A Randomized, Double-blind, Placebo-controlled, First-in-Human, Phase 1/2a Study to Evaluate Safety, Reactogenicity and Immunogenicity of Monovalent HPV16 and HPV18 Ad26-vectored Vaccine Components and an MVA-vectored HPV16/18 Vaccine Component in Otherwise Healthy Women With HPV16 or 18 Infection of the Cervix
Phase: PHASE1
Conditions: Human Papillomavirus Infections
Sponsor: Janssen Vaccines & Prevention B.V.

1
Approved, Date: 20 August 2019
Janssen Vaccines & Prevention B.V.*
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled First-in-Human, Phase 1/2a Study to 
Evaluate the Safety, Reactogenicity and Immunogenicity of Monovalent HPV16 and 
HPV18 Ad26-vectored Vaccine Components and an MVA-vectored HPV16/18 Vaccine 
Component in Otherwise Healthy Women with HPV16 or 18 Infection of the Cervix
Protocol VAC81623HPV1002; Phase 1/2a
AMENDMENT 3
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
* Janssen Vaccines & Prevention B.V. is a Janssen pharmaceutical company of Johnson & Johnson and is hereafter 
referred to as the sponsor of the study. The sponsor is identified on the Contact Information page that accompanies 
the protocol.
EudraCT NUMBER: 2018-000200-41
Status:
Approved
Date:
20 August 2019
Prepared by:
Janssen Vaccines & Prevention B.V.
EDMS number:
EDMS-ERI-146564753, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03610581

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE .............................................................................................................. 22
ABBREVIATIONS ...................................................................................................................................... 25
DEFINITIONS OF TERMS.......................................................................................................................... 26
1.
INTRODUCTION................................................................................................................................ 27
1.1.
Background .................................................................................................................................... 27
1.2.
Benefit-risk Evaluations.................................................................................................................. 33
1.2.1.
Known Benefits........................................................................................................................... 33
1.2.2.
Potential Benefits........................................................................................................................ 33
1.2.3.
Potential Risks............................................................................................................................ 33
1.2.4.
Overall Benefit-Risk Assessment ............................................................................................... 37
1.3.
Overall Rationale for the Study...................................................................................................... 38
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 38
2.1.
Objectives and Endpoints .............................................................................................................. 38
2.2.
Hypothesis ..................................................................................................................................... 41
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 41
3.1.
Overview of Study Design.............................................................................................................. 41
3.2.
Study Design Rationale.................................................................................................................. 48
4.
PARTICIPANT POPULATION .......................................................................................................... 49
4.1.
Inclusion Criteria ............................................................................................................................ 49
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 55
5.
STUDY VACCINE ALLOCATION AND BLINDING.......................................................................... 55
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 56
6.1.
General Instructions and Procedures ............................................................................................ 56
6.2.
Criteria for Postponement of Vaccination ...................................................................................... 57
7.
STUDY VACCINE COMPLIANCE .................................................................................................... 58
8.
PRE-STUDY AND CONCOMITANT THERAPY ............................................................................... 58
9.
STUDY EVALUATIONS .................................................................................................................... 59
9.1.
Study Procedures........................................................................................................................... 59
9.1.1.
Overview..................................................................................................................................... 59
9.1.2.
Visit Windows ............................................................................................................................. 59
9.1.3.
Screening Period (Days -42 to -2): Visit 1 .................................................................................. 60
9.1.4.
Vaccination and Follow-up Period (Day 1 to Day 366)............................................................... 61
9.1.4.1.
Vaccination (Day 1, and Day 57)............................................................................................. 61
9.1.4.2.
Post-first Vaccination Follow-Up.............................................................................................. 62
9.1.4.3.
Post-second Vaccination Follow-Up........................................................................................ 63

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9.1.4.4.
Early Withdrawal – Early Exit Visit........................................................................................... 64
9.2.
Study Evaluations .......................................................................................................................... 64
9.2.1.
Safety.......................................................................................................................................... 64
9.2.2.
Immunogenicity........................................................................................................................... 68
9.2.3.
Virology and Histology................................................................................................................ 69
10.
PARTICIPANT COMPLETION/DISCONTINUATION OF STUDY VACCINE/ 
WITHDRAWAL FROM THE STUDY................................................................................................. 70
10.1.
Completion ..................................................................................................................................... 70
10.2.
Discontinuation of Study Vaccine/Withdrawal from the Study....................................................... 70
10.3.
Contraindications to Vaccination.................................................................................................... 72
11.
STATISTICAL METHODS................................................................................................................. 72
11.1.
Analysis Sets.................................................................................................................................. 72
11.1.1.
Full Analysis Set ......................................................................................................................... 72
11.1.2.
Per-Protocol Immunogenicity Population ................................................................................... 72
11.2.
Sample Size Determination ........................................................................................................... 73
11.3.
Participant Information ................................................................................................................... 73
11.4.
Safety Analyses ............................................................................................................................. 73
11.5.
Immunogenicity Analyses .............................................................................................................. 74
11.6.
Virology Analyses........................................................................................................................... 75
11.7.
Planned Analyses .......................................................................................................................... 75
11.8.
Independent Data Monitoring Committee ...................................................................................... 75
11.9.
Study Safety Rules......................................................................................................................... 76
12.
ADVERSE EVENT REPORTING ...................................................................................................... 79
12.1.
Definitions ...................................................................................................................................... 80
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 80
12.1.2.
Attribution Definitions.................................................................................................................. 81
12.1.3.
Severity Criteria .......................................................................................................................... 82
12.2.
Special Reporting Situations.......................................................................................................... 82
12.3.
Procedures..................................................................................................................................... 83
12.3.1.
All Adverse Events...................................................................................................................... 83
12.3.2.
Serious Adverse Events ............................................................................................................. 84
12.3.3.
Pregnancy................................................................................................................................... 85
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 85
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 85
13.1.
Procedures..................................................................................................................................... 85
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 86
14.
STUDY VACCINE INFORMATION ................................................................................................... 86
14.1.
Physical Description of Study Vaccine........................................................................................... 86
14.2.
Packaging and Labeling................................................................................................................. 87
14.3.
Storage and Handling .................................................................................................................... 87
14.4.
Study Vaccine Accountability......................................................................................................... 88
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 88
16.
ETHICAL ASPECTS ......................................................................................................................... 88
16.1.
Study-Specific Design Considerations........................................................................................... 88
16.2.
Regulatory Ethics Compliance....................................................................................................... 89
16.2.1.
Investigator Responsibilities ....................................................................................................... 89
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 89
16.2.3.
Informed Consent ....................................................................................................................... 90
16.2.4.
Privacy of Personal Data ............................................................................................................ 91
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 92
16.2.6.
Country Selection ....................................................................................................................... 92

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17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 92
17.1.
Protocol Amendments.................................................................................................................... 92
17.2.
Regulatory Documentation ............................................................................................................ 92
17.2.1.
Regulatory Approval/Notification ................................................................................................ 92
17.2.2.
Required Prestudy Documentation............................................................................................. 93
17.3.
Participant Identification, Enrollment, and Screening Logs ........................................................... 93
17.4.
Source Documentation................................................................................................................... 94
17.5.
Case Report Form Completion ...................................................................................................... 94
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 95
17.7.
Record Retention ........................................................................................................................... 95
17.8.
Monitoring ...................................................................................................................................... 96
17.9.
Study Completion/Termination....................................................................................................... 96
17.9.1.
Study Completion/End of Study.................................................................................................. 96
17.9.2.
Study Termination....................................................................................................................... 96
17.10.
On-Site Audits ................................................................................................................................ 97
17.11.
Use of Information and Publication................................................................................................ 97
REFERENCES............................................................................................................................................ 99
INVESTIGATOR AGREEMENT ............................................................................................................... 108
LIST OF ATTACHMENTS
Attachment 1:
Definition of Woman of Childbearing Potential ............................................................ 102
Attachment 2:
Toxicity Tables ............................................................................................................. 103
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Study Design............................................................................................................................. 15
Table 2:
Summary of Immunogenicity Assays (Cellular)........................................................................ 19
Table 3:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 19
Table 4:
Study Design............................................................................................................................. 45
Table 5:
Summary of Immunogenicity Assays (Cellular)........................................................................ 69
Table 6:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 69
FIGURES
Figure 1:
Flow Chart for Identifying an HPV16 or HPV18 Infection Prior to Vaccination......................... 17
Figure 2:
Schematic Overview of the Study - HPV16 Infected Participants ............................................ 46
Figure 3:
Schematic Overview of the Study - HPV18 Infected Participants ............................................ 47
Figure 4: 
Flow Chart for Identifying an HPV16 or HPV18 Infection Prior to Vaccination......................... 50

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
PROTOCOL AMENDMENTS
Protocol Version
Date
Original Protocol
6 February 2018
Amendment 1
24 May 2018
Amendment 2
11 January 2019
Amendment 3
This document
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (this document)
The overall reason for the amendment: The inclusion/exclusion criteria have been adapted to enroll a broader 
population of women with any HPV16 or 18 infection of the cervix, not limited to persistent infection. The 
proposed changes will not impact primary and secondary study objectives. Safety of the different vaccine regimens 
is not considered to be different between participants with persistent or recently diagnosed HPV16 or 18 infection. 
Immunogenicity of the different vaccine regimens will be analyzed overall, and the sponsor is interested in 
exploring responses in recently diagnosed HPV infections for potential development of the therapeutic interventions 
in countries where the existing screening programs do not consistently identify persistent HPV infections.
Applicable Section(s)
Description of Change(s)
Rationale: The study population has been amended to also include women with recently diagnosed HPV 16 or 
18 infections of the cervix.
Synopsis, Overview of Study Design, Participant Population, Virology 
and Histology Evaluations, Statistical Methods; Time and Events 
Schedule; Definitions of terms; 1.2 Overall Rationale for the Study; 
3.1 Overview of Study Design; 4.1 Inclusion Criteria; 9.2.3 Virology 
and Histology; 11.3 Participant Information; 11.5 Immunogenicity 
Analyses; 11.6 Virology Analyses
Removal of the wording 'persistent' 
before the wording 'HPV16 or 18 
infection'. Update of inclusion 
criterion 4. Addition of persistent and 
recently diagnosed infection types.
Update of flow chart in Figures 1 and 4.
Rationale: Based on inclusion of women with recently diagnosed HPV 16 or 18 infections of the cervix, 
additional exploratory objectives/endpoints to assess clearance of recently diagnosed infections are included. 
Synopsis, Objectives, Endpoints, and Hypothesis, Statistical Methods; 
2.1 Objectives and Endpoints; 11.6 Virology Analyses
Exploratory objectives/endpoints to 
assess frequency and kinetics of 
clearance of HPV16 or 18 infection 
with/without the concomitant regression 
of CIN1 have been updated to include 
persistent and recently diagnosed 
infection types.
Rationale: Colposcopy examination has been added as study screening procedure for participants who did not 
have this examination done within the last 12 months.
Synopsis, Virology and Histology Evaluations; Time and Events 
Schedule; 4.1 Inclusion Criteria; 9.2.3 Virology and Histology
Implementing colposcopy examination 
during the screening period in case 
recent examination results are not 
available.
Rationale: Change in the visits' and vaccinations' allowed windows to keep these requirements consistent 
throughout the protocol.
Time and Events Schedule; 4.2 Exclusion Criteria; 6.2 Criteria for 
Postponement of Vaccination; 9.1.2 Visit Windows; 9.1.4 Vaccination 
and Follow-up Period (Day 1 to Day 366) 
Wording was updated to keep the 
flexibility of vaccination rescheduling 
in case of acute illness.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion 12 has been updated to include genital herpes infection. As HSV-2 infection 
might be a co-factor leading to progression of cervical disease, HSV-2 serology testing has been included on the 
day of the first vaccination and the 12-month follow-up visit (or the early exit visit, if applicable).
Time and Events Schedule; 4.2 Exclusion Criteria; 9.1.4 Vaccination 
and Follow-up Period (Day 1 to Day 366); 9.2.1 Safety;
9.2.3 Virology and Histology
The wording 'including genital herpes' 
has been added to exclusion criterion 12
as well as a note that positive HSV-2 
serology is not exclusionary. Exclusion 
criterion 13 has been removed.
HSV-2 serology testing has been 
included at Visit 2, Visit 14 and the 
early exit visit.
Rationale: Blinded interim analysis of immune responses has been added prior to the primary analysis as this 
will allow to identify immunogenicity and overall safety signals and guide further development of the vaccine.
Synopsis, Statistical Methods; 11.7 Planned Analyses
A paragraph describing the blinded 
interim immune analysis has been 
added.
Rationale: The benefit-risk evaluation has been updated to be in line with the Janssen clinical trial protocol 
template. 
1.2 Benefit-risk Evaluations; 16.1 Study-specific Design 
Considerations
The benefit-risk wording in 
Section 16.1 has been moved to a new 
Section 1.2. Additional benefit-risk 
wording from the Janssen clinical trial 
protocol template has been included.
Rationale: In the absence of suitable samples for complete qualification of the cellular assays used for the 
assessment of the secondary and exploratory endpoints, samples collected at baseline and/or post-vaccination will 
be used for completion of assay qualification concomitantly to the assessment of immunogenicity.
Synopsis, Immunogenicity Evaluations; 9.2.2 Immunogenicity 
The sentence describing baseline 
sample use for immunological assay 
characterization has been updated.
Rationale: Fibrinogen values are highly variable in the target study population. The fibrinogen levels among 
healthy women may be increased due to oral contraceptives, smoking, or hormone replacement therapy while 
there is no clinical pathology associated with this abnormality. The sponsor decided to remove this test as it has 
no added value for the eligibility assessment.
9.2.1 Safety
The fibrinogen test during screening has 
been removed.
Rationale: Sponsor’s responsible medical officer was updated to reflect current organizational structure.
Investigator agreement
Sponsor’s responsible medical officer 
was updated.
Rationale: Minor errors and unclarities were noted.
Throughout the protocol
Minor grammatical, formatting, or 
spelling changes and clarifications were 
made.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
Amendment 2 (11 January 2019)
The overall reason for the amendment: The dose of the modified vaccinia Ankara (MVA)-vectored HPV16/18 
vaccine administered in this study has been changed from 5x108 infectious unit (Inf.U) to a lower dose of
2x108 Inf.U. The use of 2x108 Inf.U MVA.HPV16/18 vaccine is supported by recent data derived from the sponsor's 
Ebola vaccine program that employed Ad26.ZEBOV, MVA-BN-Filo vaccine regimens and where no differences in 
the overall dose-dependent immunogenicity responses were observed when comparing MVA doses of 1x108 tissue 
culture infectious dose of 50% (TCID50) with 4.4x108 TCID50. Both the number of vaccine responders as well as the 
magnitude of the responses was similar for both dose levels. This was shown at the peak of the post boost immune 
response for humoral responses assessed by neutralizing and binding antibody responses, as well as for T cell 
responses assessed by IFNγ enzyme-linked immunospot (ELISpot) and intracellular cytokine staining (ICS) assay 
enumerating CD4+ and CD8+ specific T cells. In addition, no immunogenicity response differences were seen after 
peak responses, as assessed up to one year after vaccination. In addition, in previous non-human primate studies 
strong cellular immune responses were elicited with MVA-BN-HPV administered at 1.79x108 TCID50 (study DS-
TEC-117650) which is similar in strength to the proposed dose of 2x108 Inf.U. A diluent will be provided to the 
sites that will be added to the MVA.HPV16/18 vaccine supplied in vials at a concentration of 5x108 Inf.U/0.5mL.
Further, inclusion criterion 5 (requirement of recent colposcopy result) was updated in line with the current cervical 
cancer screening guidelines.30 In addition, minor edits and clarifications were made.
Applicable Section(s)
Description of Change(s)
Rationale: Change of the MVA.HPV16/18 dose from 5x108 Inf.U to 2x108 Inf.U for all subjects.
Synopsis; 1. Introduction; 3.1 Overview of Study Design;
3.2 Study Design Rationale; 6.1 General Instructions and Procedures;
14.1 Physical Description of Study Vaccine
Reduction of MVA.HPV16/18 dose
from 5x108 Inf.U to 2x108 Inf.U for all 
subjects. The dose will be reduced 
using a diluent provided to the sites.
Rationale: More information is provided on the preparation of study vaccine using diluents.
Synopsis; 3.1 Overview of Study Design; 3.2 Study Design Rationale; 
6.1 General Instructions and Procedures; 14.1 Physical Description of 
Study Vaccine
More information is provided on the 
extractable vial volumes and on the 
preparation of the study vaccine using 
diluents. Furthermore, it is clarified that 
vaccine components will be mixed at 
the pharmacy or at a designated product 
preparation area.
Rationale: Inclusion criterion 5 was updated to take into consideration the current United States cervical cancer 
screening guidelines.30 A recent colposcopy result will be defined as a colposcopy result with a maximum of 
12 months old at screening instead of less than 6 months old at screening.
4.1 Inclusion Criteria
Update of inclusion criterion 5.
Rationale: Exclusion criterion 12 was changed to clarify that symptomatic vaginal or genital infection should be 
confirmed by the physician or investigator.
4.2 Exclusion Criteria
Update of exclusion criterion 12.
Rationale: The procedure for identifying persistent HPV infection is clarified.
Synopsis; Time and Events Schedule; 4.1 Inclusion Criteria; 
9.2.3 Virology and Histology
The text explaining the different 
possibilities in the identification of 
persistent HPV infection is replaced by 
a flow chart. 
Rationale: Change in the instructions on the use of the cervico-vaginal brush.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
Applicable Section(s)
Description of Change(s)
9.1.3 Screening Period; 9.2.3 Virology and Histology; Attachment 2
Attachment 2 was removed and 
replaced in the text by a reference to the 
Laboratory Manual.
Rationale: Change in the list of manuals.
15. Study-Specific Materials
The Study Procedure Manual is 
removed from the study-specific 
materials list, because this document is 
not used in this study.
Rationale: Change of the terminology.
14.1 Physical Description of Study Vaccine 
The term solution is replaced by the 
term suspension for the 
MVA.HPV16/18 vaccine.
Synopsis; Time and Events Schedule; 2.1 Objectives and Endpoints; 
9.1.3 Screening Period; 9.1.4 Vaccination and Follow-up Period; 
9.2.3 Virology and Histology; 11.6 Virology Analyses
The term physician is replaced by the 
term healthcare provider when used in 
association with the collection of 
cervical samples.
14.4 Study Vaccine Accountability
The vaccine return form is replaced by 
the investigational product destruction 
form.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Amendment 1 (24 May 2018)
The overall reason for the amendment: Simplify the design of the study and address FDA feedback received 
during the IND review (March 2018).
Applicable Section(s)
Description of Change(s)
Rationale: Amending the study design to a non-adaptive Phase 1/2a design.
Synopsis; 1. Introduction; 3. Study Design and Rationale; 5. Study 
Vaccine Allocation and Blinding; 6. Dosage and Administration; 9. 
Study Evaluations; 10. Participant Completion/Discontinuation of 
Study Vaccine/Withdrawal from the Study; 11. Statistical Methods; 
14.3 Storage and Handling; 16.1 Study-Specific Design 
Considerations
Implementation of a Phase 1/2a study 
design, with an ascending dose component 
and a staggered time interval between the 
vaccination of each participant in Phase 1 
and study safety reviews with pauses.
Synopsis; 2. Objectives, Endpoints and, Hypothesis;
Objectives and endpoints adjusted to 
match the new study design.
11.10 Study Safety Rules
Addition of Study Stopping Rules
Synopsis; Time and Events Schedule; 3.1 Overview of Study 
Design; 9. Study Evaluations; 11.7 Planned analysis
Deletion of the immunogenicity 
evaluations at the Visit 2 months post final 
vaccination and addition of a Visit 
6 months post Dose 1.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Applicable Section(s)
Description of Change(s)
Rationale: Safety criteria are provided to determine that it is safe to initiate the Phase 2a component of the study,
the pooled assessment of safety will now be reviewed by an external IDMC and study stopping rules are added.
Synopsis; 3.1 Overview of the Study Design; 5. Study Vaccine 
Allocation and Blinding; 9.2.1 Safety; 11.7 Planned Analysis; 
11.8 Independent Data Monitoring Committee; 11.9 Study 
Vaccination Pausing and Stopping Rules
Change of DRC to an IDMC.
Synopsis; 11.9 Study Vaccination Pausing and Stopping Rules
Addition of study stopping rules.
Rationale: More information on the vaccine candidates is provided.
1.1 Background
Addition of more background information 
on the other vaccine candidates.
Rationale: Providing the FDA toxicity tables in the protocol.
Attachment 3
Providing the toxicity tables as an 
attachment to the protocol.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
SYNOPSIS
A Randomized, Double-blind, Placebo-controlled First-in-Human, Phase 1/2a Study to Evaluate the 
Safety, Reactogenicity and Immunogenicity of Monovalent HPV16 and HPV18 Ad26-vectored 
Vaccine Components and an MVA-vectored HPV16/18 Vaccine Component in Otherwise Healthy 
Women with HPV16 or 18 Infection of the Cervix
The vaccine candidates to be evaluated in this study are:

Ad26.HPV16 (JNJ-63682918), a recombinant replication-incompetent serotype 26 adenovirus 
(Ad26) vector encoding genetically modified human papillomavirus (HPV)16 early (E2, E6 and E7) 
proteins.

Ad26.HPV18 (JNJ-63682931), a recombinant replication-incompetent Ad26 vector encoding 
genetically modified HPV18 early (E2, E6 and E7) proteins.

MVA-mBN411B (JNJ-65195208) (referred to as MVA.HPV16/18 in this document), a live, 
modified vaccinia Ankara (MVA) – Bavarian Nordic A/S (BN) MVA-BN® vaccine which is non-
replicating in human cells and encodes the same genetically modified HPV16 and HPV18 early (E2, 
E6 and E7) proteins.
In this Phase 1/2a study, there will be 3 heterologous vaccine regimens administered on Day 1 and 57 
(Week 8, refer to Table 1):

Regimen 1 (low dose single, Ad26.HPV16 or Ad26.HPV18 at 5x1010 viral particles [vp] followed by
MVA.HPV16/18 at 2x108 infectious units [Inf.U]).

Regimen 2 (high dose single, Ad26.HPV16 or Ad26.HPV18 at 1x1011 vp followed by
MVA.HPV16/18 at 2x108 Inf.U).

Regimen 3 (mixing of Ad26.HPV16 at 5x1010 vp + Ad26.HPV18 at 5x1010 vp, followed by
MVA.HPV16/18 at 2x108 Inf.U).
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
a)
Objectives and endpoints
Primary
Objectives
Endpoints
To assess safety and reactogenicity of the 3 vaccine 
regimens.

Solicited local and systemic adverse events (AEs) 
for 7 days after each vaccination.

Unsolicited AEs from the time of informed 
consent form (ICF) signature until 28 days after 
the first vaccination, and thereafter, until 28 days 
after the second vaccination.

Serious adverse events (SAEs) throughout the 
study.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Secondary
Objectives
Endpoints
To assess immunogenicity of the 3 vaccine regimens.
T cell responses to the separate or combined protein 
peptide pools of HPV16 and HPV18 E2, E6 and E7 
proteins, including specific CD4+ and CD8+ T cells 
producing interferon gamma (IFNγ), tumor necrosis 
factor alpha (TNFα), or IL-2 (combined cytokine 
expression may also be assessed) will be determined by 
flow cytometry.
Exploratory
Objectives
Endpoints
To assess the frequency and kinetics of clearance of 

persistent or recently diagnosed HPV16 and
HPV18 infection (combineda) and

persistent or recently diagnosed HPV16 infection
and

persistent or recently diagnosed HPV18 infection
of the 3 vaccine regimens compared to placebo over 
the study period.
Healthcare 
provider-
and 
self-collected 
cervical 
samples obtained over the study period will be 
genotyped by a qualitative HPV genotyping test 
(Cobas®,
Roche) and a quantitative HPV PCR
genotyping test to evaluate HPV16 and/or HPV18 viral 
clearanceb, defined as:

A negative HPV16 genotype over the study 
period after having a baseline HPV16 infection
(persistent or recently diagnosed); OR

A negative HPV18 genotype over the study 
period after having a baseline HPV18 infection
(persistent or recently diagnosed).
To assess regression of CIN1 and concomitant 
clearance of HPV16 and/or HPV18 infection of the 
3 vaccine regimens compared to placebo over the study 
period.

Regression of CIN1: A colposcopic impression of 
normal after having a baseline of CIN1, 
AND
concomitant 
clearance 
of 
baseline 
(persistent or recently diagnosed) HPV16 and/or
HPV18 infection (as defined above).
To further characterize vaccine-elicited immune 
responses.
These assessments will include, but are not limited to, 
the assessments described below. Some of the 
exploratory assessments will only be initiated if 
indicated by the secondary immunogenicity data.
Cell-mediated

Flow cytometry to characterize other cellular 
immune responses to the separate or combined 
protein peptide pools of HPV16 and HPV18 E2, 
E6 and E7 proteins, including, but not limited to, 
mucosa-homing markers, Th17, Th2, regulatory 
T cell
(Treg), cytolytic markers, activation 
markers, and exhaustion markers.

Transcriptome analysis to provide phenotypic and 
functional characterization of peripheral blood 
mononuclear cells (PBMCs) ex vivo or after 
stimulation with either HPV16 and/or HPV18 E2, 
E6, and/or E7 peptide pools.

Enzyme-linked immunospot (ELISpot) assay to 

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Objectives
Endpoints
enumerate PBMCs able to produce IFNγ upon 
stimulation with HPV16 and/or HPV18 E2 
(complete, N-terminal, or C-terminal), E6 and/or 
E7 protein peptide pools.

ChipCytometry analysis of T cell responses to the 
separate or combined protein peptide pools of 
HPV16 and/or HPV18 E2, E6, and E7 proteins in 
PBMCs, including but not limited to CD4+ and 
CD8+ T cells producing IFNγ, TNFα and/or IL-2.
Humoral

Adenovirus neutralization assay to evaluate 
neutralizing antibody responses against the Ad26 
vector.

MVA neutralization assay to evaluate neutralizing 
antibody responses against the MVA vector.

Antibody responses to the HPV16 and/or HPV18 
capsid proteins L1 and/or L2 can be measured to 
investigate levels of HPV-specific antibodies 
before vaccination (not induced by vaccination 
with either Ad26.HPV16 or Ad26.HPV18), as 
well as induction of L1/L2 antibodies after 
vaccination as a “bystander” effect due to release 
of these proteins from infected cells after vaccine-
mediated cytolytic T cell
responses. L1/L2 
antibodies to other HPV genotypes might also be 
measured.

Antibody responses to E2, E6 and/or E7 of 
HPV16 and/or HPV18, or to these proteins of 
other HPV genotypes, can be evaluated.49

To explore potential immune correlates for viral 
clearance.

Immunogenicity
endpoints 
of
HPV-specific 
cellular or humoral responses described above, 
determined 
at 
multiple 
time 
points 
after 
vaccination will be used to explore potential 
immune correlates of viral clearance of HPV16 
and/or HPV18.
a The sum of women who clear an HPV16 infection plus women who clear an HPV18 infection.
b Women who receive CIN treatment will be considered as not clearing an HPV infection.
b) Hypothesis
No formal statistical hypothesis for safety or immunogenicity will be tested. 
OVERVIEW OF STUDY DESIGN
This is a multicenter, randomized, placebo-controlled, double-blind, safety, reactogenicity and 
immunogenicity Phase 1/2a study of 3 heterologous vaccine regimens with the Ad26.HPV16, 
Ad26.HPV18 and MVA.HPV16/18 recombinant vectors (Table 1). Vaccination will take place on Day 1
and Day 57. Study participants include approximately 66 women ≥18 to ≤60 years old with HPV types 16 
or 18 infection of the cervix.8

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
Vaccination and safety monitoring among the HPV16 infected participants may occur independently from
the HPV18 infected participants because the rates of enrollment of women with these 2 HPV types may
differ as cervical HPV16 infections are more prevalent than HPV18 infections.
An Independent Data Monitoring committee (IDMC) will be commissioned for this study to evaluate 
safety data over the course of the study and to review any event that meets a specific study pausing rule, 
stopping rule, or any other safety issue that may arise.
The IDMC will consist of members independent of the sponsor, including at least 1 medical expert in the 
relevant therapeutic area and at least 1 statistician. The IDMC responsibilities, authorities and procedures 
will be documented in its charter. The IDMC will review unblinded data (refer to Section 11.8 and 
Section 11.9 of the protocol for more details).
Randomization, vaccination and safety evaluation
The randomization, vaccination process and safety evaluations described below for HPV16 infected 
participants will be performed in the same manner and independently among HPV18 infected 
participants.
HPV16 infected participants (see Table 1)
Dose 1 (Ad26-based)
Phase 1 (Dose Escalation)

Step 1 [sentinels with low dose or placebo]: The first 2 participants (sentinels) will receive 
either a low dose Ad26.HPV16 (1 participant) or placebo (1 participant). Dosing of these 
2 participants may occur on the same day depending on enrollment rates. Vaccination of 
additional participants will be halted until a 24-hour and 7-day post vaccination blinded safety 
review of solicited and unsolicited AEs are performed by the principal investigator (PI) and 
the sponsor’s study responsible physician (SRP).

Step 2 [completion of Phase 1 with low dose or placebo]: In the absence of clinically 
significant findings in participants from step 1, 4 additional participants will be dosed: 
3 participants will receive low dose Ad26.HPV16 and 1 participant will receive placebo. 
There will be a staggered interval of 7 days between the vaccination of each of these 4 
participants. Vaccination of additional participants will be halted until a 7-day post 
vaccination safety review of solicited and unsolicited AEs and clinical laboratory results is 
performed by an Independent Data Monitoring Committee (IDMC) of participants in step 1 
and step 2.

Step 3 [sentinels for dose escalation with high dose or mixed regimen or placebo]: If the 
IDMC expresses no concerns on the safety data from the HPV16 participants in steps 1 and 2, 
and the first 2 HPV18 sentinels from step 1a, then 3 additional sentinel participants will be 
dosed: 1 participant will receive a high dose Ad26.HPV16, 1 participant will receive the 
Ad26.HPV16/Ad26.HPV18 mix and 1 participant will receive placebo. Dosing of these 
3 participants may occur on the same day depending on enrollment rates. Vaccination of 
additional participants will be halted until a 24-hour and 7-day post vaccination blinded 
safety review of solicited and unsolicited AE are performed by the PI and SRP.
                                                
aNo Ad26.HPV16/Ad26.HPV18 mix regimen will be administered until review of 2 sentinels HPV18 data in step 1.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019

Step 4 [completion of Phase 1 with high dose or mixed regimen or placebo]: In the absence of 
clinically significant findings in participants from step 3, 8 additional participants will be 
dosed: 3 participants will receive high dose Ad26.HPV16, 3 will receive the 
Ad26.HPV16/Ad26.HPV18 mix and 2 participants will receive placebo. There will be a 
staggered interval of 7 days between the vaccination of each of these 8 participants. 
Vaccination of additional participants will be halted until a 7-day post vaccination safety 
review of solicited and unsolicited AE and clinical laboratory results of participants in step 3 
and step 4 and all available safety data of participants in step 1 and 2 is performed by the 
IDMC. 
Phase 2a (Further Vaccination)

Step 5 [further vaccination with high dose or mixed regimen or placebo]: If the IDMC 
expresses no safety concerns on the safety data from participants in steps 1-4 and no 
participant has experienced the criteria that determine it is not safe to initiate the Phase 2a 
component of the study (see Section 11.8 and 11.9), 16 additional participants will be
randomized and dosed: 6 participants will receive high dose Ad26.HPV16, 6 will receive the 
Ad26.HPV16/Ad26.HPV18 mix and 4 participants will receive placebo. No more than 
5 participants per week will be dosed.
Dose 2 (MVA-based)
Phase 1
Completion of IDMC review in step 2 above will also allow the second dose vaccination with
MVA.HPV16/18 or placebo of the sentinel participants in step 1a. Safety reviews after MVA/placebo
vaccinations will follow the same scheme as for the Ad26 vaccinations, ie, a 24-hour and 7-day post 
vaccination blinded safety review by the PI/SRP will be performed after the MVA/placebo vaccinations 
of step 1 and 3 sentinel participants and an aggregated 7-day safety review will be performed by the 
IDMC when the MVA/placebo vaccinations of participants in step 2 and 4 have been completed. 
Phase 2a
If the IDMC expresses no safety concerns on the MVA.HPV16/18 / placebo data from participants in 
Phase 1, the 16 participants from Phase 2 will be dosed with MVA.HPV16/18 or placebo.
The HPV18 infected participants will follow the same process as described above for the HPV16-
infected participants. Vaccination and safety monitoring may occur independently to the HPV16 infected 
participants (see Table 1).
                                                
a An ad-hoc IDMC review of all available safety data may take place in case not all participants from step 1 and 2 
have been enrolled by the time the first MVA vaccination needs to take place.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
Table 1:
Study Design
Vaccine Regimen 
Phase 1
Phase 2a
HPV
Type*
Regimen
Day 1
Day 57 
(Week 8)
Step 1
sentinel;
low dose
Step 2
completion 
Phase 1;
low dose 
Step 3
sentinel dose 
escalation high 
& mixed 
regimens
Step 4
completion 
Phase 1;
high & mixed 
regimens
Subtotal
Step 5
further 
vaccination; high 
& mixed 
regimens
Total
16
Regimen 1a 
(Ad26 low dose)
Ad26.HPV16
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
1
3
-
-
4
-
4
16
Regimen 2a 
(Ad26 high dose)
Ad26.HPV16
(1x1011 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
16
Regimen 3 
(mixing of Ad26)
Ad26.HPV16
(5x1010 vp) +
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
16
Control
Placebo
(1.0 mL)
Placebo
(0.5 mL)
1
1
1
2
5
4
9
Total 
HPV16
2
4
3
8
17
16
33
18
Regimen 1b 
(Ad26 low dose)
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
1
3
-
-
4
-
4
18
Regimen 2b 
(Ad26 high dose)
Ad26.HPV18
(1x1011 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
18
Regimen 3 
(mixing of Ad26)
Ad26.HPV16
(5x1010 vp) +
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
18
Control
Placebo
(1.0 mL)
Placebo
(0.5 mL)
1
1
1
2
5
4
9
Total 
HPV18
2
4
3
8
17
16
33*
Total
4
8
6
16
34
32
66
Ad26=adenovirus serotype 26; HPV=human papillomavirus; Inf.U=infectious unit; MVA=modified vaccinia Ankara; vp=viral particles
* If enrollment is slow for HPV18-infected participants, up to 8 HPV18-infected participants can be replaced by HPV16-infected participants, hence a minimum of 25 HPV18 participants 
is required. The decision will be taken during Step 5. 
IDMC
IDMC
PI/SRP
PI/SRP

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
The study duration, from screening until the last follow-up visit, will be approximately 13.5 months per 
participant. The study consists of a screening period of up to 42 days (6 weeks), followed by vaccinations 
on Day 1 and Day 57, and follow-up visits up to 12 months after the first vaccination (target visit Day 
366±14 days).
PARTICIPANT POPULATION
Study participants must be healthy (on the basis of physical examination, medical history, vital signs 
measurement, and clinical laboratory tests performed at screening) women, aged ≥18 to ≤60 years on the 
day of signing the ICF, with HPV type 16 or 18 infection of the cervix determined within 8 weeks prior to 
screening or at the time of screening.
Women with cytology of HSIL or AIS or a colposcopy result of CIN2+ will be excluded. For the 
identification of eligible participants see Figure 1.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
Figure 1:
Flow Chart for Identifying an HPV16 or HPV18 Infection Prior to Vaccination

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
DOSAGE AND ADMINISTRATION
The following will be used to prepare the study vaccines:

Ad26.HPV16 (JNJ-63682918): supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable
volume])

Ad26.HPV18 (JNJ-63682931): supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable 
volume])

MVA.HPV16/18 (JNJ-65195208): supplied in a single use vial (5x108 Inf.U/0.5 mL; 0.5 mL
[extractable volume])

Placebo (0.9% saline): supplied in a single use vial (10 mL [filled volume])

Diluent (Diluent 5, DS-TEC-79875): supplied in a single use vial (1 mL [extractable volume]) and to 
be added to the Ad26.HPV16 or Ad26.HPV18 vials for administration of the Ad26.HPV16 or 
Ad26.HPV18 vaccines at a dose of 5x1010 vp

Diluent (tris-buffered saline [TBS] Diluent, DS-TEC-138030): supplied in a single use vial (1.5 mL
[extractable volume]), 1.0 mL is to be added to the MVA.HPV16/18 vial for administration of the 
MVA.HPV16/18 vaccine at a dose of 2x108 Inf.U
For each participant, every vaccination with Ad26.HPV16 and/or Ad26.HPV18 will be 1.0 mL in volume. 
For the low dose of Ad26.HPV16 or Ad26.HPV18 (5x1010 vp), 0.5 mL of Ad26.HPV16 or Ad26.HPV18
and 0.5 mL of diluent 5 (DS-TEC-79875) will be mixed and administered as a single injection. For the 
high dose of Ad26.HPV16 or Ad26.HPV18 (1x1011 vp), two vials of 0.5 mL of Ad26.HPV16 or 
Ad26.HPV18 will be mixed and administered as a single injection. The monovalent Ad26.HPV16 (5x1010
vp) and Ad26.HPV18 (5x1010 vp), vaccine components will be mixed at the pharmacy or at a designated 
product preparation area and administered as a single injection; denoted by Ad26.HPV16/Ad26.HPV18 in 
this document.
Vaccination with MVA.HPV16/18 at a dose of 2x108 Inf.U will be 0.5 mL in volume. Therefore, 1.0 mL 
of the diluent DS-TEC-138030 will be added to the vial of MVA.HPV16/18 (a concentration of 
5x108 Inf.U per 0.5 mL) and mixed at the pharmacy or at a designated product preparation area, and 0.5 
mL of the mix will be administered as a single injection.
To allow blinding, the volume of placebo vaccine will be the same as the volume of the corresponding 
Ad26.HPV16, Ad26.HPV18 or MVA.HPV16/18 vaccine.
Vaccine regimens are presented in Table 1.
The vaccines will be administered by intramuscular injection into the deltoid muscle of either arm by a 
blinded study vaccine administrator. Opposite arms should be used for the MVA injection.
SAFETY EVALUATIONS
An IDMC will be established to monitor the safety data over the course of the study and to review any 
events that meet a specific study pausing rule, study stopping rule, or any other safety issue that may arise
(refer to Section 11.8 and Section 11.9 of the protocol for more details).
Adverse events will be reported by the participant. Solicited AEs will be reported for 7 days after each 
vaccination. Unsolicited AEs will be reported from the time of ICF signature until 28 days after the first 
vaccination, and thereafter, until 28 days after the second vaccination. Serious adverse events and 
concomitant medications related to an SAE will be collected from the time of ICF signature until the end 
of the study.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
Other safety assessments include clinical laboratory tests (hematology, biochemistry), vital signs 
measurements (heart rate, supine systolic and diastolic blood pressure, oral body temperature), and 
physical examinations at the time points indicated in the Time and Events Schedule.
IMMUNOGENICITY EVALUATIONS
Humoral and cellular immunogenicity assays may include but are not limited to the assays summarized in 
Table 2 and Table 3. Baseline and post-vaccination samples will be used for the characterization of 
immunological assays.
Table 2:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Secondary endpoint
ICS
Analysis of T cell responses to the separate or combined protein peptide pools of 
HPV16 and HPV18 E2, E6 and E7 proteins, including specific CD4+ and CD8+
T cells producing IFNγ, TNFα, or IL-2 (combined cytokine expression may also be 
assessed)
Exploratory endpoints
ICS
Analysis of other cellular responses to the separate or combined protein peptide 
pools of HPV16 and HPV18 E2, E6 and E7 proteins (including, but not limited to, 
mucosa-homing markers, Th17, Th2, Treg, cytolytic markers, activation markers, 
exhaustion markers)
Transcriptome analysis
Analysis of gene expression patterns to provide phenotypic and functional 
characterization of PBMCs ex vivo or after stimulation with HPV16 and/or
HPV18 E2, E6, and/or E7 peptide pools.
ELISpot responses
Enumeration of IFNγ-producing HPV16 and/or HPV18 E2 (complete, N-terminal,
and/or C-terminal peptide pools), E6 and/or E7-specific T cells
ChipCytometry
Analysis of T cell responses to the separate or combined protein peptide pools of 
HPV16 and/or HPV18 E2, E6, and E7 proteins in PBMCs, including but not 
limited to CD4+ and CD8+ T cells producing IFNγ, TNFα and/or IL-2
ELISpot=enzyme-linked immunospot; HPV=human papillomavirus; ICS=intracellular cytokine staining; IFN=interferon; 
IL=interleukin; NK=natural killer: PBMC=peripheral blood mononuclear cell; Th=T-helper (cell); TNF=tumor necrosis factor; 
Treg=regulatory T cell
Table 3:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Exploratory endpoints
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus vector
MVA neutralization assay
Analysis of neutralizing antibodies to MVA vector
L1/L2 ELISA
Analysis of L1 and/or L2 antibodies by ELISA to HPV16 and/or HPV18 or 
other HPV genotypes
E2, E6 and E7 ELISA
Analysis of E2, E6 and/or E7 antibodies to HPV16 and/or HPV18 or other 
HR-HPV genotypes
ELISA=enzyme-linked immunosorbent assay; HPV=human papillomavirus; HR-HPV=high-risk human papillomavirus; 
MVA=modified vaccinia Ankara
VIROLOGY AND HISTOLOGY EVALUATIONS
HPV16 and HPV18 genotyping will be performed with a qualitative PCR test (Cobas®, Roche) on the 
cervical samples. Prior to vaccination, a participant will have a confirmed diagnosis of an HPV16 or 
HPV18 infection. More information on the identification of HPV infection is provided in the flow chart
(Figure 1).
Cervical samples will be collected by the healthcare provider and by the participant (self-sampling) at the 
time points indicated in the Time and Events Schedule. Cobas® testing will be performed by a central 

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
sponsor designated laboratory. A quantitative HPV PCR genotyping test that detects HPV16 and HPV18 
together with other individual HR-HPV types will be used on all cervical samples (healthcare 
provider-collected and self-collected).
The healthcare provider will be delegated by the PI and must be qualified by education, training, and 
experience as per local regulations to perform the delegated task. 
Colposcopy examination will occur during screening only for those participants who do not have recent 
(within the last 12 months) examination results. A mandatory colposcopy examination will occur 
12 months after the first dose for all participants. All colposcopy biopsy specimens will be sent to a 
central laboratory for standardized interpretation. 
Management and medical follow-up after the mandatory colposcopy evaluation will be at the discretion of 
the investigator and local guidelines.
STATISTICAL METHODS
Sample Size Determination
While mild to moderate local and systemic AEs are expected, AEs that preclude further vaccination or 
more serious ones that would limit product development are not anticipated. With 20 participants in 1 
vaccine regimen the observation of 0 such reactions after the first vaccination would be associated with a 
95% confidence that the true rate is less than 13.9%. Across regimens (n=48), the observation of 0 such 
reactions after the first vaccination would be associated with a 95% confidence that the true rate is less 
than 6.1%.
Planned Analyses
A blinded interim analysis may be performed after all participants from Phase 1 of the study have 
completed the 21 days post-Dose 2 visit (Week 11) or have discontinued earlier. This analysis, which will 
include immunogenicity and safety data, will allow to identify immunogenicity and overall safety signals 
and guide further development of the vaccine.
The primary analysis will occur when all participants have completed the 6 months post-Dose 1 visit
(Week 26) or have discontinued earlier. If enrollment is slow for HPV18-infected participants, an interim 
analysis may first be performed on the HPV16-infected participants. The primary analysis will then be 
performed on all participants when all HPV18 infected participants have completed the 6 months post-
Dose 1 visit (Week 26) or have discontinued earlier. These analyses will include safety and virology data 
up to the 6 months post-dose 1 visit (Week 26) and immunogenicity data up to the 21 days post-Dose 2 
visit (Week 11).
The final analysis will occur when the last participant completes the final visit at 12 months post-Dose 1 
(Week 52, Day 366) or discontinued earlier to determine the durability of the immune response and 
analyze any additional safety, virology and immunological data collected after the primary analysis. If 
enrollment is slow for HPV18-infected participants, an interim analysis may first be performed on the 
HPV16-infected participants. The final analysis will then be performed on all participants when all 
HPV18 infected participants have completed the 12 months post-Dose 1 visit (Week 52) or have 
discontinued earlier.
The safety and immunogenicity analyses will include the timepoints described in the TIME AND 
EVENTS SCHEDULE. At the time of the primary analysis, the study will be unblinded for sponsor 
personnel (including medical personnel, biomarker lead, virologist, statistician, programming and data 
management). Participants, clinical staff and study-site personnel will remain blinded to the study vaccine 
allocation until the end of the study.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
Safety Analyses
All safety analyses will be performed on the Full Analysis Set (FAS), which includes all participants with 
at least 1 vaccination. No formal statistical testing of safety data is planned. Safety data will be tabulated 
by vaccine regimens and pooled placebos and will be analyzed descriptively. The severity of abnormal 
symptoms, vital signs, AEs and abnormal laboratory values will be graded based on the adapted Food and 
Drug Administration (FDA) “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (September 2007)” (see Attachment 2).
Immunogenicity Analyses
The immunogenicity analyses will be performed on the Per-Protocol Immunogenicity (PPI) set, which 
will include all randomized and vaccinated participants for whom immunogenicity data are available 
excluding participants with major protocol deviations expecting to impact the immunogenicity outcomes. 
In addition, if participants miss the second dose, but continue the planned visit schedule, samples taken 
after the planned but missed dose will not be taken into account. An additional analysis will be done for 
the FAS.
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (geometric mean and 95% 
CI, or median and quartile range [Q1-Q3], as appropriate) will be calculated for continuous 
immunological parameters at all time points. Graphical representations of immunological parameters will 
be made as applicable. Frequency tabulations will be calculated for discrete (qualitative) immunological
parameters as applicable.
Virology Analyses
The analyses will be performed on the FAS, including participants for whom virology endpoint measures 
are available. 
Frequency and kinetics of clearance of HPV16 and HPV18 infection will be analyzed either combined or
by HPV type (HPV16, HPV18), and by infection type (persistent or recently diagnosed), using both the 
healthcare provider- and self-collected cervical samples and will be described for the vaccine regimens 
and placebo during the study duration.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
TIME AND EVENTS SCHEDULE 
Study Period
SCRN
ACTIVE
Clinic Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Early
Exit a
Study Week #
0
1
4
8
9
11
12
16
26
34
52
Target Visit Timing
DOSE
1
Dose 1
+ 1 d
Dose 1
+ 7 d
Dose 1
+ 28 d
DOSE
2
Dose 2
+ 1 d
Dose 2
+ 7 d
Dose 2
+ 21 d
Dose 2
+ 28 d
Dose 2
+ 8wks 
(2 mo)
Dose 1
+ 6 mo
Dose 2
+ 6 mo
Dose 1
+ 12 mo
Visit Day b -42to -2
1
2
8±2
29±3
57±7 b
58 b
64±2 b
78±3 b
85±3 b
113±5 b
183±14 b
239±14 b
366±14 b
Visit Type
Screening
Randomization 
and Dose 1
Safety, Immuno 
and Virology
Safety (only 
for sentinels
in Step 1 & 3; 
telephone)
Safety
Safety 
(telephone)
Dose 2
Safety, Immuno 
and Virology
Safety (only 
for sentinels
in Step 1 & 3; 
telephone)
Safety
Safety, 
Immuno and 
Virology
Safety 
(telephone)
Safety;
Virology
Safety, 
Virology
Safety, 
Immuno and 
Virology
Safety, 
Immuno and 
Virology
Early Exit
Written informed consent c

Inclusion/exclusion criteria

d
Demographics

Medical history/pre-study meds

Physical examination e











Vital signs f incl. oral temperature











Healthcare provider-collected cervical 
sample for HPV16 and HPV18 PCR g



Self-collected cervico-vaginal sample 
for HPV16 and HPV18 PCR h









Serum pregnancy test (women of 
childbearing potential only)

Urine pregnancy test (women of 
childbearing potential only)


Prevaccination symptoms check i


Randomization

Colposcopyn


HSV-2 serology test



Safety laboratory blood sample (mL)j
15
10
10
Humoral immunity (serum), mL j
10
10
10
10
Cellular immunity (whole blood), mL j
100 
60
100
60
100
100
Vaccination


30-minute post-vaccination 
observation k


Solicited AE recording
- - - - - Continuous - - - - -
- - - - - Continuous - - - - -

Unsolicited AE recording
- - - - - - - - - - - Continuous - - - - - - - - - - -
- - - - - - - - - - - - - Continuous - - - - - - - - - - - - -

SAE recording
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -


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Clinic Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Early
Exit a
Study Week #
0
1
4
8
9
11
12
16
26
34
52
Target Visit Timing
DOSE
1
Dose 1
+ 1 d
Dose 1
+ 7 d
Dose 1
+ 28 d
DOSE
2
Dose 2
+ 1 d
Dose 2
+ 7 d
Dose 2
+ 21 d
Dose 2
+ 28 d
Dose 2
+ 8wks 
(2 mo)
Dose 1
+ 6 mo
Dose 2
+ 6 mo
Dose 1
+ 12 mo
Visit Day b -42to -2
1
2
8±2
29±3
57±7 b
58 b
64±2 b
78±3 b
85±3 b
113±5 b
183±14 b
239±14 b
366±14 b
Visit Type
Screening
Randomization 
and Dose 1
Safety, Immuno 
and Virology
Safety (only 
for sentinels
in Step 1 & 3; 
telephone)
Safety
Safety 
(telephone)
Dose 2
Safety, Immuno 
and Virology
Safety (only 
for sentinels
in Step 1 & 3; 
telephone)
Safety
Safety, 
Immuno and 
Virology
Safety 
(telephone)
Safety;
Virology
Safety, 
Virology
Safety, 
Immuno and 
Virology
Safety, 
Immuno and 
Virology
Early Exit
Concomitant medications l
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Participant diary, ruler and thermometer
distribution


Participant diary review m




Approx. daily blood draw (mL)
15
110
–
10
–
60
–
10
110
–
-
-
60
110
110
Approx. cumulative blood draw (mL)
15
125
125
135
135
195
195
205
315
315
315
315
375
485
–
pre-dose; check of diary during the telephone call; pre- and post-dose; to include HIV-1/2 and hepatitis B/C serology, laboratory tests at screening are to be 
done within 42 days of randomization, retesting of laboratory values not meeting eligibility criteria at the screening visit is allowed once using an unscheduled visit 
during the 42-day screening period, at the discretion of the investigator; if within 7 days of the previous vaccination; if within 28 days of the previous vaccination; 
diary card collection
a.
For those participants who are unable to continue participation in the study up to Week 52, but for whom consent is not withdrawn, an exit visit will be conducted 
as soon as possible.
b.
The timing of the second vaccination and of Visit 12 will be determined relative to the actual day of the first vaccination. The timing of visits 7, 8, 9, 10, 11 and 13 
will be determined relative to the actual day of the second vaccination. 
c.
Signing of the ICF should be done before any study-related activity.
d.
If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose 
of study vaccination is given such that she no longer meets all eligibility criteria, then the screening laboratory tests should be repeated and the Day 1 visit re-
scheduled, or the participant should be excluded from participation in the study.
e.
A full physical examination, including height and body weight, will be carried out at screening. At other visits, an abbreviated, symptom-directed examination will 
be performed if determined necessary by the investigator.
f.
Heart rate and blood pressure measurements should be taken in supine position and preceded by at least 5 minutes of rest. Vital signs measurements should be 
performed before blood sampling. Body temperatures should be measured via the oral route.
g.
HPV16 and HPV18 genotyping will be performed with a qualitative PCR test (Cobas®, Roche) on the cervical samples. More information on the identification of 
HPV16 or HPV18 infection is provided in the flow chart in Section 4.1.
h.
Self-sampling for HPV16 and HPV18 PCR will be performed before healthcare provider-sampling of a cervical swab when procedures are indicated on the same 
day.

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i.
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of vaccination. If the vaccination visit cannot be rescheduled within the 
allowed window or the contraindications to vaccination persist, the sponsor’s medical monitor should be contacted for further guidance.
j.
If a situation arises where a study blood draw and vaccination with a licensed vaccine occur on the same day, the blood draw should be made before the vaccination.
k.
After vaccination, participants will remain under observation at the study site for at least 30 minutes. Any solicited local (at injection site) and systemic AEs,
unsolicited AEs, SAEs, concomitant medications, and vital signs will be documented by study-site personnel following this observation period and participants will 
be allowed to leave the study site at approximately 45 minutes post-vaccination.
l.
Following the 28th day after each vaccination, only concomitant medications associated to SAEs will be recorded.
m. If an event is still ongoing on Day 8 or Day 64 the participant should keep the diary after the review and collect information until resolution. The diary should be 
reviewed again at the next visit.
n.
The screening colposcopy will be performed as study procedure only if a result of colposcopy performed within last 12 months is not available.
AE=adverse event; d=day; FU=follow-up; HIV=human immunodeficiency virus; HR-HPV=high-risk human papillomavirus; ICF=informed consent form; 
immuno=immunology; mo=month; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PI=principal investigator; SAE=serious adverse event; 
SRCN=screening; SRP=study responsible physician

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ABBREVIATIONS
Ad26
adenovirus serotype 26
AE
adverse event
AIS
adenocarcinoma in situ
BN
Bavarian Nordic (A/S)
CI
confidence interval
CIN
cervical intraepithelial neoplasia
CSR
Clinical Study Report
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
ELISA
enzyme-linked immunosorbent assay
ELISpot
enzyme-linked immunospot
ER
emergency room
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
First-in-Human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
β-hCG
β-human chorionic gonadotropin
HIV
human immunodeficiency virus
HPV
human papillomavirus
HR
high-risk
HSIL
high-grade squamous intraepithelial lesion
ICF
informed consent form
ICH
International Council on Harmonisation
ICS
intracellular cytokine staining
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFNγ
interferon gamma
IL
interleukin
IRB
Institutional Review Board
Inf.U
infectious unit
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
MRK
Merck
MVA
modified vaccinia Ankara
NK
natural killer (cell)
NSAID
non-steroidal anti-inflammatory drug
p53
tumor suppressor protein 53
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PI
principal investigator

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PP
Per-Protocol
PPE
Per-Protocol Efficacy
PPI
Per-Protocol Immunogenicity
PQC
Product Quality Complaint
pRb
retinoblastoma protein
Q
quartile
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
Statistical Analysis Plan
SRP
study responsible physician
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TBS
tris-buffered saline
TCID50
50% tissue culture infectious dose
Th
T-helper (cell)
Treg
regulatory T cell
TNFα
tumor necrosis factor alpha
US
United States
VCR
viral clearance rates
vp
viral particles
DEFINITIONS OF TERMS
HPV type: 
HPV16 or HPV18
HPV infection type:
persistent or recently diagnosed

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1.
INTRODUCTION
The vaccine candidates to be evaluated in this First-In-Human (FIH) study are:

Ad26.HPV16 
(JNJ-63682918),
a
recombinant
replication-incompetent 
serotype 26 
adenovirus (Ad26) vector encoding genetically modified human papillomavirus (HPV) 16 
early (E2, E6 and E7) proteins.

Ad26.HPV18 (JNJ-63682931),
a recombinant replication-incompetent
Ad26 vector
encoding genetically modified HPV18 early (E2, E6 and E7) proteins.

MVA-mBN411B (JNJ-65195208), a live, modified vaccinia Ankara (MVA) – Bavarian 
Nordic A/S (BN) MVA-BN® vaccine which is non-replicating in human cells and encodes 
the same genetically modified HPV16 and HPV18 early (E2, E6 and E7) proteins.
MVA-mBN411B is referred to as MVA.HPV16/18 in this document.
In this Phase 1/2a study, there will be 3 heterologous vaccine regimens administered in a 2-dose 
schedule on Day 1 and Day 57 (Week 8, refer to Table 4): 

Regimen 1 (low dose single, Ad26.HPV16 or Ad26.HPV18 at 5x1010 viral particles [vp] 
followed by MVA.HPV16/18 at 2x108 infectious units [Inf.U])

Regimen 2 (high dose single, Ad26.HPV16 or Ad26.HPV18 at 1x1011 vp followed by 
MVA.HPV16/18 at 2x108 Inf.U) 

Regimen 3 (mixing of Ad26.HPV16 at 5x1010 vp + Ad26.HPV18 at 5x1010 vp, followed by
MVA.HPV16/18 at 2x108 Inf.U). 
For the most comprehensive nonclinical and clinical information regarding Ad26.HPV16, 
Ad26.HPV18 and MVA.HPV16/18, refer to the latest version of the Investigator's Brochures for
Ad26.HPV16, Ad26.HPV18 and MVA.HPV16/18.
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
HPV Infection and Disease Burden
Among the more than 150 known HPV types, 40 are sexually transmitted and, of these, about 
13 are known to be oncogenic or high-risk (HR)-HPV types.53 Genital HPV infection is the most 
common sexually transmitted infection; most sexually active men and women acquire HPV at 
some point in their lives. In a national health and nutrition survey in the United States (US) 
covering the period 2011-2014, the prevalence of any HPV infection was 26.1% among females 
14-19 years of age, increasing to 59.8% among females 20-24 years of age.26 HR-HPV types are 
the cause of almost all cervical cancers53 and a large proportion of other anogenital cancers. 
Around 90% of cervical HPV infections are cleared within 5 to 7 years42; however, in a minority 
of infected women (~1%), HPV may ultimately give rise to genital neoplastic lesions. Cervical 
cancer led to approximately 266,000 deaths worldwide in 2012, with the biggest burden of the 
disease in low-income countries.55 Among the HR-HPVs, HPV16 and HPV18 are the most 

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prevalent types in both low-grade and advanced disease.24 HR-HPV types 16 and 18 have been 
established to be the underlying causative agents of more than 50% of cervical pre-cancerous 
lesions, and more than 70% of cervical cancer cases worldwide.13,20
The 3 prophylactic HPV vaccines that are currently on the market, bivalent Cervarix® (directed 
against HR-HPV16 and 18), tetravalent Gardasil® (directed against HPV6 and 11, and HR-
HPV16 and 18) and nonavalent Gardasil® (directed against HPV6 and 11, and HR-HPV16, 18, 
31, 33, 45, 52 and 58), prevent infection through the induction of neutralizing antibodies against 
the major capsid protein L1.29 However, the prophylactic vaccines suffer from some drawbacks: 
firstly, they have no therapeutic effect on established HPV-induced genital lesions.19,21,26,27,28,51
Secondly, the vaccine uptake is well below expectations: in 2013 in the US, only 38% of females 
13-17 years of age who were eligible for prophylactic HPV vaccination completed the 3-dose 
course of therapy, suggesting that many people may be entering their sexually active years 
without protection against these HR-HPVs.7 Finally, these vaccines are not indicated for people 
over the age of 26 years, leaving a large age group unprotected.
Thus, a therapeutic HPV vaccine for the eradication of persistent HR-HPV infections and 
associated diseases such as cervical intraepithelial neoplasia (CIN) is an urgent unmet medical 
need. 
Progression of HR-HPV-positive CIN into cervical cancer is associated with the failure of the 
human immune system to induce an adequate HPV-specific T cell response.17,54 With each CIN 
stage, the likelihood of progression to cervical cancer increases, underscoring the medical need 
to stop progression by clearing HPV infection as early as possible. An efficacious therapeutic 
HPV vaccine most likely needs to elicit strong cellular immune responses, at least against 
HPV16 and HPV18 and ideally other HR-HPVs. Although the first targets would be clearance of 
persistent HR-HPV and treatment of CIN stage 1, such a vaccine is likely to have wider 
applications, because HR-HPV, and particularly HPV16, has been implicated as the causative 
agent in several other cancers, including vulvar, penile, anal, and oropharyngeal cancers.44
HPVs are double-stranded deoxyribonucleic acid (DNA) viruses that encode only a small 
number of viral proteins. HPV infection targets the cells of the basal epithelial layer. Limited 
viral replication is accompanied by expression of a number of “early” proteins, such as E2. Viral 
genomes are maintained as episomes and viral gene expression is tightly controlled as the 
infected cells move towards the epithelial surface. HPV does not induce cytolysis or cell death, 
and viral replication and release are not associated with inflammation.15 Failure to develop an 
effective cell-mediated immune response to clear or control infection results in persistent 
infection and, in the case of the oncogenic HPVs, an increased probability of progression to 
intraepithelial neoplasias and invasive carcinoma.45 Two “early” proteins, E6 and E7, promote 
cell proliferation and delay differentiation. During disease progression, the HPV DNA is 
integrated into the host genome, which coincides with the loss of E2 expression and deregulation 
of expression of E6 and E7. Increased expression of E7 leads to the degradation of 
retinoblastoma protein (pRb), which contributes to neoplastic progression, while E6-mediated 
degradation of the tumor suppressor protein 53 (p53) leads to loss of its functional activities such 

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as growth-arrest and induction of apoptosis.18 As a consequence, increased expression of E6 and 
E7 proteins leads to cell proliferation and eventually immortalization.15 In summary, cancers 
usually arise in individuals who fail to resolve their infection and who retain oncogene 
expression for years or even decades.
Different therapeutic HPV vaccine candidates are currently in clinical development. Most of 
these target the E6 and E7 proteins of HPV16 and HPV18 and are evaluated in women with 
high-grade cervical neoplasia (CIN2/3) or cervical cancer.25 In the Ad26.HPV16/Ad26.HPV18 
and MVA-BN-HPV16/18 vaccine vectors the E2 gene is included, in addition to E6 and E7. 
With this inclusion of E2, the vaccine vectors would treat both early and later stages of disease 
and the initial focus is on women with normal histology or low-grade cervical neoplasia (not 
worse than CIN1). Treatment in an early stage of disease is assumed to be less impacted by the 
immune suppression environment of the infected cells, which increases with disease severity.41
In several countries, the screening algorithm for cervical cancer is changing. Detection of HPV 
DNA instead of detection of abnormal cells in cervical smears is expected to become the primary 
diagnosis in the triage for HPV-related disease. With DNA-based screening, a large number of 
HPV16- or HPV18-positive women will be identified who will have normal cytology or low-
grade dysplasia upon further testing. The aim of the therapeutic HPV vaccine candidates is to 
clear HPV persistent infections to reduce the risk of disease progression.
Background Information on the Product
Natural resolution of HPV16-related disease has been shown to be correlated with cellular 
immune responses against the E2 protein,11,14,54 and persistence of low-grade lesions or 
progression of such lesions is associated with an inadequate immune response against the early 
antigens E6 and E7.54,12,40 E2 has higher expression levels in early stages of HPV-induced 
disease (low-grade neoplasia) than in later stages. Upon integration into the host chromosome,
E2 expression is lost, resulting in the upregulation of E6 and E7. Given the expression of these 
3 proteins in the different disease stages, the sponsor-designed HPV16- and HPV18-specific 
vaccine antigens contain these 3 proteins, with the intention to treat early stages of HPV-induced 
disease. Inclusion of E6 and E7 in the vaccine could help to prevent progression to higher grade 
disease, as E6- and E7-specific T-cell responses have been shown to play a role in the prevention 
of neoplastic lesions.
Vaccine Candidates
The HPV16-
and HPV18-directed therapeutic vaccine candidates Ad26.HPV16 and 
Ad26.HPV18 were developed based on replication-incompetent recombinant vectors derived 
from human adenovirus of the serotype 26. Replication-incompetent adenoviral vectors are 
particularly interesting vaccine candidates in the context of therapeutic vaccination due to their 
proven ability to induce strong cellular immunity to the transgenes they encode.1,4,9,38,39
These strong T cell responses, comprising interferon gamma (IFNγ) secreting CD8+ and CD4+
T cell responses, have been observed in 4 clinical trials using adenoviral vector-based vaccines, 
targeting human immunodeficiency virus (HIV) (Ad26.ENVA.01)1, ebola (Ad26.ZEBOV in 

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combination with MVA.filo)38, malaria (Ad35.CS.01)39, and tuberculosis (TB) (Ad35.TB-S).9 In
addition, prime-boost immunizations with Chimpanzee adenovirus 63 and MVA vectors have 
been shown to induce strong CD4+ and CD8+ response against HCV antigens in humans.56
E6 and E7 are viral oncogenes that are responsible for transformation of cells and, therefore, 
special consideration was given to the safety of these proteins expressed by the vaccine 
candidates. Thus, the coding regions of E6 and E7 were divided into multiple fragments and 
subsequently reorganized (shuffled) into a new order, resulting in the expression of a fusion 
protein (abbreviated as E6E7SH) without oncogenic properties, as shown in non-clinical studies. 
E2 was incorporated as an N-terminal fusion to E6E7SH. Three amino acid changes were 
introduced 
into
the 
DNA-binding site of E2 to prevent possible effects on viral gene expression, resulting in a fusion 
protein (abbreviated as E2E6E7SH).
Non-Clinical data of Ad26.HPV16/Ad26.HPV18 and MVA.HPV16/18
Strong 
cellular 
immune 
responses 
after 
prime-boost 
immunization 
with 
Ad26.HPV16/Ad26.HPV18 and MVA-BN-HPV16/18 vectors were shown in mouse and 
monkey non-clinical models (Studies DS-TEC-119232 and DS-TEC-117650). In the absence of 
HPV permissive animal models, the mouse lung tumor cell line TC-1 (derived from primary lung 
epithelial cells of C57BL/6 mice) was used to show that the vaccine vectors have therapeutic 
efficacy (Study DS-TEC-109230).
Non-Clinical Safety of Ad26HPV16 or HPV18
Absence of the oncogenic properties of E6 and E7 in the E2E6E7SH fusion proteins was 
demonstrated in 3 different in vitro models31 (Study DS-TEC121377).  Expression of the E6E7SH
proteins of either HPV16 or HPV18 did not lead to degradation of p53 or pRb or to 
transformation of NIH 3T3 cells, while expression of E6E7SH or E2E6E7SH did not immortalize 
primary human keratinocytes. 
Non-Clinical Toxicity of Ad26HPV16 or HPV18 and MVA.HPV16/18
A Good Laboratory Practice
(GLP)-compliant repeated dose toxicity study with the 
Ad26.HPV16, Ad26.HPV18 and MVA-BN-HPV16/18 vaccine components at the highest 
feasible dose by intramuscular injections in Sprague-Dawley rats has been performed. The 
injections were well tolerated, with mild reactions in-life and histopathological effects (injection 
sites and draining lymph nodes) reflecting a normal response to vaccine administration and none 
of these reactions were considered adverse. No vaccine-related serious adverse events were 
found (Study TOX1227).
Biodistribution
Ad26
The biodistribution potential of the Ad26 vector has been evaluated in combination with another 
(HIV) gene insert (Ad26.ENVA.01) (Bridge GPS, Inc, study 1645-06074). NZW rabbits were 

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Approved, Date: 20 August 2019
administered placebo or Ad26.ENVA.01 at 5x1010 vp via a single intramuscular injection on 
Study Day (SD) 1. Analysis on SD 11 indicated that the Ad26.ENVA.01 vaccine was primarily 
localized in the injection site muscle and distributed only to the draining (iliac) lymph nodes and 
spleen. By SD 61, the vaccine was no longer detected in the spleen. By SD 91, detection of the 
vector was limited to the iliac lymph nodes and injection site muscle in 2 out of 10 treated 
animals and was below the limit of detection in all of the other examined tissues, confirming 
clearance of the vector from the animals/tissues. As biodistribution is considered to be dependent 
on the viral vector and not on the inserted transgene, it can be assumed that Ad26.HPV16 and 
Ad26.HPV18 will distribute in the same way as the Ad26.ENVA.01 vaccine.
MVA
A definitive biodistribution study (STUDY NO. G216-04) in New Zealand White (NZW) rabbits 
was established to provide spatial and temporal data regarding the distribution of vaccinia 
transcripts in rabbits following a single IM or SC immunization of MVA-BN (attenuated vaccine 
against smallpox virus and used as vector for vaccination against non-pox diseases) at 
1x108 TCID50. In summary, vaccinia transcripts were detected using RT-PCR methods in several 
tissues 15 hours following IM and SC administration of MVA-BN®. Skin, muscle, blood, spleen, 
lung, liver, and pooled lymph nodes were vaccinia positive in some 15-hour samples, while 
kidney, heart, brain, mesenteric lymph node, ovary, and testes were negative in all 15-hour 
samples. Many of the positive samples were weakly positive and below the level of quantitation. 
After 48 hours, fewer samples were vaccinia positive than at the 15-hour time point, and only a 
single skin and pooled lymph node sample from the SC group were detectable by quantitative 
PCR. By Day 7, most of the samples and tissues were negative for vaccinia; only injection site 
skin or injection site muscle tissues were weakly positive in a few rabbits at levels too low to 
quantify.
Ad26.HPV16 or 18 Clinical Data
No clinical data with the Ad26HPV16 or 18 vaccine are currently available since this will be the 
FIH study.
Clinical Experience With Ad26-based Vaccines
The Janssen adenoviral vaccine safety database report2 describes safety data from completed 
clinical studies using 4 Ad26-based vaccine candidates: Ad26.CS.01 (malaria), Ad26.RSV.FA2 
(RSV), Ad26.ENVA.01 (HIV), and Ad26.ZEBOV (Ebolavirus) up to a cut-off date of 31 August 
20172.2 In these studies, 962 participants received at least 1 vaccination with an Ad26-based 
vaccine. Most participants (93.2%) received Ad26 at a dose level of 5x1010 vp and 2.6% 
participants were vaccinated with Ad26 at the highest dose level tested (1x1011 vp). 
The majority of solicited local and systemic AEs were of mild or moderate and usually started 
within 1 to 2 days after vaccination. Most of the events were transient and resolved within 1 to 3 
days. The most frequently solicited AEs include injection site pain and warmth, malaise, fatigue 
and headache. The most commonly experienced unsolicited AE was upper respiratory tract 
infection – 8.3% of Ad26 participants vs. 13.7% of placebo participants. The most commonly 

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reported unsolicited AEs considered related to the vaccine were neutropenia/neutrophil count 
decreased (4.9% of Ad26 participants vs. 4.4% of placebo participants). SAE were reported in 
17 Ad26 participants (2 participants acquired an HIV infection; 2 spontaneous abortions among 
others). Severe allergic reactions have not been reported to date and there have been no deaths. 
There was no evidence of a higher frequency of local AEs with increasing Ad26 dose. There was 
a trend towards a slight increase in the incidence of chills, pyrexia, and malaise with increasing 
Ad26 dose. 
Two suspected unexpected serious adverse reactions (SUSARs) have been reported to date 
following Ad26 vaccination in the HIV and Ebola vaccine programs. 
One serious adverse event (SAE) of severe allergic reaction/hypersensitivity starting 12 hours 
after first study product administration was reported in a 50-year-old male study participant 
following administration of the Ad26.Mos.HIV that was assessed by the investigator and the 
sponsor as related to study vaccine. Clinical observations by the emergency room physician 
noted no clinical signs of allergic reaction (no rash, no lip/tongue/oropharyngeal/uvular swelling, 
normal findings of cardiovascular and respiratory system). Diphenhydramine was administered; 
no hospitalization or administration of corticosteroids occurred. The reaction was resolved within 
1 day of onset. Concurrent medical conditions included drug abuse, bipolar disorder (not 
disclosed by the participant to the investigator) with hallucinatory decompensation and chest 
pain 1 week after the severe allergic reaction. The participant was withdrawn from the study due 
to non-compliance (history of drug abuse and non-reported psychiatric issues).
In the Ebola vaccine development program (Ad26.ZEBOV), 1 SAE of "small fibre neuropathy" 
in a 38-year-old male participant with onset of paresthesia 2 weeks after vaccination with 
Ad26.ZEBOV was considered to be possibly related to the study product by the investigator and 
the sponsor. Although this AE is possibly related to study product, the neurologist experts 
consulted have concluded that the evolution of this event is atypical for a possible vaccine-
related neuropathy.
In conclusion, the Ad26- based vaccines were safe and well-tolerated. No significant safety 
issues have been identified from the data available in the current adenoviral vaccine safety 
database. Importantly at a given dose level, no significant differences in the safety profiles of 
Ad26-based vaccines have been observed irrespective of the transgene insert used.
More detail on these studies can be found in the Janssen adenoviral vaccine safety database 
report and the Ad26.HPV16 and Ad26.HPV18 IBs.2
MVA.HPV16/18 Clinical Data
No clinical data with the MVA.HPV16/18 vaccine are currently available since this will be the 
FIH study.

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Clinical Experience With MVA-based Vaccines
The safety profile of recombinant MVA-BN-based vaccines is similar to that of MVA-BN®, 
which has been used in various clinical trials in approximately 7,500 participants. Recombinant 
MVA-BN-based vaccines, eg, MVA-BN-HIV and MVA-BN-HER2, have been tested in varying 
schedules of repeated vaccinations with doses up to 5x108 Inf.U in Phase 1 and Phase 2 studies.
The main risks associated with the administration of the MVA-BN vector is the development of 
local reactions at the vaccination site (eg, pain, erythema, induration, swelling, and pruritus), as 
well as of generalized symptoms like fatigue, headache, myalgia, and nausea which were mostly 
mild and transient. For further details on the safety profiles of other MVA-vectored vaccine 
candidates, see the MVA.HPV16/18 IB.
Clinical Experience With Heterologous Vaccine Regimen Containing Ad26-based vaccine 
and MVA-based vaccine
Four completed studies of different 2-dose regimens containing an Ad26 vector vaccine 
encoding Ebola virus glycoprotein (Ad26.ZEBOV) and the MVA vector vaccine encoding 
glycoproteins from filoviruses (MVA-BN-Filo) among 325 healthy adults in the UK, US, Kenya, 
Tanzania and Uganda have demonstrated no significant safety issues. An ongoing Phase 1/2a 
study (HIV-V-A004) consisting of distinct 4-dose heterologous regimens which include 
combinations of Ad26.Mos.HIV with MVA.Mos have also not shown any significant safety 
concerns.
1.2.
Benefit-risk Evaluations
1.2.1.
Known Benefits
The clinical benefits of Ad26.HPV16, Ad26.HPV18, and MVA.HPV16/18 have yet to be 
established.
1.2.2.
Potential Benefits
There is no direct medical benefit to the subject for participation in this clinical study. Although 
study subjects may benefit from clinical testing and physical examination, they may receive no 
direct benefit from participation. Others may benefit from knowledge gained in this study that may 
aid in the development of a HPV therapeutic vaccine.
1.2.3.
Potential Risks
The following potential risks for Ad26.HPV16, Ad26.HPV18, and MVA.HPV16/18 will be 
monitored during the study and are specified in the protocol:
Risks Related to Adenoviral-vectored Vaccines
There is no clinical experience with Ad26.HPV16 and Ad26.HPV18 and the safety profile has 
not yet been established.
Safety data available from 11 completed clinical studies among approximately 1000 participants 
that received at least 1 dose of other Ad26-vectored vaccine candidates, in which Ad26 with 
different inserts has been evaluated at dose levels ranging from 1x109 vp to 1x1011 vp, indicate 

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that no significant safety concerns would be anticipated from vaccination with Ad26.HPV at 
doses of 5x1010 vp and 1x1011 vp.
For further details on the safety profiles of other Ad26-vectored vaccine candidates, read 
Section 1.1 (Clinical Experience With Ad26-based Vaccines) in this protocol and the Ad26.HPV 
IB.
Risks Related to MVA-vectored Vaccines
There is no clinical experience with MVA. HPV16/18 and the safety profile has not yet been 
established.
The safety profile of recombinant MVA-BN-based vaccines is similar to that of MVA-BN®, 
which has been used in various clinical trials in approximately 7,800 participants. Recombinant 
MVA-BN-based vaccines, eg, MVA-BN-HIV and MVA-BN-HER2, have been tested in varying 
schedules of repeated vaccinations with doses up to 5x108 Inf.U in Phase 1 and Phase 2 studies 
providing a safety profile that does not raise significant concerns. For further details on the safety 
profiles of other MVA-vectored vaccine candidates read section 1.1 (Clinical Experience With 
MVA-based Vaccines) in this protocol and the MVA.HPV16/18 IB.
Risks Related to Vaccination
In general, IM injection may cause stinging, local itching, arm discomfort, bruising, swelling, or 
redness of the skin at vaccine injection sites. Participants may exhibit general signs and 
symptoms associated with the administration of a vaccine injection, including fever, chills, rash, 
aches and pains, nausea, headache, dizziness, and fatigue. These side effects should be 
monitored, but are generally short-term and do not require treatment. Participants may self-
administer medications such as acetaminophen, non-steroidal anti-inflammatory drugs or 
antihistamines, as required.
Allergic reactions, possibly severe reactions (eg, hypersensitivity reactions), are known to occur 
with any injected vaccine, although rarely. Therefore, study site personnel should monitor the 
participant for 30 minutes after injection of the candidate vaccine as described in the study 
protocol. Appropriate drugs and medical equipment should be readily available. 
Carcinogenicity, Mutagenicity, and Impairment of Fertility
Nonclinical carcinogenicity, mutagenicity, or fertility studies have not been conducted with 
Ad26.HPV16, Ad26.HPV18, and MVA.HPV16/18.
E6 and E7 are viral oncoproteins that are responsible for transformation of cells. In the vaccine 
component, the coding regions of E6 and E7 are divided into multiple fragments and then the 
fragments are re-ordered (shuffled), resulting in the expression of a fusion protein (abbreviated
as E6E7SH [ie, E6E7 shuffled]). Nonclinical studies using the vaccine insert E6E7SH were 
conducted to show that the oncogenic properties of E6 and E7 were not present after expression 
of the shuffled insert. The main function of HPV E2 is the regulation of viral replication, and 
expression of E2 has been shown to inhibit growth of both HPV-positive and HPV-negative 

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cells. We have assessed any potential risks associated with the E2E6E7SH vaccine insert as 
negligible.
Pregnancy
No preclinical developmental or reprotoxicity studies have yet been performed with 
Ad26.HPV16, Ad26.HPV18, or MVA.HPV16/18. However, a GLP-compliant combined 
embryo-fetal and pre- and postnatal development study has been conducted in rabbits with 
Ad26/MVA-BN vectors in combination with other inserts (Ad26.ZEBOV/MVA-BN-Filo). In 
this study, there was no maternal or developmental toxicity observed following maternal 
exposure during the premating and gestation period.
The effect of this vaccine on a fetus or nursing baby is unknown, so participants of childbearing 
potential having sexual intercourse with males will be required to agree to use birth control for 
sexual intercourse, as specified in the clinical study protocol. Participants who become pregnant 
while enrolled in a study must not receive any additional dose of study vaccine, but remaining 
visits and study procedures should be completed unless medically contraindicated or applicable 
regulations require termination from the study. All pregnancies and pregnancy outcomes will be 
recorded.
Adverse Drug Reactions
No clinical studies with Ad26.HPV16, Ad26.HPV18, or MVA.HPV16/18 have been performed 
to date. Therefore, adverse reactions have not been identified.
Additional Information
An increased risk of HIV acquisition was reported in 2007 in 2 studies in which Merck’s (MRK) 
Ad5-vectored prophylactic HIV-1 gag/pol/nef vaccine was administered. The randomized 
double-blind placebo-controlled Phase 2b STEP study performed in North America revealed a 
statistically significant increase in HIV-1 acquisition at 18 months of follow-up in both a
subgroup of Ad5 seropositive male participants who received the MRK vaccine and in a
subgroup of uncircumcised male participants who received the MRK vaccine, compared with 
placebo.6,16 The Phase 2b Phambili study performed in Africa and using the same vaccine,
revealed a statistically significant increase in HIV-1 infection for participants who received the 
vaccine compared with placebo at long-term follow-up (median of 42 months).23 An increased 
risk of HIV acquisition was however not reported in a prematurely unblinded study of 
DNA priming followed by a booster dose of rAd5 HIV-1 env/gag/pol vaccine (HIV Vaccine 
Trial Network study 505 in 2013). In this study, Ad5-seropositive participants and uncircumcised 
males were specifically excluded on the basis of the STEP data.24 It must be emphasized that 
vaccination in itself does not cause HIV; only exposure to infected fluids transmits HIV. 
The mechanism for the possible increase in HIV-1 susceptibility following vaccination with the 
MRK Ad5-vectored HIV vaccine remains unclear. The leading hypothesis is that the MRK 
Ad5-vectored HIV vaccine may have activated pre-existing Ad5-reactive CD4+ T cells that 
travel to mucosal surfaces and express HIV-coreceptors that may facilitate infection upon 

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HIV exposure.37 The currently available data are however considered insufficient to allow this 
hypothesis to be confirmed or refuted.
While the results from the STEP and Phambili studies have been considered to be specifically 
associated with the particular MRK Ad5-vectored HIV vaccine used and the specific populations 
in whom the vaccine was tested, potential implications of the findings for studies using different 
adenovirus vectors and antigen inserts were raised in 2015 in 2 letters to the British Medical 
Journal5,34 and in a subsequent review.37 The authors particularly raised their concerns in view of 
the fast track evaluation of the candidate Ebola virus vaccines in regions with concentrated 
HIV epidemics, and recommended long-term follow-up of study participants, including 
voluntary HIV counselling and testing in adenovector-based Ebola vaccine studies. 
To date, no evidence of a potential association between the administration of vaccines other than 
the MRK Ad5-vectored HIV vaccine and increased risk of HIV acquisition exists. However, 
following the publication of these 2 letters in the British Medical Journal, an internal Working 
Group co-led by representatives from Clinical Development and Global Medical Safety, and 
with input from scientists working on viral vaccines, was established by the sponsor to critically 
evaluate the potential implications of the findings from the STEP and Phambili studies for 
studies using different adenovirus vectors and antigen inserts for HIV and other indications. 
Adenoviruses such as Ad26 and Ad35 are biologically different from Ad5 in terms of receptor 
usage, endosomal escape, interaction with pattern recognition molecules, and in their 
inflammatory profiles.3,35,41,47,48,56
A clinical study with the Ad26-vectored HIV vaccine 
expressing the ENVA protein showed no increased general or adenovirus-reactive CD4+ T cells 
in the gut mucosa, regardless of baseline Ad26 seropositivity.3 Evidence from preclinical 
non-human primate studies, clinical vaccine studies, and in vitro experiments on Ad5 and other 
adenovirus serotypes is not conclusive in terms of a causative association between 
vaccine-induced cellular immune responses, immune activation and viral acquisition, whether 
specific for HIV/simian immunodeficiency virus vaccine insert or the vector backbone. 
Furthermore, analysis of historical clinical study data from 1,695 participants in 27 studies with 
the Sponsor’s Ad26/Ad35 vectored vaccine candidates showed no evidence of increased rates of 
HIV infection.2
The conclusion of the Working Group, in collaboration with an external expert Advisory Board, 
is that the possibility of an increased risk of HIV acquisition after vaccination with 
Ad26-vecored vaccines is theoretical. 
Monitoring of incident HIV infections during the clinical studies with the sponsor’s 
adenovector-based candidate vaccines will be done through its routine pharmacovigilance and 
signal detection activities and consolidated at the time of the adenoviral vaccine safety database 
updates.
Risks from Blood Draws
Blood drawing may cause pain, bruising, and, rarely, infection at the site where the blood is taken.

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Unknown Risks
There may be other serious risks that are not known.
1.2.4.
Overall Benefit-Risk Assessment
Based on the available data and proposed safety measures, the overall benefit/risk assessment for 
this clinical study is considered acceptable for the following reasons:

Currently, there is no approved therapy to eradicate HPV infection of the cervix and 
standard of care includes monitoring of early infection and treatment upon progression to 
high-grade genital lesions.
No significant safety issues have been identified from the data available for clinical 
experience with Ad26-based and MVA-BN-based vaccines. Importantly, no significant 
differences in the safety profiles of Ad26-based and MVA-BN-based vaccines have been 
observed irrespective of the transgene insert used.
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified 
in Section 4) will be allowed to participate in this study. The selection criteria include 
adequate provisions to minimize the risk and protect the well-being of participants in the 
study.
Safety will be closely monitored throughout the study:

In general, safety evaluations will be performed at scheduled visits during the study, as 
indicated in the Time and Events Schedule.

After vaccination, participants will remain under observation at the study site for at least 
30 minutes for presence of any acute reactions and solicited events and will be allowed to 
leave the vaccination site at approximately 45 minutes post-vaccination. Any unsolicited, 
solicited local or systemic AEs and vital signs will be documented during this 
observation period. Participants will use a diary to document solicited local and systemic 
symptoms for 7 days post-vaccination. Details are provided in Section 9.1.4.

Participants in Step 1 and Step 3 of Phase I of the study will undergo safety follow-up by 
study staff 24 hours after each vaccination by telephone and all participants will have 
follow-up visits 7 days after each vaccination, as indicated in the Time and Events 
Schedule.

The investigator or the designee will document unsolicited adverse events as indicated in
Section 12.3.1. 

Any clinically significant abnormalities (including those persisting at the end of the 
study/early withdrawal) will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached.

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Several safety measures are included in this protocol to minimize the potential risk to 
participants, including the following:
Post-vaccination safety review in sentinel cohorts by principal investigator (PI) and study 
responsible physician (SRP), and Independent Data Monitoring Committee (IDMC) is 
described in Section 3.1.
For all participants, there are pre-specified rules that would result in pausing of further 
vaccinations if predefined conditions occur, preventing exposure of new participants to 
study vaccine until the IDMC reviews all safety data (see Section 11.9).
Participants will discontinue study vaccine for the reasons included in Section 10.2.
Contraindications to vaccination are included in Section 10.3.
1.3.
Overall Rationale for the Study
This FIH study is part of a vaccine program which aims to generate a therapeutic vaccine for 
women persistently infected with HPV types 16 or 18, with a focus on early disease interception. 
In this study, women with HPV types 16 or 18 infection of cervix will be enrolled. For the 
purpose of early safety and immunogenicity evaluation, women with either persistent or recently 
diagnosed HPV infections will be included. Women with cytology of high-grade squamous 
intraepithelial lesion (HSIL) or adenocarcinoma in situ (AIS) or a colposcopy result of cervical 
intraepithelial neoplasia grade 2 or worse (CIN2+) will be excluded.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
Primary
Objectives
Endpoints
Primary
To assess safety and reactogenicity of the 3
vaccine regimens.

Solicited local and systemic adverse events 
(AEs) for 7 days after each vaccination.

Unsolicited AEs from the time of informed 
consent form (ICF) signature until 28 days 
after the first vaccination, and thereafter, 
until 28 days after the second vaccination.

Serious adverse events (SAEs) throughout 
the study.

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Secondary
Objectives
Endpoints
To assess immunogenicity of the 3 vaccine 
regimens.
T cell responses to the separate or combined 
protein peptide pools of HPV16 and HPV18 E2, 
E6 and E7 proteins, including specific CD4+ and 
CD8+ T cells producing IFNγ, tumor necrosis 
factor alpha (TNFα), or interleukin 2 (IL-2)
(combined cytokine expression may also be 
assessed) will be determined by flow cytometry.
Exploratory 
Objectives
Endpoints
To assess the frequency and kinetics of clearance 
of 

persistent or recently diagnosed HPV16 and
HPV18 infection (combineda) and 

persistent or recently diagnosed HPV16 
infection and

persistent or recently diagnosed HPV18
infection
of the 3 vaccine regimens compared to placebo 
over the study period.
Healthcare provider- and self-collected cervical 
samples obtained over the study period will be 
genotyped by a qualitative HPV genotyping test 
(Cobas®, Roche) and a quantitative HPV PRC
genotyping test to evaluate HPV16 and/or HPV18 
viral clearanceb, defined as:

A negative HPV16 genotype over the study 
period after having a baseline HPV16 
infection (persistent or recently diagnosed); 
OR

A negative HPV18 genotype over the study 
period after having a baseline HPV18 
infection (persistent or recently diagnosed).
To assess regression of CIN1 and concomitant 
clearance of HPV16 and/or HPV18 infection of 
the 3 vaccine regimens compared to placebo over 
the study period.

Regression 
of 
CIN1: 
A 
colposcopic 
impression of normal after having a baseline 
of CIN1, AND concomitant clearance of 
baseline (persistent or recently diagnosed)
HPV16 and/or HPV18 infection (as defined 
above).
To further characterize vaccine-elicited immune 
responses.
These assessments will include, but are not 
limited to, the assessments described below. Some 
of the exploratory assessments will only be 
initiated 
if 
indicated 
by 
the 
secondary 
immunogenicity data.
Cell-mediated

Flow cytometry to characterize other cellular 
immune
responses 
to 
the 
separate 
or 
combined protein peptide pools of HPV16 
and HPV18 E2, E6 and E7 proteins, 
including, but not limited to, mucosa-homing 
markers, Th17, Th2, regulatory T cell (Treg), 
cytolytic markers, activation markers, and

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Objectives
Endpoints
exhaustion markers.

Transcriptome 
analysis 
to 
provide 
phenotypic and functional characterization of 
peripheral blood mononuclear cells (PBMCs)
ex vivo or after stimulation with either 
HPV16 and/or HPV18 E2, E6, and/or E7 
peptide pools.

Enzyme-linked immunospot (ELISpot) assay
to enumerate PBMCs able to produce IFNγ 
upon stimulation with HPV16 and/or HPV18 
E2 (complete, N-terminal, or C-terminal), E6 
and/or E7 protein peptide pools.

ChipCytometry analysis of T cell responses 
to the separate or combined protein peptide 
pools of HPV16 and/or HPV18 E2, E6, and 
E7 proteins in PBMCs, including but not 
limited to CD4+ and CD8+ T cells producing 
IFNγ, TNFα and/or IL-2.
Humoral

Adenovirus neutralization assay to evaluate 
neutralizing antibody responses against the 
Ad26 vector.

MVA neutralization assay to evaluate 
neutralizing antibody responses against the 
MVA vector.

Antibody responses to the HPV16 and/or 
HPV18 capsid proteins L1 and/or L2 can be 
measured 
to 
investigate 
levels 
of 
HPV-specific antibodies before vaccination 
(not induced by vaccination with either 
Ad26.HPV16 or Ad26.HPV18), as well as 
induction 
of 
L1/L2 
antibodies 
after 
vaccination as a “bystander” effect due to 
release of these proteins from infected cells 
after vaccine-mediated cytolytic T cell
responses. L1/L2 antibodies to other HPV 
genotypes might also be measured.

Antibody responses to E2, E6 and/or E7 of 
HPV16 and/or HPV18, or to these proteins of 
other HPV genotypes, can be evaluated.

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Objectives
Endpoints

To explore potential immune correlates for 
viral clearance.

Immunogenicity endpoints of HPV-specific 
cellular or humoral responses described 
above, determined at multiple time points 
after vaccination will be used to explore 
potential 
immune 
correlates 
of 
viral 
clearance of HPV16 and/or HPV18.
a The sum of women who clear an HPV16 infection plus women who clear an HPV18 infection
b Women who receive CIN treatment will be considered as not clearing an HPV infection.
Refer to Section 9 for evaluations related to endpoints.
2.2.
Hypothesis
No formal statistical hypothesis for safety or immunogenicity will be tested. 
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, randomized, placebo-controlled, double-blind, safety, reactogenicity and
immunogenicity Phase 1/2a study of 3 heterologous vaccine regimens with the Ad26.HPV16, 
Ad26.HPV18, and MVA.HPV16/18 recombinant vectors (Refer to Table 4). Vaccination will 
take place on Day 1 and Day 57. Study participants include approximately 66 women ≥18 to
≤60 years old with HPV types 16 or 18 infection of the cervix. This can be either persistent or 
recently diagnosed HPV infection, see Section 11.3 for definitions. Vaccination and safety 
monitoring among the HPV16 infected participants may occur independently from the HPV18 
infected participants because the rate of enrollment of women with these 2 HPV types may differ
as cervical HPV16 infections are more prevalent than HPV18 infections.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to 
evaluate safety data over the course of the study and to review any event that meets a specific 
study pausing rule, stopping rule, or any other safety issue that may arise.
The IDMC will consist of members independent of the sponsor, including at least 1 medical 
expert in the relevant therapeutic area and at least 1 statistician. The IDMC responsibilities, 
authorities and procedures will be documented in its charter. The IDMC will review unblinded 
data (see Sections 11.8 and 11.9).

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Randomization, vaccination and safety evaluations
The randomization, vaccination process and safety evaluations described below for HPV16 
infected participants will be performed in the same manner and independently among HPV18 
infected participants.
HPV16 infected participants (Table 4 and Figure 2).
Dose 1 (Ad26-based)
Phase 1 (Dose Escalation)

Step 1 [sentinels with low dose or placebo]: The first 2 participants (sentinels) will 
receive either a low dose Ad26.HPV16 (1 participant) or placebo (1 participant). 
Dosing of these 2 participants may occur on the same day depending on enrollment 
rates. Vaccination of additional participants will be halted until a 24-hour and 7-day 
post vaccination blinded safety review of solicited and unsolicited AEs are 
performed by the principal investigator (PI) and the sponsor’s study responsible 
physician (SRP).

Step 2 [completion of Phase 1 with low dose or placebo]: In the absence of clinically 
significant findings in participants from step 1, 4 additional participants will be 
dosed: 3 participants will receive low dose Ad26.HPV16 and 1 participant will 
receive placebo. There will be a staggered interval of 7 days between the vaccination 
of each of these 4 participants. Vaccination of additional participants will be halted 
until a 7-day post vaccination safety review of solicited and unsolicited AEs and 
clinical laboratory results is performed by an IDMC of participants in step 1 and step 
2.

Step 3 [sentinels for dose escalation with high dose or mixed regimen or placebo]: If 
the IDMC expresses no concerns on the safety data from the HPV16 participants in 
steps 1 and 2, and the first 2 HPV18 sentinels from step 1a, then 3 additional sentinel 
participants will be dosed: 1 participant will receive a high dose Ad26.HPV16, 
1 participant will receive the Ad26.HPV16/Ad26.HPV18 mix and 1 participant will 
receive placebo. Dosing of these 3 participants may occur on the same day 
depending on enrollment rates. Vaccination of additional participants will be halted 
until a 24-hour and 7-day post vaccination blinded safety review of solicited and 
unsolicited AE are performed by the PI and SRP.

Step 4 [completion of Phase 1 with high dose or mixed regimen or placebo]: In the 
absence of clinically significant findings in participants from step 3, 8 additional 
participants will be dosed: 3 participants will receive high dose Ad26.HPV16, 3 will 
receive the Ad26.HPV16/Ad26.HPV18 mix and 2 participants will receive placebo. 
There will be a staggered interval of 7 days between the vaccination of each of these 
8 participants. Vaccination of additional participants will be halted until a 7-day post 
                                                
aNo Ad26.HPV16/Ad26.HPV18 mix regimen will be administered until review of 2 sentinels HPV18 data in step 1.

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vaccination safety review of solicited and unsolicited AE and clinical laboratory 
results of participants in step 3 and step 4 and all available safety data of participants 
in Step 1 and 2 is performed by the IDMC. 
Phase 2a (Further Vaccination)

Step 5 [further vaccination with high dose or mixed regimen or placebo]: If the 
IDMC expresses no safety concerns on the safety data from participants in steps 1-4
and no participant has experienced the criteria that determine it is not safe to initiate 
the Phase 2a component of the study, 16 additional participants will be randomized 
and dosed: 6 participants will receive high dose Ad26.HPV16, 6 will receive the 
Ad26.HPV16/Ad26.HPV18 mix and 4 participants will receive placebo. No more 
than 5 participants per week will be dosed.
Note: the criteria to move to Phase 2a is that no participant in Phase 1 of the study 
experiences any of the events encompassed in the study vaccination pausing rules serious 
enough to not proceed with study as per IDMC.
Dose 2 (MVA-based)
Phase 1
Completion of IDMC review in step 2 above will also allow the second dose vaccination with 
MVA.HPV16/18 or placebo of the sentinel participants in step 1a. Safety reviews after 
MVA/placebo vaccinations will follow the same scheme as for the Ad26 vaccinations, ie, a 
24-hour and 7-day post vaccination blinded safety review by the PI/SRP will be performed after 
the MVA/placebo vaccinations of step 1 and 3 sentinel participants and an aggregated 7-day 
safety review will be performed by the IDMC when the MVA/placebo vaccinations of 
participants in step 2 and 4 have been completed.
Phase 2a
If the IDMC expresses no safety concerns on the MVA.HPV16/18 / placebo data from 
participants in Phase 1, the 16 participants from Phase 2 will be dosed with MVA.HPV16/18 or 
placebo.
The HPV18 infected participants will follow the same process as described above for the 
HPV16-infected participants (Table 4 and Figure 3). Vaccination and safety monitoring may
occur independently to the HPV16 infected participants (see Table 4).
The study duration, from screening until the last follow-up visit, will be approximately 
13.5 months per participant. The study consists of a screening period of up to 42 days (6 weeks), 
followed by vaccinations on Day 1 and Day 57, and follow-up visits up to 12 months after the 
                                                
a An ad-hoc IDMC review of all available safety data may take place in case not all participants from step 1 and 2 
have been enrolled by the time the first MVA vaccination needs to take place.

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first vaccination (target visit Day 366±14 days). If a participant is unable to complete the study, 
but has not withdrawn consent, an early exit visit will be conducted.
A diagram of the study design is provided in Figure 2 and Figure 3.

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Table 4:
Study Design
Vaccine Regimen 
Phase 1
Phase 2a
HPV
Type*
Regimen
Day 1
Day 57 
(Week 8)
Step 1
sentinel; 
low dose
Step 2
completion 
Phase 1;
low dose 
Step 3
Sentinel dose
escalation high 
& mixed 
regimens
Step 4
completion 
Phase 1;
high & mixed 
regimens
Subtotal
Step 5
further 
vaccination; high 
& mixed 
regimens
Total
16
Regimen 1a 
(Ad26 low dose)
Ad26.HPV16
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
1
3
-
-
4
-
4
16
Regimen 2a 
(Ad26 high dose)
Ad26.HPV16
(1x1011 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
16
Regimen 3 
(mixing of Ad26)
Ad26.HPV16
(5x1010 vp) +
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
16
Control
Placebo
(1.0 mL)
Placebo
(0.5 mL)
1
1
1
2
5
4
9
Total 
HPV16
2
4
3
8
17
16
33
18
Regimen 1b 
(Ad26 low dose)
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
1
3
-
-
4
-
4
18
Regimen 2b 
(Ad26 high dose)
Ad26.HPV18
(1x1011 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
18
Regimen 3 
(mixing of Ad26)
Ad26.HPV16
(5x1010 vp) +
Ad26.HPV18
(5x1010 vp)
MVA.HPV16/18
(2x108 Inf.U)
-
-
1
3
4
6
10
18
Control
Placebo
(1.0 mL)
Placebo
(0.5 mL)
1
1
1
2
5
4
9
Total 
HPV18
2
4
3
8
17
16
33*
Total
4
8
6
16
34
32
66
Ad26=adenovirus serotype 26; HPV=human papillomavirus; Inf.U=infectious unit; MVA=modified vaccinia Ankara; vp=viral particles
* If enrollment is slow for HPV18-infected participants, up to 8 HPV18-infected participants can be replaced by HPV16-infected participants, hence a minimum of 25 HPV18 participants 
will be allowed. The decision will be taken during Step 5.
IDMC
IDMC
PI/SRP
PI/SRP

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Figure 2:
Schematic Overview of the Study - HPV16 Infected Participants 
* Two sentinel participants from the HPV18 group are required for IDMC review in step 2 before starting step 3.
HPV16 infected subjects (N=33)
Sentinels 
Low dose Ad26.HPV16 (5x1010 vp) (N=1)
Placebo (N=1)
The 2 subjects may be 
vaccinated on the same day 
depending on enrollment 
rates. 
Vaccination of additional subjects will be halted until a 24-hour and 7-day post 
vaccination blinded safety review are performed by PI and SRP.
Low dose Ad26.HPV16 (5x1010 vp) (N=3)
Placebo (N=1)
The 4 subjects will be 
vaccinated at a rate of no 
more than 1 subject every 
7 days.
Vaccination of additional subjects will be halted until a 7-day post vaccination 
unblinded safety review is performed by IDMC of subjects in step 1 and step 2.
Sentinels 
High dose Ad26.HPV16 (1x1011 vp) (N=1)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=1) *
Placebo (N=1)
The 3 subjects may be 
vaccinated on the same 
day depending on 
enrollment rates. 
Vaccination of additional subjects will be halted until a 24-hour and 7-day post 
vaccination blinded safety review are performed by PI and SRP.
High dose Ad26.HPV16 (1x1011 vp) (N=3)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=3)
Placebo (N=2)
The 8 subjects will be 
vaccinated at a rate of no 
more than 1 subject every 
7 days.
Vaccination of additional subjects will be halted until a 7-day post vaccination 
unblinded safety review of subjects in step 3 and step 4 and all available safety 
data of subjects in Step 1 and 2 is performed by the IDMC. 
High dose Ad26.HPV16 (1x1011 vp) (N=6)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=6)
Placebo (N=4)
The 16 subjects  will be 
vaccinated at a rate of no 
more than 5 per week 
After the 2nd vaccination with MVA.HPV16/18 among the subjects that 
received the low dose Ad26 (5x1010 vp) or placebo there will be a 24-hour 
blinded safety review by the PI /SRP and then a 7-day unblinded safety review 
by the IDMC. If no safety concerns are expressed, MVA.HPV16/18 vaccination 
among subjects immunized with the high or combined Ad26 or placebo may 
proceed. 
Phase 1
Phase 2a
Step 1
Step 2
Step 3
Step 4
Step 5

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Figure 3:
Schematic Overview of the Study - HPV18 Infected Participants
* Two sentinel participants from the HPV16 group are required for IDMC review in step 2 before starting step 3.
HPV18 infected subjects (N=33)
Sentinels 
Low dose Ad26.HPV18 (5x1010 vp) (N=1)
Placebo (N=1)
The 2 subjects may be 
vaccinated on the same 
day depending on 
enrollment rates. 
Vaccination of additional subjects will be halted until a 24-hour and 7-day post 
vaccination blinded safety review are performed by PI and SRP.
Low dose Ad26.HPV18 (5x1010 vp) (N=3)
Placebo (N=1)
The 4 subjects will be 
vaccinated at a rate of no 
more than 1 subject every 
7 days.
Vaccination of additional subjects will be halted until a 7-day post vaccination 
unblinded safety review is performed by IDMC of subjects in step 1 and step 2.
Sentinels 
High dose Ad26.HPV18 (1x1011 vp) (N=1)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=1) *
Placebo (N=1)
The 3 subjects may be 
vaccinated on the same 
day depending on 
enrollment rates. 
Vaccination of additional subjects will be halted until a 24-hour and 7-day post 
vaccination blinded safety review are performed by PI and SRP.
High dose Ad26.HPV18 (1x1011 vp) (N=3)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=3)
Placebo (N=2)
The 8 subjects will be 
vaccinated at a rate of no 
more than 1 subject every 
7 days.
Vaccination of additional subjects will be halted until a 7-day post vaccination 
unblinded safety review of subjects in step 3 and step 4 and all available safety 
data of subjects in Step 1 and 2 is performed by the IDMC. 
High dose Ad26.HPV18 (1x1011 vp) (N=6)
Mix of Ad26.HPV16 (5x1010 vp) + Ad26.HPV18 
(5x1010 vp) (N=6)
Placebo (N=4)
The 16 subjects  will be 
vaccinated at a rate of no 
more than 5 per week 
After the 2nd vaccination with MVA.HPV16/18 among the subjects that 
received the low dose Ad26 (5x1010 vp) or placebo there will be a 24-hour 
blinded safety review by the PI /SRP and then a 7-day unblinded safety review 
by the IDMC. If no safety concerns are expressed, MVA.HPV16/18 vaccination 
among subjects immunized with the high or combined Ad26 or placebo may 
proceed. 
Phase 1
Phase 2a
Step 1
Step 2
Step 3
Step 4
Step 5

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3.2.
Study Design Rationale
Rationale for Heterologous Immunizations
The study will use heterologous immunizations with replication-incompetent adenovirus- and 
MVA-vectored vaccine components that express HPV16 and HPV18 proteins. So far, in other 
programs conducted by the sponsor, such heterologous regimens have shown successful 
induction of strong, long-lived antigen-specific T cell responses. Strong T cell responses were 
seen in clinical studies with vectors expressing antigens from HIV-1, and Ebola.10,38 In the latter, 
heterologous regimens using an Ad26-based immunization, followed by immunization with 
MVA-based vectors within a timeframe of 8 weeks induced strong and durable T cell responses 
to Ebola antigens. 
Supporting the Ad/MVA approach, strong HPV-specific T cell responses were observed in 
non-human primate studies conducted by the sponsor, using regimens that consisted of 
Ad26.HPV16 and Ad26.HPV18, each at 1x1011 vp followed with MVA.HPV16/18 at 
1.79x108 Inf.U with an 8-week interval between immunizations. (see Section 1.1)
Rationale for Dose Selection
Safety data from clinical studies with other Ad26-vectored vaccines expressing different antigens 
are supportive of dosing the Ad26-based HPV vaccine components in this study at 5x1010 vp and 
1x1011 vp. Both doses have been used in other Ad26 vaccine programs to successfully induce 
cellular immunity against the transgene, and results from the studies in non-human primates 
using 1x1011 vp of Ad26.HPV16 and 1x1011 vp of Ad26.HPV18 indicate that strong cellular 
immune responses were elicited at this dose. 
The current study will use MVA.HPV16/18 at a dose of 2x108 Inf.U per immunization. In 
recombinant MVA-BN vaccine studies
(HIV and therapeutic breast cancer vaccine 
[MVA-BN-HER2]), doses up to 5x108 TCID50 were administered in varying schedules (refer to 
the IB for MVA.HPV16/18). In addition, an adequate safety profile has been established for the 
heterologous regimen of Ad26.ZEBOV and MVA-BN-Filo with doses up to 4x108 TCID50.2
Rationale for Choice of Regimens
Regimen 1: Separate administration of low dose Ad26.HPV16 or Ad26.HPV18 (matching the 
participant’s underlying HPV infection) at Day 1, followed by MVA.HPV16/18 at Day 57 will 
be part of the ascending dose design. We will assess safety initially among a small group of 
participants immunized with this low dose Ad26.HPV16 or 18 regimen. After satisfactory 
completion of the safety review the next participants enrolled may receive the higher dose regimens 
(2 and 3).
Regimen 2: Separate administration of 1x1011 vp of Ad26.HPV16 or 1x1011 vp of Ad26.HPV18 
(matching the participant’s underlying HPV infection) at Day 1, followed by MVA.HPV16/18 at 
Day 57 will be used to assess safety and immunogenicity.

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Regimen 3: Mixing of a single-syringe administration of 5x1010 vp of Ad26.HPV16 and 
5x1010 vp of Ad26.HPV18 (ie, Ad26.HPV16/Ad26.HPV18) at Day 1, followed by 
MVA.HPV16/18 at Day 57 will be used to assess safety and immunogenicity and data will be 
compared to regimen 2.
4.
PARTICIPANT POPULATION
Screening for eligible participants will be performed within 42 days before administration of the 
first dose of study vaccine.
The inclusion and exclusion criteria for enrolling participants in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a participant in the study. Waivers are not allowed.
4.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
must sign an ICF indicating that she understands the purpose, procedures and potential 
risks and benefits of the study, and is willing to participate in the study.
2.
willing and able to adhere to the prohibitions and restrictions specified in this protocol.
3.
female, ≥18 and ≤60 years of age, inclusive, on the day of signing the ICF.
4.
Criterion modified per Amendment 3:
4.1 must have an HPV type 16 or 18 infection of the cervix as determined by a
qualitative PCR test (Cobas®, Roche) within 8 weeks prior to screening or at the time of 
screening. Available history of HR-HPV positivity and HPV16 or HPV18 positivity will 
be recorded in the CRF (Figure 4). 
Note: To be eligible for screening, all participants must have at least 1 historical positive 
cervical HR-HPV PCR test result. If the genotype of the previous test is unknown, the 
participant will be screened after consultation with the sponsor.

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Figure 4: 
Flow Chart for Identifying an HPV16 or HPV18 Infection Prior to Vaccination

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5.
Criterion modified per Amendment 3:
5.1 Criterion modified per Amendment 2
5.2 must have a recent colposcopy result (with a maximum of 12 months old at 
screening); in case a colposcopy has not been performed before, it will be done as 
screening procedure.
6.
contraceptive (birth control) use by participants should be consistent with local 
regulations regarding the acceptable methods of contraception for those participating in 
clinical studies.
Before randomization, participants must be either (as defined in Attachment 1):
a.
Not of childbearing potential
b.
Of childbearing potential and practicing an acceptable effective method of 
contraception and agree to remain on such a method of contraception from 
signing the ICF until 3 months after the last dose of study vaccine. Use of 
hormonal contraception should start at least 28 days before the first 
administration of study vaccine. Acceptable methods for this study include:

Hormonal contraception;

Intrauterine device;

Intrauterine hormone-releasing system;

Male or female condom with or without spermicide;

Cap, diaphragm or sponge with a vaginal spermicide;

Vasectomized partner (the vasectomized partner should be the sole 
partner for that participant);

Sexual abstinence*
*Sexual abstinence is considered an effective method only if defined as refraining 
from heterosexual intercourse from signing the ICF until 3 months after the last 
dose of study vaccine. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
7.
all participants of childbearing potential must:
a.
Have a negative highly sensitive serum β-human chorionic gonadotropin 
(β-hCG) pregnancy test at screening
b.
Have a negative urine β-hCG pregnancy test immediately prior to each study 
vaccine administration
8.
must be healthy as confirmed by medical history, physical examination, vital signs, and 
clinical laboratory tests performed at screening.

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If laboratory screening tests are outside the normal reference ranges, repeat of screening 
tests is permitted once during screening to assess eligibility, provided there is no clear 
explanation for the out-of-range value. If the repeated tests are again outside the normal 
reference ranges, but within the limits representing Food and Drug Administration 
(FDA) toxicity grade 1 (see Attachment 2:
Toxicity Tables), the participant may be 
included only if the investigator judges the abnormalities or deviations from normal to 
be not clinically significant. This determination must be recorded in the participant’s 
source documents by the investigator. For repeated tests that show abnormalities of 
toxicity grade 2 or above, the investigator’s judgment needs to be confirmed by the 
sponsor’s medical monitor.
9.
agrees not to donate blood until 3 months after receiving the last dose of study vaccine.
4.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
in case cytology results are available, participant has current or history of HSIL, AIS 
or any high-grade vulvar, vaginal or anal intraepithelial neoplasia.
2.
current or history of CIN2+ or cervical cancer.
3.
confirmed co-infection with both HPV16 and HPV18.
4.
Criterion modified per Amendment 3:
4.1 acute illness (this does not include minor illnesses such as diarrhea or mild upper 
respiratory tract infection) or temperature ≥38.0 ºC within 24 hours prior to the first 
dose of study vaccine; enrollment at a later date is permitted.
Note: Before vaccination, the investigator must check for any symptoms of an acute 
illness or oral temperature ≥38.0 °C. If the randomization visit cannot be rescheduled 
within the allowed screening window or the contraindications to vaccination persist, 
the sponsor should be contacted for further guidance.
5.
history of an underlying clinically significant acute or chronic medical condition, 
other than infection with HPV, or physical examination findings for which, in the 
opinion of the investigator, participation would not be in the best interest of the 
participant (eg, compromise the well-being) or that could prevent, limit, or confound 
the protocol-specified assessments.
6.
had major surgery (per the investigator’s judgment), within 12 weeks before first 
vaccination, or will not have fully recovered from surgery, or has surgery planned 
within 6 months after the last dose of study vaccine.

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Note: Participants with planned surgical procedures to be conducted under local or 
locoregional anesthesia and not judged as major by the investigator may participate.
7.
tests positive for HIV at screening. 
8.
chronic active hepatitis B or hepatitis C infection, verified at screening by hepatitis B 
surface antigen or anti-hepatitis C virus antibody, respectively.
9.
vaginal atrophy with or without topical hormonal therapies or systemic selective 
estrogen receptor modulators.
10.
exposed to at least 1 dose of an HPV prophylactic vaccine or participant has 
participated in the past in another preventive or therapeutic HPV vaccine study.
11.
clinically significant gynecological abnormalities that could, in the judgment of the 
investigator, interfere with study evaluation (eg, prolapse, myoma, fibroid, 
hysterectomy).
12.
Criterion modified per Amendment 3:
12.1 Criterion modified per Amendment 2
12.2 symptomatic vaginal or genital infection (including genital herpes) as confirmed 
by physician or investigator. Note: positive HSV-2 serology is not exclusionary.
13.
Criterion removed per Amendment 3.
14.
has had major psychiatric illness or drug or alcohol abuse which in the investigator’s 
opinion would compromise the participant’s safety or compliance with the study 
procedures.
15.
received or plans to receive:
a.
licensed live attenuated vaccines - within 28 days before or after planned 
administration of the first or subsequent study vaccinations
b.
other licensed (not live) vaccines - within 14 days before or after planned 
administration of the first or subsequent study vaccinations.
16.
received an investigational drug or used an invasive investigational medical device 
within 30 days or received an investigational vaccine within 6 months before the 
planned administration of the first dose of study vaccine or is currently enrolled or 
plans to participate in another investigational study during the course of this study. 
Note: participation in an observational clinical study is allowed with prior approval of 
the sponsor.
17.
received treatment with immunoglobulins in the 2 months, or blood products in the 

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4 months before the planned administration of the first dose of study vaccine or has 
any plans to receive such treatment up to 12 months after the first dose of study 
vaccine.
18.
known allergy or history of anaphylaxis or other serious adverse reactions to vaccines
or vaccine products (including any of the constituents of the study vaccine(s)) (refer to 
Investigator's Brochures).
19.
history of chronic urticaria (recurrent hives), eczema and/or atopic dermatitis.
20.
history of acute polyneuropathy (eg, Guillain-Barré syndrome).
21.
abnormal function of the immune system resulting from:
a.
Clinical conditions (eg, autoimmune disease or immunodeficiency);
b.
Chronic (longer than 10 days) or recurrent use of systemic corticosteroids 
during the study and within 6 months before first administration of study 
vaccine (Note: ocular, topical or inhaled steroids are allowed);
c.
Administration of antineoplastic and immunomodulating agents, including 
herbal products, or radiotherapy during the study and within 6 months before 
first administration of study vaccine.
22.
history of malignancy within 5 years before screening (exceptions are squamous and 
basal cell carcinomas of the skin or malignancy which is considered cured with 
minimal risk of recurrence).
23.
contraindication to intramuscular injections and blood draws, eg, bleeding disorders.
24.
pregnant, or breast-feeding, or planning to become pregnant while enrolled in this 
study or within 3 months after the last dose of study vaccine.
25.
employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator, or an employee of the sponsor.
26.
cannot communicate reliably with the investigator.
27.
who, in the opinion of the investigator, is unlikely to adhere to the requirements of the 
study, or is unlikely to complete the full course of vaccination and observation.
NOTE: Investigators should ensure that all study enrollment criteria have been met prior to the 
first vaccination. If a participant's clinical status changes (including any available laboratory 
results or receipt of additional medical records) after screening but before the first dose of study 
vaccination is given such that she no longer meets all eligibility criteria, then the screening 
laboratory tests should be repeated and the Day 1 visit re-scheduled, or the participant should be 
excluded from participation in the study. Section 9.1.3, Screening Period, describes options for 

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retesting. Section 17.4 Source Documentation, describes the required documentation to support 
meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential participants must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8, Pre-study and Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the inclusion 
and exclusion criteria (Section 4.1 and Section 4.2, respectively).
5.
STUDY VACCINE ALLOCATION AND BLINDING
Study Vaccine Allocation
Randomization will be stratified by HPV type (16 and 18) and within each HPV type, 
randomization will be performed in different steps (see Table 1). Between the steps, 
randomization will be halted until a 24-hour and 7-day review by the PI and SRP or an IDMC 
review have been performed. For HPV16 infected participants the following randomization steps 
will take place:

Step 1: 2 participants will be randomly assigned to receive low dose Ad26.HPV16 or 
placebo. These participants may be randomized on the same day.

Step 2: 4 participants will be randomly assigned to receive low dose Ad26.HPV16 
(3 participants) or placebo (1 participant). There will be a staggered interval of 7 days 
between the vaccination of each of these 4 participants.

Step 3: 3 participants will be randomly assigned to receive high dose Ad26.HPV16 or the
Ad26.HPV16/Ad26.HPV18 mix or placebo. These participants may be randomized on the 
same day.

Step 4: 8 participants will be randomly assigned to receive high dose Ad26.HPV16 
(3 participants)
or the
Ad26.HPV16/Ad26.HPV18
mix (3 participants) or placebo 
(2 participants). There will be a staggered interval of 7 days between the vaccination of each 
of these 8 participants.

Step 5: 16 participants will be randomly assigned to receive high dose Ad26.HPV16 
(6 participants), Ad26.HPV16/Ad26.HPV18 mix (6 participants) or placebo (4 participants). 
No more than 5 participants will be vaccinated per week.
The same randomization process will be used for the HPV18-infected participants.
If enrollment is slow for HPV18-infected participants, up to 8 HPV18-infected participants can 
be replaced by HPV16-infected participants, hence a minimum of 25 HPV18 participants will be 
allowed; the decision will be taken during Step 5.

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Blinding
The participants, study-site personnel (including vaccine administrator) and investigator will be
blinded to study vaccine allocation throughout the study, except for the pharmacist or
qualified staff member with primary responsibility for study vaccine preparation and dispensing.
At the time of the primary analysis, the study will be unblinded for sponsor personnel (including 
medical personnel, biomarker lead, virologist, statistician, programming and data management). 
Participants, clinical staff and study-site personnel will remain blinded to the study vaccine 
allocation until the end of the study.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
The investigator may in an emergency determine the identity of the intervention by contacting 
the IWRS. While the responsibility to break the intervention code in emergency situations 
resides solely with the investigator, it is recommended that the investigator contact the sponsor 
or its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented in the appropriate section of the electronic 
case report form (eCRF), and in the source document.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed.
6.
DOSAGE AND ADMINISTRATION
6.1.
General Instructions and Procedures
The following will be used to prepare the vaccines:

Ad26.HPV16: supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable volume])

Ad26.HPV18: supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable volume])

MVA.HPV16/18: supplied in a single use vial (5x108 Inf.U/0.5 mL; 0.5 mL [extractable 
volume])

Placebo (0.9% saline): supplied in a single use vial (10 mL [filled volume])

Diluent (Diluent 5, DS-TEC-79875): supplied in a single use vial (1 mL [extractable 
volume]) and to be added to the Ad26.HPV16 or Ad26.HPV18 vials for administration of the 
Ad26.HPV16 or Ad26.HPV18 vaccines at a dose of 5x1010 vp

Diluent (tris-buffered saline [TBS] Diluent, DS-TEC-138030): supplied in a single use vial 
(1.5 mL [extractable volume]), 1.0 mL is to be added to the MVA.HPV16/18 vial for 
administration of the MVA.HPV16/18 vaccine at a dose of 2x108 Inf.U

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For each participant, every vaccination with Ad26.HPV16 and/or Ad26.HPV18 will be 1.0 mL 
in volume. For the low dose of Ad26.HPV16 or Ad26.HPV18 (5x1010 vp), 0.5 mL of 
Ad26.HPV16 or Ad26.HPV18 and 0.5 mL of diluent 5 (DS-TEC-79875) will be mixed and 
administered as a single injection. For the high dose of Ad26.HPV16 or Ad26.HPV18 (1x1011
vp), two vials of 0.5 mL of Ad26.HPV16 or Ad26.HPV18 will be mixed and administered as a 
single injection.
The monovalent Ad26.HPV16 (5x1010 vp) and Ad26.HPV18 (5x1010 vp), vaccine components 
will be mixed at the pharmacy or at a designated product preparation area and administered as a 
single injection.
Vaccination with MVA.HPV16/18 at a dose of 2x108 Inf.U will be 0.5 mL in volume. Therefore,
1.0 mL of the diluent DS-TEC-138030 will be added to the vial of MVA.HPV16/18 (a 
concentration of 5x108 Inf.U per 0.5 mL) and mixed at the pharmacy or at a designated product 
preparation area, and 0.5 mL of the mix will be administered as a single injection. 
To allow blinding, the volume of placebo vaccine will be the same as the volume of the 
corresponding Ad26.HPV16, Ad26.HPV18 or MVA.HPV16/18 vaccine. 
The vaccines will be administered by intramuscular injection into the deltoid muscle of either 
arm by a blinded study vaccine administrator. Opposite arms should be used for the MVA 
injection unless local site reaction cannot be assessed reliably in the opposite arm. The arm in 
which the vaccine has been administered should be recorded in the eCRF. The injection site 
should be free from any injury, local skin problem, significant tattoo or other issue that might 
interfere with evaluating the arm after injection (eg, participants with a history of skin cancer 
must not be vaccinated at the previous tumor site). No local or topical anesthetic will be used 
prior to injection.
Blinding will be achieved by preparation of study vaccine by an unblinded pharmacist or other 
qualified study-site personnel with primary responsibility for study vaccine preparation and 
dispensing, and by the administration of vaccine in a masked syringe by a blinded study vaccine 
administrator. Full details of the study vaccine preparation will be provided in the Site 
Investigational Product and Procedures Manual.
6.2.
Criteria for Postponement of Vaccination
A participant will not be given the first or second vaccination if she experiences any of the 
following events at the scheduled time for vaccination:

Severe acute illness at the time of vaccination (this does not include minor illnesses such as 
diarrhea)

Fever (body temperature ≥38.0°C/100.4°F) at the time of vaccination.
If the vaccination visit cannot be rescheduled within the allowed window or the contraindications 
to vaccination persist, the sponsor should be contacted for further guidance.
For contraindications to vaccination that result in discontinuation of study vaccine, refer to 
Section 10.2.

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7.
STUDY VACCINE COMPLIANCE
Study vaccine will be administered intramuscularly by a blinded study vaccine administrator.
The vaccine administrator will be a trained and qualified study nurse, medical doctor, or 
otherwise qualified health care professional. The date and time of each study vaccine 
administration will be recorded in the eCRF.
8.
PRE-STUDY AND CONCOMITANT THERAPY
Pre-study specific therapies such as analgesic/antipyretic medications and non-steroidal 
anti-inflammatory drugs (NSAIDs), administered up to 30 days before first vaccination must be 
recorded at screening.
Concomitant therapies must be recorded from the time of ICF signature through 28 days after 
each vaccination, and additionally outside of these periods when associated with an SAE meeting 
the criteria outlined in Section 12.3.2. Information on concomitant use of herbal supplements or 
vitamins will not be collected.
Use of any experimental medication (including experimental vaccines other than the study 
vaccine) during the study is not allowed. Participants may not receive an investigational drug or 
use an investigation medical device within 30 days or receive an investigational vaccine within 
6 months before the planned administration of the first dose of study vaccine.
Vaccination with licensed live-attenuated vaccines within 28 days of a study vaccination (ie, 
before and after) is not allowed. Other licensed vaccines (eg, tetanus, hepatitis A, hepatitis B, 
rabies) should be given at least 14 days before (or at least 14 days after) administration of study 
vaccine. If a vaccine is indicated in a post-exposure setting (eg, rabies or tetanus), it must take 
priority over the study vaccine.
Participants can receive medications such as acetaminophen, NSAIDs, or antihistamines as 
needed, although their use must be documented and use of these medications as routine 
prophylaxis prior to study vaccination is discouraged.
Chronic (longer than 10 days) or recurrent use of immunomodulators/suppressors, eg, cancer 
chemotherapeutic agents, systemic corticosteroids is prohibited during the study and within 
6 months before the planned administration of the first dose of study vaccine (Note: Ocular, 
topical or inhaled steroids are allowed). Antineoplastic and immunomodulating agents, including 
herbal products, or radiotherapy are prohibited during the study and within 6 months before the 
planned administration of the first dose of study vaccine. If chronic use of such medicines 
becomes medically indicated during the course of the study for any participant, the sponsor 

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should be contacted. The participant should remain in the study but should not receive further 
study vaccinationa.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The TIME AND EVENTS SCHEDULE
summarizes the frequency and timing of 
immunogenicity, safety and virology measurements applicable to this study.
Evaluation of the safety/reactogenicity of the vaccine regimens will include laboratory 
assessments, physical assessment by study-site personnel, and participant reports on signs and 
symptoms following vaccinations. Additional unscheduled study visits may be required if in the 
investigator’s opinion, further clinical or laboratory evaluation is needed.
Participants will be provided with a thermometer (to measure body temperature), ruler (to 
measure local injection site reactions), and participant diary to record body temperature and 
solicited local (at injection site) and systemic events.
The diary includes instructions on how to capture the data and grading scales to assess severity 
of the symptoms. The study staff is responsible for providing appropriate training to the 
participant to avoid missing or incorrect data (refer to Study Training Manual). The diary card 
will be reviewed by the study personnel at visits indicated in the Time and Events Schedule. 
If the diary card review is missed, the diary card will be reviewed in the following visit. If a 
participant misses a vaccination, the diary covering the period after the missed vaccination does 
not have to be filled in.
The total blood volume to be collected during the study from each participant will be 
approximately 485 mL, which is considered acceptable based on the US Department of Health 
and Human Services Office for Human Research Protections, and the US FDA guidelines.49,50
9.1.2.
Visit Windows
Participants should be encouraged to come on the exact day planned and use the visit window 
only if necessary. For the following visits, windows will be allowed as indicated:

Second vaccination: ± 7 days
                                                
a Depending on the time of the occurrence, any participant who receives a prohibited concomitant medication will 
not be included in the immunogenicity analyses.

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
7 days post-vaccination safety only visit: ± 2 days

21 days post-Dose 2 vaccination safety, immunogenicity and virology visit: ± 3 days

28 days post-vaccination safety only visit (telephone call): ± 3 days

2 months post-Dose 2 vaccination safety and virology visit: ± 5 days

6 months post-Dose 1 safety and virology visit: ± 14 days 

6 months post-Dose 2 vaccination safety, immunogenicity and virology visit: ± 14 days

12 months post-Dose 1 safety, immunogenicity and virology visit: ± 14 days
If a participant cannot be vaccinated within the allowed window, then that vaccination should not 
be administered. However, vaccination outside of the window (in particular if the window is 
missed due to a study pause) can be assessed on a case-by-case basis upon discussion between 
investigator and sponsor.
No visit windows are applicable for telephone calls to sentinel participants at 1 day post 
vaccination.
The timings of the second vaccination and of Visit 12 will be determined relative to the actual 
day of the first vaccination. The timing of visits 7, 8, 9, 10, 11 and 13 will be determined relative 
to the actual day of the second vaccination.
9.1.3.
Screening Period (Days -42 to -2): Visit 1
Only participants complying with the inclusion and exclusion criteria specified in Section 4.1
and Section 4.2, respectively, will be included into the study. The investigator will provide 
detailed information on the study to the participants and will obtain written informed consent
prior to each participant’s participation in the study. All the procedures described in the 
Time and Events Schedule will only take place after written informed consent has been signed.
The following evaluations will be performed on participants to determine overall eligibility:

Review of inclusion/exclusion criteria

Demographic information

Medical history and pre-study medications

Physical examination including vital signs measurement (supine systolic and diastolic blood 
pressure, heart rate and oral temperature) and height and weight

Healthcare provider-collected cervical sample for HPV16 and HPV18 PCR (If no recent 
HPV16 or HPV18 Cobas® test result is available at screening, the test will be performed on 
a stored cervical sample [if collected within a period of 8 weeks before screening] or on a 
new healthcare provider-collected sample)

Self-collected cervico-vaginal sample for HPV16 and HPV18 PCR

Serum β-hCG pregnancy testing (women of childbearing potential only)

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
Blood sampling for HIV type 1 or type 2, hepatitis B and hepatitis C serology, and for safety
laboratory testing (hematology and biochemistry)
General eligibility for this clinical study will be dependent on results of laboratory tests and
the medical assessment. Study participants who qualify for inclusion based on the medical
history, physical examination, and laboratory results will be contacted and scheduled for
enrollment and first vaccination (Visit 2) within 42 days from signing the ICF.
Participants with laboratory values or vital signs not meeting eligibility criteria at the screening 
visit may have one repeat testing at the discretion of the investigator using an unscheduled visit 
during the 42-day screening period. Enrollment of a participant with laboratory values that are 
outside the laboratory normal reference ranges, and additionally within the limits representing 
FDA toxicity Grade 1 (see Attachment 2), is allowed if the investigator considers the values to 
be not clinically significant and reasonable for the population under study.
9.1.4.
Vaccination and Follow-up Period (Day 1 to Day 366)
9.1.4.1.
Vaccination (Day 1, and Day 57)

Day 1/Day of Randomization/Vaccination 1: Visit 2
After an abbreviated physical examination (at the discretion of the investigator),
measurement of vital signs, urine pregnancy test (for women of childbearing potential), self-
collected 
cervico-vaginal 
sample 
for 
type-specific 
HPV16 
and 
HPV18
PCR, 
HSV-2 serology test, and pre-vaccination symptoms check, eligible participants will be 
randomized as described in Section 5. If a participant’s clinical status changes (including 
any available laboratory results or receipt of additional medical records) after screening but 
before the first dose of study vaccination is given such that she no longer meets all eligibility 
criteria, then the screening laboratory tests should be repeated and the Day 1 visit re-
scheduled, or the participant should be excluded from participation in the study. Pre-dose 
samples for baseline immunogenicity assessments will be collected. Before vaccination, the 
investigator must check for any symptoms of an acute illness or oral temperature ≥38.0 °C. 
If the vaccination visit cannot be rescheduled within the allowed window or the 
contraindications to vaccination persist, the sponsor should be contacted for further 
guidance.
Administration of first dose of study vaccine.
After vaccination, participants will remain under observation at the study site for at least 
30 minutes for presence of any acute reactions and solicited events and will be allowed to 
leave the vaccination site at approximately 45 minutes post-vaccination. Any unsolicited, 
solicited local or systemic AEs and vital signs will be documented in the eCRF by study-site 
personnel following this observation period.
Participants will be provided with a participant diary, thermometer, and ruler to measure and 
record oral body temperature, solicited local and systemic AEs for 7 days post-vaccination.

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Unsolicited AEs will be recorded on the AE page of the eCRF from the time of ICF 
signature until 28 days after the first vaccination, together with information about any 
concomitant medications. SAEs will be collected until the study end (Day 366).

Day 57/Vaccination 2: Visit 6
An abbreviated physical examination (at the discretion of the investigator), measurement of 
vital signs, urine pregnancy test (for women of childbearing potential), self-collected 
cervico-vaginal sample for type-specific HPV16 and HPV18 PCR and pre-vaccination 
symptoms check will be performed for all participants pre-vaccination. Pre-dose samples for 
immunogenicity assessments will be collected. Before vaccination, the investigator must 
check for any symptoms of an acute illness or oral temperature ≥38.0 °C. If the vaccination 
visit cannot be rescheduled within the allowed window or the contraindications to 
vaccination persist, the sponsor should be contacted for further guidance.
Administration of second dose of study vaccine.
After vaccination, participants will remain under observation at the study site for at least 
30 minutes for presence of any acute reactions and solicited events. Any unsolicited, 
solicited local or systemic AEs and vital signs will be documented in the eCRF by study-site
personnel following this observation period.
Participants will be provided with a participant diary, thermometer, and ruler to measure and 
record oral body temperature, solicited local and systemic AEs for 7 days post-vaccination.
9.1.4.2.
Post-first Vaccination Follow-Up
The randomization, vaccination process and safety evaluations described below for HPV16 
infected participants will be performed in the same manner and independently among HPV18 
infected participants.

1 Day Post-first Vaccination: Sentinel Participants: Visit 3 
At 1 day after the first vaccination, a telephone call will be made to the 5 sentinel 
participants (2 in Step 1 and 3 in Step 3); vaccination of additional participants will be 
halted until a 24-hour and 7-day post vaccination blinded safety review of solicited and 
unsolicited AEs are performed by the PI and the SRP. 

7 Days Post-first Vaccination: Visit 4
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, and recording of any AEs/SAEs and concomitant 
medications. Samples for safety laboratory testing (hematology and biochemistry) will be 
collected. The participant diary will be collected and reviewed.

28 Days Post-first Vaccination: Visit 5 
This visit will be a telephone call to collect safety information (unsolicited AEs, SAEs and 
concomitant medications).

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
6 Months Post-first Vaccination (Week 26): Visit 12
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, self-collected cervico-vaginal sample for type-
specific 
HPV16 and HPV18 PCR and recording of any SAEs and concomitant medications (related 
to SAEs only).

12 Months Post-first Vaccination (Week 52): Visit 14
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, healthcare provider-collected cervical sample for 
type-specific HPV16 and HPV18 PCR,
self-collected cervico-vaginal sample for 
type-specific HPV16 and HPV18 PCR and recording of any SAEs and concomitant 
medications (related to SAEs only). At this visit all participants will undergo a colposcopic 
evaluation and an HSV-2 serology test. Samples will be shipped and tested in a central 
sponsor designated laboratory. Samples for immunogenicity assessments will be collected.
9.1.4.3.
Post-second Vaccination Follow-Up

1 Day Post-second Vaccination (sentinel participants only): Visit 7
This visit will be a telephone call to check participant diaries and to collect safety 
information (solicited and unsolicited AEs, SAEs and concomitant medications).

7 Days Post-second Vaccination: Visit 8
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, and recording of any AEs/SAEs and concomitant 
medications. Samples for safety laboratory testing (hematology and biochemistry) will be 
collected. The participant diary will be collected and reviewed.

21 Days Post-second Vaccination: Visit 9 
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, self-collected cervico-vaginal sample for type-
specific 
HPV16 and HPV18 PCR and recording of any AEs/SAEs and concomitant medications. 
Samples for immunogenicity assessments will be collected.

28 Days Post-second Vaccination: Visit 10 
This visit will be a telephone call to collect safety information (unsolicited AEs, SAEs and 
concomitant medications).

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
2 Months Post-second Vaccination: Visit 11
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, a self-collected cervico-vaginal sample for 
type-specific HPV16 and HPV18 PCR and recording of any SAEs and concomitant 
medications (related to SAEs only).

6 Months Post-second Vaccination: Visit 13
This visit will include an abbreviated physical examination (at the discretion of the 
investigator), vital signs measurement, self-collected cervico-vaginal sample for type-
specific 
HPV16 and HPV18 PCR and recording of any SAEs and concomitant medications (related 
to SAEs only). 
Samples for immunogenicity assessments will be collected.
9.1.4.4.
Early Withdrawal – Early Exit Visit
In the event of early withdrawal from the study (ie, before Week 52), an exit visit will be 
conducted as soon as possible. The following procedures will be performed: an abbreviated 
physical examination, vital signs measurement, healthcare provider-collected cervical sample, 
and self-collected cervico-vaginal sample for type-specific HPV16 and HPV18 PCR, an 
HSV-2 serology test, recording of concomitant medications and any AEs, and collection of 
samples for immunogenicity assessments.
9.2.
Study Evaluations
9.2.1.
Safety
An IDMC will be commissioned to evaluate safety data over the course of the study and to 
review any events that meet a specific study pausing or stopping rule or any other safety issue 
that may arise. Details regarding the IDMC are provided in Section 11.8.
Any clinically relevant changes occurring from the signing of the ICF until 28 days after the first 
vaccination and from the second vaccination through the following 28 days must be recorded on 
the AE section of the eCRF. Outside these periods, reporting will be limited to all SAEs.
Any clinically significant abnormalities (including those persisting at the end of the study/early 
exit) will be followed by the investigator until resolution or until a clinically stable endpoint is 
reached. All AEs and laboratory data will be coded for severity according to the criteria 
presented in Section 12.1.3 (see Attachment 2).
The PI, together with the sponsor’s SRP, will be responsible for the safety monitoring of the 
study, and will halt vaccination of further subjects in case any of the pre-specified pausing or 
stopping rules described in Section 11.9 have been met.
The study will include the following evaluations of safety and reactogenicity according to the 
time points provided in the Time and Events Schedule:

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Adverse Events
All AEs will be reported as specified in Section 12.
For solicited AEs, the following applies.
Solicited Adverse Events
After each vaccination, participants will remain under observation at the study site for at least 
30 minutes for presence of any acute reactions and solicited events. In addition, participants will 
record solicited symptoms in a diary for 7 days post-vaccination. All participants will be 
provided with a diary and instructions on how to complete the Diary (Section 9.1.1). Diary 
information will be transcribed by the study personnel in the diary eCRF pages. Once a solicited 
symptom from a diary is considered to be of severity Grade 1 or above, it will be referred to as a 
solicited AE.
Solicited Injection Site (Local) Adverse Events
Participants will be asked to note in the diary occurrences of pain/tenderness, erythema and 
induration/swelling at the study vaccine injection site daily for 7 days post-vaccination (day of 
vaccination and the subsequent 7 days). The extent (largest diameter) of any erythema, and 
induration/swelling should be measured (using the ruler supplied) and recorded daily.

Injection Site Pain/Tenderness
Injection site pain (eg, stinging, burning) is an unpleasant sensory and emotional experience 
associated with actual or potential tissue damage and occurring at the immunization site 
(with or without involvement of surrounding tissue). Injection site tenderness is a painful 
sensation localized at the injection site upon palpation or movement of the limb. Due to 
subjective nature of the reaction, the severity assessment of pain/tenderness is self-reported 
(if a participant is unable to provide self-report, other reporters include parent/care giver or 
health care provider).22

Injection Site Erythema
Injection site erythema is a redness of the skin caused by dilatation and congestion of the 
capillaries localized at the injection site. It can best be described by looking and measuring.

Injection Site Swelling/Induration
Injection site swelling is a visible enlargement of an injected limb. It may be either soft 
(typically) or firm (less typical). Injection site induration is a palpable thickening, firmness, 
or hardening of soft tissue, usually has well-demarcated palpable borders, can be visible 
(raised or sunken compared to surrounding skin), is often ‘woody’ to touch and has a flat 
shape. As differentiation between swelling and induration may be difficult without health 
care professional’s assessment, both symptoms have been combined to allow self-
assessment by the participants. Both swelling and induration can best be described by 
looking and measuring.
Note: any other injection site events not meeting the above case definitions should be 
reported separately as unsolicited AEs.32,33

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Solicited Systemic Adverse Events
Participants will be instructed on how to record daily temperature using a thermometer provided 
for home use. Participants should record the oral body temperature in the diary in the evening of 
the day of vaccination, and then daily for the next 7 days approximately at the same time each 
day (preferably in the evening). If more than one measurement is made on any given day, the 
highest temperature of that day will be used in the eCRF. Temperatures to be taken 7 days after 
the vaccination at the end of the diary period, may be collected earlier to coincide with the clinic 
visit.
Fever is defined as endogenous elevation of body temperature ≥38° C, as recorded in at least one 
measurement.36
Participants will also be instructed on how to note daily in the diary symptoms for 7 days 
post-vaccination (day of vaccination and the subsequent 7 days) of the following events: fatigue, 
headache, nausea, myalgia, arthralgia, and chills.
Unsolicited Adverse Events
The investigator or study-site staff will document any reported unsolicited AEs and perform 
causality evaluations from the time of ICF signature through 28 days after the first vaccination, 
and from the time of the second vaccination until 28 days afterwards. SAEs will be collected 
from the time of ICF signature until the study end.
Laboratory Safety Assessments
Blood
samples
will be collected for safety laboratory assessments (hematology and
biochemistry) as follows on all participants:

At screeninga

At 7 days post-Dose 1 and post-Dose 2
The following tests will be performed by a central laboratory:

Hematology Panel
Hemoglobin
White blood cell count with differential
Platelet count
Prothrombin timeb
Activated partial thromboplastin timeb    
                                                
a Clinical laboratory tests will be collected on all participants screened for this study.
b Parameters only measured at screening

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
Biochemistry Panel
Sodium
Potassium
Creatinine
Blood urea nitrogen
Aspartate aminotransferase
Alanine aminotransferase
Review and Grading of Laboratory Data
The investigator must review the laboratory results, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. Laboratory 
reports must be filed with the source documents.
Laboratory values will be initially evaluated by the investigator according to central laboratory 
criteria. Abnormal values outside the central laboratory range of normal will be graded according 
to the toxicity tables from the FDA Guidance document “Toxicity Grading Scale from Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see Attachment
2). Laboratory values within central laboratory normal limits will not be FDA graded and will be 
considered as normal.
Any clinically significant abnormal laboratory value occurring during the 28-day follow-up after 
each vaccination will be captured as an AE. For clinically significant abnormal laboratory
values, the test must be repeated within a reasonable period of the site becoming aware of the 
abnormal value.
Additional Clinical Laboratory Assessments
Additional clinical laboratory assessments will be performed:

Serum pregnancy testing (-hCG) for women of childbearing potential at screening

Urine pregnancy testing for women of childbearing potential on the day of each 
vaccination (pre-vaccination)

Serology testing (HIV type 1 or type 2, hepatitis B, hepatitis C) at screening

Serology testing (HSV-2) on the day of the first vaccination and the 12-month follow-up 
visit (or the early exit visit, if applicable).
Vital Signs
Vital sign measurements will be performed at time points specified in the Time and Events 
Schedule. Supine blood pressure and pulse/heart rate measurements should be preceded by at 
least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).

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The following measurements will be performed:

Heart rate (beats per minute), systolic blood pressure (mmHg) and diastolic blood 
pressure (mmHg). Confirmatory vital signs measurement can be performed if inconsistent 
with a prior measurement

Body temperature (preferably orally)
If any clinically significant changes in vital signs are noted, they will be reported as AEs
and followed to resolution, or until reaching a clinically stable endpoint.
Physical Examination
Full physical examination, including height and weight, will be carried out at screening. At all 
other visits, an abbreviated, symptom-directed examination will be performed by the investigator
based on any clinically relevant issues, clinically relevant symptoms and medical history.
Symptom-directed physical examination may be repeated if deemed necessary by the 
investigator.
Physical examinations will be performed by the investigator or designated medically trained 
clinician. Any abnormalities or changes in severity noted during the review of body systems 
should be documented in the source document and recorded in the eCRF.
9.2.2.
Immunogenicity 
Venous blood samples will be collected for the determination of humoral and cellular responses, 
according to the Time and Events Schedule. Sample collection and processing will be performed 
by the staff at the clinical site according to current versions of the approved clinical site’s 
standard procedures.
Since the vaccine targets a cellular therapeutic response, the emphasis will be on the assessment 
of cellular immune responses. During the study, cellular immune responses will be measured in 
all participants at 5 time points during the 12-month follow-up period after the first vaccination: 

pre-Dose 1, pre-Dose 2, at 21 days, 6 months post-Dose 2 and 12 months post-Dose 1
Cellular immunological assays are summarized in Table 5. Humoral immunological assays are 
summarized in Table 6. Exploratory analyses may be performed, including, but not limited to,
the listed assays. Baseline and post-vaccination samples will be used for the characterization of 
immunological assays.

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Table 5:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Secondary endpoints
ICS
Analysis of T cell responses to the separate or combined protein peptide pools of 
HPV16 and HPV18 E2, E6 and E7 proteins, including specific CD4+ and CD8+
T cells producing IFNγ, TNFα, or IL-2 (combined cytokine expression may also be 
assessed)
Exploratory endpoints
ICS
Analysis of other cellular responses to the separate or combined protein peptide pools 
of HPV16 and HPV18 E2, E6 and E7 proteins (including, but not limited to, mucosa-
homing markers, Th17, Th2, Treg, cytolytic markers, activation markers, exhaustion 
markers)
Transcriptome analysis
Analysis of gene expression patterns to provide phenotypic and functional 
characterization of PBMCs ex vivo or after stimulation with HPV16 and/or HPV18 
E2, E6, and/or E7 peptide pools.
ELISpot responses
Enumeration of IFNγ-producing HPV16 and/or HPV18 E2 (complete, N-terminal,
and/or C-terminal peptide pools), E6 and/or E7-specific T cells
ChipCytometry
Analysis of T cell responses to the separate or combined protein peptide pools of 
HPV16 and/or HPV18 E2, E6, and E7 proteins in PBMCs, including but not limited 
to CD4+ and CD8+ T cells producing IFNγ, TNFα and/or IL-2
ELISpot=enzyme-linked immunospot; HPV=human papillomavirus; ICS=intracellular cytokine staining; IFN=interferon; 
IL=interleukin; NK=natural killer; PBMC=peripheral blood mononuclear cell; Th=T-helper (cell); TNF=tumor necrosis factor; 
Treg=regulatory T cell
Table 6:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Exploratory endpoints
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus vector
MVA neutralization assay
Analysis of neutralizing antibodies to MVA vector
L1/L2 ELISA
Analysis of L1 and/or L2 antibodies by ELISA to HPV16 and/or HPV18 or 
other HPV genotypes
E2, E6 and E7 ELISA
Analysis of E2, E6 and/or E7 antibodies to HPV16 and/or HPV18 or other 
HR-HPV genotypes
ELISA=enzyme-linked immunosorbent assay; HPV=human papillomavirus; HR-HPV=high-risk human papillomavirus; 
MVA=modified vaccinia Ankara
Sample collection and processing will be performed by study-site personnel according to current 
versions of approved SOPs.
9.2.3.
Virology and Histology
HPV16 and HPV18 genotyping will be performed with a qualitative PCR test (Cobas®, Roche) 
on the cervical samples. Prior to vaccination, a participant will have a confirmed diagnosis of an
HPV16 or HPV18 infection. More information on the identification of an HPV infection is 
provided in the flow chart (Figure 4).
Cervical samples will be collected by the healthcare provider and by the participant
(self-sampling) at the time points indicated in the Time and Events Schedule. Healthcare 
provider-obtained cervical samples collected using an endocervical brush will be processed in a 
transport medium and send to the central laboratory. Participants will self-collect cervico-vaginal 
samples with a dry self-sampling device (Evalyn® Brush, Rovers Medical Devices) at the study 
site. Immediately after collection of the cervico-vaginal specimen for this study, the Evalyn® 

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Brush should be dispensed in ThinPrep® following the procedure described in the Laboratory 
Manual. After collection of the cervico-vaginal sample, the dry Evalyn® Brush will be 
suspended in transport medium at the study site and sent to the central laboratory.
Cobas® testing will be performed by a central sponsor designated laboratory.
A quantitative HPV PCR genotyping test that detects HPV16 and HPV18 together with other 
individual HR-HPV types will be used on all cervical samples (healthcare provider-collected and 
self-collected) to address the exploratory endpoints.
Colposcopy examination will occur during screening only for those participants who do not have 
recent (within the last 12 months) examination results. A mandatory colposcopy examination 
will occur 12 months after the first dose for all participants. All colposcopy biopsy specimens 
will be sent to a central laboratory for standardized interpretation. Histopathological reports on 
biopsy and excision specimens will classify findings as: negative, CIN1, CIN2, CIN3, AIS and 
invasive malignancy. Note: All participants will have HSV-2 serology testing on the day of the 
first vaccination and the 12-month follow-up visit (or the early exit visit, if applicable).
Should a participant have an examination or treatment with a non-study gynecologist, she will be 
asked if she consents to allow study staff to access her medical records and obtain slide and 
tissue for evaluation.
Management and medical follow-up after the mandatory colposcopy evaluation will be at the 
discretion of the investigator and local guidelines.
Participants who discontinue the study will be recommended to continue regular cervical cancer 
screening.
10.
PARTICIPANT COMPLETION/DISCONTINUATION OF STUDY VACCINE/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A participant will be considered to have completed study vaccination if she has received all 
study vaccinations. A participant will be considered to have completed the study if she has 
completed assessments through to the end of the study (ie, Day 366) even if she did not receive 
the second vaccination.
10.2.
Discontinuation of Study Vaccine/Withdrawal from the Study
Discontinuation of Study Vaccine
Participants will discontinue further study vaccine administration for the reasons listed below. 
These participants must not receive any additional dose of study vaccine but should be followed-
up until the end of the follow-up period at Week 52 (12 months post-Dose 1 visit) with 
assessments of safety, immunogenicity and virology. Additional unscheduled visits may be 

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performed for safety/reactogenicity reasons, if needed. In case of questions, the investigator is 
encouraged to contact the sponsor.

Any related AE, worsening of health status or intercurrent illnesses that, in the opinion of the 
investigator, required discontinuation from study vaccine

The participant becomes pregnant

Unblinding on the participant level that, in the opinion of the sponsor, would compromise 
the integrity of the data

Anaphylactic reaction following vaccination 

SAE or other potentially life-threatening (Grade 4) event that is determined to be related to 
study vaccine

Chronic or recurrent use of immunosuppressants (after discussion with the sponsor)

Missing a study vaccination
Withdrawal From the Study
Each participant has the right to withdraw from the study at any time for any reason. The 
investigator should make an attempt to contact participants who did not return for scheduled 
visits or follow-up. Although the participant is not obliged to give reason(s) for withdrawing 
prematurely, the investigator should make a reasonable effort to ascertain the reason(s) while 
fully respecting the participant’s rights.
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death 

Repeated failure to comply with protocol requirements

Decision by the sponsor or the investigator to stop or cancel the study

Decision by local regulatory authorities or Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) to stop or cancel the study
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented.
When a participant withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study vaccine assigned to the withdrawn 
participant may not be assigned to another participant. In general, participants who withdraw will 
be replaced, as long as the participant has not been vaccinated yet. However, any randomized 
participant withdrawn from the study for reasons other than due to an AE after the first dose but 

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before the last dose might be replaced at the discretion of the sponsor. If a participant withdraws 
early from the study, assessments for early withdrawal should be obtained (see Section 9.1.4.4).
Participants who wish to withdraw consent from participation in the study will be offered a 
single Exit visit (see Section 9.1.4.4) for safety follow-up (prior to formal withdrawal of 
consent). They have the right to refuse.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for future research (refer to Section 
16.2.5). In such a case, samples will be destroyed after they are no longer needed for the clinical 
study. Details of the sample retention for research are presented in the main ICF.
10.3.
Contraindications to Vaccination
The following events constitute a temporary contraindication to study vaccination. If any of these 
events occur at the scheduled time for vaccination, the participant may be vaccinated up to 
10 days beyond the scheduled vaccination:

Acute illness at the time of vaccination. This does not include minor illnesses, such as 
diarrhea or mild upper-respiratory tract infection.

Fever (body temperature ≥38.0°C) at the planned time of vaccination.
If the vaccination visit cannot be rescheduled within the allowed window or the contraindications 
to vaccination persist, the sponsor should be contacted for further guidance.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the safety, immunogenicity and 
virology data is outlined below. Specific details will be provided in the statistical analysis plan 
(SAP).
Planned analyses are described in Section 11.7.
11.1.
Analysis Sets
Vaccination assignment will follow the as treated principle.
11.1.1.
Full Analysis Set
The Full Analysis Set (FAS) will include all participants with at least 1 vaccination.
11.1.2.
Per-Protocol Immunogenicity Population
The Per-Protocol Immunogenicity (PPI) population will include all randomized and vaccinated 
participants for whom immunogenicity data are available excluding participants with major 
protocol deviations expecting to impact the immunogenicity outcomes. In addition, if 
participants miss the second dose, but continue the planned visit schedule, samples taken after 
the planned but missed dose will not be taken into account.

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11.2.
Sample Size Determination
While mild to moderate local and systemic AEs are expected, AEs that preclude further 
vaccination or more serious ones that would limit product development are not anticipated. With 
20 participants in 1 vaccine regimen, the observation of 0 such reactions after the first 
vaccination would be associated with a 95% confidence that the true rate is less than 13.9%.
Across regimens (n=48), the observation of 0 such reactions after the first vaccination would be 
associated with a 95% confidence that the true rate is less than 6.1%.
11.3.
Participant Information
For all participants, demographic characteristics (eg, age, height, weight, body mass index, and 
race), and other baseline characteristics (eg, physical examination, medical history, and 
concomitant diseases) will be tabulated and summarized with descriptive statistics.
Baseline characteristics will include HPV infection history as well as HPV infection type, the 
latter being categorized as follows:

Participants with persistent infection defined as at least 2 positive cervical HPV PCR 
tests with an interval of at least 11 months as follows: 2 positive HPV16 (or 2 positive 
HPV18 tests) or, if the genotype of the first test is unknown and after consultation with 
the sponsor, HR-HPV positivity followed by HPV16 (or HPV18) positivity. Note: the 
historical positive cervical HPV PCR test will be taken into account for the definition 
regardless of the length of the interval (>11 months) as long as there were no known 
negative results in between.

Participants with recently diagnosed (within 12 months prior to baseline) HPV infection 
which is not persistent as defined above.
11.4.
Safety Analyses
All safety analyses will be performed on the FAS.
No formal statistical testing of safety data is planned. Safety data will be tabulated by vaccine
regimens and pooled placebos and will be analyzed descriptively. The severity of abnormal 
symptoms, vital signs, AEs and abnormal laboratory values will be graded based on the toxicity 
table from the FDA “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (September 2007, see Attachment 2)”.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs (solicited local, 
solicited systemic, and unsolicited), event-related diary information, and all SAEs with onset or 
worsening within 28 days after each vaccination will be included in the analysis. For each AE, 
the percentage of participants who experience at least one occurrence of the given event will be 
summarized by vaccine schedule. 

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Summaries, listings, datasets, or narratives may be provided, as appropriate, for those 
participants who die, who discontinue study vaccine due to an AE, or who experience a severe 
AE or an SAE.
Summaries and listings may be provided separately for AEs with onset outside the above defined 
timeframe that were reported pre-dose at the moment of subsequent vaccinations for studies 
using multiple doses.
Solicited local (at injection site) and systemic AEs will be summarized descriptively. The overall 
frequencies per vaccine group as well as frequencies according to severity and duration will be 
calculated for solicited AEs. In addition, the number and percentages of participants with at least 
1 solicited local (at injection site) or systemic AE will be presented. Frequencies of unsolicited 
AEs, separately for all and vaccination-related only, will be presented by System Organ Class 
and preferred term, while those of solicited AEs will be presented only by preferred term.
Clinical Laboratory Tests
Laboratory data will be reported by type of laboratory test. Actual values and changes from 
baseline will be summarized for each laboratory analyte at baseline and at each scheduled time
point (ie, Visits 1, 4 and 8 ). Graphical presentation of changes in laboratory tests will be made 
as applicable. Baseline refers to the last value prior to first vaccination. 
Laboratory abnormalities will be determined according to the FDA toxicity grading tables (see 
Attachment 2) or, for tests for which no grades are available, in accordance with the normal 
ranges of the clinical laboratory. Any laboratory value shown as a “graded” value in the FDA 
table that is within the institutional normal ranges will not be graded for severity.
Vital Signs
Values and changes from baseline of supine heart rate and blood pressure (systolic and diastolic) 
will be summarized at each scheduled time point (baseline refers to the last value prior to first 
vaccination). The percentage of participants with values beyond pre-specified limits will be 
reported.
Physical Examination
Physical examination findings at baseline will be summarized. Abnormalities during the study 
will be listed.
11.5.
Immunogenicity Analyses
The immunogenicity analyses will be performed on the PPI set. An additional analysis will be 
done for the FAS.
Immunogenicity analyses for HPV16 and HPV18 participants will be performed either combined
or by HPV type (HPV16 or HPV18), and by infection type (persistent or recently diagnosed). 
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (geometric mean 
and 95% CI, or median and quartile range [Q1-Q3], as appropriate) will be calculated for 

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continuous immunological parameters at all time points. Graphical representations of 
immunological parameters will be made as applicable. Frequency tabulations will be calculated 
for discrete (qualitative) immunological parameters as applicable.
11.6.
Virology Analyses
The analyses will be performed on the FAS data set for whom virology endpoint measures are 
available. 
Frequency and kinetics of clearance of HPV16 or HPV18 infection will be analyzed either 
combined or by HPV type (HPV16 or HPV18), and by infection type (persistent or recently 
diagnosed) using both the healthcare provider- and self-collected cervical samples and will be 
described for the vaccine regimens and placebo during the study duration.
11.7.
Planned Analyses
A blinded interim analysis may be performed after all participants from Phase 1 of the study 
have completed the 21 days post-Dose 2 visit (Week 11) or have discontinued earlier. This 
analysis, which will include immunogenicity and safety data, will allow to identify 
immunogenicity and overall safety signals and guide further development of the vaccine.
The primary analysis will occur when all participants have completed the 6 months post-Dose 1 
visit (Week 26) or have discontinued earlier. If enrollment is slow for HPV18-infected 
participants, an interim analysis may first be performed on the HPV16-infected participants. The 
primary analysis will then be performed on all participants when all HPV18 infected participants 
have completed the 6 months post-Dose 1 visit (Week 26) or have discontinued earlier. These 
analyses will include safety and virology data up to the 6 months post-dose 1 visit (Week 26) and 
immunogenicity data up to the 21 days post-Dose 2 visit (Week 11).
The final analysis will occur when the last participant completes the final visit at 12 months post-
Dose 1 (Week 52, Day 366) or discontinued earlier to determine the durability of the immune 
response and analyze any additional safety, virology and immunological data collected after the 
primary analysis. If enrollment is slow for HPV18-infected participants, an interim analysis may 
first be performed on the HPV16-infected participants. The final analysis will then be performed 
on all participants when all HPV18 infected participants have completed the 12 months post-
Dose 1 visit (Week 52) or have discontinued earlier.
The safety, virology and immunogenicity analysis will include the timepoints described in the 
TIME AND EVENTS SCHEDULE. At the time of the primary analysis, the study will be 
unblinded for sponsor personnel (including medical personnel, biomarker lead, virologist, 
statistician, programming and data management). Participants, clinical staff and study-site 
personnel will remain blinded to the study vaccine allocation until the end of the study.
11.8.
Independent Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the participants enrolled in this study. It will consist of members independent of the sponsor, 

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including at least 1 medical expert in the relevant therapeutic area and at least 1 statistician. The 
PI and SRP will inform the IDMC of any AE of concern.
The IDMC will convene to discuss any situation that meets a study vaccination pausing or 
stopping rule as outlined in Section 11.9. The IDMC responsibilities, authorities and procedures 
will be documented in its charter. In addition, the IDMC will review the 7-day safety data post-
Dose 1 among all participants in Phase 1; initially in those receiving the low dose of 
Ad26.HPV16 or Ad26 HPV18 vaccine and then among all those dosed with high dose vaccine 
(Ad26.HPV16 or Ad26.HPV18) or the mixed vaccine (Ad26.HPV16/Ad26.HPV18). Further 
randomization and vaccination of participants will be suspended until this IDMC review is 
completed. The IDMC will also review 7-day safety data post-Dose 2 (MVA.HPV16/18) among 
all participants in Phase 1. Safety data for review will include solicited and unsolicited AEs, 
SAEs, and laboratory assessments. After these reviews, the IDMC will make recommendations 
regarding the continuation of the study. The conclusion of the IDMC will be communicate to the 
investigators, the IEC/IRB and the national regulatory authorities as appropriate. 
The IDMC will review unblinded data. Details on the intervals of the safety evaluations and on 
how the integrity of the study will be maintained when the blind is broken with an IDMC 
analysis will be provided in the IDMC charter. Safety data from the primary analysis will be 
shared with the IDMC.
11.9.
Study Safety Rules
Study Pausing Rules
If a study vaccination is considered to raise significant safety concerns (and a specific set of 
pausing criteria have been met), further vaccination of participants will be paused. The 
concerned data will be reviewed by the IDMC, after which the IDMC will recommend whether 
the pause can be lifted or not, or whether other steps are needed.
The occurrence of any of the following events will lead to a pause in further study vaccination. 
This list is only applicable for concerned AEs that occur up to 28 days after each vaccination and 
to concerned SAEs throughout the study.
1.
Death of a participant; OR
2.
One or more participants experience a SAE or a Grade 4 (solicited or unsolicited) AE
or a persistent (upon repeat testing) Grade 4 laboratory abnormality; OR 
3.
One or more participants experience a diagnostic level 1, 2 or 3 criterion for 
anaphylaxis43 within 24 hours of vaccination; OR
4.
Two or more participants experience a Grade 3 unsolicited AE of the same type (as 
per medical judgment of the sponsor); OR
5.
Two or more participants experience a persistent (upon repeat testing) Grade 3 
laboratory abnormality; OR

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6.
Two or more participants experience a Grade 3 solicited AE of the same type and 
persisting as Grade 3 for longer than 3 consecutive daysa.
For number 2 and number 5: to assess abnormal laboratory values, the test must be repeated at 
least once, within 48 hours of the site becoming aware of the abnormal value.
For number 4, number 5, and number 6: after each IDMC review of similar AEs, the Committee 
will indicate the conditions under which it requires further notification and review of the 
subsequent similar AEs.
To enable prompt response to a situation that could trigger pausing rules, the investigator should 
notify the sponsor’s medical monitor or designee (AND fax or email SAE form to Global 
Medical Safety Operations, if applicable), immediately and no later than 24 hours after becoming 
aware of any related AE of Grade 3 or above (AND update the eCRF with relevant information 
on the same day the AE information is collected).
A thorough analysis of all Grade 3 cases will be carried out by the sponsor’s medical monitor or 
designee, irrespective of whether the criteria for pausing the study are met. 
Based on the pausing criteria, the sponsor’s medical monitor or designee then decides whether a 
study pause is warranted. All sites will be notified immediately in case of a study pause. The 
sponsor’s medical monitor or designee is responsible for the immediate notification of IDMC
members and coordination of a IDMC meeting in case of a study pause.
Vaccinations for an individual participant may be suspended for safety concerns other than those 
described in the pausing criteria, at the discretion of the investigator if he/she feels the 
participant’s safety may be threatened. The sponsor’s medical monitor or designee or the 
investigator(s) (upon consultation with the sponsor’s medical monitor or designee) may initiate 
IDMC review for any single event or combination of multiple events which, in their professional 
opinion, could jeopardize the safety of the participants or the reliability of the data.
Vaccinations for the study may be suspended for safety concerns other than those described 
above, or before pausing rules are met, if, in the judgment of the IDMC, participant safety may 
be threatened.
Resumption of vaccinations will start only upon sponsor receipt of the written recommendations 
by the IDMC. The clinical site(s) will be allowed to resume activities upon receipt of a written 
notification from the sponsor. The communications from the IDMC will be forwarded by the 
investigator to the IRB/IEC and by the sponsor to the relevant health authorities, according to 
local standards and regulations.
                                                
a The day of occurrence of the AE is counted as Day 1.

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Stopping Rules for Study Termination
If any of the conditions below (stopping rules) are met, further vaccination of subjects will be 
stopped and following consultation with the IDMC the study terminated except for the safety 
evaluations of already immunized participants specified in the protocol and any further safety 
evaluations recommended by the IDMC:

Death of a participant, considered related to study vaccine or if the causal relationship to 
the study vaccine cannot be excluded; OR

One or more participants experience diagnostic level 1 criterion for anaphylaxis43 within 
24 hours of vaccination, clearly not attributable to other causes than vaccination with 
study vaccine. 
o
Level 1 definition of anaphylaxis: 

≥1 major (see below) dermatological AND

≥1 major cardiovascular AND/OR ≥1 major respiratory criterion (see 
below)

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12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.

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Solicited Adverse Events
Solicited AEs are predefined local (at the injection site) and systemic events for which the 
participant is specifically questioned and symptoms of which are noted by participants in their 
diary (see Section 9.1.1).
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is NOT specifically questioned in the 
participant diary.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have a 
causal relationship with the product. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council
on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects unsolicited AEs starting from the time of ICF signature until 28 days
after the first vaccination, and from the time of the second vaccination through the following 28 
days, and solicited AEs from the time of each vaccination for 7 days post-vaccination (refer to 
Section 12.3.1 for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union (EU) Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

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
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study vaccine and the event (eg, death from anaphylaxis), the event 
must be reported as a suspected unexpected serious adverse reaction by the sponsor to Health 
Authorities and by the investigator to the IRB/IEC according to regulatory and local 
requirements.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For Ad26.HPV16, Ad26.HPV18 and MVA.HPV16/18, the 
expectedness of an AE will be determined by whether or not it is listed in the Investigator's 
Brochures.
Adverse Event Associated With the Use of the Study Vaccine
An AE is considered associated with the use of the study vaccine if the attribution is related by 
the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Every effort should be made by the investigator to explain any AE and assess its potential causal 
relationship, ie, to administration of the study vaccine or to alternative causes (eg, natural history 
of the underlying diseases, concomitant therapy). This applies to all AEs, whether serious or 
non-serious.
Causality of AEs should be assessed by the investigator based on the following:
Related: there is suspicion that there is a relationship between the study vaccine and the AE 
(without determining the extent of probability); there is a reasonable possibility that the study 
vaccine contributed to the AE.
Unrelated: there is no suspicion that there is a relationship between the study vaccine and the 
AE; there are other more likely causes and administration of the study vaccine is not suspected to 
have contributed to the AE.
By definition, all solicited AEs at the injection site (local) will be considered related to the study 
vaccine administration.

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12.1.3.
Severity Criteria
All AEs and laboratory data reported as AEs will be coded for severity using the FDA toxicity 
grading tables (see Attachment 2). Note that laboratory values within laboratory normal ranges 
(even if within a toxicity grade range), or laboratory values outside normal ranges that are not 
clinically significant in the judgment of the investigator, should not be recorded as AEs. For AEs 
not identified in the grading table, the following guidelines will be applied:

Mild (Grade 1): Awareness of symptoms that are easily tolerated, causing minimal 
discomfort and not interfering with everyday activities.

Moderate (Grade 2): Sufficient discomfort is present to cause interference with normal 
activity.

Severe (Grade 3): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.

Potentially life-threatening (Grade 4): Symptoms causing inability to perform basic 
self-care functions OR medical or operative intervention indicated to prevent permanent 
impairment, persistent disability.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
The toxicity grading scale used for laboratory assessments is based on the FDA toxicity grading 
table (see Attachment 22), consistent with the assessment grading used throughout the protocol. 
If a laboratory value falls within the grading as specified in the FDA table, but also within the 
laboratory normal limits, the value is considered as normal. For hemoglobin, both the actual 
value and the change from reference will be graded.
The severity of solicited AEs will be graded in the diary by the subject based on the severity 
assessment provided in the diary and then verified by the investigator using the FDA toxicity 
grading table (see Attachment 2).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study vaccine that may require expedited reporting or 
safety evaluation include, but are not limited to:

Suspected abuse/misuse of a sponsor study vaccine

Overdose of a sponsor study vaccine

Accidental or occupational exposure to a sponsor study vaccine

Medication error involving a sponsor product (with or without participant/patient exposure 
to the sponsor study vaccine, eg, name confusion)

Exposure to a sponsor study vaccine from breast-feeding

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Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
Unsolicited AEs and special reporting situations will be reported from the time of ICF signature
until 28 days after the first vaccination, and thereafter, for 28 days after each subsequent dose of 
study vaccine. Unsolicited AEs with the onset date outside the time frame defined above (>28 
days after previous study vaccination) that are ongoing on the day of the subsequent vaccination 
should be recorded on the eCRF AE page.
Solicited AEs will be recorded by each participant in the participant diary for 7 days after each 
dosing. The investigator will review each participant’s diary at the subsequent in-clinic visit; 
diary information will be transcribed by the study personnel in the on-site assessment forms in 
the eCRF.
All SAEs and AEs leading to discontinuation from the study vaccination (regardless of the causal 
relationship) are to be reported for the duration of the study. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All AEs, regardless of seriousness, severity, or presumed relationship to study vaccine, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory 
infection”). Investigators must record in the eCRF their opinion regarding the relationship of the 
AE to study vaccine. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all SUSARs. The investigator (or sponsor where required) must report SUSARs 
to the appropriate IEC/IRB that approved the protocol unless otherwise required and documented 
by the IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating 
investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.
Participants will be provided with a “wallet (study) card” and instructed to carry this card with 
them for the duration of the study indicating the following:

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator’s name and 24-hour contact telephone number

Local sponsor’s name and 24-hour contact telephone number (for medical staff only)

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
Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All SAEs occurring from the time of ICF signature until the end of the study must be reported to 
the appropriate sponsor contact person by study-site personnel within 24 hours of their 
knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must 
be completed and signed by a physician from the study site, and transmitted to the sponsor 
within 24 hours. The initial and follow-up reports of an SAE should be made by facsimile (fax)
and/or through secure email.
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant’s participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study vaccine or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (participant or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant’s participation in a study must be reported as an SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

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The cause of death of a participant in a study during the entire study period, whether or not the 
event is expected or associated with the study vaccine, is considered an SAE and must be 
reported.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form(s). If a participant becomes pregnant during the course of the study, no more injections of 
study product will be given during the pregnancy, but remaining visits and study procedures 
should be completed unless medically contraindicated or applicable regulations require 
termination from the study. If the participant terminates from the study prior to the pregnancy 
outcome, the site should make every effort to keep in touch with the participant in order to 
ascertain the pregnancy outcome. All pregnancies and pregnancy outcomes should be recorded.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies and ectopic pregnancy) are considered SAEs and must be reported using the SAE 
Form.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of 
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established procedures in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of PQC information; all studies conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor.

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13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY VACCINE INFORMATION
14.1.
Physical Description of Study Vaccine
Human replication-incompetent adenovirus-vectored vaccine candidates (manufactured and 
provided under the responsibility of the sponsor), as well as a MVA-based replication-
incompetent vaccine (developed in collaboration with Bavarian Nordic A/S) (MVA-BN®) will 
be assessed in this study:
Ad26.HPV16 (JNJ-63682918)
Ad26.HPV16 is a recombinant replication-incompetent Ad26 vector encoding genetically 
modified HPV16 early (E2, E6 and E7) proteins.
For this study, Ad26.HPV16 will be formulated as a solution for intramuscular injection and
supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable volume]).
Ad26.HPV18 (JNJ-63682931)
Ad26.HPV18 is a recombinant replication-incompetent Ad26 vector encoding genetically 
modified HPV18 early (E2, E6 and E7) proteins.
For this study, Ad26.HPV18 will be formulated as a solution for intramuscular injection and 
supplied in a single use vial (1x1011 vp/mL; 0.5 mL [extractable volume]).
For Regimen 3 of this study, the monovalent Ad26.HPV16 and Ad26.HPV18 vaccine 
component will undergo mixing and will be given as a single injection; denoted by 
Ad26.HPV16/Ad26.HPV18 in this document.
MVA-mBN411B (JNJ-65195208)
MVA-mBN411B, referred to as MVA.HPV16/18 in this document, is a live vaccine which is 
non-replicating in human cells and encodes the same genetically modified HPV16 and HPV18 
early (E2, E6 and E7) proteins.
For this study, MVA.HPV16/18 will be formulated as a suspension for intramuscular injection 
and supplied in a single use vial (5x108 Inf.U/0.5 mL; 0.5 mL [extractable volume]). The 
MVA.HPV16/18 vaccine will be administered at a dose of 2x108 Inf.U by mixing with the 
diluent DS-TEC-138030.
Placebo
Placebo will be supplied as sterile 0.9% saline for injection in 10 mL (filled volume) vials.

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Diluent
Diluent 5 (20 mM histidine, 75 mM NaCl, 0.02% [w/v] tween-80, 5% [w/v] sucrose, 
0.1 mM ethylenediaminetetraacetic acid [EDTA], 0.5% [v/v] ethanol, pH 6.5), DS-TEC-79875, 
will be supplied in a single use vial (1 mL [extractable volume]). This diluent is to be added to 
the Ad26.HPV16 or Ad26.HPV18 vials for administration of the Ad26.HPV16 or Ad26.HPV18 
vaccines at a dose of 5x1010 vp.
A diluent consisting of TBS (10 mM tris, 140 mM NaCl, pH 7.7), DS-TEC-138030, will be 
supplied in a single use vial (1.5 mL [extractable volume]). One mL of this diluent is to be added 
to the MVA.HPV16/18 vial for administration of the vaccine at a dose of 2x108 Inf.U.
14.2.
Packaging and Labeling
All study vaccines were manufactured and packaged in accordance with Current Good 
Manufacturing Practice. All study vaccines will be packaged and labeled under the responsibility 
of the sponsor. Study vaccine labels will contain information to meet the applicable regulatory 
requirements.
No study vaccine can be repacked or relabeled without prior approval from the sponsor.
Further details for study vaccine packaging and labeling can be found in the Site Investigational 
Product Procedures Manual.
14.3.
Storage and Handling
Ad26.HPV16, Ad26.HPV18, MVA.HPV16/18 and placebo must be stored as specified on the 
study vaccine labels. 
Vials must be stored in a secured location under controlled temperature with no access for 
unauthorized personnel. The study refrigerator/freezer must be equipped with a continuous 
temperature monitor and alarm. Study refrigerators/freezers should be equipped with back-up 
power systems. In the event that study vaccine is exposed to temperatures outside the specified 
temperature range, all relevant data will be sent to the sponsor to determine if the affected study 
vaccine can be used or will be replaced. The affected study vaccine must be quarantined and not 
used until further instruction from the sponsor is received.
Blinding will be achieved by preparation of study vaccine by an unblinded pharmacist or other 
qualified study-site personnel with primary responsibility for study vaccine preparation and 
dispensing, and by the administration of vaccine in a masked syringe by a blinded study vaccine 
administrator.
Refer to the Site Investigational Product and Procedures Manual for additional guidance on study 
vaccine preparation, handling and stability, and storage.

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14.4.
Study Vaccine Accountability
The investigator is responsible for ensuring that all study vaccine received at the site is 
inventoried and accounted for throughout the study. The study vaccine administered to the 
participant must be documented on the vaccine accountability form. All study vaccine will be 
stored and disposed of according to the sponsor’s instructions.
Study vaccine must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study vaccine must be available for verification by the 
sponsor’s study-site monitor during on-site monitoring visits. The return to the sponsor of unused 
study vaccine will be documented on the investigational product destruction form. When the 
study site is an authorized destruction unit and study vaccine supplies are destroyed on-site, this 
must also be documented on the investigational product destruction form.
Potentially hazardous materials such as used ampoules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for vaccine accountability purposes.
Study vaccine should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study vaccine will be 
supplied only to participants participating in the study. Returned study vaccine must not be 
dispensed again, even to the same participant. Study vaccine may not be relabeled or reassigned 
for use by other participants. The investigator agrees neither to dispense the study vaccine from, 
nor store it at, any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for Ad26.HPV16, Ad26.HPV18 and MVA.HPV16/18

Site Investigational Product Procedures Manual

Laboratory Manual

Electronic Data Capture (eDC) eCRF completion guidelines and randomization instructions

Sample ICF

Diary cards

Rulers, thermometers

Participant wallet cards
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, 
during the study, participants will be given any new information that may affect their decision to 

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continue participation. They will be told that their consent to participate in the study is voluntary 
and may be withdrawn at any time with no reason given and without penalty or loss of benefits 
to which they would otherwise be entitled. Only participants who are fully able to understand the 
risks, benefits, and potential AEs of the study, and provide their consent voluntarily will be 
enrolled.
The total blood volume drawn from each participant will not exceed the US Department of Health 
and Human Services Office for Human Research Protections, and US FDA guidelines of 550 mL 
in any 8-week period.49,50
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human participants. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct, unless required locally), the ICF, applicable 

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recruiting materials, and participant compensation programs, and the sponsor has received a copy 
of this approval. This approval letter must be dated and must clearly identify the IEC/IRB and 
the documents being approved.
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study vaccine

New information that may adversely affect the safety of the participants or the conduct of 
the study

Deviations from or changes to the protocol to eliminate immediate hazards to the 
participants

Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each participant must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 

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reviewing IEC/IRB and be in a language that the participant can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants the aims, methods, reasonably anticipated 
benefits, and potential hazards of the study, and any discomfort participation in the study may 
entail. Participants will be informed that their participation is voluntary and that they may 
withdraw consent to participate at any time. They will be informed that choosing not to 
participate will not affect the care the participant will receive. Finally, they will be told that the 
investigator will maintain a participant identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the participant, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF, the participant is authorizing such 
access. It also denotes that the participant agrees to allow her study physician to recontact the 
participant for the purpose of obtaining consent for additional safety evaluations, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the participant's personally dated signature. After having obtained the consent, a 
copy of the ICF must be given to the participant.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing 
of personal data and for the investigator/institution to allow direct access to her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The participant has the right to request through the investigator access to her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.

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16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand Ad26.HPV16, 
Ad26.HPV18 and MVA.HPV16/18, to understand persistent HPV16 or 18 infection, and to 
develop tests/assays related to Ad26.HPV16, Ad26.HPV18 and MVA.HPV16/18. The research 
may begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2).
16.2.6.
Country Selection
This study will only be conducted in the US.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the participants, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.

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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study vaccines to 
the study site:

Protocol and amendment(s), if any, signed and dated by the PI

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the PI, where required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant

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identification. In cases where the participant is not randomized into the study, the date seen will 
be used.
The investigator must also complete a participant screening log, which reports on all participants 
who were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and immunogenicity parameters as required by 
the protocol; record of all AEs and follow-up of AEs; concomitant medication; vaccine
receipt/dispensing/return records; study vaccine administration information; and date of study 
completion and reason for early discontinuation of study vaccine or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The participant’s diary used to collect information regarding solicited symptoms after 
vaccination will be considered source data.
An eSource system may be utilized, which contains data traditionally maintained in an hospital 
or clinic record to document medical care (eg, electronic source documents) as well as the 
clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If eSource is utilized, references made to the eCRF in the 
protocol include the eSource system but information collected through eSource may not be 
limited to that found in the eCRF.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All eCRF entries, corrections, and alterations must be made by the investigator or 
authorized study-site personnel. The investigator must verify that all data entries in the eCRF are 
accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant’s source documents. Data must be entered 
into eCRF in English. The eCRF must be completed as soon as possible after a participant visit 
and the forms should be available for review at the next scheduled monitoring visit.

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If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed 
after the initial entry into the eCRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during on-
site monitoring visits and after their return to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database, 
the data will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each participant, as well as all 
study documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must 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 until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period 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.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.

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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last visit for the last participant participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final participant visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study vaccine development
17.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding Ad26.HPV16, Ad26.HPV18 
and MVA.HPV16/18
or the sponsor’s operations (eg, patent application, formulas, 
manufacturing processes, basic scientific data, prior clinical data, formulation information) 
supplied by the sponsor to the investigator and not previously published, and any data generated 
as a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor’s prior 
written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of Ad26.HPV16, Ad26.HPV18 and 
MVA.HPV16/18, and thus may be disclosed as required to other clinical investigators or 
regulatory agencies. To permit the information derived from the clinical studies to be used, the 
investigator is obligated to provide the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report (CSR) generated by the 
sponsor and will contain data from all study sites that participated in the study as per protocol. 
Recruitment performance or specific expertise related to the nature and the key assessment 
parameters of the study will be used to determine a coordinating investigator. Results of analyses 
performed after the CSR has been issued will be reported in a separate report and will not require 
a revision of the CSR. Study participant identifiers will not be used in publication of results. Any 

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work created in connection with performance of the study and contained in the data that can 
benefit from copyright protection (except any publication by the investigator as provided for 
below) shall be the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary data and information 
without approval from the investigator. The investigator has the right to publish study site-
specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.

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Attachment 1:
Definition of Woman of Childbearing Potential
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral 
tubal occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin an acceptable effective method of contraception, as 
described throughout the inclusion criteria.

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Attachment 2:
Toxicity Tables
From the FDA Guidance document “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” (September 2007)
A: Tables for Clinical Abnormalities
Local Reaction to
Injectable Product
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening
(Grade 4)
Pain
Does not interfere
with activity
Repeated use of 
non-narcotic
pain reliever
> 24 hours or
interferes with
activity
Any use of
narcotic pain
reliever or
prevents daily
activity
Emergency room
(ER) visit or
hospitalization
Tenderness
Mild discomfort
to
Touch
Discomfort with
Movement
Significant
discomfort at rest
ER visit or
Hospitalization
Erythema/redness*
2.5 – 5 cm
5.1 – 10 cm
> 10 cm
Necrosis or
exfoliative
dermatitis
Induration/swelling**
2.5 – 5 cm and
does not interfere
with activity
5.1 – 10 cm or
interferes with
activity
> 10 cm or
prevents daily
activity
Necrosis
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a
continuous variable.
** Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement.
Vital Signs *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening
(Grade 4)
Fever** (°C)
Fever** (°F)
38.0 – 38.4
100.4 – 101.1
38.5 – 38.9
101.2 – 102.0
39.0 – 40
102.1 – 104
>40
>104
Tachycardia - beats per 
minute
101 – 115
116 – 130
> 130
ER visit or hospitalization for 
arrhythmia
Bradycardia - beats per 
minute***
50 – 54
45 – 49
< 45
ER visit or hospitalization for 
arrhythmia
Hypertension (systolic) 
- mmHg
141 – 150
151 – 155
>155
ER visit or hospitalization for 
malignant hypertension
Hypertension 
(diastolic) - mmHg
91 – 95
96 – 100
>100
ER visit or hospitalization for 
malignant hypertension
Hypotension (systolic) 
- mmHg
85 – 89
80 – 84
< 80
ER visit or hospitalization for 
hypotensive shock
Respiratory Rate -
breaths per minute
17 – 20
21 – 25
>25
Intubation
* 
Subject should be at rest for all vital sign measurements.
** 
Oral temperature; no recent hot or cold beverages or smoking.
***
When resting heart rate is between 60 - 100 beats per minute. Use clinical judgment when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes.

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Systemic
(General)
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening 
(Grade 4)
Nausea/vomiting
No interference 
with activity or 
1 - 2 episodes/24 
hours
Some interference 
with activity or > 2 
episodes/24 hours
Prevents daily 
activity, requires 
outpatient IV 
hydration
ER visit or hospitalization for 
hypotensive shock
Diarrhea
2 - 3 loose stools 
or < 400 gms/24 
hours
4 - 5 stools or 400 -
800 gms/24 hours
6 or more watery 
stools or 
>800gms/24 
hours or requires 
outpatient IV 
hydration
ER visit or hospitalization
Headache
No interference 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or some 
interference with 
activity
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or hospitalization
Systemic Illness
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening 
(Grade 4)
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
requires medical 
intervention
ER visit or hospitalization

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Approved, Date: 20 August 2019
B: Tables for Laboratory Abnormalities
The grading scale used for laboratory assessments is based on the FDA Guidance document “Toxicity 
Grading Scale from Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. Any laboratory value shown as a “graded” value in the table that is within the institutional normal 
ranges will not be graded for severity or recorded as AE. For hemoglobin, both the actual value and the 
change from reference will be graded. For the change from reference, the corresponding actual value 
should also be graded.
Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-
threatening
(Grade 4) **
Sodium –
Hyponatremia - mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium –
Hypernatremia -
mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium –
Hyperkalemia - mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium –
Hypokalemia - mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose –
Hypoglycemia - mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose –
Hyperglycemia Fasting 
- mg/dL
100 – 110
111 – 125
> 125
Insulin requirements 
or hyperosmolar 
coma
Random Glucose -
mg/dL
110 – 125
126 – 200
>200
Blood Urea Nitrogen 
BUN - mg/dL
23 – 26
27 – 31
> 31
Requires dialysis
Creatinine - mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Calcium –
hypocalcemia - mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium –
hypercalcemia - mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium –
hypomagnesemia -
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous –
hypophosphatemia -
mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK - mg/dL
1.25 – 1.5 x ULN***
1.6 – 3.0 x ULN
3.1 –10 x ULN
> 10 x ULN
Albumin –
Hypoalbuminemia -
g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein –
5.5 – 6.0
5.0 – 5.4
< 5.0
--

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Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-
threatening
(Grade 4) **
Hypoproteinemia -
g/dL
Alkaline phosphate –
increase by factor
1.1 – 2.0 x ULN
2.1 – 3.0 x ULN
3.1 – 10 x ULN
> 10 x ULN
Liver Function Tests –
ALT, AST increase by 
factor
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
Bilirubin – when 
accompanied by any 
increase in Liver 
Function Test increase 
by factor
1.1 – 1.25 x ULN
1.26 – 1.5 x ULN
1.51 – 1.75 x ULN
> 1.75 x ULN
Bilirubin – when Liver 
Function Test is 
normal; increase by 
factor
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
Cholesterol
201 – 210
211 – 225
> 226
--
Pancreatic enzymes –
amylase, lipase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory 
abnormalities as potentially life-threatening (Grade 4). For example, a low sodium value that falls within a Grade 3 parameter 
(125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new seizure associated with the low 
sodium value.
***ULN is the upper limit of the normal range.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002 Amendment 3
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Approved, Date: 20 August 2019
Hematology *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-
threatening
(Grade 4) **
Hemoglobin (Female) -
gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female) 
change from baseline 
value - gm/dL
Any decrease – 1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) -
gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male) 
change from baseline 
value - gm/dL
Any decrease – 1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase -
cell/mm3
10,800 – 15,000
15,001 – 20,000
20,001 – 25,000
> 25,000
WBC Decrease -
cell/mm3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease 
- cell/mm3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease -
cell/mm3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm3
650 – 1500
1501 – 5000
> 5000 
Hypereosinophilic
Platelets Decreased -
cell/mm3
125,000 – 140,000
100,000 – 124,000
25,000 – 99,000
< 25,000
PT - increase by factor 
(prothrombin time)
1.0 – 1.10 x ULN** 
1.11 – 1.20 x ULN
1.21 – 1.25 x ULN
> 1.25 ULN
PTT - increase by 
factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN
1.21 – 1.4 x ULN
1.41 – 1.5 x ULN
> 1.5 x ULN
Fibrinogen increase -
mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease -
mg/dL
150 – 200
125 – 149
100 – 124
< 100 or associated 
with gross bleeding 
or disseminated 
intravascular 
coagulation 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** ULN is the upper limit of the normal range.

VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
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Approved, Date: 20 August 2019
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study vaccine, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Michal Sarnecki, MD
Institution:
Janssen Vaccines & Prevention B.V.
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.

 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Michal Sarnecki
20Aug2019, 12:20:32 PM, UTC
Document Approval

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 03 July 2020
Janssen Vaccines & Prevention*
Clinical Protocol
COVID-19 Appendix
Protocol Title
Randomized, Double-blind, Placebo-controlled First-in-Human, Phase 1/2a Study to 
Evaluate the Safety, Reactogenicity and Immunogenicity of Monovalent HPV16 and 
HPV18 Ad26-vectored Vaccine Components and an MVA-vectored HPV16/18 Vaccine 
Component in Otherwise Healthy Women with HPV16 or 18 Infection of the Cervix
Protocol VAC81623HPV1002; Phase 1/2a
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)  
*Janssen Vaccine & Prevention is a Janssen pharmaceutical company of Johnson & Johnson and is hereafter 
referred to as the sponsor of the study. The sponsor is identified on the Contact Information page that 
accompanies the protocol.
EudraCT NUMBER: 2018-000200-41
Status:
Approved
Date:
03 July 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-72803 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
VAC81623HPV1002 (EDMS-ERI-146564753).
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT03610581

COVID-19 Appendix
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 03 July 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/at home or delayed until such time that on-site visits can be resumed.a The actual 
visit date and the type of visit (ie, telephone or videoconference) should be captured in the 
electronic case report form (eCRF). The missed procedures should be recorded as “missed due to 
COVID-19”. At each contact, participants will be interviewed to collect safety data. Key efficacy 
endpoint assessments should be performed if required and as feasible. Participants will also be 
questioned regarding general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the eCRF. 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
COVID-19 related changes will be communicated to the sites and to the health authorities 
according to local guidance.  If a participant has tested positive for COVID 19, the investigator 
should contact the sponsor’s responsible medical officer to discuss plans for study intervention 
and follow-up. Modifications made to the study conduct as a result of the COVID-19 pandemic 
should be summarized in the clinical study report.
                                                
a An on-site visit is defined as a visit during which the participant and the qualified and blinded site staff are both 
present in person at the study site.
A remote visit is defined as a visit during which the participant and the qualified and blinded site staff interact via 
phone or video call in case the participant is not able to be physically present at the study site.
A home visit is defined as a visit during which the participant and the qualified and blinded site staff are both present 
at the participant’s home.

COVID-19 Appendix
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 03 July 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure participant safety on study while site 
capabilities are compromised by COVID-19-related restrictions. Remote medical consultation and 
alternatives to study intervention dispensing, administration, and clinical laboratory assessments 
may allow continued study participation for participants in this trial. As local restrictions are lifted 
and the acute phase of the COVID-19 pandemic resolves, sites should revert to original protocol 
conduct as soon as feasible and in accordance with any country-specific regulatory requirements.
If due to the COVID-19 pandemic, screening assessments fall outside of the window allowed per 
protocol, re-screening would be allowed once.
Study visits and assessments
To safely maintain participants on study intervention while site capabilities are compromised by 
COVID-19-related restrictions, participants may have tele-health visits until such time that on-site 
visits can be resumed. These remote visits will be conducted by qualified and blinded study site 
staff via phone or video conversation as per local regulation. Note that study vaccinations should 
always be given on site.

Physical examination (PE): PEs at study visits other than screening visits are abbreviated, 
symptom-directed assessments. Therefore, a protocol deviation would not be documented
for a missed physical exam if there are no symptoms present. However, if it is not possible 
to make any PE assessments when symptoms are present, then a COVID-19 protocol 
deviation would be reported and the participants would need to be referred to their 
respective primary care physician or emergency room as required. 

Temperature measurements: it would be acceptable to have the patient recording his/her 
temperature at home and reporting that to the study site staff during remote visits in order 
to avoid missing data. If it is not possible for the participant to have his/her temperature 
measured, then a missed value would be reported as a COVID-19 protocol deviation.

Diary review: it would be acceptable to review diary data with study site staff during 
remote visits (teleconference/videoconference) and have the data immediately entered on 
the eCRF.

Adverse events: Standard adverse event (AE)/serious adverse event (SAE) reporting 
requirements apply.

Out of window vaccinations: In the event site capabilities are compromised by COVID-
19-related restrictions, out of window vaccinations would be allowed on a case-by-case 
basis and after discussion between the investigator and the sponsor.
Informed consent
A revised informed consent form (ICF) or an addendum to the ICF, arising from this amendment, 
is to be signed by the participants during a site visit. For any informed consent that cannot be 
performed in person (eg, verbal consent by telephone), the process must be documented in the 

COVID-19 Appendix
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 03 July 2020
source documents and confirmed by way of normal consent procedures at the earliest opportunity. 
If consent is given verbally by phone, an impartial witness should be present at the study site, if 
required by local regulations, for the entire informed consent process (which includes reading and 
explaining all written information) and should personally date and sign the ICF after the oral 
consent is obtained.
Source data verification/monitoring
In case on-site monitoring visits are not possible, the site monitor may contact the investigator to 
arrange monitoring activities remotely (in accordance with site and local requirements). Additional 
on-site monitoring visits may be needed in the future to catch up on source data verification. 
Any deviations to study procedures occurring during the COVID-19 pandemic would be captured 
appropriately in the clinical trial management system (or eCRF), with the prefix “COVID-19-
RELATED” (including actual visit date documented or reasons for withdrawals specified; 
discontinuations of study interventions and withdrawal from the study if applicable).
Audits
During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct 
impact/engagement from the investigator and study site staff would be not conducted in order to 
comply with national, local and/or organizational social distancing restrictions. Additional quality 
assurance activities such as remote audits or focused review of study-related documents may take 
place with limited impact/engagement if possible.

COVID-19 Appendix
VAC81623 (JNJ-63682918, JNJ-63682931 and JNJ-65195208)
Clinical Protocol VAC81623HPV1002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 03 July 2020
INVESTIGATOR AGREEMENT