (optional) for cellular-mediated immunity 
assessments on Day 85 and Day 113 (optional extra blood collection for up to 45 substudy 
participants). 
All AEs will be collected following re-vaccination/attenuated challenge on Day 85 through 
Day 113. Following Day 113, only MAAEs, AESIs, and SAEs will be collected though 
Day 169/EOS. 

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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
Approximately 360 subjects will be enrolled at approximately 30 centres in the United 
Kingdom, European/Commonwealth countries and/or Costa Rica. Subjects will be enrolled 
only if they meet all the inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in this study: 
1. The subject is male or female 6 to 17 years of age, inclusive, on Day 1 (day of study 
vaccination). 
2. The subject (and/or legal guardian) is capable of understanding the written informed 
consent, providing signed and witnessed written informed consent (or assent, 
depending on age), and understanding and complying with protocol requirements. 
3. Female subjects of reproductive age must be nonpregnant and nonlactating, and if of 
childbearing potential (defined as any female who has experienced menarche at any 
time prior to or during the study), must agree to be heterosexually inactive from at 
least 21 days prior to enrolment and through 90 days following any study vaccination 
or agrees to consistently use any of the following methods of birth control from at 
least 21 days prior to enrolment and through 90 days following any study vaccination: 
a) Condoms (male or female) with or without spermicide* 
b) Diaphragm with or without spermicide* 
c) Cervical cap with or without spermicide* 
* NOTE: The highest level of protection is required, in accordance with local 
regulations. 
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e) Oral or patch contraceptives 
f) Norplant®, Depo-Provera®, or other acceptable method of birth control that 
is designed to protect against pregnancy 
NOTE: Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of birth 
control. 
4. The subject has a stable health status, as established by physical examination, vital 
sign measurements (body temperature and heart rate), and medical history. 
5. The subject (and/or legal guardian) has access to a consistent and reliable means of 
electronic or telephone contact, which may be in the home, workplace, school, or by 
personal mobile electronic device. 
6. The subject is willing to refrain from routine nasal sprays (including steroid sprays) 
or washes for at least 7 days following any study vaccination. 
7. The subject (and/or legal guardian) lives within a reasonable distance from the 
clinical site, is willing and able to travel to and from the clinical site for follow-up 
visits, and agrees to seek medical evaluation in the event of an AE requiring acute 
assessment. 
8. The subject (and/or legal guardian) agrees to stay in contact with the clinical site for 
the duration of the study, has no current plans to move from the study area, and agrees 
to provide updated contact information, as necessary. 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria (by review of medical history and subject 
intake) will be excluded from the study:` 
1. The subject has a history of pertussis-containing vaccination (inclusive of school 
vaccination programs) or documented B. pertussis infection within 3 years prior to 
Day 1 and/or a history of Td-containing vaccination (without pertussis vaccine 
component) within 1 month prior to Day 1. 
 

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2. The subject has a chronic significant illness actively being treated or a history of 
recent intervention for worsening or fluctuating symptoms (at the discretion of the 
investigator). 
3. The subject has a history of cancer (malignancy). 
4. The subject has a congenital, hereditary, or acquired disease or disorder classified as 
autoimmune, immunodeficient, coagulopathy, hepatic, renal, neurologic (including a 
history of Bell’s palsy), or moderate to severe cognitive. (Attention deficit 
hyperactivity disorder permitted.) 
5. The subject currently uses smoking products (including vaping and e-cigarettes) and 
is unwilling to refrain from use from Day 1 through Day 29 following any study 
vaccination. 
6. The subject has received immunoglobulin, blood-derived products, systemic 
corticosteroids (at a dose of >10 mg per day for more than 10 days), or other 
immunosuppressant drugs within 90 days prior to Day 1. 
7. The subject has any chronic pulmonary disease requiring active medication or 
pulmonary therapies, with the following exceptions: 
a) Subjects with exercise-induced bronchospasm, if currently well controlled, who 
are willing to refrain from intense exercise for 7 days following study 
vaccination or 
b) Subjects with Step 1 (intermittent) asthma classification who have not had an 
exacerbation requiring oral systemic corticosteroids in the past year; have an 
FEV1 documented to be >80%; do not have restrictions in normal activity due 
to breathing issues; and have used a short-acting beta-agonist less than or 
equal to 2 days per week over the past 2 months. 
NOTE: Subjects in the safety lead-in cohort are not allowed to have these 
exceptions. 
8. The subject has a history of oro/nasopharynx surgery (eg, adenoidectomy, 
tonsillectomy) within 60 days prior to Day 1. 
9. The subject has a known hypersensitivity to latex or any component of any study 
vaccine. Specific to Boostrix: the subject has known hypersensitivity to neomycin or 

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polymyxin; hypersensitivity after previous administration of diphtheria, tetanus, or 
pertussis vaccines; or has experienced transient thrombocytopenia or neurological 
complications following an earlier immunisation against diphtheria and/or tetanus. 
10. The subject has participated in any other clinical trial for the testing of an unlicensed 
product where such product was received within 6 months prior to Day 1 or is 
planning to participate in any other clinical trial during study conduct through Day 85 
following last study vaccination. 
NOTE: Exceptions may be considered for an investigational COVID-19 vaccine if 
the product has entered into adult Phase 3 efficacy trials or is part of a mass 
vaccination rollout in this age group of subjects within a country. Direct guidance will 
be provided by the sponsor prior to study initiation. 
11. The subject has routine and/or repeated contact with, or is currently living in a 
household with, an immunocompromised individual. 
12. The subject has any medical condition that, in the opinion of the investigator, might 
interfere with the evaluation of the study objectives or might affect the safety of the 
individual (eg, eating disorder, major depression or anxiety disorder, history of 
alcohol or drug use). 
13. The subject is a study team member or first-degree relative of a study team member. 
14. The subject resides in a residence during the vaccination period (defined as through 
Day 85 following any study vaccination) where an infant less than 6 months of age 
resides or may reside. 
 
4.1.2.1 Additional Exclusion Criteria (Substudy Subjects ONLY) 
Subjects meeting any of the following criteria will be excluded from participation in the 
optional substudy (Section 3.1.1): 
15. Has received a pertussis-containing vaccination outside of study conduct since 
enrollment. 
16. Has received any form of immunotherapy determined to potentially have an effect on 
immune response (as determined by medical consultation, when necessary). 

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4.1.3 Other Considerations for Temporarily Holding Vaccination (Days 1 
or Substudy Day 85) 
Subjects meeting any of the following criteria may have a planned study vaccination deferred 
to a later date, but these criteria are not exclusionary for study enrolment/participation. For 
Visit 1, Day 1, subjects may be enrolled on a return visit if they remain within 45 days of 
consenting. Otherwise, subjects must be reconsented and reassessed per the inclusion and 
exclusion criteria (ie, re-enrolled). 
• The subject has or reports acute respiratory tract symptoms/infection or rhinorrhoea 
within the past 3 days. Subject may be vaccinated once all symptoms have been resolved 
for at least 3 days. 
• The subject has or reports a body temperature of 100.4°F (38°C) or higher within the 
past 3 days. The subject may be vaccinated once the fever resolves and body 
temperature (site-measured or subject-measured) remains below 100.4°F (38°C) for at 
least 3 days. 
• The subject used antibiotics within the past 10 days. 
• The subject received a licensed vaccine (including any vaccine under emergency use 
authorization) within the past 14 days. 
• The subject has a positive SARS-CoV-2 test result (eg, infection is ongoing) within the 
3 days preceding vaccination. For those subjects testing positive, they must have a 
subsequent negative SARS-CoV-2 test result prior to vaccination (visit window may be 
extended to accommodate retesting needs).  
4.2 
Withdrawal of Subjects From Study Treatment and/or the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the last follow-up visit (whether in person or via telemedicine). 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw/discontinue from the study at any time and for any reason without 
prejudice to their future medical care by the investigator or at the study centre. Every effort 

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should be made to keep subjects in the study for safety monitoring (at a minimum), which 
includes telemedicine/phone call for long-term safety follow-up (in such a case subjects will 
not be considered ‘discontinued’). The reasons for subjects not completing the study will be 
recorded. A subject may be withdrawn from the study for any of the following reasons: 
1. Significant noncompliance with the protocol, as determined by the 
medical monitor(s). 
2. Serious or intolerable AE(s) that in the investigator’s opinion requires 
withdrawal or discontinuation from the study; however, every effort 
should be made to keep the subject in the study for safety follow-up 
via telemedicine (eg, telephone, internet). 
3. The subject is lost to follow-up. 
4. The subject withdraws consent. 
5. The investigator decides it is in the subject’s best interest to 
discontinue the study; however, every effort should be made to keep 
the subject in the study for safety follow-up via telemedicine (eg, 
telephone, internet). 
6. The sponsor decides to discontinue the subject’s participation in the 
study or to terminate the study. 
Upon occurrence of a serious or intolerable AE, the investigator will confer with the sponsor 
prior to withdrawal of a subject. Any subject may withdraw his or her consent at any time. 
4.2.2 Handling of Withdrawals 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page in the eCRF. 
Whenever possible, rather than lose subjects to withdrawal, any subject enrolled and 
vaccinated prior to withdrawal will be given the option to be followed for safety follow-up 
via telemedicine (eg, phone, internet) if they refuse further protocol-specified procedures. In 
addition, subjects who fail to return for final assessments will be contacted by the clinical site 
in an attempt to have them followed for safety follow-up via telemedicine. In all such cases if 
a phone call/telemedicine contact is made for safety follow-up then the subject is still 

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considered as enrolled and not discontinued. A subject will not be considered lost to follow-
up until every attempt to contact the subject has been made, at minimum 2 (documented) 
telephone calls, followed by a registered letter. Every effort should be made to collect safety 
data on subjects through the Day 169/EOS visit. 
4.2.3 Replacements 
Subjects who subsequently withdraw, are terminated from the study, or are lost to follow-up 
prior to completing Day 29 assessments may be replaced during the enrolment period at the 
discretion of the sponsor. 
5 
Study Treatments 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to 1 of 3 treatment groups, in a 1:1:1 ratio, as presented 
in Table 3-1, and operationally managed to maintain a minimum number of subjects enrolled 
in 2 age groups: 6 to 10 years, inclusive; and 11 to 17 years, inclusive. A staggered enrolment 
is planned: the first 45 subjects enrolled will be in the older age group of 11 to 17 years, 
inclusive, and designated the safety lead-in cohort. After reactogenicity for the safety lead-in 
cohort is reviewed by the medical monitor, medical lead, and SMC chairman (with 
appropriate consultation with investigators, if needed), the remainder of subjects will be 
enrolled. An interactive response technology (IRT) system will be used to administer the 
randomization schedule centrally. The IRT system will also be designed to distribute the full 
cohort into groups to provide mid-turbinate/nasopharyngeal samples for B. pertussis culture 
or PCR on Day 29 or 85; however, if a subject cannot provide a sample on Day 29 (for any 
reason), the subject should provide a sample on Day 85 (this will not be considered a 
protocol deviation). Biostatistics will generate the randomization schedule using SAS® 
software Version 9.3 or later (SAS Institute Inc, Cary, North Carolina) for the IRT, which will 
link sequential subject randomization numbers to treatment codes. The randomization 
schedule will be created by the dedicated randomization team, stored in a separate project 
area, and will be blinded to the project team with the exception of an unblinded team who 
will manage vaccine logistics, preparation, and administration, but will not be involved in 

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study-related assessments or have subject contact for data collection following study 
vaccination. 
Enrolled subjects may participate in an optional substudy in which subjects may elect to 
participate at any time from the day of enrolment through Day 85. No randomization is 
planned for the substudy as all subjects participating in the open-label substudy will receive 
an intranasal re-vaccination/attenuated challenge with BPZE1 on Day 85. It is recognized 
this may introduce some subject bias due to the opt-in nature, but this has been deemed 
acceptable by the sponsor. 
5.2 
Treatments Administered 
Subjects in Treatment Group A (N ~120) will receive an intranasal application of 109 CFU 
BPZE1, with approximately 0.4 mL per nostril (0.8 mL total volume delivered); and an IM 
injection of 0.5 mL placebo (sterile normal saline for injection) to the deltoid region on 
Day 1. Intranasal application of BPZE1 or placebo should precede IM injection of Boostrix 
or placebo by at least 10 minutes (minimum of 30 minutes for subjects in the safety lead-in 
cohort of 11 to 17 year olds). For the safety lead-in cohort, a minimum of 30 minutes must 
occur between intranasal and IM vaccinations on Day 1. 
Subjects in Treatment Group B (N ~120) will receive an intranasal application of 109 CFU 
BPZE1, with approximately 0.4 mL per nostril (0.8 mL total volume delivered); and an IM 
injection of 0.5 mL Boostrix (aP vaccine, manufactured by GlaxoSmithKline) to the deltoid 
region on Day 1. Intranasal application of BPZE1 or placebo should precede IM injection of 
Boostrix or placebo by at least 10 minutes (minimum of 30 minutes for subjects in the safety 
lead-in cohort of 11 to 17 year olds). 
Subjects in Treatment Group C (N ~120) will receive an intranasal application of lyophilized 
buffer reconstituted in sterile water, with approximately 0.4 mL per nostril (0.8 mL total 
volume delivered); and an IM injection of 0.5 mL Boostrix (aP vaccine, manufactured by 
GlaxoSmithKline) to the deltoid region on Day 1. Intranasal application of BPZE1 or placebo 
should precede IM injection of Boostrix or placebo by at least 10 minutes (minimum of 
30 minutes for subjects in the safety lead-in cohort of 11 to 17 year olds).  

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All subjects participating in the optional substudy will receive a second intranasal application 
of 109 CFU BPZE1, with approximately 0.4 mL per nostril (0.8 mL total volume delivered) 
on Day 85. 
All subjects will be monitored for study vaccination-related events for at least 30 minutes 
following the last vaccination (eg, 30 minutes following IM vaccination). 
5.3 
Identity of Investigational Product 
The BPZE1 investigational vaccine is for intranasal administration and is an off-white 
lyophilized cake that contains genetically modified, live B. pertussis strain BPZE1 bacteria in 
lyophilization buffer. Refer to the most recent version of the investigator’s brochure (IB) for 
additional details. 
The sponsor will provide the CRO with the investigational vaccine and lyophilized buffer, 
properly labelled, and the CRO will ensure labelling complies with local regulations and is 
distributed to the clinical sites. 
The following supplies will be used for vaccination in the study: 
Product 
Dosage and Route of Administration: 
BPZE1 
Reconstituted with sterile water to provide 109 CFU 
per 0.8 mL; administered intranasally, with 
approximately 0.4 mL per nostril (0.8 mL total 
volume delivered), by syringe with MAD  
Boostrix (Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, Adsorbed) 
injectable suspension, for IM use 
Administered as a single 0.5 mL IM injection to the 
deltoid region 
Intranasal placebo (lyophilized BPZE1 buffer 
reconstituted with sterile water) 
Administered intranasally, with approximately 
0.4 mL per nostril (0.8 mL total volume delivered), 
by syringe with MAD 
IM placebo (sterile normal saline for injection) 
Administered as a single 0.5 mL IM injection to the 
deltoid region 
 
The intranasal placebo consists of lyophilized buffer reconstituted with sterile Water for 
Injection (WFI), which has the same constituents in approximately the same quantities as the 
BPZE1 investigational vaccine excluding the attenuated B. pertussis cells, Tris buffer, and 
sodium chloride. The IM placebo is sterile normal saline for injection. 

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A detailed description regarding the storage, reconstitution, and handling of investigational 
vaccines will be in the pharmacy manual. 
5.3.1 Investigational Product Packaging and Storage 
BPZE1 and lyophilized placebo will be shipped from the sponsor’s European contract 
manufacturing organization to the CRO’s repository and distribution centre. The primary 
packaging for BPZE1 is a sterile glass 2R DIN vial with a chlorobutyl lyophilization stopper. 
The vial closure system is a combination of the stopper and the aluminium cap. The vials are 
crimped directly after the lyophilization process using the automated Fill & Finish unit that 
filled the vials with 1.0 mL suspension. The intranasal placebo will be packaged in a similar 
fashion. A 1:1 subject to vial randomization is planned. 
Boostrix will be procured from commercial stock and supplied as either single dose vials 
(ideally) or prefilled syringes containing a 0.5 mL suspension for injection. The IM placebo 
will be sterile normal saline for injection from a commercial supplier, supplied in single- or 
multi-dose vials, and must be appropriately blinded at the syringe level to coincide with 
Boostrix supply. 
Study vaccines must be stored in a secure area (eg, locked refrigerator/freezer), protected 
from light and moisture, and kept at a controlled temperature. Refer to the IB and pharmacy 
manual for specific storage conditions as appropriate for BPZE1 and comparators. BPZE1 
and formulation buffer control is to be stored at 8°C or lower at all times. 
5.3.2 Investigational Product Accountability 
The investigator will maintain accurate records of receipt of all study vaccine and placebo 
vials, including dates of receipt. In addition, accurate records will be kept regarding when 
and how much study vaccine is dispensed and used by each subject in the study. Reasons for 
departure from the expected dispensing regimen must also be recorded. At the completion of 
the study, to satisfy regulatory requirements regarding drug accountability, all study vaccine 
will be reconciled and retained or destroyed according to applicable regulations. No study 
vaccine will be destroyed until authorized in writing by the sponsor. 

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5.3.3 Other Supplies 
Other clinical supplies that will be provided to the clinical sites for distribution to subjects 
include subject diaries, a measuring tool for measuring injection site erythema and swelling, 
and a thermometer for measuring body temperature. 
Supplies for sample collection will be provided in sufficient quantity. Bar coding will be 
applied to allow for sample tracking at the time of collection and throughout storage, 
transport, and testing. 
Adequate supplies for immunization of individuals, including 18G (or larger) needles for 
reconstitution, 25G or smaller needles for vaccination (age-appropriate), syringes (1-mL 
tuberculin) for IM and intranasal vaccinations and for reconstitution purposes, sterile WFI, 
normal saline, the MAD, and blinding tape, will be supplied. All supplies can be stored at 
ambient temperature in a secure area. 
Mucosal atomization devices (MADs) with CE marking will be provided to be used with a 
1-mL tuberculin syringe for each intranasal vaccination. The MAD is a conical shape plastic 
component that Luer-locks onto a 1-mL syringe. The MAD atomizes the liquid vaccine as it 
exits the syringe. The conical shape forms a plug in the nostril and high applied pressure 
atomizes the liquid into a fine mist to provide broad mucosal surface delivery. 
5.4 
Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the CRO’s pharmacovigilance reporting centre. In case of any 
AEs associated with the overdose, these should be reported on relevant AE/SAE sections in 
the eCRF. Any overdose should be recorded as a protocol deviation and promptly reported to 
the sponsor. No overdoses are expected as the vaccine and adjuvant will be administered by 
clinical staff. 
5.4.1 Treatment of Overdose 
Treatment of overdose would include supportive and symptomatic care, according to the 
standards of care at the site. The investigator should promptly notify the medical monitor 
about the overdose and seek his/her input on the medical management, as needed. BPZE1 is 

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a live attenuated B. pertussis bacterium and is susceptible to an erythromycin/azithromycin 
antibiotic treatment. 
5.5 
Blinding 
This is an observer-blinded study. To maintain the blind, placebo vaccination via intranasal 
and IM routes will be included and an unblinded team will manage vaccine logistics, 
preparation, and administration (when/if necessary) so as to maintain the blind from the 
remainder of the study personnel and subjects. The unblinded team will not be involved in 
study-related assessments or have subject contact for data collection following study 
vaccination. 
The optional substudy includes an open-label re-vaccination/attenuated challenge with 
BPZE1. 
5.5.1 Breaking the Blind Due to Medical Emergency 
A subject’s treatment assignment will not be broken until the end of the study for the clinical 
site study team unless medical treatment of the subject depends on knowing the study 
treatment the subject received. In the event that the blind needs to be broken because of a 
medical emergency, the investigator will have direct access to unblinding and may unblind an 
individual subject’s treatment allocation. 
The treatment assignment for a subject can be unblinded by request of the investigator using 
the IRT system at the site. Reasons for treatment unblinding must be clearly explained and 
justified in the eCRF. The date on which the code was broken together with the identity of 
the person responsible must also be documented. An IRT-triggered notification indicating 
that a code break has occurred will be sent to the designated team following unblinding, 
which will include the role performing the code break. 
5.6 
Treatment Compliance 
The study vaccination will be administered to maintain the blind to site personnel conducting 
subject assessments. The location (in case of IM administration, right or left arm), date, and 
timing of all product administrations will be recorded in the eCRF. Compliance will be 
determined by the number and percentage of subjects who receive study vaccination. Any 
deviations from the dosing schedule outside the defined visit windows (refer to Table 13-1) 

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will be flagged in the clinical database unless noted as an allowance in the protocol (eg, acute 
illness, vaccination pause). 
5.7 
Prior and Concomitant Medications, Therapies, or Vaccines 
Restrictions for prior medications, therapies, or vaccines are provided in Section 4.1. 
Administration of concomitant medications, therapies, or vaccines will be recorded in the 
eCRF. Concomitant medications will include all medications and over-the-counter (OTC) 
products (including herbal supplements and multivitamins) taken by the subject from the 
time of signing the ICF through Day 29 (and from Day 85 [following study vaccination] 
through Day 113 for subjects participating in the optional substudy), or through an early 
termination visit, if prior to these time points. The use of anti-pyrogenic medication will be 
specifically queried by diary during the 7 days following any study vaccination. Concomitant 
medications received associated with any MAAE will be recorded through 84 days following 
any study vaccination; and concomitant medications received associated with any AESI or 
SAE will be recorded through Day 169/EOS. 
Vaccines received outside of the study will be specifically queried during each visit and 
recorded through Day 169/EOS. Necessary vaccinations (eg, seasonal influenza, COVID-19, 
standard pediatric vaccines such as HPV, IPV, MenACWY) are allowed during the study, but 
should ideally be delayed until at least 28 days after any study vaccination whenever 
possible. Administration of tetanus and diphtheria toxoids (Td) vaccine during the first 
90 days of the study is allowed only for emergency needs, but not as a standard schedule. 
Use of new medication should prompt evaluation for the presence of a new diagnosis of 
chronic medical disease or condition. 

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6 
Study Assessments and Procedures 
6.1 
Demographic and Baseline Data 
Demographic and baseline data, such as date of birth (where allowed by local regulations), 
sex, race, ethnicity, weight, and height (with derived body mass index [BMI] and Z-score 
when appropriate for age), should be collected at screening and recorded in the eCRF. 
6.2 
Medical History 
A medical history (including vaccination history, prior and concomitant medical conditions, 
and surgeries/significant procedures for medical conditions [eg, endoscopy, tonsillectomy]) 
will be collected at screening and reviewed and/or updated on Day 1 if screening occurs prior 
to Day 1. 
Ideally, the subject will provide a vaccination card (or equivalent) or the subject’s vaccination 
history can be accessed via a centralized vaccination register to record last known pertussis 
vaccination. If the subject’s vaccination history is not available, the timing of prior pertussis 
vaccine may be estimated based on the national vaccination schedule appropriate for the age 
of subject. 
6.3 
Safety Assessments 
Safety assessments for all subjects will include the following: vital sign measurements 
(including body temperature and heart rate), targeted physical examinations, reactogenicity, 
and AEs (including MAAEs, AESIs, and SAEs). The timing and frequency of all safety 
assessments are listed in the schedules of events (refer to Table 13-1). 
6.3.1 Vital Sign Measurements 
Vital sign measurements will include body temperature (oral, tympanic, or noncontact) and 
heart rate. If temperature is to be taken orally, the subject must not eat or drink anything hot 
or cold within 10 minutes prior to measurement. 

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6.3.2 
Post-Vaccination Evaluation 
All subjects will be monitored for at least 30 minutes after final study vaccination. The 
following evaluations will be performed: 
1. Obtain heart rate (refer to Table 13-1). 
2. Assess for reactogenicity based on injection site examination with FDA toxicity grade 
(refer to Section 6.3.5.1.2) 
3. Assess for reactogenicity based on nasal/respiratory and systemic (including oral 
temperature) FDA toxicity grading scales (refer to Section 6.3.5.1.2) 
Immediate reactogenicity (including grade any actual measurements) will be recorded at 
30 (+30) minutes following study vaccination. On Day 1, intranasal vaccination will occur 
prior to IM vaccination with a minimum of 10 minutes (minimum of 30 minutes for subjects 
in the safety lead-in cohort of 11 to 17 year olds) between intranasal and IM vaccinations. 
Immediate reactogenicity will be assessed at 30 minutes (+30 minutes) after the last study 
vaccination of the Day (ie, after IM vaccination on Day 1, after nasal vaccination on Day 85), 
prior to release from clinical observation. 
All subjects will record maximum daily reactogenicity in a subject diary for 7 consecutive 
days starting the day following any study vaccination (retrospective of the highest value in 
the previous 24 hours). Subject diaries will be age-adjusted as appropriate. In addition, a 
measuring tool for measuring injection site erythema and swelling (after IM injection only) 
and a thermometer for measuring body temperature (oral or tympanic) will also be 
distributed to subjects. The use of anti-pyrogenic medication will also be specifically queried 
by subject diary during the 7 days following study vaccination. 
Local (arm; after IM injection only), nasal/respiratory, and general systemic reactogenicity 
events will be recorded, including start and stop dates, and including actual measurements of 
body temperature, and if applicable, swelling and redness at the injection site (after IM 
injection only). Trained clinical staff will review the information from the subject diary with 
the subjects at the following visit and apply a standard toxicity grade (refer to Section 13.2) 
to any reactogenicity event. Subjects will be instructed that should they have reactogenicity 
with a potential toxicity grade 3 at any time, they should contact the site on the same day and 
be seen or referred to a qualified medical facility within 24 hours. Any discrepancies between 

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investigator- and subject-reported outcomes of reactogenicity will be noted in the source 
documents prior to entry into the clinical database. 
6.3.3 Physical Examination 
A targeted physical examination will include the following: head and neck (inclusive of nasal 
cavity and oropharynx), respiratory, cardiac, abdomen, and lymph nodes associated with the 
upper extremity, head, and neck. Height and weight will be measured at the screening visit 
only. 
Additional targeted physical examinations will be symptom-directed and performed at the 
discretion of the investigator, including unscheduled visits, if necessary, to evaluate AEs. 
6.3.4 Clinical Safety Laboratory Assessments 
6.3.4.1 Urine Pregnancy Test  
For female subjects of childbearing potential who have been heterosexually active in their 
lifetime, a urine pregnancy test will be performed at screening and prior to any study 
vaccination (at the discretion of the investigator based on history taking). 
6.3.4.2 SARS-CoV-2 Test 
Given the ongoing pandemic, a SARS-CoV-2 test for active infection (an approved local test 
accepted by public health authorities and readily available) will be administered to subjects 
within 72 hours prior to vaccination (Day 1 for all subjects or Day 85 if in substudy). Should 
the subject have a positive SARS-CoV-2 test result, regardless of symptomatology, then 
vaccination will be temporarily held until the subject has a negative test result.   
6.3.5 Adverse Events 
6.3.5.1 Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study vaccination or their clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study vaccination. Subjects will be instructed to 
contact the investigator at any time after study vaccination if any symptoms develop. 

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6.3.5.1.1 
Serious Adverse Events 
An SAE is defined as any event that 
• results in death 
• is immediately life threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
At the discretion of the investigator, additional local laboratory or diagnostic assessments 
(including additional blood sampling) may be performed on any subject who experiences an 
SAE. 
6.3.5.1.2 
Local (Arm), Nasal/Respiratory, and General Systemic 
Reactogenicity 
Reactogenicity events are common and known to occur following administration of vaccines, 
indicating a positive immune response is being mounted. Site-specific local (arm), 
nasal/respiratory, and general systemic reactogenicity events including start and stop 
dates/times will be recorded and a standard toxicity grade (refer to Section 13.2) will be 
applied to any reactogenicity event. 
6.3.5.1.3 
Medically Attended Adverse Events 
A medically attended AE is defined as any unsolicited AE that leads to an unscheduled visit 
to a healthcare provider, or any grade 3 solicited reactogenicity event that leads to an 
unscheduled visit to a healthcare provider. 

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6.3.5.1.4 
Adverse Events of Special Interest 
If the COVID-19 pandemic remains ongoing in the region or if there are mass vaccinations 
using a COVID-19 vaccine during study conduct, any symptoms associated with COVID-19 
infection or vaccination will be collected as an AESI on a unique COVID-19 eCRF through 
Day 169/EOS. 
6.3.5.2 Assessing and Documenting Adverse Events 
Safety will be assessed by the frequency and severity of: 
1. All AESIs and SAEs occurring from the time of vaccination through Day 169/EOS. 
2. All MAAEs occurring through 84 days following any vaccination. 
3. Solicited reactogenicity events occurring from the time of any study vaccination for 
7 consecutive days starting the day following study vaccination, including: 
a. Nasal/respiratory reactions (runny/congested nose, sore/irritated throat, cough, 
sneeze, nasal or sinus pain/irritation, difficulty breathing/wheezing; if epistaxis 
occurs it should be listed as an AE); 
b. Systemic reactions (fever, headache, fatigue/malaise, loss of appetite/anorexia, 
vomiting, diarrhoea, nausea, myalgia, acute allergic reaction/urticaria); and 
c. Local reactions (pain/tenderness, redness, swelling [after IM injection only]). 
4. Unsolicited AEs – all AEs regardless of causality, will be collected for 28 days after any 
vaccination. Between screening (signing of ICF) and Day 1, AEs will be collected if 
classified as serious or if considered related to study procedure or study involvement. 
Any event that results in vaccination delay (eg, temporary exclusions due to acute 
upper respiratory symptoms/illness or fever, or investigator determined medical 
condition) during screening or during study conduct will also be recorded as an AE. 
Should any reactogenicity event extend beyond 7 days following vaccination, it will be 
recorded as an AE with the same start date as the reactogenicity event and followed 
until considered resolved. 

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At every study visit, subjects will be asked a standard non-leading question to elicit any 
medically related changes in their well-being that would pertain to the AEs being collected at 
the time. They will also be asked if they have been hospitalized, had any accidents, used any 
new medications, received a vaccination or changed concomitant medication regimens (both 
prescription and OTC medications). 
6.3.5.3 Reporting Adverse Events 
Adverse events reported or observed during the study will be recorded on the AE page in the 
eCRF. 
An AE is any unfavourable and unintended sign, symptom, or disease. The occurrence of an 
AE may come to the attention of study personnel during study visits and interviews of a 
study recipient presenting for medical care, or upon review by a study monitor. A single AE 
may have a constellation of signs/symptoms and the single most precise Medical Dictionary 
for Regulatory Activities (MedDRA) term should be utilized as the AE classification to avoid 
duplication of AEs. 
Adverse events will be captured on the appropriate data collection form and eCRF. 
Information to be collected for unsolicited nonserious AEs includes event description, date of 
onset, licensed study physician’s assessment of severity and relationship to study vaccination 
and alternate aetiology (if not related to study vaccination), date of resolution of the event, 
seriousness, and outcome. Adverse events occurring during the collection and reporting 
period will be documented appropriately regardless of relationship (as defined in 
Section 6.3.5.7). 
Any medical condition that is present at the time that the subject is screened will be 
considered as baseline (recorded as medical history) and not reported as an AE; however, if 
the severity of any pre-existing medical condition increases, it will be recorded as an AE. 
Adverse events must be graded for severity and assessed for relationship to study 
vaccination. Adverse events characterized as intermittent require documentation of onset and 
duration of each episode. The start and stop date of each reported AE will be recorded on the 
appropriate data collection form and eCRF. 

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Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The MedDRA will be used to code all AEs. 
6.3.5.4 Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.3.5.2) must be reported to the CRO immediately 
(ie, within 24 hours) after the time site personnel first learn about the event. The contact 
information to be used for SAE reporting will be provided to the CRO and the CRO will 
oversee the SAE reporting. 
6.3.5.5 Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate any new suspected unexpected serious adverse reactions 
(SUSARs) and expeditiously communicate possible new safety findings to investigators, 
institutional review boards or independent ethics committees, and applicable health 
authorities based on applicable legislation. Any SAE considered to be related to BPZE1 will 
be classified as a SUSAR. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the most recent version of the IB or the package insert for 
Boostrix (BOOSTRIX 2020). A summary of the possible undesirable effects from Boostrix 
(Boostrix 2021) is provided in Section 1.3.1.3. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
6.3.5.6 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s normal daily activity. 

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Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
Severe: 
These events interrupt a subject’s normal daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent require documentation of onset and duration of each episode. 
6.3.5.7 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study vaccination is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Related: 
There is a reasonable possibility that the study vaccination caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study vaccination and the AE. 
Not Related: 
There is not a reasonable possibility that the study vaccination caused the 
event. 
 
6.3.5.8 Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. Adverse events will be collected, 
assessed, and followed through resolution, considered stable or when subject completes EOS 
and based on Section 6.3.5.4. Serious AEs will be collected, assessed, and followed through 
EOS or until satisfactory resolution or clinically stable. 

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Resolution of an AE/SAE is defined as the return to pre-treatment status or stabilization of 
the condition with the expectation that it will remain chronic. 
If the investigator becomes aware of an acute illness and the investigator decides to bring the 
subject in for an evaluation to determine aetiology, then the investigator, at their own 
discretion, can determine the specific testing that should be performed (including additional 
blood sampling). Follow-up procedures, evaluations, and outcomes will be recorded on the 
appropriate data collection form. 
6.4 
Immunogenicity and Colonization Assessments 
Immune measurements will be conducted on serum (IgG and IgA) and nasal mucosal 
secretion (S-IgA) samples for anti-pertussis antibodies of WCE, PT, FHA, and PRN as well 
as any additional anti-pertussis antibodies included in assay development. Serum bactericidal 
activity (or other functional assays identified) will be measured in a subset of subjects. 
Cellular-mediated response to BPZE1 and Boostrix (Th1/Th17 vs Th2) will be assessed by 
ELISpot or flow cytometry at baseline and Day 8 (safety lead-in cohort) and Day 85 and 
Day 113 (subset of substudy subjects). Additional testing for antigens specific to B. pertussis 
may be performed at a later date as BPZE1 induces broader immunity more similar to natural 
infection induced immunity and does not contain the purified antigen levels of PT, FHA, and 
PRN found in Boostrix. Mid-turbinate/nasopharyngeal samples will be evaluated by real-
time PCR or by B. pertussis culture for colonization of BPZE1. 
Subjects will consent for the use of samples for further anti-pertussis antibody testing or 
other assay development as part of the standard consenting process. Aliquots of collected 
samples from this study may be retained for additional testing of biological responses (eg, 
antibodies, T-cell responses, microbiome) specific to future development of BPZE1 and 
ILiAD Biotechnologies’ B-Tech program for a maximum of 15 years (starting from the date 
at which the last subject had the last study visit), unless local rules, regulations, or guidelines 
require different time frames or different procedures, and in accord with subject consent. 
Procedures for the handling and processing of immunogenicity samples are provided in the 
laboratory manual or the site manual. 

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6.5 
Vaccination Pause Rules 
Further enrolment and study vaccinations will be halted (paused) for SMC 
review/recommendation if any of the following are reported: 
• Any subject experiences ulceration, abscess, or necrosis in the nose that is considered 
related to study vaccination, through 28 days following study vaccination. 
• Any subject experiences severe respiratory symptoms of laryngospasm, shortness of 
breath or wheezing (grade 3 or greater) within 3 days of study vaccination. 
• Any subject experiences an SAE considered related to study vaccination from the time 
of the vaccination through the subject’s last study visit. 
• More than 12 subjects report a grade 3 fever within 7 days of study vaccination that is 
attributed to study vaccination when no other cause can be found (corresponding to an 
incidence rate of approximately 3% for Boostrix). 
Grading scales for solicited reactogenicity events are included in Section 13.2. 
If any of the vaccination pause rules are met following any subject receipt of study 
vaccination, then this study will not continue with the remaining enrolments or future study 
vaccinations without a review by the SMC and a recommendation from the SMC to proceed 
(with or without alteration of protocol). Vaccination windows will be adjusted for any such 
pause to allow subjects to remain within the expected schedule of events. All events that 
classify for vaccination pause rules will be entered as AEs. 
The sponsor retains the authority to suspend additional enrolment and study interventions or 
administration of study vaccine during the entire study, as applicable. 
6.6 
Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational vaccine 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs in a study participant and during study participation must be reported using a clinical 
study pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
sponsor within 2 weeks of learning of its occurrence. The pregnancy must be followed-up to 
determine outcome (including spontaneous miscarriage, elective termination, normal birth, or 

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congenital abnormality) and status of mother and child, even if the subject was discontinued 
from the study. Pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any pregnancy, brought to the investigator’s attention after the subject has completed the 
study, but occurring while the subject was in the study, must be promptly reported to the 
sponsor. 
Pregnancy is an exclusion criterion, and a urine pregnancy test is required in sexually active 
heterosexual females a) at the time of enrolment; and b) on the day of and preceding any 
study vaccination. 

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7 Statistical and Analytical Plan 
7.1 Sample Size Calculations 
Approximately 360 subjects will be enrolled and randomly assigned (1:1:1) to 
1 of 3 treatment groups (refer to Table 3-1) to contribute to safety and efficacy assessments. 
Enrolment will be operationally managed at the study level to maintain a minimum number 
of subjects enrolled in 2 age groups: 6 to 10 years, inclusive; and 11 to 17 years, inclusive. It 
is estimated that a 10% drop-out rate will occur, allowing for approximately 108 evaluable 
subjects per treatment group. 
Primary immunogenicity endpoints: The sample size is based on calculations to achieve 
adequate response on Day 29 over baseline of mucosal S-IgA for WCE assay in the BPZE1 
and BPZE1 + Boostrix groups. Assuming the GMT follows a log-normal distribution, by 
applying a natural logarithmic transformation of the GMT, a paired t-test will be used to test 
the difference of mucosal S-IgA against WCE at Day 29 compared with baseline (equivalent 
to natural logarithmic transformation of the GMFR). With an effective sample size of N=108 
subjects per group, the study provides 95% power for detecting an effect size of 0.35 for each 
of the two primary comparisons with a two-sided significance level of 0.05. By multiplying 
the power for each of the two comparisons, the study provides an overall power of 90% 
(=95%*95%) for testing both primary comparisons. Factoring in an estimated 10% drop-out 
rate, each treatment group would include approximately 120 subjects for a total of 
approximately 360 subjects in the study.  
Key secondary endpoints: To demonstrate non-interference of IgG serum responses for the 
Boostrix-containing antigens (diphtheria, tetanus) at Day 29 when BPZE1 is co-administered 
with Boostrix (BPZE1 + Boostrix vs Boostrix), the test for non-inferiority of BPZE1 + 
Boostrix to Boostrix for the proportion with titer ≥ 0.1 IU/mL (for diphtheria, tetanus) has 
power exceeding 92% with approximately N=120 subjects per treatment group, assuming a 
noninferiority margin of -0.1, one-sided significance level of 0.025, 10% drop-out rate and 
the proportion with titer ≥ 0.1 IU/mL for the Boostrix treatment being at least 0.95.  
To demonstrate non-interference of IgG serum responses for the Boostrix-containing antigens 
(PT, FHA, PRN) at Day 29 when BPZE1 is co-administered with Boostrix (BPZE1 + 
Boostrix vs Boostrix), the tests for non-inferiority of BPZE1 + Boostrix to Boostrix for each 
of the three IgG parameters (PT/FHA/PRN) have power of 97%, 100%, and 88%, 

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respectively, for detecting between group differences as observed in study IB-200P, with 
approximately 120 subjects per treatment group, one-sided significance levels of 0.025, 10% 
drop-out rate and non-inferiority margin of -0.693. 
7.2 Blinded Sample Size Recalculation 
A blinded sample size recalculation may occur when immunogenicity data for approximately 
40 to 60 subjects per group are available. The standard deviation of the Day 29 change from 
baseline of S-IgA for WCE of natural logarithmic transformed GMFR will be computed. The 
standard deviation of natural logarithmic transformed GMTs of the IgG serum responses for 
the Boostrix-containing antigens (PT, FHA, PRN) at Day 29 will also be computed. 
Proportions with titer ≥ 0.1 IU/mL for the IgG serum responses for the Boostrix-containing 
antigens (diphtheria, tetanus) at Day 29 will be estimated.  
The standard deviations and proportions with titer ≥ 0.1 IU/mL will be computed in the full 
dataset and not by treatment group to ensure that the blinding is maintained. The sample size 
will then be recalculated with the potential to adjust the sample size accordingly. 
A small committee consisting of select ILiAD leadership and an independent blinded 
statistician will evaluate the need to change sample size. The independent blinded statistician 
will use the standard deviation values estimated from the full dataset to recalculate the 
sample size. In addition to these pooled standard deviation values, the committee will also 
assess data completeness for the primary endpoint and drop-out rate. 
The committee will meet and document its decision in a memorandum. This memorandum 
will include the pooled standard deviations, the updated power/sample size computations, 
and the final decision regarding any change in sample size. 
7.3 Analysis Sets 
The safety analysis set will consist of all randomized subjects who receive study vaccine and 
have any safety data available. Subjects will be classified according to the actual vaccine 
received. The safety analysis will be done on this analysis set. 

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The intent-to-treat analysis set will consist of all randomized subjects. Subjects will be 
classified according to the randomized treatment group. Subject disposition, demographics, 
and medical history will be summarized on this analysis set. 
The immunogenicity analysis set will consist of all subjects in the intent-to-treat analysis set 
who receive study vaccine, have a baseline and at least 1 post-vaccination sample (mucosal 
or serum immunogenicity testing, respectively) for which valid results were reported for the 
test being analysed, and have not received any component of a licensed pertussis vaccine in 
the past 3 years or through Day 85 of the study. Subjects will be classified according to the 
actual vaccine received. All immunogenicity analyses will be done on this analysis set. The 
substudy analysis set will also be based on this analysis set but including only subjects who 
are enrolled in the optional open-label substudy. 
The per-protocol analysis set will consist of all subjects in the immunogenicity analysis set, 
with the following exclusions: 
• Data from all available visits for subjects following the receipt of unsuitable 
investigational product (either via dispensed and/or assigned or delivered). 
• Data from all available visits for subjects found to be ineligible at baseline per-protocol. 
• Data from all available visits for subjects following the use of major immune modulators 
or immunosuppressants or following the receipt of blood products. 
• Data from all available visits for subjects following clinically significant protocol 
deviations that can affect the efficacy (immunogenicity) results as determined by clinical 
review. 
• Data from any visit that occurs substantially out of window as defined by exceeding 
30 days past the visit window or the time point whereby the follow-up visit should have 
occurred, whichever is most restrictive. Standard visit windows are described in 
schedule of events (Table 13-1). 
For analyses using the per-protocol analysis set, subjects will be classified according to the 
randomized treatment group. 
The safety lead-in analysis set will consist of the first 45 subjects who are randomized to the 
study. Subjects will be classified according to the actual vaccine received. The first 

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45 subjects enrolled will be in the older age group of 11 to 17 years, inclusive. 
Cellular-mediated responses in this group following study vaccination will be analysed if 
subjects contribute a baseline sample and the required post-vaccination sample (ie, Day 8) 
that has at least 85% recovery following peripheral blood mononuclear cell (PBMC) 
procedures. Similarly, cellular-mediated immunity of the optional substudy will occur in a 
subset of subjects who contribute to Day 85 and Day 113 samples and have a similar 
recovery of PBMCs. 
7.4 
Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.3 or later. Continuous 
variables will be summarized using the mean, standard deviation, median, first quartile, third 
quartile, minimum value, and maximum value. Categorical variables will be summarized 
using frequency counts and percentages, as well as a two-sided 95% confidence interval (CI) 
for proportions computed using the Agresti-Coull method when appropriate. Data will be 
listed in data listings. 
Immunogenicity endpoints (seroconversion, GMT, and GMFR) will be summarized by 
baseline negative and positive status (by quantiles) of each anti-pertussis antibody (WCE, PT, 
FHA, PRN, and any additional anti-pertussis antibodies) and by antibody type (eg, S-IgA, 
IgA, and IgG separately), by the 2 age groups (6 to 10 years and 11 to 17 years, inclusive) 
and across age groups. Substudy analyses will assess immunity at baseline and Days 85 and 
113 (independently for substudy subjects) and relative to colonization status 
(colonized/non-colonized) at either Day 92 or Day 99 following re-vaccination/attenuated 
challenge at Day 85. The mucosal and serum immunogenicity endpoints will be summarized 
by treatment group and by day (all subjects), including a separate analysis after Day 85 for 
the open-label substudy. Analyses will include the GMTs with 95% CIs and GMFRs with 
95% CIs. The 95% CIs will also be provided for mucosal and serum seroconversion. For 
immunogenicity analysis, it is assumed that the natural log of the data is normally distributed. 
All statistical tests will be two-sided at 0.05 significance level. 
There are 2 primary comparisons that will be tested at a two-sided significance level of 0.05. 
The study is considered a success if both primary comparisons meet statistical significance. 
The Holm procedure (also known as a stepdown Bonferroni procedure) will be used to 
control for multiplicity when evaluating the key secondary endpoints.  

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Further details of the planned statistical analyses, methods, and data conventions will be 
described in the SAP. 
7.4.1 Analyses of Primary Endpoints 
7.4.1.1 Analyses of Primary Immunogenicity Endpoints 
For mucosal S-IgA against WCE at Day 29, the two-sided 95% CI for change from baseline 
in GMFR will be calculated. A superiority hypothesis will be tested to demonstrate BPZE1 
can adequately induce mucosal S-IgA against WCE at Day 29 by GMFR. 
The formal superiority hypothesis is: 
 
𝐻𝐻0: 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 ≤ 1 𝑣𝑣𝑣𝑣. 𝐻𝐻𝐴𝐴 ∶𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺> 1 
The GMFR is defined as the ratio of GMT at Day 29 and GMT at baseline, i.e.,  
𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺=   ቀ 
𝜇𝜇𝐷𝐷29
𝜇𝜇𝐵𝐵𝐵𝐵ቁ, with µD29 and µBL being the GMTs at Day 29 and baseline, respectively. 
After natural logarithmic transformation, 𝑙𝑙𝑙𝑙( 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺) = 𝑙𝑙𝑙𝑙( 𝜇𝜇𝐷𝐷29) −𝑙𝑙𝑙𝑙( 𝜇𝜇𝐵𝐵𝐵𝐵). Therefore, the 
hypothesis can be expressed in the natural log scale as: 
 
𝐻𝐻0: 𝑙𝑙𝑙𝑙( 𝜇𝜇𝐷𝐷29) −𝑙𝑙𝑙𝑙( 𝜇𝜇𝐵𝐵𝐵𝐵) ≤ 0 vs. 𝐻𝐻𝐴𝐴: 𝑙𝑙𝑙𝑙( 𝜇𝜇𝐷𝐷29) −𝑙𝑙𝑙𝑙( 𝜇𝜇𝐵𝐵𝐵𝐵) > 0 
After natural logarithmic transformation, a paired t-test will be used to test the difference of 
mucosal S-IgA against WCE at Day 29 compared with baseline. The superiority objective 
will be demonstrated if the lower limit of the 95% CI for the difference of mucosal S-IgA 
against WCE at Day 29 compared to baseline on the natural log scale is greater than 0 within 
the treatment group. The superiority hypothesis will be tested in treatment groups BPZE1 and 
BPZE1 + Boostrix separately. 
7.4.1.2 Analyses of Primary Safety Endpoints 
The number and percentage of subjects with solicited AEs (local, nasal/respiratory, and 
systemic reactogenicity events) through 7 days following first study vaccination with any 
combination of pertussis-containing vaccines (BPZE1, BPZE1 + Boostrix, Boostrix) will be 
calculated by treatment group.  

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7.4.2 Analyses of Key Secondary Serum Immunogenicity (IgG) Endpoints 
Descriptive statistics (GMT, GMFR, seroconversion) for serum IgG against PT, FHA, and 
PRN will be presented at baseline and Day 29 and by treatment group (BPZE1 + Boostrix, 
Boostrix). For serum IgG against PT, FHA, and PRN at Day 29, the two-sided 95% CI for 
group difference in GMT in natural log will be calculated. A two-sample t-test will be used to 
compare the natural log-transformed GMTs between groups for serum IgG against each of 
PT, FHA, and PRN at Day 29. The non-inferiority objective will be demonstrated if the lower 
limit of the 95% CI of group difference in natural log is greater than -0.693. 
For serum IgG against diphtheria and tetanus, the two-sided 95% CI for group difference in 
the proportion of subjects with antibody concentration ≥0.1 international units (IU)/mL will 
be calculated using the Agresti-Caffo method. The non-inferiority objective will be 
demonstrated if the lower limit of 95% CI of group difference is greater than -0.1. 
The Holm procedure (also known as a stepdown Bonferroni procedure) will be used to 
control for multiplicity when evaluating the key secondary endpoints. 
7.4.3 Analyses of Secondary Endpoints  
7.4.3.1 
Analyses of Secondary Mucosal Secretory Immunogenicity (S-
IgA) Endpoints 
Descriptive statistics (GMT, GMFR, seroconversion) for mucosal S-IgA against WCE, PT, 
FHA, PRN, and any other anti-pertussis mucosal antibodies identified during assay 
development will be presented at each time point and by treatment group. 
Comparisons between two time points (eg, Day 29 and baseline) will be conducted using a 
paired t-test as outlined in Section 7.4.1.1. Non-interference or non-inferiority comparisons 
between two treatment groups (eg, BPZE1 + Boostrix being non-inferior to Boostrix by 
GMT at Day 29) will be conducted using a two-sample t-test as outlined in Section 7.4.2. 
Non-inferiority comparisons between two proportions will be conducted using the Agresti-
Caffo method as outlined in Section 7.4.2.  
Analysis of covariance (ANCOVA) model will be used to examine the effects of age or other 
baseline demographics on differential responses to induction of mucosal S-IgA immunity.   

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Subgroup analyses by age (6 to 10 years and 11 to 17 years, inclusive), time since last aP 
vaccination (prior to study entry), or other baseline demographics and by baseline antibody 
level (by quantile) will be conducted for BPZE1, BPZE1 + Boostrix, and Boostrix treatment 
groups. In addition to descriptive summaries, a forest plot of the corresponding 95% CIs will 
be generated for each subgroup. 
Mucosal S-IgA seroconversion rate (2-fold increase over baseline value or a 4-fold increase 
over the lower limit of assay detection [whenever the baseline value falls below the lower 
limit of assay detection]) with 95% CI will be calculated by treatment group at Day 29. A 
chi-square test will be used to compare seroconversion rates between treatment groups. 
Additional combinations of antibody response (WCE, PT, FHA, PRN, and any additional 
anti-pertussis antibodies) may also be tested.  
Plots of the reverse cumulative distribution curves of each anti-pertussis mucosal antibody 
titre for mucosal S-IgA GMT will be generated for Day 29 by treatment group. 
Further details will be provided in the SAP. 
7.4.3.2 Analyses of Secondary Serum Immunogenicity (IgA and IgG) 
Endpoints 
All analyses will use the approaches outlined in Section 7.4.1.1 for the primary analyses, in 
Section 7.4.2 for the key secondary analyses and those outlined in Section 7.4.3.1 for 
secondary analyses. 
7.4.3.3 Analyses of Secondary Safety Endpoints 
The number and percentage of subjects will be summarized for each solicited AE by 
timepoint, severity grade, and treatment group. Additionally, solicited AEs will be analysed 
by taking the maximum severity through 7 days following any study vaccination to 
summarize the frequency and percentage of subjects reporting each local [if applicable; after 
IM injection only], nasal/respiratory, or systemic event. Mean response (for any 
measurement) and duration through 7 days following any study vaccination will be 
summarized daily using descriptive statistics. Solicited AEs will be reported separately 
following study vaccination on Day 85 in the substudy. 

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Adverse events will be coded by preferred term and system organ class using the latest 
version of MedDRA. 
The following unsolicited AEs will be summarized as number and percentage of subjects 
reporting at least 1 event in each preferred term and system organ class and cross-tabulated 
by severity and relationship to study vaccination. 
• All AEs through 28 days following first study vaccination and following 
re-vaccination/attenuated challenge (substudy) by severity and relationship to study 
vaccination, and by treatment group. 
• All MAAEs through 84 days following first study vaccination and 
re-vaccination/attenuated challenge (substudy) by treatment group by severity and 
relationship to study vaccination, and by treatment group and time since study 
vaccination. 
• All AESIs and SAEs through Day 169/EOS by treatment group by severity and 
relationship to study vaccination, and by treatment group and time since study 
vaccination. 
Serious AEs will be summarized by detailed listing showing the event description, preferred 
term and system organ class, relevant dates (study vaccinations and AEs), severity, 
relatedness, and outcome for each event. Any SAE considered related to BPZE1 will be 
classified as a SUSAR. 
The number and percentage of subjects with SARS-CoV-2 infections or AESIs associated 
with COVID-19 infection or SARs-CoV-2 vaccine-related events will be summarized, if the 
COVID-19 pandemic remains ongoing in the region or if there are mass vaccinations using a 
COVID-19 vaccine during study conduct. 
The number and percentage of subjects with colonization or clearance by real-time PCR or 
B. pertussis culture following study vaccination (subsets of subjects) will be summarized 
over time using the methods outlined in Section 7.4.2 for proportions. 
Secondary safety endpoints following re-vaccination/attenuated challenge for the optional 
substudy will be analysed in a similar fashion as the secondary safety endpoints for the main 
study. 

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7.4.4 Analyses of Endpoints for the Optional Substudy 
All analyses will use the approaches outlined in Section 7.4.1.1 for the primary analyses, in 
Section 7.4.2 for the key secondary analyses and those outlined in Section 7.4.3.1 for 
secondary analyses. 
The number and percentage of subjects without colonization at either Day 92 or Day 99 will 
be calculated by treatment group (BPZE1, BPZE + Boostrix, BPZE1 and BPZE1 + Boostrix, 
Boostrix control). The number and percentage of subjects without colonization at Day 92 and 
Day 99 will also be calculated by treatment group (see Section 7.4.2 for a description of the 
approach). 
BPZE1, BPZE1 + Boostrix, BPZE1 and BPZE1 + Boostrix, and Boostrix control of 
induction of mucosal S-IgA at Day 29 and Day 85 will be summarized and compared by 
protection against colonization (Colonizers/Non-colonizers) using a two-sample t-test. 
BPZE1 induction of mucosal S-IgA immunity at Day 113 will be compared with that at 
Day 29 and Day 85 (by treatment group) using a paired t-test to assess if a 
re-vaccination/attenuated challenge with BPZE1 provides significantly more mucosal S-IgA 
induction by treatment group (BPZE1, BPZE1 + Boostrix). To demonstrate that BPZE1 
following Boostrix provides a similar level of induction as BPZE1 alone, a two-sample t-test 
will be used to test for the difference of mucosal S-IgA immunity at Day 113 (Boostrix 
versus BPZE1). 
BPZE1, BPZE1 + Boostrix, or control (Boostrix) induction of mucosal S-IgA at Day 113 and 
Day 169/EOS will be summarized and compared using a two-sample t-test between subjects 
who participated in the substudy and subjects who did not participate in the substudy by 
treatment group. 
Bordetella pertussis colony counts at each of Day 92 and Day 99 (individual and total) will 
be summarized descriptively and the Wilcoxon Rank-Sum test will be used to compare 
colony counts. Mean counts and AUC will be calculated across Day 92 and Day 99. 
Colonization versus non-colonization status for Day 92, Day 99, and for the combined result 
over Day 92 and Day 99 will be tabulated. 

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To assess if prior BPZE1 induced mucosal immunity substantially reduces colonization at 
Day 92 and Day 99, the number and percentage of subjects with colonization at each of 
Day 92 and Day 99 will be analysed based on mucosal S-IgA at Day 29 and Day 85 (see 
Section 7.4.2 for analysis approach). The percent reduction (with 95% CI) relative to the 
Boostrix control group at each of Day 92 and Day 99 will be summarized. 
7.4.5 Other Analyses 
Summary statistics will be provided for exploratory endpoints, demographic and baseline 
data, medical history, vital sign measurements, physical examination, study vaccination 
compliance, and prior and concomitant medications. 
Cellular immune response (Th1 and Th2) following study vaccination will be evaluated in 
the safety lead-in analysis set using baseline and Day 8 and in the substudy using Day 85 and 
Day 113 (subset). Parameters will be summarized using descriptive statistics and a formal 
test of differences in Th1 vs Th2 pathway induction between treatment groups. The 95% CI 
of median will be provided. Median of fold rise over baseline will also be provided. 
If a substantial number of subjects receive a COVID-19 vaccine that is under an emergency 
use authorization only, then safety analysis may also assess any AEs that may be confounded 
by such concomitant vaccine administration during the study. 
7.4.6 Interim Database Lock  
An interim database lock may occur after all subjects have completed Day 29 and sample 
testing for all primary and select secondary immune endpoints has been completed (mucosal 
and serum), but results will only be provided at treatment assignment level to maintain the 
blind. The site and those interacting directly with the site or subject data (eg, CRO, 
laboratories) will remain blinded to subject assignment until EOS or end of sample testing, 
depending on the activities of the associated entities. 

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8 
Data Quality Assurance 
The sponsor will perform quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any subjects in this study, sponsor personnel and the investigator 
will review the protocol, the package inserts, investigator brochures, the eCRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs. A qualified representative of the sponsor will monitor 
the conduct of the study by visiting the site and by contacting the site by telephone and 
e-mail. During these site visits, information recorded in the eCRFs will be verified against 
source documents. 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include subject diaries for 
reactogenicity reporting. 
Investigative site staff will enter subject data into an approved and auditable data 
management system. The analysis data sets will be a combination of these data and data from 
other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable CRO and/or 
sponsor standards and data cleaning procedures to ensure the integrity of the data 
(eg, removing errors and inconsistencies in the data). Adverse event terms (including SAEs) 
will be coded using MedDRA, an internal validated medical dictionary, and concomitant 
medications will be coded using the WHO Drug Dictionary. 

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9 
Ethics 
9.1 
Independent Ethics Committee 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an independent ethics committee (IEC) before participation of 
human subjects in research studies. Before study onset, the protocol, informed consent, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IEC. Documentation of all IEC approvals and of the IEC 
compliance with ICH harmonised tripartite guideline E6 (current version): Good Clinical 
Practice (GCP) will be maintained by the site and will be available for review by the sponsor 
or its designee. 
All IEC approvals should be signed by the IEC chairman or designee and must identify the 
IEC name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favourable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IEC. The 
investigator must promptly supply the sponsor or its designee, the IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 
Subject Information and Consent 
A written informed consent (and assent, if applicable) in compliance with regulatory 
authority regulations shall be obtained from each subject and/or his or her legal guardian 
before entering the study or performing any unusual or nonroutine procedure that involves 
risk to the subject. An ICF and subject information sheet/authorization form template may be 
provided by the sponsor to investigative sites. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the ICF and subject information 

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sheet/authorization form should be reviewed by the sponsor or its designee or both before 
IEC submission. Once reviewed, the ICF and subject information sheet/authorization form 
will be submitted by the investigator to his or her IEC for review and approval before the 
start of the study. If the ICF or subject information sheet/authorization form is revised during 
the course of the study, all active participating subjects and or legal guardians must sign the 
revised form(s). A separate ICF will be utilized for subjects participating in the substudy. 
Before recruitment and enrolment, each prospective subject and/or his or her legal guardian 
will be given a full explanation of the study, be allowed to read the approved ICF (or subject 
information sheet/authorization form, if applicable), and have any questions answered. Once 
the investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent (and assent, 
if applicable) to participate in the study by signing the ICF (and subject authorization form, if 
applicable). The authorized person obtaining the informed consent also signs the ICF (and 
subject authorization form, if applicable). 
The ICF and subject information sheet/authorization form will contain separate sections that 
address the use of remaining mandatory samples for optional exploratory research (if 
applicable) and explain/address the exploratory research portion of the study. Subject medical 
records need to state that written informed consent was obtained. 
The investigator shall retain the signed original ICF(s) (and subject authorization form[s], if 
applicable) and give copies of the signed original form(s) to the subject and/or legal 
guardian. 

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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IEC 
but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, or the IEC. 
The investigator and all employees and co-workers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Neither the sponsor nor the CRO is financially responsible for further testing or treatment of 
any medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor the CRO is financially responsible 
for further treatment of the subject’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 (current 
version) by providing all essential documents. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6 (current version). The investigator will conduct all aspects of this study in accordance 
with all national, state, and local laws or regulations. Study information from this protocol 

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will be posted on publicly available clinical trial registers before enrolment of participants 
begins. 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 (current version) and all applicable guidelines and regulations. 
10.5 Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the sponsor and/or IEC according to the 
timeline and method outlined in the protocol. In addition, the investigator agrees to submit 
annual reports to the study site IEC as appropriate. 
10.6 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IEC with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.7 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
No records may be transferred to another location or party without written notification to the 
sponsor. 
10.8 Publications 
After completion of the study, the data may be considered for reporting at scientific meetings 
or for publication in scientific journals. In these cases, the sponsor will be responsible for 
these activities to determine how the manuscript is written and edited, the number and order 
of authors, the publication to which it will be submitted, and other related issues. The sponsor 
has final approval authority over all such issues. 

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Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 

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11 Study Management 
The administrative structure will include an unblinded biostatistics team (statisticians and 
programmers) and an external SMC. 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
11.1.1.1 Safety Monitoring Committee 
Safety oversight will be conducted by an SMC that is an independent group of experts that 
monitors subject safety and advises the sponsor. The SMC members will be separate and 
independent of study personnel participating in this study and should not have scientific, 
financial, or other conflict of interest related to this study. The SMC will consist of members 
with appropriate expertise to contribute to the interpretation of the data from this study. 
The SMC will convene prior to study initiation, if a pause is triggered, or upon the request of 
the medical monitor and/or sponsor. The medical monitor and sponsor are empowered to 
request a review by the SMC for any safety reason. 
The SMC will operate under the rules of a sponsor-approved charter that will be approved at 
the organizational meeting of the SMC. At this time, each data element that the SMC needs 
to assess will be clearly defined. Procedures for SMC reviews/meetings will be defined in the 
charter. The SMC will review applicable data to include, but not limited to subject’s clinical 
course or safety results (eg AEs, reactogenicity). Reports may include enrolment and 
demographic information, medical history, concomitant medications, physical assessments, 
and solicited and unsolicited AE/SAEs. Additional data may be requested by the SMC, and 
interim statistical reports may be generated as deemed necessary and appropriate by the 
sponsor. The SMC may receive data in aggregate and presented by treatment group. 
The SMC will review grouped and unblinded data in the closed session only. As an outcome 
of each review/meeting, the SMC will make a recommendation as to the advisability of 
proceeding with study vaccinations (as applicable), and to continue, modify, or terminate this 
study. 

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11.1.2 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the clinical monitor will visit the investigator and study site at periodic 
intervals (including remote monitoring activities), in addition to maintaining necessary 
telephone and letter contact. The clinical monitor will maintain current personal knowledge 
of the study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IEC review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and the CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the subject, must be reviewed and approved by the 
sponsor or its designee. Amendments to the protocol must be approved by the IEC before 
subjects can be enrolled into an amended protocol. Letters of amendment or clarification do 
not need to be approved by the IEC. 
11.2.2 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IEC and agreed to by the 

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investigator. A significant deviation occurs when there is nonadherence to the protocol or to 
local regulations or ICH GCP guidelines that may or may not result in a significant, 
additional risk to the participant or impacts the integrity of study data. Deviations will be 
assessed with Sponsor involvement and deemed significant (major) or of minor significance 
prior to database lock. 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to 
study participants without prior IEC approval. As soon as possible after such an occurrence, 
the implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IEC for review and approval, to the sponsor for 
agreement, and to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the investigator and relevant site 
personnel will be trained in all aspects of study conduct by the sponsor/sponsor 
representative. This training will occur either as part of the investigator meeting or site 
initiation. Ongoing training may also be performed throughout the study during routine site 
monitoring activities. 
11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow-up telephone call for long-term safety). 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report (CSR) is prepared and provided to the regulatory agency(ies) as required 
by the applicable regulatory requirement(s). The sponsor will also ensure that the CSRs in 
marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of CSRs. 

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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the investigator with a summary of 
the study results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. The study summary results will be posted on publicly available 
clinical trial registers. 

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World Health Organization (WHO). Pertussis vaccines: WHO position paper − August 2015. 
Weekly Epidemiological Record. 2015;90(35):433-60. 
Xu Z, Octavia S, Luu LDW et al. Pertactin-negative and filamentous hemagglutinin-negative 
Bordetella pertussis, Australia, 2013-2017. Emerg Infect Dis. 2019;25(6):1196-99. 
Zerbo O, Bartlett J, Goddard K, et al. Acellular Pertussis Vaccine Effectiveness Over Time. 
Pediatrics. 2019;144(1):e20183466. 

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13 Appendices 
13.1 Appendix: Schedule of Events 

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b 
Safety lead-in subjects (only) to complete procedures listed under Study Visit S1; PBMCs to be collected in a subset of subjects. 
c 
Subjects not participating in the substudy are to complete procedures listed under Study Visit V3 for Day 85. Subjects in the safety lead-in cohort who are 
not participating in the substudy are not required to provide samples on Day 85 and may complete this visit remotely. 
d 
Subjects participating in the substudy (only) to complete procedures listed under Study Visits SSV3, SSV4, SSV5, and SSV6.  
e 
Procedures listed for an Unscheduled study visit are optional and dependent on the cause for the visit itself. An unscheduled study visit may occur at any 
time between enrolment and Day 169/EOS. 
f 
Reviewed and/or updated. 
g 
Performed prior to vaccination. 
h 
Such as date of birth (where allowed by local regulations), sex, race, ethnicity, weight, and height (with derived BMI and Z-score). 
i 
Including prior and ongoing chronic medical conditions and past surgeries. 
j 
Concomitant medications will include all medications and OTC products (including herbal supplements and multivitamins) taken by the subject from the 
time of signing the ICF through Day 29 (and from Day 85 [following study vaccination] through Day 113 for subjects participating in the optional substudy), 
or through an early termination visit, if prior to these time points. The use of anti-pyrogenic medication will be specifically queried by diary during the 
7 days following any study vaccination. 
k 
Only concomitant medications associated with any MAAE (through 84 days following any study vaccination); or AESI or SAE (through Day 169/EOS) will 
be recorded. 
l 
Vaccines received outside of the study will be specifically queried during each visit and recorded through Day 169/EOS. 
m 
Targeted physical examination at screening and Day 1 (prior to vaccination) to include head and neck (inclusive of nasal cavity and oropharynx), respiratory, 
cardiac, abdomen, and lymph nodes associated with the upper extremity, head, and neck. Targeted physical examination at all other times will be 
symptom-directed and performed at the discretion of the investigator. Height and weight will be measured at screening only. 
n 
Vital sign measurements (heart rate, body temperature) will be collected once before vaccination and then at 30 (+30) minutes after the last study vaccination 
(i.e., after IM vaccination on Day 1). For the safety lead-in cohort, a minimum of 30 minutes must occur between intranasal and IM vaccinations on Day 1, 
and medical assessment will occur prior to the second vaccination to allow for advancement. Temperature (oral or tympanic) will also be recorded daily in a 
subject diary for 7 consecutive days starting the day following any study vaccination (retrospective of the highest value in the previous 24 hours). 
o 
Female subjects of childbearing potential only who have become heterosexually active. To be performed at the discretion of the investigator based on history 
taking. 
p 
SARS-CoV-2 testing should be performed within approved national guidelines with tests that are approved through a (minimum) of emergency use 
authorization. Minimally invasive testing should be considered for the comfort of subjects. Subjects need to have accepted negative test results within 
72 hours prior to vaccination. Repeat testing is allowed on multiple occasions. For the substudy, subjects are not considered to have a protocol violation if a 
retest for SARS-CoV-2 exceeds the study window. 
 

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q 
On Day 1, intranasal vaccination will occur prior to IM vaccination with a minimum of 10 minutes (minimum of 30 minutes for subjects in the safety lead-in 
cohort of 11 to 17 year olds) between intranasal and IM vaccinations.  
r 
Immediate reactogenicity will be assessed at 30 minutes (+30 minutes) after the last study vaccination of the Day (i.e., after IM vaccination on Day 1, after 
nasal vaccination on Day 85), prior to release from clinical observation. 
s 
All subjects will record maximum daily reactogenicity in a subject diary for 7 consecutive days starting the day following any study vaccination 
(retrospective of the highest value in the previous 24 hours). Subjects will be instructed that should they have reactogenicity with a potential toxicity grade 3 
at any time, they should contact the site on the same day and be seen or referred to a qualified medical facility within 24 hours. 
t 
Trained clinical staff will review the information from the subject diaries with the subjects and apply a standard toxicity grade (refer to Section 13.2) to any 
reactogenicity event. The diary will be reviewed following the first visit after vaccination for all subjects. 
u 
Subjects not in the safety lead-in cohort will be randomly assigned (1:1) to provide mid-turbinate/nasopharyngeal samples on either Day 29 or Day 85; 
however, if a subject cannot provide a sample on Day 29 (for any reason), the subject should provide a sample on Day 85 (this will not be considered a 
protocol deviation). 
v 
Collection of an extra 20 mL of blood for cellular-mediated immunity may be an option in a select number of individuals who are in the substudy (up to 
45 subjects). This will not involve extra venipuncture, but only collection of additional volume. 
w  
Medically attended AEs will be monitored through 84 days following any study vaccination. 
 
 

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13.2 Appendix: Toxicity Grading Scales 
Table 13-2 
Local Reactogenicity Grading Scale 
Variable 
Grade 1 
Grade 2 
Grade 3 
Pain/tendernessa 
Easily tolerated, causes 
no or minimal 
limitation of use of limb  
Sufficiently 
discomforting, 
interferes with greater 
than minimal limitation 
of use of limb  
Causing inability to 
perform usual social 
and functional activities 
Rednessb,c 
 
Evidence of redness 
that is <2.5 cm in 
diameter  
>2.5 cm in diameter 
with <50% of upper 
extremity surface area 
segment involved 
>50% upper extremity 
surface area segment 
involved OR ulceration 
OR infection OR 
phlebitis OR sterile 
abscess OR drainage  
Swellingb,c 
 
Evidence of swelling 
that is <2.5 cm in 
diameter  
>2.5 cm in diameter 
with <50% of upper 
extremity surface area 
segment involved 
>50% upper extremity 
surface area segment 
involved OR ulceration 
OR infection OR 
phlebitis OR sterile 
abscess OR drainage  
Note: Local reactogenicity to be evaluated after an IM injection only. Grade 0 will be the classification if the 
observation is less than a grade 1. Any grade 3 reactogenicity event that leads to an unscheduled visit to a 
healthcare provider will be recorded as an MAAE. 
a 
To be graded by investigator based on subject diary. 
b 
Grade to be applied by data management based on measurement recording unless grade 3 is noted with 
other characteristics by the investigator. 
c 
If redness or swelling exceeds 100 mm or >50% of upper extremity surface area, or involves the shoulder, 
elbow, or chest, or prevents everyday activity, then subjects must be evaluated and a swelling assessment 
eCRF will be completed. 
Source: Adapted from DAIDS Version 2.1, 2017. 
 

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Table 13-3 
Nasal/Respiratory Reactogenicity Grading Scale 
Variable 
Grade 1 
Grade 2 
Grade 3 
Runny nose/nasal 
congestion 
Noticeable but does not 
interfere with normal 
everyday activity (eg, 
aware but not troubled, 
rarely wipes/blows 
nose, breathing through 
nose noted) 
Moderate discomfort that 
interferes with normal 
everyday activity, 
troublesome (eg, 
wipe/blow nose 
occasionally, noisy nose 
breathing, occasional 
mouth breathing, 
“nasally” speech) 
Significant discomfort, 
prevents normal everyday 
activity, and/or seeks 
medical care (eg, 
wipe/blow nose frequently, 
mouth breathing most of 
the time due to congestion, 
consistent “nasally” speech) 
Sore/irritated throat 
(‘scratchy’) 
Noticeable but does not 
interfere with eating or 
drinking (eg, aware but 
not troubled) 
Moderate discomfort that 
interferes with eating or 
drinking, troublesome, 
affects oral intake 
Significant discomfort, 
prevents eating or drinking, 
and/or seeks medical care; 
troublesome to the level of 
preventing oral intake 
Cough 
Noticeable but does not 
interfere with normal 
everyday activity or 
sleeping (eg, aware but 
not troubled, a few short 
episodes) 
Frequent cough that 
interrupts normal 
everyday activity or 
sleeping, troublesome 
(eg, coughing but only 
rare episodes of 
prolonged coughing) 
Significant and repetitive 
coughing that prevents 
everyday activity or sleep, 
or seeks medical care (eg, 
frequent coughing, 
occasional episodes of 
prolonged coughing) 
Sneezing  
Noticeable but does not 
interfere with normal 
everyday activity (eg, 
aware but not troubled, 
a few short episodes) 
Moderate discomfort that 
interferes with normal 
everyday activity, 
troublesome (eg, 
occasional bouts of 
sneezing) 
Significant discomfort, 
prevents everyday activity, 
and/or seeks medical care 
(eg, frequent/repeated 
sneezing episodes) 
Nasal or sinus 
pain/irritation  
Noticeable but does not 
interfere with normal 
everyday activity (eg, 
aware but not troubled, 
noted discomfort) 
Moderate discomfort that 
interferes with normal 
everyday activity, 
troublesome (facial 
pain/pressure) 
Significant discomfort, 
prevents everyday activity, 
and/or seeks medical care; 
or induces nosebleeda 
Difficulty 
breathing/wheezing 
Audible wheeze 
(whistling sound) 
occasionally noted with 
exhale or inhale but 
does not interfere with 
normal everyday 
activity 
Audible wheeze and or 
shortness of breath with 
activity (eg, nasal flaring, 
chest tightness, rapid 
breathing at rest/minimal 
activity), interferes with 
normal everyday activity 
Requires bronchodilator use 
or accompanied by 
respiratory distress or 
hypoxemia 
Note: Grade 0 will be the classification if the observation is less than a grade 1. Any grade 3 reactogenicity 
event that leads to an unscheduled visit to a healthcare provider will be recorded as an MAAE. 
a 
Epistaxis (nosebleed) should be entered as an AE and graded accordingly. 
Source: Adapted for age and aligned with FluMist Monograph. 
 

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Table 13-4 
Systemic Reactogenicity Grading Scale 
Variable 
Grade 1 
Grade 2 
Grade 3 
Fevera 
 
38.0 – 38.4 °C 
(100.4°F – 101.1°F) 
38.5 – 38.9 °C 
(101.2°F – 102.0°F) 
39.0 – 40.0 °C 
(102.1°F – 104.0°F) 
Headache 
Easily tolerated, causing no 
or minimal interference 
with daily activities 
Causing greater than 
minimal interference 
with usual social and 
functional activities 
Interferes with normal 
everyday activity 
Prevents performance of 
normal social and 
functional activities 
Fatigue/malaise 
(decreased activity) 
Easily tolerated 
Interferes with normal 
everyday activity 
Prevents normal everyday 
activity 
Loss of 
appetite/anorexia 
loss of appetite but no 
decrease in oral intake 
Decreased oral intake 
but no weight loss 
Decreased oral intake with 
weight loss or evidence of 
dehydration 
Vomiting 
Transient or intermittent 
AND no or minimal 
interference with oral 
intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in need of 
aggressive rehydration (eg 
IV hydration) 
Diarrhoea 
Transient or intermittent 
episodes of unformed 
stools OR increase of <3 
stools over normal in a 
24-hr period 
Persistent episodes of 
unformed or watery 
stools OR increase of 
4-6 stools over 
normal in a 24-hr 
period 
Increase of >7 stools a 
24-hr period OR IV fluid 
replacement indicated 
Nausea 
Transient or intermittent 
AND no or minimal 
interference with oral 
intake 
Persistent nausea with 
decrease in oral intake 
for 24 hrs 
Persistent nausea with need 
for fluid replacement (eg, 
IV hydration) 
Myalgia (muscle 
aches) 
Muscle pain beyond the site 
of injection causing no or 
minimal interference with 
usual social and functional 
activities 
Muscle pain beyond 
the site of injection 
causing greater than 
minimal interference 
with usual social and 
functional activities 
Muscle pain causing 
inability to perform usual 
social and functional 
activities 
Acute allergic 
reaction/urticaria 
Localized without medical 
intervention 
Localized with 
medical intervention 
OR mild angioedema 
without intervention 
Generalized OR 
angioedema with 
intervention 
Note: Grade 0 will be the classification if the observation is less than a Grade 1. Any grade 3 reactogenicity 
event that leads to an unscheduled visit to a healthcare provider will be recorded as an MAAE. 
a 
Temperature may be oral, tympanic, or noncontact (clinic only). Temperature greater than 40.0 °C 
(104.0 °F) is considered an SAE and subjects should seek medical attention immediately. 
Source: Adapted from DAIDS Version 2.1, 2017. 
 

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13.3 Appendix: Expected Normal Ranges in School-Age Children and 
Adolescents 
Table 13-5 
Expected Normal Ranges for Heart Rate and Respiratory Rate in 
School-Age Children and Adolescents 
Population 
Respiratory Rate 
(breaths per minute) 
Heart Rate 
(beats per minute) 
School-age children 
(6 to 12 years of age; 20 to 
42 kg) 
18-30 
60-140 
Adolescents 
(13 years of age or older; and/or 
>42 kg) 
12-16 
50-100 
Source: Adapted from ACLS 2021.