A First-in-human, Phase 1, Randomized, Observer-blind, Controlled Study to Assess the Safety and Immunogenicity of Novel Live Attenuated Type 1 and Type 3 Oral Poliomyelitis Vaccines in Healthy Adults
Phase: PHASE1
Conditions: Poliomyelitis
Sponsor: PATH

NCT ID: NCT04529538

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TABLE OF CONTENTS 
Title Page .................................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF TABLES ..................................................................................................................... 5 
LIST OF FIGURES .................................................................................................................... 6 
ABBREVIATIONS AND ACRONYMS .................................................................................. 7 
INVESTIGATOR’S AGREEMENT ....................................................................................... 11 
KEY ROLES AND CONTACT INFORMATION.................................................................. 12 
PROTOCOL SUMMARY ....................................................................................................... 14 
 
BACKGROUND AND RATIONALE ........................................................................ 20 
 
Burden of Disease ....................................................................................................... 20 
 
Pathogen ...................................................................................................................... 21 
 
Description of Study Vaccine ..................................................................................... 21 
 
Summary of Nonclinical Studies of Study Vaccine ................................................... 23 
1.4.1 
Growth and yield in Vero cells .......................................................................... 24 
1.4.2 
Antigenicity........................................................................................................ 25 
1.4.3 
Immunogenicity ................................................................................................. 25 
1.4.4 
Attenuation phenotypes ..................................................................................... 26 
 
Summary of Clinical Studies of Study Vaccine ......................................................... 26 
1.5.1 
Safety ................................................................................................................. 27 
1.5.2 
Immunogenicity ................................................................................................. 28 
1.5.3 
Viral Shedding ................................................................................................... 28 
1.5.4 
Genetic Stability................................................................................................. 28 
 
Overall Development Strategy .................................................................................... 28 
 
HYPOTHESIS, OBJECTIVES AND ENDPOINTS ................................................... 28 
 
Study Hypotheses........................................................................................................ 28 
 
Study Objectives ......................................................................................................... 29 
2.2.1 
Primary Objective: ............................................................................................. 29 
2.2.2 
Secondary Objectives: ....................................................................................... 29 
2.2.3 
Exploratory Objectives: ..................................................................................... 29 
 
Study Endpoints .......................................................................................................... 29 
2.3.1 
Primary Endpoints: ............................................................................................ 29 
2.3.2 
Secondary Endpoints: ........................................................................................ 30 
2.3.3 
Exploratory Endpoints: ...................................................................................... 30 
 
STUDY DESIGN ......................................................................................................... 31 
 
STUDY POPULATION............................................................................................... 32 

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Description of Study Population ................................................................................. 32 
 
Inclusion Criteria ........................................................................................................ 32 
 
Exclusion Criteria ....................................................................................................... 33 
 
STUDY PRODUCTS ................................................................................................... 34 
 
Study Vaccine ............................................................................................................. 34 
5.1.1 
Product Description ........................................................................................... 34 
5.1.2 
Manufacturer ...................................................................................................... 35 
5.1.3 
Presentation and Formulation ............................................................................ 35 
5.1.4 
Stability and Storage .......................................................................................... 35 
 
Dose Preparation and Administration ......................................................................... 36 
 
Accountability and Disposal ....................................................................................... 36 
 
STUDY PROCEDURES .............................................................................................. 36 
 
Recruitment ................................................................................................................. 36 
 
Study Visits ................................................................................................................. 36 
6.2.1 
Screening – Day -90 to Day 1 ............................................................................ 36 
6.2.2 
First Vaccination Visit – Day 1 Visit ................................................................. 37 
6.2.3 
Day 8 Visit, 7 (+1) days after the study vaccination – Clinic follow-up 
visit..................................................................................................................... 39 
6.2.4 
Day 29 Visit, 28 (+2) days after the study vaccination – Clinic follow-up 
visit..................................................................................................................... 39 
6.2.5 
Day 36 Visit, 7 (+1) days after the second study vaccination – Clinic 
follow-up visit .................................................................................................... 41 
6.2.6 
Day 57 Visit, 28 (+2) days after the second study vaccination – Clinic 
follow-up visit .................................................................................................... 41 
6.2.7 
Day 169 Telephone Visit, 168 (+14) days after the initial study 
vaccination – Final Study Visit .......................................................................... 42 
6.2.8 
Unscheduled Visits ............................................................................................ 43 
 
Discontinuation of Vaccination or Study Procedures ................................................. 43 
 
Withdrawal from Study............................................................................................... 43 
 
Loss to Follow-up ....................................................................................................... 44 
 
Use of Concomitant Medications During the Study ................................................... 44 
 
Emergency Unblinding ............................................................................................... 45 
 
Management of Birth Control and Pregnancy During Study...................................... 45 
 
Clinical Assessments .................................................................................................. 45 
 
LABORATORY EVALUATIONS/REQUIREMENTS ............................................. 46 
 
Sample Collection, Distribution and Storage.............................................................. 46 
 
Clinical Laboratory Tests ............................................................................................ 47 
 
Assessment of Shed Poliovirus ................................................................................... 47 
 
Future Use of Stored Samples..................................................................................... 48 

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Biohazard Containment .............................................................................................. 48 
 
SAFETY ASSESSMENT AND REPORTING ........................................................... 48 
 
Definitions................................................................................................................... 48 
8.1.1 
Adverse Event (AE) ........................................................................................... 48 
8.1.2 
Adverse reaction / Suspected Adverse Reaction (21CFR Part 312.32) ............. 49 
8.1.3 
Serious Adverse Event (SAE) ............................................................................ 50 
 
Reporting Period and Parameter ................................................................................. 50 
 
Severity of Adverse Events ......................................................................................... 50 
 
Causality of Adverse Event ........................................................................................ 52 
 
Follow-up of Adverse Event ....................................................................................... 52 
 
General Guidance on Recording Adverse Events ....................................................... 53 
 
Reporting of SAEs ...................................................................................................... 53 
 
Protocol Deviations ..................................................................................................... 54 
 
SAFETY OVERSIGHT ............................................................................................... 55 
 
Routine Reviews by Protocol Safety Review Team (PSRT) ...................................... 55 
 
Independent Data Monitoring Committee (IDMC) Reviews ..................................... 55 
 
Study Pause Rules ....................................................................................................... 55 
 
Study Pause Procedure ................................................................................................ 56 
 
DATA HANDLING and RECORDKEEPING ............................................................ 56 
 Definitions................................................................................................................... 56 
10.1.1 Source Data ........................................................................................................ 56 
10.1.2 Source Documents ............................................................................................. 57 
 Data Capture Methods (Case Report Form Development and Completion) .............. 57 
 Data Management ....................................................................................................... 57 
 Retention of Study Records ........................................................................................ 57 
 
STATISTICAL CONSIDERATIONS ......................................................................... 58 
 Overview and General Design .................................................................................... 58 
 Randomization Procedures ......................................................................................... 58 
 Sample Size ................................................................................................................. 58 
 Definitions of Populations to be Analyzed ................................................................. 61 
11.4.1 Enrolled Population ........................................................................................... 61 
11.4.2 Safety Population ............................................................................................... 61 
11.4.3 Full Analysis Population .................................................................................... 61 
11.4.4 Per-Protocol Population ..................................................................................... 61 
11.4.5 Other Populations............................................................................................... 62 
 Analytical Methodology ............................................................................................. 62 
11.5.1 Descriptive Methodology................................................................................... 62 

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11.5.2 Analysis Sequence ............................................................................................. 62 
11.5.3 Changes in Analysis Plan................................................................................... 62 
11.5.4 Baseline and Demographic Characteristics, and Participant Disposition .......... 62 
11.5.5 Safety Analysis .................................................................................................. 63 
11.5.6 Immunogenicity Analysis .................................................................................. 64 
11.5.7 Viral Shedding Analysis .................................................................................... 65 
11.5.8 Genetic Stability Analyses ................................................................................. 66 
11.5.9 Handling of Dropouts and Missing Data ........................................................... 67 
 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 67 
 General Considerations ............................................................................................... 67 
 Study Monitoring ........................................................................................................ 67 
 Independent Auditing.................................................................................................. 68 
 Regulatory Agency Auditing ...................................................................................... 68 
 
ETHICAL CONSIDERATIONS (AND INFORMED CONSENT)............................ 68 
 Ethical Standards ........................................................................................................ 68 
 Ethical Review ............................................................................................................ 68 
 Informed Consent Process .......................................................................................... 68 
 Participant Confidentiality .......................................................................................... 69 
 Reimbursement ........................................................................................................... 69 
 Risk and Benefits ........................................................................................................ 70 
 Reporting to Local Health Department ....................................................................... 71 
 Compensation for Research Related Injury ................................................................ 71 
 
FINANCING AND INSURANCE .............................................................................. 72 
 
PUBLICATION POLICY ............................................................................................ 72 
 
REFERENCES ............................................................................................................. 73 
APPENDICES .......................................................................................................................... 74 
APPENDIX 1:  SCHEDULE OF STUDY VISITS AND EVALUATIONS .......................... 74 
 
LIST OF TABLES 
Table 1: Genetic modifications of Sabin-2 in nOPV2-c1 and their purposes. .............................. 22 
Table 2: Methods and criteria on which nOPV1 was evaluated. .................................................. 24 
Table 3: Methods and criteria on which nOPV3 was evaluated. .................................................. 25 
Table 4: Grading scale to grade the severity of solicited AEs ...................................................... 50 
Table 5: Grading scale to grade the severity of abnormal clinical safety laboratory test results 
reported as AEs ............................................................................................................ 51 
 

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LIST OF FIGURES 
Figure 1: Modifications in nOPV1 and nOPV3 viruses. .............................................................. 23 

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ABBREVIATIONS AND ACRONYMS 
 
Ab 
 
Antibody 
AE 
 
Adverse Event 
ALT 
 
Alanine Transaminase 
AUC 
 
Area Under the Curve 
BSL-2  
Biosafety Level 2 
CBC 
 
Complete Blood Count 
CCID50  
Cell Culture Infectious Dose 50% 
CDC 
 
United States Centers for Disease Control and Prevention 
cDNA  
Complementary Deoxyribonucleic Acid 
CFR 
 
Code of Federal Regulations 
CI 
 
Confidence Interval 
CONSORT  
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CRE 
 
Cis-acting Replication Element 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CSR 
 
Clinical Study Report 
CTA 
 
Clinical Trial Agreement 
cVDPV  
circulating Vaccine-Derived Poliovirus 
DM 
 
Data Management 
DRM  
Data Review Meeting 
eCRF  
Electronic Case Report Form 
EIA 
 
Enzyme Immunoassay 
FAP 
 
Full Analysis Population 
FDA 
 
(United States) Food and Drug Administration 

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FOCP  
Female of Childbearing Potential 
GCP 
 
Good Clinical Practice 
GMFR  
Geometric Mean Fold Rise 
GMT 
 
Geometric Mean Titer 
HBV 
 
Hepatitis B Virus  
HCV  
 
Hepatitis C Virus  
HIV 
 
Human Immunodeficiency Virus  
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Council for Harmonisation 
ICMJE  
International Committee of Medical Journal Editors 
IDMC  
Independent Data Monitoring Committee 
IEC 
 
Independent Ethics Committee 
IgA 
 
Immunoglobulin A 
IgG 
 
Immunoglobulin G 
IND 
 
Investigational New Drug 
IPV 
 
Inactivated Poliovirus Vaccine 
IRB 
 
Institutional Review Board 
 
IWRS  
Interactive Web Response System 
LLN 
 
Lower Limit of Normal 
LLOQ  
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
 
milligram 
mL 
 
milliliter 
mOPV  
monovalent Oral Poliomyelitis Vaccine (Sabin) 
NAb 
 
Neutralizing Antibody 

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NGS 
 
Next Generation Sequencing 
NRA 
 
National Regulatory Authority 
nOPV  
novel Oral Poliomyelitis Vaccine 
nOPV1  
novel Oral Poliomyelitis Vaccine type 1 
nOPV3  
novel Oral Poliomyelitis Vaccine type 3 
OPV 
 
Oral Poliomyelitis Vaccine 
PCR 
 
Polymerase Chain Reaction 
PI 
 
Principal Investigator 
PID 
 
Participant Identification 
PP 
 
Per-protocol 
PSRT  
Protocol Safety Review Team 
PT 
 
Preferred Term 
RNA 
 
Ribonucleic Acid 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard Deviation 
SIE 
 
Shedding Index Endpoint 
SMP   
Study Monitoring Plan 
SOC 
 
System Organ Class 
SOP 
 
Standard Operating Procedure 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
ULN 
 
Upper Limit of Normal 
ULOQ  
Upper Limit of Quantification 
US(A)  
United States (of America) 
UTR 
 
Untranslated Region 
VAPP  
Vaccine-Associated Paralytic Polio 
VDPV  
Vaccine-Derived Poliovirus 

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VS 
 
Vital Signs 
WBC 
 
White Blood Cell 
WHO  
World Health Organization 
WPV 
 
Wild Poliovirus 
 
 

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INVESTIGATOR’S AGREEMENT 
 
 
Protocol Title: A first-in-human, phase 1, randomized, observer-blind, controlled study to 
assess the safety and immunogenicity of novel live attenuated type 1 and type 3 oral 
poliomyelitis vaccines in healthy adults 
 
‘The signature below constitutes approval of this protocol and the attachments and provides 
the required assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and ICH E6 guidelines.’ 
 
_______________________________________________  
 
_______________ 
Signature of Principal Investigator at 
 
 
 
 
 
Date 
 
 
_______________________________________________  
 
_______________ 
Signature of Principal Investigator at 
 
 
 
 
 
Date 
 
 
_______________________________________________  
 
_______________ 
Signature of Principal Investigator at 
 
 
 
 
 
Date 
 
 
_______________________________________________  
 
_______________ 
Signature of Principal Investigator at 
 
 
 
 
 
Date 
 
 
 

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PROTOCOL SUMMARY 
Title 
A first-in-human, phase 1, randomized, observer-blind, controlled study to assess 
the safety and immunogenicity of novel live attenuated type 1 and type 3 oral 
poliomyelitis vaccines in healthy adults 
Short Title 
Phase 1 study of novel types 1 and 3 oral poliomyelitis vaccines 
Protocol 
Number 
CVIA 076 
Trial 
Registration 
ClinicalTrials.gov: NCT04529538 
FDA Reference 
Number 
BB-IND 026305 
Trial Phase 
Phase 1 
Investigational 
Products 
Novel oral poliomyelitis vaccines (nOPVs):   
• 
Novel OPV type 1 (nOPV1), containing 106.5 CCID50/dose, manufactured by Bio 
Farma, Indonesia 
• 
Novel OPV type 3 (nOPV3), containing 106.5 CCID50/dose, manufactured by Bio 
Farma, Indonesia 
Both nOPVs are live, attenuated polioviruses derived from a modified Sabin 
type-2 infectious complementary deoxyribonucleic acid (cDNA) clone and 
propagated in Vero cells. Modifications were introduced in the viral nucleotide 
sequences in part of the 5ʹ-untranslated region (UTR) to improve the genetic 
stability of this major attenuating determinant of Sabin type-2, and two 
modifications were made in the 3D polymerase to further improve stability of 
the attenuation and reduce recombination. In addition, a key replication 
element was relocated from the 2C coding region to the 5ʹ UTR to reduce the 
risk of loss of stabilized 5’ UTR through recombination. The cDNA plasmid was 
then further modified by replacement of the capsid (P1) region of the genome 
with the capsid from a Sabin-1 (nOPV1) or Sabin-3 (nOPV3) clone, generating 
chimeric viruses with novel type 2 non-structural regions coupled with Sabin-
1 or -3 structural proteins.  
In addition to the attenuated poliovirus, the vaccine formulation includes 
sucrose, acetic acid or NaHCO3, and Basal Medium Eagle (BME) solution. 
Active control monovalent oral poliomyelitis vaccines (mOPVs), Sabin:   
• 
Sabin mOPV1 containing not less than 106.0 CCID50/dose, manufactured by 
Bio Farma (Indonesia) 
• 
Sabin mOPV3 containing not less than 105.8 CCID50/dose, manufactured by 
Bio Farma (Indonesia) 
The live types 1 & 3 OPVs contain suspensions of types 1 and 3 attenuated 
poliomyelitis viruses (Sabin strains) prepared in primary monkey kidney cells. 
Each dose (2 drops = 0.1 mL) of the two vaccines contains not less than 106.0 

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infective units of type 1 and 105.8 of type 3, respectively. Sucrose is used as a 
stabilizer. The vaccines may contain trace amounts of not more than 2 mcg 
erythromycin and not more than 10 mcg kanamycin. 
Study 
Hypotheses 
Safety 
• 
The live attenuated, novel oral poliomyelitis vaccine type 1 (nOPV1) is safe 
and well-tolerated in healthy adults 
• 
The live attenuated, novel oral poliomyelitis vaccine type 3 (nOPV3) is safe 
and well-tolerated in healthy adults 
Immunogenicity 
• 
nOPV1 and nOPV3 elicit demonstrable immune responses in healthy 
adults 
Study 
Objectives 
 
 
 
 
 
 
 
Primary Objective:   
 
Safety 
• 
To evaluate the safety and tolerability of nOPV1 and nOPV3 in healthy 
adults 
Secondary Objectives: 
Immunogenicity 
• 
To assess the humoral immune responses (neutralizing antibody titers) 
elicited by nOPV1 and nOPV3, and compare to that of mOPV1 and mOPV3, 
respectively, in healthy adults  
Fecal Shedding of Study Vaccine Viruses 
• 
To assess the duration of fecal shedding (as determined by polymerase 
chain reaction [PCR]) of nOPV1 and nOPV3 after the initial dose and 
compare to that of the homotypic mOPVs 
• 
To assess the rate of fecal shedding (as determined by PCR) of nOPV1 and 
nOPV3 and compare to that of the homotypic mOPVs in participants with 
an exclusive inactivated poliovirus vaccine (IPV) prior vaccination history 
• 
To assess the extent of shedding (as determined by a shedding index 
endpoint [SIE] and the area under the curve [AUC]) of nOPV1 and nOPV3 
and compare to that of the homotypic mOPVs in participants with an 
exclusive IPV prior vaccination history 
Exploratory Objectives: 
• 
To assess the duration of fecal shedding (as determined by PCR) of nOPV1 
and nOPV3 after the second dose and compare to that of the homotypic 
mOPVs 
• 
To assess the rate of fecal shedding (as determined by PCR) of nOPV1 and 
nOPV3 and compare to that of the homotypic mOPVs in participants with 
an OPV-containing prior vaccination history 

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• 
To assess the extent of shedding (as determined by an SIE and the AUC) 
of nOPV1 and nOPV3 and compare to that of the homotypic mOPVs in 
participants with an OPV-containing prior vaccination history 
• 
To assess the potential for neurovirulence of nOPV shed virus as measured 
by a transgenic mouse neurovirulence assay, and compare to that of 
mOPV1 and mOPV3 
• 
To assess genetic stability of nOPV shed virus as determined by next-
generation sequencing (NGS) 
• 
To assess the humoral immune responses elicited by nOPV1 and nOPV3 
against non-vaccine poliovirus types 
Study Endpoints 
 
 
 
Primary Endpoints: 
Safety: 
• 
Frequency of serious adverse events (SAEs) from Day 1 study vaccination 
through the end of the study 
• 
Frequency of solicited adverse events (AEs) for 7 days (day of study 
vaccination and 6 following days) after each dose of study vaccine 
• 
Frequency of unsolicited AEs for 28 days (day of study vaccination and 27 
following days) after each dose of study vaccine [including clinically 
significant aberrant safety monitoring laboratory values on Day 8 reported 
as AEs] 
Secondary Endpoints: 
Immunogenicity: 
• 
Median type-specific anti-polio serum neutralizing antibody titers at 
baseline and post-vaccination 
• 
Type-specific anti-polio serum neutralizing antibody Geometric Mean 
Titer (GMT) at baseline and post-vaccination 
• 
Post-vaccination GMT ratios of type-specific anti-polio serum neutralizing 
antibody, adjusted for baseline immunity  
• 
Post-vaccination frequency of any fold-rise (titer increased from baseline), 
a minimum 2-fold rise, and a minimum 4-fold rise (seroconversion), in 
type-specific anti-polio serum neutralizing antibody responses   
Fecal Shedding of Study Vaccine Viruses  
• 
Time to cessation of fecal shedding (days) of the vaccine virus, following 
initial dose 
• 
Proportion of participants shedding type-specific vaccine virus at each 
post-vaccination stool collection, as assessed by PCR in participants with 
an exclusive IPV prior vaccination history 
• 
Amount of vaccine virus in each stool sample (log10 CCID50 per gram) 
positive for virus (PCR) in participants with an exclusive IPV prior 
vaccination history 

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• 
Shedding Index of vaccine virus shedding in stool, defined as the mean of 
log10 CCID50 per gram of stool at 7, 14, 21 and 28 days following each dose 
in participants with an exclusive IPV prior vaccination history 
• 
 AUC of vaccine virus shed in stool in participants with an exclusive IPV 
prior vaccination history 
Exploratory Endpoints 
• 
Time to cessation of fecal shedding (days) of the vaccine virus, following 
second dose 
• 
Proportion of participants shedding type-specific vaccine virus at each 
post-vaccination stool collection, as assessed by PCR in participants with 
an OPV-containing prior vaccination history 
• 
Amount of vaccine virus in each stool sample (log10 CCID50 per gram) 
positive for virus (PCR) in participants with an OPV-containing prior 
vaccination history 
• 
Shedding Index of vaccine virus shedding in stool, defined as the mean of 
log10 CCID50 per gram of stool at 7, 14, 21 and 28 days following each 
dose in participants with an OPV-containing prior vaccination history 
• 
AUC of vaccine virus shed in stool in participants with an OPV-containing 
prior vaccination history 
• 
Neurovirulence of shed vaccine virus from select stool samples as 
measured by a transgenic mouse neurovirulence test 
• 
Deep sequencing of shed vaccine virus from select stool samples using 
NGS 
• 
Serum neutralizing antibody titers against non-vaccine poliovirus types at 
baseline and post-vaccination  

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Study Design 
This multicenter trial is the first-in-human assessment of these novel oral 
poliomyelitis vaccines. It will be an 8-arm, randomized, observer-blind, controlled 
trial, with Sabin monovalent vaccines serving as the control for each type (see 
study schema, below). 150 to 230 healthy, adult participants will be recruited. 30 
to 40 of 60 to 80 participants with an exclusive IPV prior vaccination history 
(cohort 1) will be randomized in a 1:1 ratio to study groups 1 and 2 and allocated 
to receive nOPV1 or mOPV1, and once these study arms are completely accrued, 
the other 30 to 40 exclusively-IPV vaccinated participants (cohort 3) will be 
randomized in a 1:1 ratio to study groups 5 and 6 and allocated to receive nOPV3 
or mOPV3. 
In parallel, 45 to 75 of 90 to 150 participants with an OPV-containing prior 
vaccination history (cohort 2) will be randomized in a 2:1 ratio to study groups 3 
and 4 and allocated to receive two doses of nOPV1 or mOPV1, respectively, and 
once these study arms are completely accrued, the other 45 to 75 participants 
with an OPV-containing prior vaccination history (cohort 4) will be randomized in 
a 2:1 ratio to study groups 7 and 8 and allocated to receive two doses of nOPV3 
or mOPV3, respectively. 
Study Schema 
Cohort 
Group 
Prior 
Vaccination 
Number of 
Participants 
(Min-Max) 
Dosage 
CCID50 
 
Day 1 
Day 29 
 
 
 
 
 
 
 
 
1 
1 
IPV 
15-20 
106.5 
 
nOPV1 
- 
2 
15-20 
≥106 
 mOPV1 
- 
Subtotal 
 
 
30-40 
 
 
 
 
2 
3 
OPV 
30-50 
106.5 
 
nOPV1 
nOPV1 
4 
15-25 
≥106 
 mOPV1 mOPV1 
Subtotal 
 
 
45-75 
 
 
 
 
3 
5 
IPV 
15-20 
106.5 
 
nOPV3 
- 
6 
15-20 
≥105 8 
 mOPV3 
- 
Subtotal 
 
 
30-40 
 
 
 
 
4 
7 
OPV 
30-50 
106.5 
 
nOPV3 
nOPV3 
8 
15-25 
≥105 8 
 mOPV3 mOPV3 
Subtotal 
 
 
45-75 
 
 
 
 
Total 
 
 
150-230 
 
 
 
 
 
Participants assigned to two doses of vaccine will receive the second dose 28 days 
following the first dose. Initial vaccination for Cohorts 1 and 2 participants will be 
limited to no more than 5 participants per day and a total of 10 participants during 
the first week of vaccination. Participants will be followed until 24 weeks after 
their Day 1 study vaccination. 
Study 
population 
Healthy adults, 18-45 years of age (inclusive) 

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Participating 
sites 
  
 
 
 
 
 
 
Study Duration 
Study participation will last about 7 months, allowing for 24 weeks of follow-up 
after the receipt of the initial study vaccination. 
 
 
 

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 BACKGROUND AND RATIONALE 
Global efforts to immunize children with Sabin strain oral poliomyelitis vaccines (OPVs) have reduced wild 
poliovirus cases by 99.9% since 1988 [1]. These vaccines have been demonstrated to be safe and interrupt 
person-to-person spread of polioviruses. However, on extremely rare occasions, use of OPV can result in 
cases of polio due to vaccine-associated paralytic polio (VAPP) and circulating vaccine-derived poliovirus 
(cVDPV). Central to both VAPP and disease induced by cVDPVs is reversion of the vaccine strain to a more 
neurovirulent phenotype, which occurs during intestinal replication in vaccine recipients. These reverted 
viruses can either cause disease in the vaccine recipient or be transmitted to contacts or community 
members. In addition, the ability of cVDPVs to survive in the environment and be transmitted to others 
without being detected through acute flaccid paralysis surveillance, given most infections are 
asymptomatic, is a major risk to the entire polio eradication effort. The risk of VAPP and cVDPV, in 
particular, resulted in the decision to globally discontinue routine use of Sabin type 2 OPV (OPV2) in April 
2016 and the planned withdrawal of Sabin types 1 and 3 OPV (OPV1 and OPV3, respectively) in the coming 
decade. The intent of the novel OPV program is to develop more genetically stable versions of type 1 and 
type 3 oral poliomyelitis vaccines to reduce the risk of VAPP and cVDPV from vaccine administered to 
combat outbreaks by types 1 and 3 polioviruses.  
Genetically modified candidate viruses for both polioviruses type 1 and type 3 have been developed that 
retain similar immunogenicity and antigenicity to the parental Sabin OPV strains in animal models, while 
demonstrating significantly less potential to revert during cell culture passaging. These viruses also appear 
to have a reduced neurovirulence in a transgenic mouse disease model. The proposed indication and 
usage is for prevention of type 1 or type 3 poliovirus disease and transmission during outbreaks of either 
wild-type poliovirus or cVDPV.  
The proposed study is the first-in-human evaluation of novel OPVs types 1 and 3 (nOPV1 and nOPV3, 
respectively) in healthy males and females, from 18 to 45 years of age (inclusive) at the time of enrollment. 
Should results in adults indicate the nOPVs are safe and have demonstrable immunogenicity, they will 
progress to phase 2 testing in target pediatric populations (young children and then infants).  
A similar novel, genetically stable OPV type 2 (nOPV2) strain has advanced into phase 2 clinical 
development (adults in Belgium and young children and infants in Panama) with encouraging study 
results. Since nOPV1 and nOPV3 are chimeric viruses with novel type 2 non-structural regions coupled 
with Sabin-1 or -3 structural proteins, the clinical experience to date with nOPV2 is relevant.  
 
Burden of Disease  
Polio is an infectious disease caused by polioviruses that are transmitted by person-to-person spread, 
mainly through the fecal-oral route or, less frequently, by a common vehicle, such as contaminated water 
or food. Three poliovirus types 1, 2, and 3 exist and infection with each confers type-specific life-long 
immunity to disease but little or no immunity to disease caused by heterologous types. Over 90% of 
poliovirus infections are asymptomatic. Symptomatic disease is more often an acute self-limited non-
neurologic febrile illness with non-specific symptoms, such as headache, sore throat, fatigue, and 
gastrointestinal symptoms. Less often, disease may manifest with myalgias, meningitis, and other 
neurologic findings, with overt paralysis occurring in less than 1% of all infections. A major complication 
of paralytic poliomyelitis is respiratory failure. There are no licensed antiviral drugs available to treat 
poliomyelitis and treatment is supportive. 
Since the introduction of IPVs and OPVs in the 1950s and the launching of the Global Polio Eradication 
Initiative campaign in 1988, transmission of wild poliovirus (WPV) has been interrupted in most 

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populations. Globally, type 2 WPV was declared eradicated in 2015, type 3 WPV declared eradicated in 
2019, with current transmission of WPV limited to type 1 and confined to a few regions within only three 
endemic countries, Nigeria, Pakistan, and Afghanistan. For the year 2019, there were 176 type 1 WPV 
cases reported, all from two of the three endemic countries, Pakistan, and Afghanistan, while there were 
365 cVDPV cases (mostly type 2) reported, 324 of these cases from non-endemic countries 
[http://polioeradication.org]. Until all WPV transmission is interrupted globally and eradicated, all 
countries remain at risk of importation of polio from endemic countries, especially vulnerable countries 
with weak public health and immunization services and travel or trade links to endemic countries. The 
WHO estimates that failure to eradicate polio from these last remaining regions could result in as many 
as 200,000 new cases every year, within 10 years, all over the world. 
As long as OPV remains the vaccine used globally to achieve eradication, there remains the risk of vaccine-
derived poliovirus (VDPV) emergence and spread, which is why eradication of WPV is to be followed with 
cessation of OPV use in routine immunization, as was done for OPV2 in 2016, with the switch from 
trivalent OPV to bivalent OPV 1,3. In 2019, three years following the end of immunization with nOPV2, 
there has been a notable increase in the number of cVDPV type 2 cases compared to prior years, reflecting 
the increased susceptibility to type 2 infection in at risk regions. From 2000 to 2019, 1085 cases of paralytic 
cVDPV have been reported, 932 (86%) of which were type 2, notwithstanding that it is estimated that 
during the same period, over 10 million cases of paralytic polio were averted [2]. With the eradication of 
type 3 and expected eventual eradication of type 1 WPV, it is anticipated that the concern over cVDPV 
shall remain. It is hoped that if the nOPVs prove to be safe and effective in the planned and ongoing 
studies, future cVDPV outbreaks and associated paralytic cases in communities with low immunity could 
be addressed with these novel vaccines. 
 
Pathogen  
Polioviruses are small, non-enveloped viruses with a single positive strand ribonucleic acid (RNA) genome 
of approximately 7,400 nucleotides. The genome contains a relatively long non-coding region in the 5’ 
end, referred to as 5’ untranslated region (5’ UTR), which is highly structured and contains the internal 
ribosome entry site that is required for translation. The genome is translated as a single polyprotein, which 
is cleaved during translation by genome-encoded proteases into three regions referred to as P1, P2, and 
P3. The P1 region is further processed into viral structural (capsid) proteins, while P2 and P3 encode the 
non-structural proteins that are involved in protein processing and viral replication. There are three 
serotypes, defined by their capsid (P1) regions, with limited cross-neutralization across the three. 
 
Description of Study Vaccine  
The Sabin OPV strains have been studied intensively for decades and, because of the knowledge and 
experience gained, several approaches to the design of improved OPV strains have been investigated. In 
2011, a consortium of researchers was formed to develop improved strains, with the belief that a 
collaborative effort using a combination of strategies would have the greatest chance of success. Novel 
OPV (nOPV) strains were designed, produced, and tested in a variety of non-clinical studies. Two type 2 
strains have advanced into clinical development with encouraging phase 1 and 2 study results. 
The approach to the design of nOPV strains addressed five critical inter-related properties: cell-culture 
growth, attenuation, genetic stability (encompassing reversion through mutation and recombination), 
antigenicity, and immunogenicity. The designs involved innovative strategies and their success was 
assessed by rigorous testing carried out in parallel for all strains to facilitate the choice of suitable 
candidates.  

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With the overall goal of seeking novel OPV1 and OPV3 (nOPV1, nOPV3) vaccines which have less chance 
of reversion to a neurovirulent phenotype and comparable immunogenicity to the current Sabin vaccines, 
one candidate for each type has been selected for clinical development thus far. 
The candidate OPV1 and OPV3 strains include 4 distinct modifications of the Sabin-2 genome, including 
changes to the RNA sequence in the 5’ UTR, the non-structural protein 2C, and the polymerase 3D (Table 
1 and Figure 1) [3]. Of these modifications, only the changes to polymerase 3D result in a change in the 
amino acid sequence. The modifications aim to stabilize the genetic sequence against reversion in the 5’ 
UTR and to reduce recombination. The vaccine virus initially containing these modifications—a novel oral 
poliomyelitis vaccine type 2 candidate 1 (nOPV2-c1) has been advanced into clinical development. The 
cDNA plasmid used to derive nOPV2-c1 was then further modified by replacement of the capsid (P1) 
region of the genome with the capsid from a Sabin-1 (nOPV1) or Sabin-3 (nOPV3) clone, generating 
chimeric viruses with novel type 2 non-structural regions coupled with Sabin-1 or -3 structural proteins. 
The nOPV study vaccines are named nOPV1 candidate 1 and nOPV3 candidate 1 (abbreviated nOPV1-c1 
and nOPV3-c1, respectively). The use of the designation ‘candidate 1’ is due to the potential subsequent 
development of additional candidate type-specific vaccines. For purposes of simplification, in this protocol 
these study vaccines will be referred to as nOPV1 and nOPV3, respectively.  
  
Table 1: Genetic modifications of Sabin-2 in nOPV2-c1 and their purposes. 
Modification 
Purpose 
S15 dom V 
-Improved stability of attenuated phenotype. 
Specifically, improve genetic stability of the domain V 
attenuating mutation to avoid reversion by single 
nucleotide changes. 
-Lack of reversion may reduce shedding and 
transmission risk. 
Cre relocation 
 
-Reduce frequency of recombination events. 
Specifically, a single recombination event replacing 
dom V will also remove cre, making virus non-viable 
and non-infectious. 
Polymerase  
(higher fidelity) 
-Improved stability of attenuated phenotype. 
Specifically, improve fidelity of replication leading to 
less genetic drift and reversion.  
-Additional attenuation. 
Polymerase (rec) 
-Reduce frequency of recombination events, thereby 
reducing ability of population to improve replication 
fitness.  
-Additional attenuation. 

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sacrificed, bled, and sera frozen. Neutralizing antibody titers in sera were determined by standard 
methods using 100 TCID50 units of corresponding Sabin strain as the challenge virus.  
In this model, mice receiving placebo consistently have titers of less than 4. For nOPV1 and the Sabin-1 
control, consistent positive responses were seen across the dosage range, with similar titers for the two 
at the higher dosages. For type 3, nOPV3 and the Sabin-3 control responses were similar across the full 
dosage range. 
As noted above, in this model seroconversion is dependent on replication; inactivated preparations are 
not immunogenic. Hence the immunogenicity, and by implication, infectivity of these two nOPVs was 
confirmed to be similar to the Sabin controls. It is not suggested that this model reflects the environment 
of the human gut; however, the assay provides evidence that the candidates are phenotypically similar to 
Sabin-2 in a model that depends on replication and antigen presentation in vivo. These data, when coupled 
with the encouraging immunogenicity of the parental nOPV2 strain in humans, provides confidence that 
these nOPV strains are likely to be immunogenic in humans. 
1.4.4 
Attenuation phenotypes 
The non-clinical data suggest that these nOPVs have an improved risk profile as compared to the Sabin 
OPV strains. Regarding risk reduction, the following observations on the nOPV virus seeds supporting this 
position were made: 
• 
Both nOPV1 and nOPV3 passed the WHO monkey neurovirulence test, with lower lesion scores 
than the reference controls and no paralysis of any monkeys. 
• 
In a transgenic mouse neurovirulence model, no dose of either nOPV could be established that 
resulted in paralysis of any mice.  
• 
The temperature-sensitive phenotype, a marker for attenuation, was retained for both nOPVs. 
• 
Upon passaging in cell culture under conditions known to lead to reversion, both deep sequencing 
and mouse neurovirulence testing confirmed that the nOPVs did not revert to any meaningful 
extent, while the Sabin strains showed clear reversion by both methods. 
Incremental benefits of the polymerase modifications and cre relocation on genetic stability also were 
demonstrated using targeted experiments. 
In total, these results suggest that the potential risks associated with OPV use (VAPP and cVDPV 
circulation) should be lower for nOPV1 and nOPV3 than for the Sabin comparators. This conclusion is 
further supported by results from phase 1 and 2 clinical studies of the parental nOPV2 strain (from which 
these nOPVs are derived) which demonstrated an absence of reversion of domain V and limited increases 
in virulence for shed virus [9]. 
 
Summary of Clinical Studies of Study Vaccine  
Although nOPV1 and nOPV3 have not previously been tested in humans, two candidates of novel OPV2 
(nOPV2-c1 and nOPV-c2) have been tested in three clinical trials: phase 1 and 2 trials in adults in Belgium 
and a phase 2 trial in young children and infants in Panama. As described earlier, the construct of one of 
these vaccine candidates, nOPV2-c1, is very similar to nOPV1 and nOPV3, with the only difference being 
the type-specific capsid. For both phase 2 studies, safety, immunogenicity, shedding and genetic stability 
data were compared to data from studies performed 2 to 3 years prior with mOPV2 and designed to 
provide data for the comparison (historical control studies). Data for genetic stability in the pediatric study 
have not yet been finalized, but interim data are available from the young children in that study. A 

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summary of the three study descriptions followed by the data for nOPV2-c1, which is also the candidate 
moving forward into phase 3 testing, is presented below, and more detailed results can be found in the 
IB.  
Phase 1, First-in-Human Study in Adults in Belgium 
A phase 1, first-in-human study was performed under containment at the University of Antwerp [9]. Two 
cohorts of 15 adult participants each were enrolled sequentially, with all participants in each cohort 
receiving the same vaccine candidate (at a 106 CCID50 dosage) to avoid cross-contamination between the 
two candidates (nOPV2-c1 and nOPV2-c2). All participants had previously received at least 3 doses of IPV, 
and none had a history of receiving OPV (per eligibility criteria). The assignment of product to the cohorts 
was performed randomly, and neither study staff nor participants were aware of which product was 
administered to which cohort. Containment of each cohort lasted until the last participants in each had 
been in containment for 28 days following administration of study product. 
Phase 2 Study in Adults in Belgium 
The study was performed at two sites in Belgium (Antwerp and Ghent). The study population of healthy 
adults included 200 participants who had previously received OPV (100 receiving nOPV2-c1 and 100 
receiving nOPV2-c2, half of whom received a single dose (106 CCID50) and the other half two doses) and 
another 50 who had previously received only IPV (17 receiving nOPV-c1, 16 receiving nOPV2-c2 and 17 
receiving placebo). Participants were sequentially enrolled, with completion of enrollment of those to 
receive nOPV2-c2 (IPV and OPV groups simultaneously) before initiation of enrollment of those to receive 
nOPV2-c1 (IPV and OPV groups simultaneously). IPV-only vaccinated participants were randomized 2:1 to 
receive one of the two vaccine candidates or placebo. Data from participants who had previously received 
OPV were compared to those of a previous study, also in Belgium and similarly designed, in which 
previously OPV-vaccinated healthy adults were vaccinated with mOPV2. 
Phase 2 Study in Young Children and Infants in Panama 
This was a single-center, multi-site, age de-escalation, partly-randomized study performed in Panama. 
Two different cohorts of participants were recruited: healthy young children enrolled and vaccinated at 1 
to 5 years of age and healthy infants enrolled at 6 weeks of age and vaccinated at 18-22 weeks of age. 
Infants were recruited at 6 weeks of age to assure vaccination with 3 doses of bOPV and 1 dose of IPV 
prior to vaccination with nOPV2 at 18-22 weeks of age.  
The study was performed in two consecutive stages, Stage I and Stage II. In Stage I, young children and 
infants were vaccinated with nOPV2-c2 manufactured in 2016. In Stage II, young children and infants were 
vaccinated with nOPV2-c1 and nOPV2-c2 manufactured in 2018. The difference between nOPV2-c2 
manufactured in 2016 and 2018 was the working virus seed used for each. Children received 106 
CCID50/dose (high dose), and infants received either 105 CCID50/dose (low dose) or 106 CCID50/dose (high 
dose). All 1-5 year old children were to receive two doses of vaccine, and a subset of 50 infants from each 
of the six groups were to receive two doses (the balance to receive a single dose). In Stage II, 49 1-5 year 
old children were vaccinated with the high dose, 138 infants were vaccinated with the low dose, and 150 
infants were vaccinated with the high dose of nOPV2-c1. 
1.5.1 
Safety 
The candidate vaccine, nOPV2-c1, was generally well-tolerated in all three studies. Safety data were 
reassuring, with overall safety profiles similar to those of applicable control groups for the phase 2 studies 

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(adults in Belgium, and 1-5 year old children and 12-22 week old infants in Panama). No SAE was assessed 
as causally related to vaccine. Most solicited and unsolicited adverse events (AEs) were mild or moderate, 
and they were infrequently severe. No unsolicited severe AEs were assessed as related to vaccination in 
young children and infants, and no AEs resulted in termination from subsequent dosing (in those 
scheduled to receive two doses) or in withdrawal from the study. 
1.5.2 
Immunogenicity 
In all three studies, nOPV2-c1 was immunogenic, and the immune responses were non-inferior to those 
following vaccination with mOPV2 in the historical control studies. 
1.5.3 
Viral Shedding 
Results of stool testing for virus shedding generally indicate that nOPV2-c1 is not shed in a substantially 
greater rate or quantity as compared to mOPV2, and the rate of viral shedding is lower at four weeks 
following vaccination in a key demographic subgroup (bOPV/IPV-vaccinated infants). 
1.5.4 
Genetic Stability 
Genetic stability assessment of shed virus from the adult participants in the phase 1 and 2 studies in 
Belgium were consistent with improved genetic and phenotypic stability of the nOPV2 candidates. Interim 
results from 1-5 year old children in the phase 2 study in Panama are consistent with data from adults and 
show improved genetic and phenotypic stability of nOPV2-c1; data from infants are pending. 
 
Overall Development Strategy  
The objectives of the nOPV1,3 program are (1) to achieve licensure and World Health Organization (WHO) 
prequalification of novel OPV1 and OPV3 monovalent vaccines (nOPV1 and nOPV3) with an indication for 
active immunization against disease caused by poliomyelitis virus type 1 or 3, respectively; (2) to provide 
sufficient evidence to support a policy decision to stockpile these monovalent vaccines in lieu of the 
current Sabin vaccines, and (3) to potentially make nOPV1 and/or nOPV3 available pre-licensure during 
outbreaks, provided the early data demonstrate appropriate safety and immunogenicity. If use of bivalent 
OPV (bOPV, which includes the Sabin type 1 and type 3 strains) continues for longer than anticipated, 
nOPV1 and nOPV3 could also be considered for routine use. 
 HYPOTHESIS, OBJECTIVES AND ENDPOINTS 
 
Study Hypotheses 
Safety 
• 
The live attenuated, novel oral poliomyelitis vaccine type 1 (nOPV1) is safe and well-tolerated in 
healthy adults 
• 
The live attenuated, novel oral poliomyelitis vaccine type 3 (nOPV3) is safe and well-tolerated in 
healthy adults 
Immunogenicity 
• 
nOPV1 and nOPV3 elicit demonstrable immune responses in healthy adults 

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Study Objectives 
2.2.1 
Primary Objective:   
 
Safety    
To evaluate the safety and tolerability of nOPV1 and nOPV3 in healthy adults 
2.2.2 
Secondary Objectives: 
Immunogenicity 
To assess the humoral immune responses (neutralizing antibody titers) elicited by nOPV1 and nOPV3, and 
compare to that of mOPV1 and mOPV3, respectively, in healthy adults  
Fecal Shedding of Study Vaccine Viruses 
• 
To assess the duration of fecal shedding (as determined by PCR) of nOPV1 and nOPV3 after the 
initial dose and compare to that of the homotypic mOPVs 
• 
To assess the rate of fecal shedding (as determined by PCR) of nOPV1 and nOPV3 and compare to 
that of the homotypic mOPVs in participants with an exclusive IPV prior vaccination history 
• 
To assess the extent of shedding (as determined by an SIE and the AUC) of nOPV1 and nOPV3 and 
compare to that of the homotypic mOPVs in participants with an exclusive IPV prior vaccination 
history 
2.2.3 
Exploratory Objectives: 
• 
To assess the duration of fecal shedding (as determined by PCR) of nOPV1 and nOPV3 after the 
second dose and compare to that of the homotypic mOPVs 
• 
To assess the rate of fecal shedding (as determined by PCR) of nOPV1 and nOPV3 and compare to 
that of the homotypic mOPVs in participants with an OPV-containing prior vaccination history 
• 
To assess the extent of shedding (as determined by an SIE and the AUC) of nOPV1 and nOPV3 and 
compare to that of the homotypic mOPVs in participants with an OPV-containing prior vaccination 
history 
• 
To assess the potential for neurovirulence of nOPV shed virus as measured by a transgenic mouse 
neurovirulence assay, and compare to that of mOPV1 and mOPV3 
• 
To assess genetic stability of nOPV shed vaccine virus as determined by NGS 
• 
To assess the humoral immune responses elicited by nOPV1 and nOPV3 against non-vaccine 
poliovirus types 
 
Study Endpoints 
2.3.1 
Primary Endpoints:  
 
Safety 
• 
Frequency of serious adverse events (SAEs) from Day 1 study vaccination through the end of the 
study 

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• 
Frequency of solicited adverse events (AEs) for 7 days (day of study vaccination and 6 following 
days) after each dose of study vaccine 
• 
Frequency of unsolicited AEs for 28 days (day of study vaccination and 27 following days) after 
each dose of study vaccine [including clinically significant aberrant safety monitoring laboratory 
values on Day 8 reported as AEs] 
2.3.2 
Secondary Endpoints: 
Immunogenicity 
• 
Median type-specific anti-polio serum neutralizing antibody titers at baseline and post-
vaccination 
• 
Type-specific anti-polio serum neutralizing antibody Geometric Mean Titer (GMT) at baseline and 
post-vaccination 
• 
Post-vaccination GMT ratios of type-specific anti-polio serum neutralizing antibody, adjusted for 
baseline immunity  
• 
Post-vaccination frequency of any fold-rise (titer increased from baseline), a minimum 2-fold rise, 
and a minimum 4-fold rise (seroconversion), in type-specific anti-polio serum neutralizing 
antibody response 
Fecal Shedding of Study Vaccine Viruses  
• 
Time to cessation of fecal shedding (days) of the vaccine virus, following initial dose 
• 
Proportion of participants shedding type-specific vaccine virus at each post-vaccination stool 
collection, as assessed by PCR in participants with an exclusive IPV prior vaccination history 
• 
Amount of vaccine virus in each stool sample (log10 CCID50 per gram) positive for virus (PCR) in 
participants with an exclusive IPV prior vaccination history 
• 
Shedding Index of vaccine virus shedding in stool, defined as the mean of log10 CCID50 per gram of 
stool at 7, 14, 21 and 28 days following each dose in participants with an exclusive IPV prior 
vaccination history 
• 
AUC of vaccine virus shed in stool in participants with an exclusive IPV prior vaccination history 
2.3.3 
Exploratory Endpoints: 
• 
Time to cessation of fecal shedding (days) of the vaccine virus, following second dose 
• 
Proportion of participants shedding type-specific vaccine virus at each post-vaccination stool 
collection, as assessed by PCR in participants with an OPV-containing prior vaccination history 
• 
Amount of vaccine virus in each stool sample (log10 CCID50 per gram) positive for virus (PCR) in 
participants with an OPV-containing prior vaccination history 
• 
Shedding Index of vaccine virus shedding in stool, defined as the mean of log10 CCID50 per gram of 
stool at 7, 14, 21 and 28 days following each dose in participants with an OPV-containing prior 
vaccination history 
• 
AUC of vaccine virus shed in stool in participants with an OPV-containing prior vaccination history 

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• 
Neurovirulence of shed vaccine virus from select stool samples as measured by a transgenic 
mouse neurovirulence test 
• 
Deep sequencing of shed vaccine virus from select stool samples, using NGS 
• 
Serum neutralizing antibody titers against non-vaccine poliovirus types at baseline and post-
vaccination 
 STUDY DESIGN 
This multicenter trial is the first-in-human assessment of these novel oral poliomyelitis vaccines. It will be 
an 8-arm, randomized, observer-blind, controlled trial, with Sabin monovalent vaccines serving as the 
control for each type (see study schema, below). 150 to 230 healthy, adult participants will be recruited. 
30 to 40 of 60 to 80 participants with an exclusive IPV prior vaccination history (cohort 1) will be 
randomized in a 1:1 ratio to study groups 1 and 2 and allocated to receive nOPV1 or mOPV1, and once 
these study arms are completely accrued, the other 30 to 40 exclusively-IPV vaccinated participants 
(cohort 3) will be randomized in a 1:1 ratio to study groups 5 and 6 and allocated to receive nOPV3 or 
mOPV3. 
In parallel, 45 to 75 of 150 participants with an OPV-containing prior vaccination history (cohort 2) will be 
randomized in a 2:1 ratio to study groups 3 and 4 and allocated to receive two doses of nOPV1 or mOPV1, 
respectively, and once these study arms are completely accrued, the other 45 to 75 participants with an 
OPV-containing prior vaccination history (cohort 4) will be randomized in a 2:1 ratio to study groups 7 and 
8 and allocated to receive two doses of nOPV3 or mOPV3, respectively. 
Participants assigned to two doses of vaccine will receive the second dose 28 days following the first dose. 
Initial vaccination for Cohorts 1 and 2 participants will be limited to no more than 5 participants per day 
and a total of 10 participants during the first week of vaccination. Participants will be followed until 24 
weeks after their Day 1 study vaccination. 
Study Schema 
Cohort 
Group 
Prior 
Vaccination 
Number of 
Participants 
(Min-Max) 
Dosage 
CCID50 
 
Day 1 
Day 29 
 
 
 
 
 
 
 
 
1 
1 
IPV 
15-20 
106 5 
 
nOPV1 
- 
2 
15-20 
≥106 
 
mOPV1 
- 
Subtotal 
 
 
30-40 
 
 
 
 
2 
3 
OPV 
30-50 
106 5 
 
nOPV1 
nOPV1 
4 
15-25 
≥106 
 
mOPV1 
mOPV1 
Subtotal 
 
 
45-75 
 
 
 
 
3 
5 
IPV 
15-20 
106 5 
 
nOPV3 
- 
6 
15-20 
≥105.8 
 
mOPV3 
- 
Subtotal 
 
 
30-40 
 
 
 
 
4 
7 
OPV 
30-50 
106 5 
 
nOPV3 
nOPV3 
8 
15-25 
≥105.8 
 
mOPV3 
mOPV3 
Subtotal 
 
 
45-75 
 
 
 
 
Total 
 
 
150-230 
 
 
 
 
 

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 STUDY POPULATION 
 
Description of Study Population 
The study population will include a total of 150 to 230 healthy adults, between the ages of 18 and 45 
years, inclusive. Following informed consent, potentially eligible participants will continue to be screened 
until 150 to 230 adults have been found to be eligible, randomized and vaccinated. Participants withdrawn 
for any reason before vaccination will be replaced, participants withdrawn for any reason after vaccination 
will not be replaced. Enrollment into the study will be competitive in that clinical sites will enroll as many 
subjects as they can, until the overall study enrollment goal is achieved; the total number of trial 
participants enrolled study-wide does not change. 
To be eligible for randomization and vaccination, participants must meet all the inclusion criteria and none 
of the exclusion criteria for the study. The investigator should always use good clinical judgement in 
considering a participant’s overall eligibility based on the inclusion and exclusion criteria. 
 
Inclusion Criteria 
 
1. Males or females, from 18 to 45 years of age (inclusive) at the time of enrollment 
2. Healthy, as defined by the absence of any clinically significant medical conditions, either acute or 
chronic, as determined by medical history, physical examination, screening laboratory test results, 
and clinical assessment of the investigator 
3. Willing and able to provide written informed consent prior to performance of any study-specific 
procedure 
4. If female and of childbearing potential*, be not breastfeeding and not pregnant (based on a 
negative serum pregnancy test at screening and a negative urine pregnancy test during the 24 
hours prior to any study vaccination), agreeing to have repeated pregnancy tests prior to any 
study vaccination, and having practiced adequate contraception** for 30 days prior to first study 
vaccination and willing to continue using adequate contraception consistently for at least 90 days 
after the last study vaccination and until cessation of vaccine virus shedding is confirmed 
* Females can be considered not of childbearing potential if they are with current bilateral tubal 
ligation, occlusion or removal, or post-total hysterectomy, or post-bilateral ovariectomy 
** Adequate contraception is defined as a contraceptive method with failure rate of less than 
1% per year when used consistently and correctly and when applicable, in accordance with the 
product label, for example: 
• 
Abstinence from penile-vaginal intercourse 
• 
Combined estrogen and progesterone oral contraceptives 
• 
Hormonal (e.g., progestogen) injections 
• 
Hormonal (e.g., etonogestrel or levonorgestrel) implants 
• 
Contraceptive vaginal ring 
• 
Percutaneous contraceptive patches 
• 
Intrauterine device  
• 
Intrauterine hormonal system 
• 
Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository), and/or progesterone alone oral contraceptive 
• 
Monogamous relationship with vasectomized (≥ 180 days prior to enrollment) partner 

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5. Resides in study area and is able and willing to adhere to all study restrictions and to all study 
visits and procedures (as evidenced by a signed informed consent form [ICF] and assessment by 
the investigator) 
6. Agrees not to and has no plans to travel outside the United States (US) until confirmation of 
cessation of vaccine virus shedding in stool at or after the study Day 57 stool collection 
7. Able and willing to be contacted by telephone or text, and willing for study staff to leave telephone 
voice or electronic messages as needed 
8. Neutralizing antibody titer ≥ 1:8 for poliovirus type 1 (for participants in cohorts 1 and 2) and ≥ 
1:8 for poliovirus type 3 (for participants in cohorts 3 and 4) 
9. For Cohorts 1 and 3 only: previously received at least 3 doses of IPV and with no history of receipt 
of OPV. For Cohorts 2 and 4 only: previously received a primary polio immunization series 
containing OPV 
 
Exclusion Criteria 
1. Have any condition (medical, psychiatric or behavioral) that, in the opinion of the investigator, 
would increase the participant’s health risks in study participation or would increase the risk of 
not achieving the study’s objectives (e.g., would compromise adherence to protocol requirements 
or interfere with planned safety and immunogenicity assessments) 
2. Receipt of polio vaccine within 12 months before the start of the study 
3. Having Crohn’s disease or ulcerative colitis or having had major surgery of the gastrointestinal 
tract involving significant loss or resection of the bowel 
4. A known allergy, hypersensitivity, or intolerance to any components of the study vaccines, 
including all macrolide and aminoglycoside antibiotics (e.g., erythromycin and kanamycin) 
5. Any confirmed or suspected immunosuppressive or immunodeficiency condition (human 
immunodeficiency virus [HIV] infection, or total serum immunoglobulin A (IgA) or immunoglobulin 
G (IgG) level below the testing laboratory’s lower limit of normal [LLN]) 
6. Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the 
chronic administration (i.e., longer than 14 days) of immunosuppressant drugs (e.g., oral or 
systemic steroids) or other immune-modifying drugs within 6 months prior to the first vaccine 
dose or planned use during the study (inhaled and topical steroids are allowed whereas intra-
articular and epidural injection/administration of steroids are not allowed) 
7. Will have household direct or close professional contact during the study with individuals 
expected to be immunosuppressed (due to underlying condition or treatments) or individuals 
who have not yet completed their primary infant polio immunization series (i.e., three doses)  
8. Will have household direct or close professional contact during the study with pregnant women 
9. Will have household direct or close professional (e.g., neonatal nurses) contact during the study 
with children less than 2 years of age or with individuals who are encopretic (i.e., infants/toddlers 
who are not yet toilet trained or other individuals, including adults, with fecal incontinence)   
10. Will have professional handling of food, catering, or food production activities during the study 
11. Reside in homes with septic tanks 
12. Acute illness or fever (body temperature measured orally ≥ 38°C or 100.4°F) at the time of study 
vaccine administration (once acute illness/fever is resolved, if appropriate, as per investigator 
assessment, participant may complete screening) 
13. Indications of drug abuse or excessive use of alcohol as deemed by the investigator to confound 
safety assessments or render the participant unable or unlikely to adhere to protocol 
requirements or provide accurate safety reports  

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14. Participation in another investigational product (drug or vaccine) clinical trial within 30 days prior 
to entry in this study or receipt of any such investigational product other than the study vaccine 
within 30 days prior to the first administration of study vaccine, or planned use during the study 
period 
15. Administration of any vaccine or any intramuscular injection (except seasonal inactivated 
influenza and COVID-19 vaccines which are prohibited for only 14 days prior to or following each 
study vaccination) other than the study vaccine within 30 days prior to the first dose of study 
vaccine or planned administration within 30 days prior to or after any study vaccination. 
16. Receipt of transfusion of any blood product or application of immunoglobulins within the 
12 weeks prior to the first administration of study vaccine or planned use during the study period 
17. Hepatitis B or C virus infection 
18. Any hematological# or chemistry** parameter that is out of range of normal†† and is considered 
clinically significant by the investigator 
#Complete blood count (CBC), includes hemoglobin, hematocrit, white blood cell (WBC) count, 
neutrophil count, lymphocyte count, eosinophil count, and platelet count 
**Creatinine, alanine transaminase (ALT), total bilirubin 
††Per the site clinical laboratory’s reference ranges. All tests with out of range results that are 
regarded as clinically significant by the clinician must be repeated and determined to be not 
clinically significant before any participant can be enrolled. 
19. The following hematological or chemistry laboratory results will be considered exclusionary, 
irrespective of assessment of clinical significance: 
Hemoglobin (Male) < 12.5 g/dL 
Hemoglobin (Female) < 11.0 g/dL 
Neutrophil count < 1,000 cells/mm3 
Eosinophil count > 650 cells/mm3 
Platelet count < 125,000 cells/mm3 
Creatinine > 1.4 mg/dL 
ALT > 1.1 X Upper limit of normal (ULN) †† 
††Per the site clinical laboratory’s reference ranges 
 STUDY PRODUCTS  
 
Study Vaccine  
5.1.1 
Product Description 
5.1.1.1 
nOPV study vaccines 
Both nOPVs are live, attenuated polioviruses derived from a modified Sabin type-2 infectious cDNA clone 
and propagated in Vero cells. Modifications were introduced in the viral nucleotide sequences in part of 
the 5ʹ UTR to improve the genetic stability of this major attenuating determinant of Sabin type-2, and two 
modifications were made in the 3D polymerase to further improve stability of the attenuation and reduce 
recombination. In addition, a key replication element from the 2C coding region was relocated to the 5ʹ 
UTR to reduce the risk of loss of stabilized 5’ UTR through recombination. The cDNA plasmid was then 
further modified by replacement of the capsid (P1) region of the genome with the capsid from a Sabin-1 
(nOPV1) or Sabin-3 (nOPV3) clone, generating chimeric viruses with novel type 2 non-structural regions 
coupled with Sabin-1 or -3 structural proteins.  

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For this study, a 106.5 ± 0.5 CCID50 dosage is planned for both nOPV1 and nOPV3. The dosage is considered 
likely to be similar to the actual dosages of Sabin-1 and Sabin-3 released by manufacturers, considering 
overages above the expiry label claim (106.0 and 105.8 CCID50) for stability losses as well as process and 
analytical variability. Moreover, if in vitro culture data suggesting a fitness reduction at 37oC compared to 
the homotypic Sabin strains transfers to human infectivity, this dosage allows a reasonable margin over 
the historical Sabin monovalent dosage known to be immunogenic (105.0 CCID50 [10]) to have a reasonable 
expectation of responses. The safety of a 106 5 CCID50 dose is not considered a concern, as most of the 
viral exposure for OPV comes from replication in vivo, and Sabin strains have been studied at 107.0 CCID50. 
5.1.1.2 
Sabin mOPV control vaccines 
Both control vaccines are Sabin mOPVs that are constituent components of the WHO prequalified bivalent 
OPV manufactured by Bio Farma. Bio Farma also manufactures a WHO prequalified mOPV1 for 
supplemental campaigns. Both mOPV1 and mOPV3 will be manufactured and vialled by Bio Farma for this 
trial. 
In addition to the attenuated poliovirus, the vaccine formulation includes sucrose and may contain trace 
amounts of not more than 2 mcg erythromycin and not more than 10 mcg kanamycin. 
5.1.2 
Manufacturer   
All vaccines to be used in this trial, both the nOPV study vaccines and the Sabin mOPV control vaccines 
are manufactured by Bio Farma, Indonesia. 
5.1.3 
Presentation and Formulation   
5.1.3.1 
nOPV study vaccines 
In addition to the attenuated poliovirus, the vaccine formulation includes sucrose, acetic acid or NaHCO3, 
and Basal Medium Eagle (BME) solution. The nOPVs are clear solutions, yellow to pink in color. The 
multidose vaccine vials (20 doses) contain approximately 2.2 mL of vaccine and are packaged with the 
dropper that is attached for administration directly from the vial. Each 0.1 mL (2 drops) dose of vaccine 
contains approximately 106 5 CCID50. In this study, only a single dose is to be administered from each 
multidose vial provided. 
5.1.3.2 
Sabin control vaccines 
The control vaccines are clear and light yellow to light red. The multidose vaccine vials (20 doses) contain 
approximately 2.2 mL of vaccine and are packaged with the dropper that is attached for administration 
directly from the vial. The mOPV1 control vaccine contains >106.0 CCID50 per 0.1 mL (2 drops) dose, and 
the mOPV3 control vaccine contains >105.8 CCID50 per 0.1 mL (2 drops) dose. In this study, only a single 
dose is to be administered from each multidose vial provided. 
5.1.4 
Stability and Storage 
Both nOPVs and Sabin control mOPVs are to be transported and stored at ≤-20oC and thawed prior to 
administration. Unopened vaccine vials may be thawed and kept at 2-8oC for up to 14 days prior to 
administration, although it is preferred to administer the vaccines the same day as they are thawed. The 
thawed vaccines should not be left at ambient temperature for more than one hour and must not be 
refrozen. 

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Dose Preparation and Administration 
Dose preparation, as described in detail in the Pharmacy Manual, will be carried out by a qualified 
unblinded research pharmacist and witnessed by another unblinded study staff member. The unblinded 
pharmacist will affix the dropper to the vial and apply an overlay on the vial on which the participant ID is 
printed, masking the identity of the contents of the vial. Study nOPVs and control mOPVs will be dispensed 
directly from the vials by unblinded staff who will dispense 2 drops of study vaccine directly from the 
dropper into the participant’s mouth. To maintain the observer-blind study design, these unblinded staff 
will not be involved in any other study assessments (e.g., safety assessments) of the participants. Any 
vomiting following study vaccination during the post-vaccination observation period, including the precise 
time of the onset of vomiting, will also be recorded. There will be no vaccine redosing to compensate for 
any vomited vaccine. 
 
Accountability and Disposal 
The site pharmacist is required to maintain complete records of all study vaccines received from PATH 
and will be responsible for maintaining an accurate record of the randomization codes, inventory, and an 
accountability record of vaccines for this study.  The site pharmacist will also be responsible for ensuring 
the security of these documents.   Partially used vials will not be used for human administration or for in 
vitro experimental studies. At the end of the study, the site will receive instruction from PATH regarding 
the final disposition of any remaining study vaccines.   
 STUDY PROCEDURES 
 
Recruitment 
Study participants will be recruited from the local community and reflect the demographics of the 
community yet keeping with the strict eligibility criteria. The sites selected have ample prior experience 
in the recruitment of healthy adult participants from their local community for participation in preventive 
vaccine clinical trials. Information regarding this trial may be provided to potential participants who have 
previously participated in vaccine trials conducted at the site. Other forms and mechanisms of recruitment 
may also be used. The local Institutional Review Board/Independent Ethics Committee (IRB/IEC) will 
approve all materials prior to use. Careful recruitment and communication about all aspects of the study 
will be critical to ensure eligible participants who eventually participate in the trial are committed to 
participate for the full length of the study. It is anticipated that the sites selected will recruit the required 
study sample size over a period of approximately sixteen months. 
 
Study Visits 
A schedule of study visits and evaluations for the participants with an exclusive IPV vaccination history 
(single dose study groups) and participants with an OPV-containing vaccination history (two dose study 
groups) can be found in Appendix 1. 
6.2.1 
Screening – Day -90 to Day 1 
After the site Principal Investigator (PI) or designee has obtained informed consent from participants, the 
participant will be considered enrolled, and the following procedures will be completed during screening 
to determine study eligibility and may occur over multiple screening visits. Additional screening visits may 
be scheduled for any follow up, as needed, but are not required. At the screening visit(s), the site PI or 
designee will provide prospective participants a detailed description of the study objectives and study 

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participation requirements, as well as potential health risks and benefits associated with study 
participation. Baseline data are obtained during the screening period, which has an allowable window up 
to no more than 90 days prior to Day 1, the day of first vaccination. It is anticipated that it may take up to 
two weeks to receive and evaluate all screening laboratory tests to confirm eligibility and allow for 
randomization. All inclusion/exclusion criteria must be assessed from data obtained within the screening 
period, unless otherwise specified in the eligibility criteria.  
After study information has been provided and the appropriate informed consent has been obtained, the 
following procedures are performed during the screening period before the Day 1 Visit: 
• 
Confirm written informed consent has been obtained and solicit/discuss any remaining 
questions the participant may have 
• 
Assign participant ID once study specific consent form has been signed 
• 
Obtain demographic and contact (e.g., address, telephone, email) information 
• 
Obtain medical history 
• 
Obtain history of prior COVID-19 vaccinations and ongoing concomitant medication use and any 
prior use that impacts eligibility, including poliovirus vaccination history (documented 
vaccination records is preferred; however, if not obtainable, to ascertain if vaccination history 
can be reasonably established by history of lifelong residency locations and polio vaccines that 
were available for routine immunizations at the relevant time periods in these locations)  
• 
Measure height and weight 
• 
Perform complete physical examination (including vital signs [VS]) 
• 
Collect venous blood samples (approximately 45 mL) for 
o CBC, including hemoglobin, hematocrit, WBC count, neutrophil count, lymphocyte count, 
eosinophil count, and platelet count 
o Serum chemistries to include creatinine, ALT, and total bilirubin 
o Human immunodeficiency viruses 1 and 2 (HIV 1/2) infection testing 
o Hepatitis B virus surface antigen (HBsAg)  
o Hepatitis C virus antibody (HCV Ab) and if positive, HCV PCR 
o Total IgG and total IgA 
o Serum pregnancy test for females of childbearing potential (FOCB) 
o Neutralizing antibodies to type-specific polioviruses (in addition to sample sent to the 
Polio and Picornavirus Laboratory Branch at the CDC, a sample will be sent to a 
commercial qualified laboratory, Quest Diagnostics, for screening purposes [eligibility 
determination] only 
 
After confirmation of eligibility, participants can be randomized prior to Day 1. 
6.2.2 
First Vaccination Visit – Day 1 Visit 
Prior to Vaccine Administration 
• 
Review concomitant medications 
• 
Review inclusion/exclusion criteria and ensure continued eligibility for study vaccination, 
including absence of symptoms that may confound later safety and solicited AE assessments 
• 
If any interim symptoms, perform a targeted physical examination 
• 
Measure vital signs 

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• 
For females of childbearing potential (FOCB), assess and document continuing use of 
contraceptives and perform urine pregnancy test 
• 
Collect venous blood samples (approximately 15 mL) for 
o CBC, including hemoglobin, hematocrit, WBC count, neutrophil count, lymphocyte count, 
eosinophil count, and platelet count 
o Serum chemistries to include creatinine, ALT, and total bilirubin 
• 
If not done earlier than Day 1, once eligibility is confirmed, randomize participant 
Clinical safety laboratory test results used to determine participant eligibility will be those obtained at 
screening, but the Day 1 test results will be used as baseline for analyses. 
Vaccine Administration 
• 
If an eligible participant is disqualified prior to study vaccine administration (e.g., participant 
withdraws consent or the investigator reconsiders and disqualifies for a documented reason), 
another eligible participant will be selected for randomization in place of the disqualified 
participant 
• 
The vaccine will be administered – 2 drops (0.1 mL) by unblinded study staff directly from the 
masked vaccine vial’s dropper into the participant’s mouth 
Post Vaccination 
• 
Observe participant for at least 30 minutes post-vaccination with medical treatment readily 
available in case of any immediate hypersensitivity reactions 
• 
Assess and document any interim adverse events, and if a participant requires further on-site 
observation, additional site or clinical assessments may be completed as needed 
• 
Provide participant with supplies (including a thermometer and a memory aid) to record solicited 
AE information and instruct the participant in their use 
• 
Prior to discharge from the clinic, once the required observation period is over, the Day 1 solicited 
AE memory aid entries may be completed by the participant and reviewed on site to further 
support good comprehension 
• 
Provide participants in Cohorts 1 or 3 with instructions and supplies to collect stool specimens 
within the appropriate windows on study Days 3, 5, and 8, and participants in Cohorts 2 or 4 to 
collect a stool specimen within the appropriate windows 7 days after vaccination (study Day 8), 
prior to their next scheduled visit. Cohorts 1 and 3 participants may contribute additional stool 
samples between study Days 8 and 29, in addition to the nominal study stool sampling days, if 
available. These optional samples will be used to increase the number of samples available for 
the exploratory genetic stability evaluation. Similar to future use samples, participants’ refusal 
to provide the additional stool sampling timepoints should not affect their eligibility to enroll 
into the study. 
• 
Provide participant clear guidance on appropriate hygienic measures and supplies to minimize 
contact and contamination during the stool collection process (e.g., collection kit, sanitizer, 
disinfectant, gloves) and minimize risk of transmission of vaccine virus to others. Ask participant 
to describe these measures (‘teach back method’) for hand washing and stool collection before 
leaving the clinic and correct any errors 
• 
Provide participant information about storage and transport of stool specimens to the study site 
• 
Schedule next study visit (Day 8 Visit) and instruct participant to contact study staff for any 
symptoms of concern, and irrespective, for any solicited AE defined greater than moderate in 
severity, and ensure participant has appropriate contact details for the study team 

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• 
Once all study related procedures are complete and the investigator determines that the 
participant’s condition is acceptable, the participant may be discharged from the study clinic  
6.2.3 
Day 8 Visit, 7 (+1) days after the study vaccination – Clinic follow-up visit 
At the Day 8 Visit, the participant will return to the study clinic for the following procedures: 
• 
Collect any pending stool samples from the participant 
• 
Review with participant the completed memory aid and ensure that the participant has correctly 
interpreted the instructions in completing the memory aid; any required corrections to be clearly 
documented 
• 
Collect any new AEs since Day 1 Visit that have not already been captured and review any AEs 
that are currently ongoing 
• 
Collect any new concomitant medications since Day 1 Visit that have not already been captured 
and review any concomitant medications that are currently ongoing 
• 
If the participant reports any intervening symptom or AE since the previous visit, perform a 
targeted physical examination, which is to include vital signs 
• 
Any topics or new information considered by investigator to be important to continued informed 
consent to be shared with the participant 
• 
Collect venous blood samples (approximately 15 mL) for 
o CBC, including hemoglobin, hematocrit, WBC count, neutrophil count, lymphocyte count, 
eosinophil count, and platelet count 
o Serum chemistries to include creatinine, ALT, and total bilirubin 
• 
Provide participants in Cohorts 1 or 3 with instructions and supplies to collect stool specimens 
within the appropriate windows on study Days 10, 15, 22, and 29, and participants in Cohorts 2 
or 4 to collect stool specimens on study Days 15, 22, and 29 prior to their next scheduled visit. 
Cohorts 1 and 3 participants may contribute additional stool samples between study Days 8 and 
29, in addition to the nominal study stool sampling days, if available. These optional samples will 
be used to increase the number of samples available for the exploratory genetic stability 
evaluation. Similar to future use samples, participants’ refusal to provide the additional stool 
sampling timepoints should not affect their eligibility to enroll into the study. 
• 
Provide participant clear guidance on appropriate hygienic measures and supplies to minimize 
contact and contamination during the stool collection process (e.g., collection kit, sanitizer, 
disinfectant, gloves) and minimize risk of transmission of vaccine virus to others 
• 
Provide participant information about storage and transport of stool specimens to the study site 
• 
Schedule next study visit (Day 29 Visit) and instruct participant to contact study staff for any 
symptoms of concern, and ensure participant has appropriate contact details for the study team 
6.2.4 
Day 29 Visit, 28 (+2) days after the study vaccination – Clinic follow-up visit 
At the Day 29 Visit, the participant will return to the study clinic for the following procedures: 
• 
Collect any pending stool samples from the participant 
• 
Collect any new AEs since Day 8 Visit that have not already been captured and review any AEs 
that are currently ongoing 
• 
Collect any new concomitant medications since Day 8 Visit that have not already been captured 
and review any concomitant medications that are currently ongoing 

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• 
If the participant reports any intervening symptom or AE since the previous visit, perform a 
targeted physical examination, which is to include vital signs 
• 
Any topics or new information considered by investigator to be important to continued informed 
consent to be shared with the participant 
• 
Collect venous blood sample (approximately 10 mL) for neutralizing antibodies to type-specific 
polioviruses 
For participants in Cohorts 1 or 3, who were randomized to receive only a single dose of study vaccine: 
• 
Provide participant with instructions and supplies to collect stool specimens within the 
appropriate windows on study Days 36, 43, 50, and 57 prior to their next scheduled visit 
• 
Provide participant clear guidance on appropriate hygienic measures and supplies to minimize 
contact and contamination during the stool collection process (e.g., collection kit, sanitizer, 
disinfectant, gloves) and minimize risk of transmission of vaccine virus to others. Ask participant 
to describe these measures (‘teach back method’) for hand washing and stool collection before 
leaving the clinic and correct any errors 
• 
Provide participant information about storage and transport of stool specimens to the study site 
• 
Schedule next study visit (Day 169 Visit), which will occur via telephone, and instruct participant 
to contact study staff for any symptoms of concern and ensure participant has appropriate 
contact details for the study team 
• 
Inform participant that if cessation of vaccine virus shedding is not confirmed by Day 57 stool 
sample, they will be asked to continue with stool collections and the associated protocol 
restrictions until they are informed that cessation of shedding has been confirmed 
If poliovirus shedding is detected by PCR on one of the last two scheduled stool samples, stool sample 
collection duration for that participant will be extended. As soon as the shedding results are known 
(anticipated approximately two weeks after the last stool sample provided for evaluation) the participant 
will be asked to collect additional stool samples after the last per protocol sample obtained over a period 
no shorter than 24 hours, and to repeat this until shedding is PCR-negative for poliovirus on two 
consecutive stool samples collected. They will be provided additional stool collection kit for each sampling 
day.  
If the last stool sample is missing the participant will be asked to provide a new sample as soon as possible 
in order to determine the need for further stool sample collection until poliovirus shedding is PCR negative 
on two consecutive stool samples. 
For participants in Cohorts 2 or 4, who were randomized to receive two doses of study vaccine: 
• 
Review inclusion/exclusion criteria and ensure continued eligibility for study vaccination, 
including absence of symptoms that may confound later safety and solicited AE assessments 
• 
Measure vital signs 
• 
For females of childbearing potential (FOCB), assess and document continuing use of 
contraceptives and perform urine pregnancy test 
• 
If eligibility criteria are still met, 2 drops (0.1 mL) of study vaccine will be administered by 
unblinded study staff directly from the masked vaccine vial’s dropper into the participant’s 
mouth 
• 
Observe participant for at least 30 minutes post vaccination with medical treatment readily 
available in case of any immediate hypersensitivity reactions 

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• 
Assess and document any interim adverse events, and if a participant requires further on-site 
observation, additional site or clinical assessments may be completed as needed 
• 
Provide participant with supplies (including a thermometer and a memory aid) to record solicited 
AE information and review its use again 
• 
Prior to discharge from the clinic, once the required observation period is over, the first day 
solicited AE memory aid entries may be completed by the participant and reviewed on site to 
further support retained comprehension 
• 
Provide participant with instructions and supplies to collect a stool specimen 7 days after second 
vaccination (study Day 36) prior to their next scheduled visit 
• 
Provide participant clear guidance on appropriate hygienic measures and supplies to minimize 
contact and contamination during the stool collection process (e.g., collection kit, sanitizer, 
disinfectant, gloves) and minimize risk of transmission of vaccine virus to others 
• 
Provide participant information about storage and transport of stool specimen to the study site 
• 
Schedule next study visit (Day 36 Visit) and instruct participant to contact study staff for any 
symptoms of concern, and irrespective, for any solicited AE defined greater than moderate in 
severity, and ensure participant has appropriate contact details for the study team 
• 
Once all study related procedures are complete and the investigator determines that the 
participant’s condition is acceptable, the participant may be discharged from the study clinic 
6.2.5 
Day 36 Visit, 7 (+1) days after the second study vaccination – Clinic follow-up visit 
Only for those in Cohorts 2 or 4, who have received a second study vaccination 
 
At the Day 36 Visit, the participant will return to the study clinic for the following procedures: 
• 
Review with participant the completed memory aid and ensure that the participant has correctly 
interpreted the instructions in completing the memory aid; any required corrections to be clearly 
documented 
• 
Collect any new AEs since Day 29 Visit that have not already been captured and review any AEs 
that are currently ongoing 
• 
Collect any new concomitant medications since Day 29 Visit that have not already been captured 
and review any concomitant medications that are currently ongoing 
• 
If the participant reports any intervening symptom or AE since the previous visit, perform a 
targeted physical examination, which is to include vital signs 
• 
Any topics or new information considered by investigator to be important to continued informed 
consent to be shared with the participant 
• 
Provide participant with instructions and supplies to collect stool specimens within the 
appropriate windows on study Days 43, 50, and 57 prior to their next scheduled visit 
• 
Provide participant clear guidance on appropriate hygienic measures and supplies to minimize 
contact and contamination during the stool collection process (e.g., collection kit, sanitizer, 
disinfectant, gloves) and minimize risk of transmission of vaccine virus to others 
• 
Provide participant information about storage and transport of stool specimens to the study site 
• 
Schedule next study visit (Day 57 Visit) and instruct participant to contact study staff for any 
symptoms of concern, and ensure participant has appropriate contact details for the study team 
6.2.6 
Day 57 Visit, 28 (+2) days after the second study vaccination – Clinic follow-up visit 
Only for those in Cohorts 2 or 4, who have received a second study vaccination 

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At the Day 57 Visit, the participant will return to the study clinic for the following procedures: 
• 
Collect any new AEs since Day 36 Visit that have not already been captured and review any AEs 
that are currently ongoing 
• 
Collect any new concomitant medications since Day 36 Visit that have not already been captured 
and review any concomitant medications that are currently ongoing 
• 
If the participant reports any intervening symptom or AE since the previous visit, perform a 
targeted physical examination, which is to include vital signs 
• 
Any topics or new information considered by investigator to be important to continued informed 
consent to be shared with the participant 
• 
Collect venous blood sample (approximately 10 mL) for neutralizing antibodies to type-specific 
polioviruses 
• 
Schedule next study visit (Day 169 Visit), which will occur via telephone and instruct participant 
to contact study staff for any symptoms of concern and ensure participant has appropriate 
contact details for the study team 
• 
If cessation of vaccine virus shedding has not been confirmed by Day 57 stool sample, ask 
participant to continue with stool collections and the associated protocol restrictions until 
informed that cessation of shedding has been confirmed. Ensure that cessation of vaccine virus 
shedding has been ultimately confirmed. 
If poliovirus shedding is detected by PCR on one of the last two scheduled stool samples, stool sample 
collection duration for that participant will be extended. As soon as the shedding results are known 
(anticipated approximately two weeks after the last stool sample provided for evaluation) the participant 
will be asked to collect additional stool samples after the last per protocol sample obtained over a period 
no shorter than 24 hours, and to repeat this until shedding is PCR-negative for poliovirus on two 
consecutive stool samples collected. They will be provided additional stool collection kit for each sampling 
day.  
If the last stool sample is missing the participant will be asked to provide a new sample as soon as possible 
in order to determine the need for further stool sample collection until poliovirus shedding is PCR negative 
on two consecutive stool samples. 
6.2.7 
Day 169 Telephone Visit, 168 (+14) days after the initial study vaccination – Final Study 
Visit 
At Day 169, the participant is expected to be available for a telephone follow-up for the following 
procedures: 
• 
Collect any new SAEs reported since previous Visit that have not already been captured and 
review SAEs that are currently ongoing 
• 
Collect any new SAE associated concomitant medications reported since previous Visit that have 
not already been captured and review any SAE associated concomitant medications that are 
currently ongoing 
• 
Instruct participant to come to the clinic for a targeted physical exam, including vital signs, if they 
report any intervening symptom or AE since the previous visit that is of clinical concern 

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6.2.8 
Unscheduled Visits 
Unscheduled visits (those between regularly scheduled follow up visits) may be performed at participant 
request or as deemed necessary by the investigator at any time during the study. All unscheduled contacts 
and visits will be documented in the participant’s study records and on applicable case report forms.   
 
Discontinuation of Vaccination or Study Procedures  
Participants have the right to decline study vaccinations or procedures for any reason and at any time 
during the study. If a participant declines further vaccination or study procedures, this will be recorded as 
a study deviation and the reason will be clearly documented in the source document. The participant will 
be encouraged to complete the remaining applicable safety related follow-ups and immunogenicity blood 
draw.  If the participant does not wish to remain in the study by declining any follow-up or procedures, 
the participant can choose to withdraw consent and be withdrawn from the study. 
Discontinuation from further vaccination may be at the discretion of the investigator or Protocol Safety 
Review Team (PSRT), if determined to be in the participant’s best interest to do so (e.g., safety concern). 
In addition, participants will be discontinued from further vaccination for the following reasons: 
• 
Pregnancy 
• 
Ineligibility (either arising during the trial or retrospectively having been overlooked at screening) 
• 
Significant or repeated non-compliance with trial requirements 
• 
An adverse event which requires discontinuation of study vaccination or results in inability to continue 
to comply with trial procedures 
• 
Intercurrent illness or diseases or medical treatment that occur during the trial and might influence 
the study results or ability to continue to comply with trial procedures 
 
Withdrawal from Study 
Participation in the study is strictly voluntary. Participants have the right to withdraw from the study at 
any time and for any reason, without penalty. The investigator or PATH may, at their discretion, withdraw 
a participant from continuing in the study if it is considered to be in the participant’s best interest to do 
so, or if the participant is not willing or able to comply with the study requirements. The reason for 
withdrawal will be documented in source document and relevant case report form (CRF). 
In the event of withdrawal from study, reasonable efforts should be made to conduct the following 
procedures: 
• 
Review memory aid if still in use prior to withdrawal 
• 
Update any ongoing AE/SAEs that remain ongoing at time of participant’s last visit prior to withdrawal  
• 
Query about AEs/SAEs and concomitant medications if the interval between the participant’s last visit 
and the time of withdrawal is within the protocol defined reporting period 
• 
Physical examination including vital signs 
• 
Obtain any interim stool samples the participant may have collected for the study 
• 
Collect venous blood samples for safety laboratory testing if withdrawal occurs before Day 8 Visit, and 
for immunological testing if withdrawal occurs before Day 57 Visit 
• 
Update contact information 
All participants who withdraw from the study following study vaccination and in whom cessation of 
vaccine virus shedding has not been confirmed, will be required to continue providing stool specimens for 
analysis and continue with requirements for mitigating the risk of fecal transmission until cessation of 

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shedding is confirmed. If a participant does not adhere to the required provision of stool specimens to 
enable confirmation of cessation of shedding, the investigator shall notify the relevant local health 
department. 
 
Loss to Follow-up 
To avoid participants being lost to follow-up, participants will be reminded by email or text message within 
a few days before scheduled visit. In the event of a missed visit, participants will be contacted by phone, 
email, or text message the next business day following the missed visit. Any participant who fails to attend 
the final study visit will be classified as lost to follow-up. In addition, a participant who cannot be located 
or fails to respond after three attempted contacts and has missed two consecutive visits (other than those 
scheduled primarily to provide stool samples) will be considered lost to follow-up. Efforts to contact the 
participant will be documented in source documents. There will be no replacement of participants who 
are lost to follow-up.   
 
Use of Concomitant Medications During the Study 
Prior to study start, participants will be encouraged to receive Coronavirus Disease 2019 (COVID-19) 
vaccines, and receipt of COVID-19 vaccine prior to study will be reported in the Concomitant Medication 
CRF. At each study visit, the investigator will ask whether the participant has taken any prescription or 
over the counter medication since the last visit. 
Any medication (includes vaccines not administered as part of study) administered to a participant at any 
time between the Day 1 visit and 28 days following each study vaccination during the study period must 
be recorded on source documents and the CRF with generic and/or trade name, indication, dosage, 
regimen, route of administration, and start and end dates. Between the end of these periods and the final 
study visits only concomitant medications associated with an SAE need to be recorded in the CRF. 
The following concomitant medications/vaccinations are prohibited during the study; however, they must 
not be withheld by the treating physician if clinically indicated to treat a participant (e.g., response to 
epidemic, or post-exposure tetanus or rabies vaccine prophylaxis): 
• 
Any investigational drug or vaccine throughout the duration of the study 
• 
Any immunosuppressant or immune-modifying drug (includes systemic steroids) throughout the 
duration of the study 
• 
Any immunoglobulin or blood product through study Day 57  
• 
Any vaccine other than the study vaccines through study Day 57, which are prohibited for 30 days 
prior to or following each study vaccination (except for seasonal inactivated influenza and COVID-
19 vaccines, which are prohibited for only 14 days prior to or following each study vaccination) 
• 
Any intramuscular injection (except seasonal inactivated influenza and COVID-19 vaccines which 
are prohibited for only 14 days prior to or following each study vaccination) for 30 days prior to 
or following each study vaccination 
Note: Medication (e.g., antipyretic) should not be recommended prophylactically prior to study vaccine 
administration to prevent the onset of any post study vaccine administration symptoms, although may be 
administered after study vaccine administration as clinically indicated. 
Use of any prohibited medication must be recorded in the CRF and as such participant’s inclusion in the 
Per Protocol Population will be evaluated on a case by case basis. 

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Emergency Unblinding  
In the event of a medical emergency, the investigator may request that the blind be broken for the 
participant experiencing the emergency if knowledge of the participant’s study vaccine assignment may 
influence the participant’s clinical care. Prior to unblinding, the investigator is encouraged (to the extent 
possible, without jeopardizing the participant’s health) to contact the study medical monitor to discuss 
the decision to break the blind. Unblinding will occur through the secure interactive web response system 
(IWRS), to which there will be 24-hour access. Documentation of the unblinding event will be captured by 
the IWRS. The investigator will be expected to provide the rationale for the necessity of unblinding based 
on the reasonable expectation that knowledge of the participant’s treatment assignment will have a 
meaningful impact on the participant’s medical care in the short term. If a participant’s treatment 
assignment is unblinded, the participant will remain in the study and continue with protocol-defined 
follow-up evaluations, including provision of biological samples, but will not receive further study 
vaccinations. The decision to unblind will be recorded in the participant’s study record and communicated 
to the IRB/IEC and other regulatory bodies, as required.  
 
Management of Birth Control and Pregnancy During Study 
Contraception status is assessed and documented prior to enrollment and each study visit for female 
participants who are of childbearing potential. Prior to enrollment and at each vaccination visit, staff will 
ask volunteers to confirm their use of adequate contraception methods if they are able to become 
pregnant and remind participants about the need to continue using adequate contraception consistently 
for at least 90 days after the last study vaccination and until cessation of vaccine virus shedding is 
confirmed. If a female participant becomes pregnant following randomization, no further study vaccines 
will be administered to that participant, and she will be encouraged to complete remaining visits and 
study procedures unless medically contraindicated.  The investigator is required to notify Emmes within 
24 hours of knowledge of a pregnancy. Any participant who becomes pregnant during the period between 
first vaccination and the last study visit will continue to be followed for pregnancy outcome, even if birth 
occurs after the scheduled end of the study for the participant, if possible. The pregnancy and its outcome 
will be reported on the Pregnancy CRF. 
 
Clinical Assessments  
Vital Signs (VS) 
• 
 For vaccination visits, the site must measure oral temperature in degrees Celsius or Fahrenheit 
(recorded to the nearest 0.1 degree) using the same thermometer that will be used subsequently by 
the participant to measure oral temperature during the post-vaccination period for assessing 
reactogenicity. For all non-vaccination visits, sites may record temperature using any route (aural, 
axillary, tympanic, temporal, etc.), and document the method used. 
• 
Respiratory rate will be recorded in breaths per minute.  
• 
Pulse rate in beats per minute will be measured by automated device or manually. 
• 
Non-invasive systolic and diastolic blood pressure will be measured in millimeters of mercury (Hg) by 
automated device or manually. 
• 
Vital signs will be taken during all targeted physical exams 
Height and Weight 
• 
Height will be measured and recorded to the nearest centimeter (cm).  

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• 
Weight will be measured in kilogram (kg) and recorded to the nearest 0.1 kg.  
Physical Examination 
Complete physical examination will include assessment of vital signs, head, eyes, ears, nose, oropharynx, 
neck, respiratory/pulmonary, cardiovascular, abdomen, musculoskeletal, lymph nodes (neck, 
supraclavicular, axillary, inguinal), extremities, skin, and neurological.  
Targeted Physical Examination 
A focused physical examination based on any interim symptoms/AEs reported by the participant. 
Whenever required, to always include an assessment of vital signs.  
Medical History 
A comprehensive medical history will be collected at screening, including details of any previous 
vaccinations in the past 30 days, any history of reactions to vaccinations, participation in clinical trials 
(especially clinical trials of vaccines), prior surgery or hospitalization, allergy to food/drugs, current 
medication and history of any chronic or recurrent medical conditions. Detailed poliovirus vaccination 
history to be collected, including requests to review poliovirus vaccination records. If records not 
obtainable, to ascertain if vaccination history can be reasonably established by history of lifelong 
residency locations and polio vaccines that were available for routine immunizations at the relevant time 
periods in these locations. 
 LABORATORY EVALUATIONS/REQUIREMENTS 
 
Sample Collection, Distribution and Storage 
Blood samples to evaluate vaccine safety will be obtained and processed at the clinical trial site and 
transported to each site’s designated laboratory for clinical testing.  
Serum specimens collected for assessment of immunogenicity will be separated into aliquots per study 
specific process and stored at ≤-20° C before being shipped to the Polio and Picornavirus Laboratory 
Branch at the United States Centers for Disease Control and Prevention (CDC). For screening purposes 
(eligibility determination) only, a sample will be shipped to a commercial qualified laboratory, Quest 
Diagnostics. Samples will be stored in controlled-temperature freezers, with backup power supply to 
assure proper sample storage.  
Stool samples to assess presence of poliovirus and genetic stability of shed virus will be processed at the 
clinical trial site in a Biosafety Level 2 (BSL-2) laboratory and stored at ≤-20°C before being transported to 
the Polio and Picornavirus Laboratory Branch at the CDC or Viroclinics Biosciences B.V., Rotterdam, The 
Netherlands. 
After either reference laboratory (CDC or Viroclinics) completes a successful test on any serum or stool 
sample that has a back-up sample in storage, the laboratory will destroy any of the remaining sample used 
for the testing within six months. 
Details as to how blood and stool specimens should be collected, processed, aliquoted, labeled, stored, 
and shipped will be provided in the study-specific Laboratory Manual. 

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Clinical Laboratory Tests 
Protocol mandated clinical screening and safety laboratory tests will be conducted in real time by site 
local laboratories that are properly accredited and subscribed to a proficiency testing program. These 
tests include: 
• 
CBC:  hemoglobin, hematocrit, WBC count, neutrophil count, lymphocyte count, eosinophil count, and 
platelet count, performed at screening, and at Day 1 and Day 8 visits 
• 
Serum Chemistry:  ALT, total bilirubin, and creatinine, performed at screening, and at Day 1 and Day 
8 visits 
• 
Pregnancy test: Serum β-HCG at screening, then urine β-HCG prior to each study vaccination 
(conducted on site) 
• 
Human immunodeficiency viruses 1 and 2 (HIV 1/2) infection testing performed at screening 
• 
Hepatitis B virus surface antigen performed at screening (HBsAg) 
• 
Hepatitis C virus antibody (HCV Ab), if positive, HCV PCR, performed at screening 
• 
Total IgG and IgA performed at screening 
 
Laboratory results will be reviewed promptly by the investigator. Participants will be notified of any 
clinically significant abnormalities. If clinically significant abnormalities are identified during screening, 
participants will be referred to their primary health provider or appropriate medical center. If identified 
during the study, participants may be asked to return to the study site for further evaluation, including 
clinical evaluation and repeat laboratory testing (e.g., monitoring for resolution or stabilization) as 
warranted. Any test may be repeated for test results determined to be spurious by the investigator (e.g., 
following improper specimen collection) or if a valid test cannot be performed on the original blood 
collected (e.g., collection tube broken during transportation). 
 
The immunological assays to be performed include:  
• 
Serum neutralizing antibodies to type-specific polioviruses at screening and 28 days after each vaccine 
dose, to be performed at the Polio and Picornavirus Laboratory Branch at the CDC (for screening 
purposes [eligibility determination] only, baseline assays will be performed at a commercial qualified 
laboratory, Quest Diagnostics) 
 
Assessment of Shed Poliovirus 
• 
Multiplex real-time PCR for identification of type-specific poliovirus in stool, to be performed at the 
Polio and Picornavirus Laboratory Branch at the CDC 
• 
CCID50 for quantification of type 1 or 3 poliovirus in stool, to be performed at the Polio and 
Picornavirus Laboratory Branch at the CDC 
• 
Quantitative PCR for quantification of type 1 or 3 poliovirus in stool may be performed at Viroclinics 
Biosciences B.V. 
• 
Neurovirulence of fecally shed vaccine virus as assessed by a transgenic mouse neurovirulence test 
(TgmNVT), to be performed at Viroclinics Biosciences B.V. 
• 
NGS of fecally shed vaccine virus, to be performed by Viroclinics Biosciences B.V. 
The operational definition of cessation of vaccine virus shedding in stool is 2 consecutive stool 
specimens determined to be negative by PCR obtained over a period no shorter than 24 hours.  

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Future Use of Stored Samples 
Participants will be informed about and asked whether they agree to the long-term storage of their 
biological (stool and serum) specimens for use in future research as part of the informed consent process. 
Participants need not agree to this long-term storage component of the study to otherwise be consented 
to take part in the study.  Participants who do agree to this will be consenting to the indefinite long-term 
storage of their remaining biological samples and data for use in future research, which unless further 
consent and IRB/IEC approvals are obtained, will be restricted to further knowledge about polio, the study 
vaccines, immune responses to the study vaccines, and the development of assays to measure these 
immune responses. No tests will be performed on the participant’s genome. At study closure, these 
additional remaining samples will continue to be stored at the Polio and Picornavirus Laboratory Branch 
at the CDC, and/or if required, another PATH-designated biorepository that meets all current poliovirus 
containment requirements. 
 
Biohazard Containment 
As transmission of blood-borne pathogens can occur through contact with contaminated needles, blood, 
and blood products, appropriate blood and secretion precautions will be employed by all personnel in the 
drawing of blood and shipping and handling of all specimens for this study as recommended by the CDC. 
Risk mitigation procedures for the prevention of transmission of shed vaccine poliovirus during the 
collection, processing, storage, and transport of stool specimens will also follow CDC guidelines as stated 
in this protocol and detailed in the study-specific Laboratory Manual. All biological specimens will be 
transported using packaging mandated by United States Code of Federal Regulations (CFR) 42 Part 72. All 
dangerous goods materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. Biohazardous waste will be contained according to institutional, 
transportation/carrier, and all other applicable regulations.   
All protocol specimens will be shipped using packing that meets requirements specified by the 
International Air Transport Association Dangerous Goods Regulations for UN 3373, Biological Substance, 
Category B, and Packing Instruction 650.  Culture isolates, if obtained in this study, are to be shipped as 
specified for UN 2814 Category A Infectious Substances. 
 SAFETY ASSESSMENT AND REPORTING 
 
Definitions 
8.1.1 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a participant after administration of the 
study vaccine and that does not necessarily have a causal relationship with the study vaccine. An AE can 
therefore be any unfavorable and unintended sign (including clinically significant abnormal laboratory 
finding), symptom, physical examination, or disease temporally associated with the use of the study 
vaccine, whether or not related to the study vaccine.  This definition includes exacerbations of pre-existing 
conditions.  Stable pre-existing conditions that do not change in nature or severity during the study are 
not considered AEs; however, these should be reported as part of the medical history. 
Solicited AEs are pre-specific AEs that are common or known to be associated with vaccination that are 
actively monitored as potential indicators of vaccine reactogenicity. Investigators will not be required to 

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assess causality of solicited AEs if the onset is during the solicitation periods. Solicited AEs with onset after 
the solicitation period will be captured as unsolicited AEs. 
For this trial, solicited AEs will be assessed on the day of study vaccination and for the 6 following days 
after each dose of study vaccine. Participants will be provided a memory aid to record the presence and 
severity or absence of solicited AEs. The memory aid may be accessed by smartphone or any device that 
connects to the internet. Solicited AEs with onset during the solicitation period that persist beyond the 
solicitation period will continue to be captured as solicited AEs. 
The following specific solicited AEs will be monitored for this trial (Cohort 1): 
• 
Fever (oral temperature ≥ 38.0°C or 100.4°F). (The temperature comparison table with the 
different methods used can be found in the study MOP.) 
• 
Chills 
• 
Fatigue 
• 
Headache  
• 
Muscle aches/Myalgias 
• 
Joint aches/Arthralgias 
• 
Nausea 
• 
Vomiting 
• 
Abdominal pain 
• 
Diarrhea 
The following specific solicited AEs will be monitored for this trial (F Cohorts 2 and 3): 
• 
Fever (axillary temperature ≥ 37.5°C) 
• 
Vomiting 
• 
Diarrhea 
• 
Irritability 
• 
Decreased feeding 
• 
Decreased activity 
Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study personnel 
during study visits or those identified during review of medical records or source documents. 
In the absence of a diagnosis, abnormal physical examination findings or abnormal clinical safety 
laboratory test results that are assessed by the investigator to be clinically significant will be reported as 
an AE. 
8.1.2 
Adverse reaction / Suspected Adverse Reaction (21CFR Part 312.32) 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that the 
vaccine caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" 
means there is evidence to suggest a causal relationship between the vaccine and the adverse event. 
Suspected adverse reaction implies less certainty about causality than adverse reaction, which means any 
adverse event caused by a vaccine. 
Adverse reaction is any adverse event caused by the vaccine.  Adverse reactions are a subset of suspected 
adverse reactions for which there is reason to conclude that the vaccine caused the event. 
Unexpected adverse event or unexpected suspected adverse reaction refers to an event or reaction that 
is not listed in the IB or is not listed at the specificity or severity that has been observed. 

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8.1.3 
Serious Adverse Event (SAE)  
Serious adverse event is any adverse event that results in any of the following outcomes: 
• 
Death 
• 
Is life-threatening (life-threatening means that the study participant was, in the opinion of the 
investigator or PATH, at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
Congenital anomaly or birth defect 
• 
Important medical event that may not result in one of the above outcomes, but based upon 
appropriate medical judgment, may jeopardize the health of the study participant, and require 
medical or surgical intervention to prevent one of the outcomes listed above  
Suspected unexpected serious adverse reaction (SUSAR) is any suspected adverse reaction that is both 
unexpected and serious. 
 
Reporting Period and Parameter 
Safety events are reported from the time of signing the ICF through each participant’s completion of the 
study 168 days after their Day 1 study vaccination.  Specifically, solicited AEs will be collected for 7 days 
(day of study vaccination and 6 following days) after each dose of study vaccine. If a solicited AE started 
during the 7 days post-vaccination and continues beyond the 7 days, it will continue to be reported as a 
solicited AE. Unsolicited AEs will be collected for 28 days (day of study vaccination and 27 following days) 
after each dose of study vaccine. SAEs will be collected from Day 1 study vaccination through the end of 
the study (Day 169 Telephone visit). 
Any untoward medical occurrence after signing the ICF but before receipt of study vaccine, although not 
to be reported as an AE, if it is assessed as related to participation in the study, must still be reported by 
email to PATH within 3 days of awareness. 
Due to uncertainties around the COVID-19 pandemic and the potential for stay-at-home orders, if a 
subject is unable to come to the clinic for a visit, the scheduled and applicable safety assessments may be 
conducted by telephone. 
 
 
Severity of Adverse Events 
Solicited AEs: 
The severity of all solicited AEs will be graded based on the grading scale in Table 4 below. 
Table 4: Grading scale to grade the severity of solicited AEs 
Solicited AE 
Grade 
Definition 
 
 
 
Fever 
(oral body 
temperature) 
0 
< 100.4°F (none) 
1 
≥ 100.4°F to < 101.5°F 
2 
≥ 101.5°F to < 102.7°F 
3 
≥ 102.7°F 

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Diarrhea 
0 
None 
1 
2 to 3 loose stools per 24 hours 
2 
4 to 5 stools per 24 hours 
3 
6 or more watery stools per 24 hours 
Chills or fatigue or 
headache or myalgias 
or arthralgias or 
nausea or vomiting 
or abdominal pain 
0 
None 
1 
Causes no or minimal interference with usual social & functional 
activities 
2 
Causes greater than minimal interference with but does not prevent 
usual social & functional activities 
3 
Causes inability to perform usual social & functional activities 
 
Abnormal clinical safety laboratory test results reported as AEs: 
The severity of abnormal clinical safety laboratory test results reported as AEs will be graded based on 
the grading scale in Table 5 below. The table is adapted from the FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(September 2007). In the absence of a diagnosis, any clinical safety laboratory test result that meets the 
definition of an SAE as determined by the investigator (e.g., life-threatening) must be reported as an SAE. 
Table 5: Grading scale to grade the severity of abnormal clinical safety laboratory test results 
reported as AEs 
Parameter 
Grade 1 (Mild) 
Grade 2 (Moderate) 
Grade 3 (Severe) 
 
 
 
 
Hemoglobin [Female] (g/dL) 
11.0 – 12.0 
9.5 – 10.9 
< 9.5 
Hemoglobin [Female] change from 
baseline value (g/dL) 
Any decrease – 1.5 
1.6 – 2.0 
> 2.0 
Hemoglobin [Male] (g/dL) 
12.5 – 13.5 
10.5 – 12.4 
< 10.5 
Hemoglobin [Male] change from 
baseline value (g/dL) 
Any decrease – 1.5 
1.6 – 2.0 
> 2.0 
WBC Increase (cell/mm3) 
10,800 – 15,000 
15,001 – 20,000 
> 20,000 
WBC Decrease (cell/mm3) 
2,500 – 3,500 
1,500 – 2,499 
< 1,500 
Lymphocytes Decrease (cell/mm3) 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease (cell/mm3) 
1,500 – 2,000 
1,000 – 1,499 
< 1,000 
Eosinophils (cell/mm3) 
650 – 1,500 
1,501 – 5,000 
> 5,000 
Platelets Decreased (cell/mm3) 
125,000 – 140,000 
100,000 – 124,000 
< 100,000 
Creatinine (mg/dL) 
1.5 – 1.7 
1.8 – 2.0 
> 2.0 
ALT increase by factor  
1.1 – 2.5 x ULN* 
> 2.5 – 5.0 x ULN* 
> 5.0 x ULN* 
Total bilirubin increase by factor 
1.1 – 1.5 x ULN* 
> 1.5 – 2.0 x ULN* 
> 2.0 x ULN* 
*ULN = upper limit of normal 
Other AEs: 
The severity of all AEs other than solicited AEs and abnormal clinical safety laboratory test results reported 
as AEs will be assessed by the investigator and participant (as applicable) based on the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1, July 
2017, of the US National Institute of Health, available from: 

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 https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
The severity grading criteria provided grade AEs from mild (grade 1) to life threatening (grade 4). All AEs 
leading to death are Grade 5 events. AEs are graded with the worst severity grade during the 
illness/symptoms. Life threatening events and events leading to death must be reported as SAEs. 
 
Causality of Adverse Event  
The study investigators will determine the causal relationship between the study vaccine and the AE.  The 
causality assessment is made based on the available information at the time of reporting and can be 
subsequently changed according to follow-up information.  Assessment of causality is based on clinical 
judgment and should take into consideration the following factors: 
• 
Is there a temporal relationship between the event and administration of the study vaccine? 
• 
Is there a plausible biological mechanism for the study vaccine to cause the AE? 
• 
Is there a possible alternative etiology for the AE such as concurrent illness, concomitant medications?  
• 
Are there previous reports of similar AEs associated with the study vaccine or other vaccines in the 
same class? 
For this study, the investigator must classify the causality of the AE according to the categories defined 
below:  
Related: There is a reasonable possibility that the study vaccine caused the event. “Reasonable possibility” 
means that there is evidence to suggest a causal relationship between the study vaccine and the AE. 
Not Related: There is not a reasonable possibility that the administration of the study vaccine caused the 
event. 
 
Follow-up of Adverse Event 
All reported AEs should be followed until resolution or stabilization, or until the participant’s participation 
in the study ends. The investigator must ensure that any AEs that are ongoing at study completion have 
been appropriately referred to the local health care system for continuation of care. Participants who 
have an ongoing study vaccine related SAE at study completion or at discontinuation from the study will 
be followed by the investigator until the event is resolved or determined to be irreversible, chronic, or 
stable by the investigator. 
The outcome of adverse events will be assessed at the time of last observation as per the following 
categories:  
• 
Recovered/resolved without sequelae 
• 
Recovered/resolved with sequelae 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Fatal 
• 
Unknown.  The outcome of the AE is not known 
Due to uncertainties around the COVID-19 pandemic, if a subject has a reportable adverse event that 
meets the clinical criteria of the current CDC case definition of COVID-19, the investigator will ensure that 
the subject will undergo standard of care diagnostic testing and if needed, a quarantine period for SARS-
CoV-2. 

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General Guidance on Recording Adverse Events  
To improve the quality and precision of acquired AE data, the investigator should observe the following 
guidelines: 
• 
AEs must be assessed for severity (graded) and causality and reviewed by the site investigator. 
• 
If an AE (e.g., low hemoglobin) meets the criteria for two different severity grades simultaneously 
(e.g., Grade 1 for absolute hemoglobin level and Grade 2 for change from baseline value), the severity 
grade reported should be the most severe grade (i.e., Grade 2 in the example provided). 
• 
Whenever possible, use recognized medical terms when recording AEs on the AE CRF. Do not use 
colloquialisms or abbreviations. 
• 
If known, record the diagnosis (i.e., disease or syndrome) rather than component signs, symptoms 
and laboratory values (e.g., record congestive heart failure rather than dyspnea, rales, and cyanosis); 
however signs and symptoms that are considered unrelated to an encountered syndrome or disease 
should be recorded as individual AEs (e.g., if congestive heart failure and severe headache are 
observed at the same time, each event should be recorded as an individual AE). 
• 
AEs occurring secondary to other events (e.g., sequelae) should be identified by the primary cause. A 
“primary” AE, if clearly identifiable, generally represents the most accurate clinical term to record.  If 
a primary serious AE (SAE) is recorded, events occurring secondary to the primary event should be 
described in the narrative description of the case. For example: 
Orthostatic hypotension ®   Fainting and fall to floor ®   Head trauma®   Neck pain 
The primary AE is orthostatic hypotension. 
• 
Death is an outcome of an event. The event that resulted in the death should be recorded and 
reported on the SAE CRF. 
• 
For hospitalizations for surgical or diagnostic procedures, the illness leading to the surgical or 
diagnostic procedure should be recorded as the SAE, not the procedure itself. The procedure should 
be captured in the case narrative as part of the action taken in response to the illness. 
• 
Pregnancies that occur in study participants are not considered AEs and will be recorded on a separate 
Pregnancy CRF. Pregnancy outcomes that include spontaneous abortion, stillbirth or any congenital 
anomaly must be reported as SAEs. 
 
Reporting of SAEs 
PATH has designated Emmes with authority to coordinate SAE reporting activities. All SAEs which occur 
during the study, whether considered to be associated with the study vaccine or not, must be reported 
within 24 hours of the site becoming aware of the event to the Emmes Medical Monitor by one of the 
mechanisms provided (e.g., electronic data capture [EDC] system, email, or fax). Contact details and 
instructions for submitting SAEs will be provided in a handout located in the Investigator Site File. If the 
SAE is fatal or life-threatening, the study medical monitor shall be informed immediately by email.  
The investigator should not wait for additional information to fully document the event before notifying 
Emmes. When additional information becomes available, follow-up submissions will be submitted. The 
initial SAE form should be completed with all information known at the time and should include minimal 
elements for initial assessment: 
• 
Name and contact of the investigator submitting the SAE report 
• 
Participant ID number  
• 
Date participant received study vaccine  

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• 
Description of the SAE and date of event onset 
• 
Investigator’s preliminary assessment of severity and causality  
When applicable, hospital case records and autopsy reports should be obtained (without name or 
personal identifiers). 
The investigator is also responsible for reporting all SAEs to their IRB/IEC in accordance with institutional 
policy and adequate documentation of this reporting must be provided to Emmes. 
Reporting procedures for all SAEs will be followed as per FDA regulatory guidelines. The study Safety 
Management Plan (SMP) will contain all the details of safety and regulatory reporting. Emmes is 
responsible for safety reporting to the FDA within the following time periods: 
• 
Serious and unexpected suspected adverse reaction within 15 days of awareness 
• 
Fatal or life-threatening suspected adverse reaction within 7 days of awareness 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or site SOP requirements. 
The noncompliance may be either on the part of the participant, the PI, or the study site staff. As per ICH 
E6(R2), the investigator must not deviate from the protocol unless it is required to eliminate an immediate 
hazard to a trial participant. If required, as soon as is possible, the implemented deviation and the reason 
for it should be submitted to the IRB/IEC and PATH and a determination made as to whether a protocol 
amendment is required.  
Deviations can be categorized as either major or minor. Reporting requirements of deviations depend on 
the type or degree of deviation. The procedures for handling protocol deviations will occur as follows: The 
PI will be notified by study staff as soon as possible if he or she is not present when the deviation is 
discovered. 
The timeline for reporting protocol deviations to the IRB and PATH is determined by the categorization of 
the deviation as major or minor. Major protocol deviations are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, or reliability of the study data or that may significantly 
affect a participant's rights, safety, or well-being. For example, major protocol deviations may include 
failure to obtain informed consent, failure to report SAEs, enrolling participants in violation of key 
eligibility criteria designed to ensure a specific participant population or failing to collect data necessary 
to interpret primary endpoints, as this may compromise the scientific value of the trial. Major deviations 
that occur in this protocol will be reported to PATH in an expedited manner (within 48 hours) and to the 
IRB/IEC as per their stated requirements. 
Minor deviations are departures from the protocol that do not involve participant safety or integrity of 
the study data. Minor deviations will be reported to the IRB/IEC in the context of the annual Continuing 
Review Report or as per their stated requirements if any different. Major deviations should also be 
summarized in the continuing review reports. 
Knowledge of any instances of serious or continuing non-compliance with the regulations or requirements 
will be reported immediately to PATH and the IRB/IEC.  

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 SAFETY OVERSIGHT 
The site PIs and designated site staff will be responsible for continuous close safety monitoring of all study 
participants and for alerting PATH if unexpected concerns arise or once aware that any study pause criteria 
are met.   
 
Routine Reviews by Protocol Safety Review Team (PSRT) 
The Protocol Safety Review Team (PSRT), composed of the site PIs, the PATH Medical Officer and Emmes 
medical monitor, will routinely monitor safety throughout the duration of the trial. The PSRT will be 
chaired by the PATH Medical Officer and may seek additional independent expert medical opinion as 
dictated by needs, including referral to the IDMC, particularly for consideration of unblinded review. The 
Emmes statistician, with assistance of the data management staff, will prepare blinded safety reports for 
review by the PSRT. These reports will provide at a minimum the following information:  
• 
accrual and participant status data regarding completion of study vaccinations and study visits  
• 
summaries of solicited, unsolicited, and serious adverse events 
• 
predefined abnormal safety laboratory test results 
• 
updated medical history and concomitant medication listings 
The PSRT safety review will be conducted by teleconference (or electronically when appropriate) 
occurring at least once monthly until all participants have completed their Day 57 study visits and as 
needed thereafter for the remainder of the study. In addition to safety review, the PSRT may elect to 
discuss trial conduct issues that impact study integrity and participant safety. These may include, but are 
not limited to, data quality, critical monitoring findings, study vaccine concerns, and issues with research 
specimens.  Emmes will also notify the PSRT of the need for ad hoc safety reviews whenever it is aware 
of a SUSAR or adverse events that meet pre-specified study pause criteria as per section 9.3. 
 
Independent Data Monitoring Committee (IDMC) Reviews         
An IDMC composed of at least three independent members with expertise in vaccine clinical trials will be 
convened by PATH to periodically review the conduct and safety of the study. The responsibilities and 
procedures of the IDMC are defined in the IDMC Charter.  
The IDMC will convene for an organizational meeting prior to study initiation and then for at least three 
scheduled meetings during the conduct of the study.  For each of the two nOPV types, one meeting will 
be scheduled once 15 participants have completed their one week post-initial dose study vaccination 
visits. The third meeting will be scheduled based upon observed enrollment rates and study progress. In 
addition to these routinely scheduled meetings, if the PSRT has serious safety concerns or study pause 
criteria are met, the IDMC will convene by teleconference to jointly review the data. The IDMC reviews 
will be summarized with recommendations to PATH as to whether there are safety concerns and whether 
the study should continue without change, be modified, or be terminated.  
If, at any time, a decision is made to permanently discontinue administration of study vaccines in all 
participants, PATH will notify the FDA and the site investigators of record will notify the responsible 
IRB/IEC expeditiously. 
 
Study Pause Rules 
The following study pause rules will automatically halt any further study vaccinations; however, 
participants already vaccinated will continue to be followed for safety during the pause. These pause rules 

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refer to suspected adverse reactions and will be triggered automatically if any of the criteria described 
below are met in a specific study group during the conduct of the study: 
• 
One or more participants experience an SAE that cannot reasonably be attributed to a cause other 
than study vaccine 
• 
Three or more participants experience the same severe (grade 3) solicited AE within 7 days following 
study vaccination that cannot reasonably be attributed to a cause other than study vaccine 
• 
Three or more participants experience the same severe (grade 3) unsolicited AE (including laboratory 
abnormality) within 28 days following study vaccination that cannot reasonably be attributed to a 
cause other than study vaccine 
 
Study Pause Procedure 
The PSRT will be notified immediately by Emmes if they ascertain that a pause rule has been met. If a site 
investigator or the PSRT first become aware that a pause rule has been met, they will inform Emmes 
immediately. Emmes will cease randomization and notify the site PIs that a pause rule has been met and 
that no further enrollment should occur, and no study vaccines are to be administered until specific 
notification is provided that study vaccinations can resume.  
As soon as it is confirmed that a study pause rule has been met, the IDMC will be notified and will 
expeditiously (within 48 hours, if possible) convene by teleconference to review all available, relevant 
information, including initial exclusive access to unblinded data. The IDMC reviews will be summarized 
with recommendations to PATH as to whether there are safety concerns and whether the study should 
continue without change, be modified, or be stopped. 
If at any time, a decision is made to permanently discontinue administration of study vaccine in all 
participants, notification will be provided by PATH to the NRA and by the PI to the IRB/IEC within 48 hours. 
If PATH re-starts the study after IDMC review and recommendation, enrollment and study vaccination 
may resume. The PIs will report the study pause and decision to resume to their IRB/IEC. 
 DATA HANDLING and RECORDKEEPING 
The investigator is responsible for assuring that the data collected are complete, legible, attributable, 
accurate, and recorded in a timely manner. Data collection is the responsibility of the site clinical trial staff 
under the supervision of the site PI. All source documents and laboratory reports must be reviewed by 
the clinical team and data entry staff, who will ensure that they are accurate and complete. 
Emmes is responsible, under oversight of PATH, for data management activities, including quality review, 
analysis, and reporting of the study data according to Standard Operating Procedures (SOPs). 
 Definitions 
10.1.1 Source Data 
All information in original records and certified copies of original records or clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents (original records or certified copies; ICH E6[R2] section 1.51). 

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10.1.2 Source Documents 
Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, participants' diaries of evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, participant files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial (ICH E6[R2] section 1.52). 
 Data Capture Methods (Case Report Form Development and Completion) 
The clinical data in source documents will be entered directly into a 21 CFR Part 11-compliant EDC system 
by trained and qualified study staff. The electronic CRF (eCRF) for the EDC system will be developed by 
the Emmes data management center with input from study staff and approval of PATH. Clinical data for 
each participant will be entered directly into the eCRF from the source documents. 
It is the site PIs’ responsibility to ensure the accuracy, completeness, and timeliness of the data reported 
in the participant’s eCRF and any supporting documentation. All source documents should be completed 
in a neat, legible manner to ensure accurate interpretation of data. Source documentation supporting the 
eCRF data should document the dates and details of study procedures, AEs and participant status. The 
site PIs/institutions will maintain all information in the eCRFs and all source documents that support the 
data collected from each participant in a secure area and treated as confidential material. 
   
 Data Management 
A thorough Data Management Plan and corresponding database compliant with ICH requirements will be 
developed by Emmes Data Management (DM). Emmes DM will build, validate, and maintain a Good 
Clinical Practice (GCP) compliant EDC system. The data system will include password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Write access to the system will be limited to authorized Investigators and study 
staff, and the system will automatically keep an audit trail of all entries and corrections in the eCRF.  
Emmes DM will perform all activities as per their SOPs, and in accordance with PATH SOPs. Coding of 
medical history and adverse events will be performed using the latest version of MedDRA. Medications 
will be coded using the latest World Health Organization Drug Dictionary. The eCRFs and any supporting 
documentation should be available for retrieval or review at any given time. 
 Retention of Study Records 
The site PIs are responsible for retaining study records for a period of 2 years following the date that a 
marketing application is approved for the product or, if no application is to be filed or, if a file application 
is not approved, until 2 years after the investigation is discontinued and the NRA is notified. PATH will be 
responsible for providing the site with date of vaccine approval or IND/regulatory withdrawal. No records 
will be destroyed without the written consent of PATH. PATH will notify the investigator in writing when 
the trial related records are no longer needed. 
These records are also to be maintained in compliance with local IRB/IEC and local authority medical 
records retention requirements, whichever is longest. Storage of all trial-related documents will be such 
that confidentiality will be strictly maintained to the extent provided by local law.  

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20 
13.9 
(0.0, 16.8) 
(0.1, 24.9) 
25 
11.3 
(0.0, 13.7) 
(0.1, 20.4) 
50 
5.8 
(0.0, 7.1) 
(0.1, 10.6) 
70 
4.2 
(0.0, 5.1) 
(0.04, 7.7) 
Minimum adverse event rates required to have ≥95% probability of detecting at least one such event with given sample sizes, 
along with two-sided 95% exact confidence intervals if 0 or 1 events are observed. 
Immunogenicity Evaluation 
Assessment of immunogenicity is a secondary objective in this study. Due to the prior vaccinations 
received by those to be enrolled into the study, baseline immunity (titer of type-specific neutralizing 
antibody) to poliovirus types 1 and 3 is expected to be high, with the level boosted by study vaccination. 
While it is expected that the presence of an immune response can be observed by an increase in 
neutralizing antibody titer following vaccination, and because the post-vaccination immunity is 
anticipated to exceed the assay upper limit of quantification (ULOQ) for some participants, definitive 
comparisons of study vaccination groups to the relevant control (nOPV vs type-specific control, within 
cohort according to prior vaccination [exclusively IPV vs OPV-containing]) will not be possible within this 
phase 1 study. Evaluation of immunogenicity, therefore, will be primarily descriptive in nature; 
comparisons to the relevant control will be made, but the sample size is not based on achieving a specific 
level of statistical power for these comparisons. Comparative evaluation for immunogenicity will focus on 
the cohorts previously receiving OPV vaccinations but will also be conducted among exclusively IPV-
vaccinated participants. 
Prior studies of type 2 in OPV-vaccinated adult populations indicate baseline immunity within the 
quantifiable range, with mean log2 neutralizing antibody (NAb) titers ranging from 7.8 to 8.8 (unpublished 
data), and with the majority of participants achieving NAb titer >ULOQ 28 days following a single dose of 
a Sabin-2 vaccine as well as investigational type 2 vaccines. Using a regression model permitting censoring 
at assay lower limit of quantification (LLOQ) and ULOQ, the standard deviation (SD) of post-vaccination 
NAb titers is estimated to be in the range of 3 – 3.5 on the log2 scale, which is consistent with other 
published data for type 1 (prior to a boost vaccination in adulthood) [11]. In the study involving type 2, 
the post-vaccination GMT ratio (candidate/control) and its corresponding CI were able to be estimated; 
similar methods will be employed here (see below). With respect to binary immune response endpoints 
(seroconversion, other seroresponse rates), data from the type 2 study indicate seroconversion rates 
ranging from approximately 30% to 75%, depending on the vaccine and potency level administered. Rates 
of a minimum 2-fold response ranged from approximately 50% to 75%, with rates of any fold-rise ranging 
from approximately 60% to 85%. 
Using these values, simulation studies were conducted to evaluate the precision of estimates of the GMT, 
GMT ratio, response rates, and differences in response rates, assuming that 48 and 24 of the 50 and 25 
or 28 and 14 of the 30 and 15 prior OPV participants randomized to receive nOPV or mOPV, respectively, 
provide samples for analysis. The figure below displays the average half-width of the two-sided 95% 
confidence intervals for the four evaluations across the range of relevant inputs (log2 NAb SD for GMTs, 
true rate for the various response rates). The level of precision expected to be available, described within 
the figures, is considered adequate to determine if there is sufficient evidence of an immune response to 
warrant progressing into populations where the immune response may be more thoroughly described 
and compared. 

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The figure indicates, for example, that if the SD of the log2 post-baseline serum NAbs is 3.0 and both 
candidate and control vaccines are equally immunogenic, then one can expect, on average, that the CI for 
the difference in mean log2 NAbs will be approximately (-1.48, 1.48) with 48:24 or (-1.92, 1.92) with 28:14 
when the estimated difference is 0 (ratio = 1), providing high confidence that the actual absolute log2 
difference is <2 (ratio <4). If instead the SD is 2.0, the CI would be approximately (-0.97, 0.97) with 48:24, 
providing confidence that the actual absolute difference is <1 (ratio <2). For the lower sample size, with 
an SD of 2.0, the CI would be approximately (-1.25, 1.25), providing high confidence that the actual 
absolute log2 difference is <1.58 (ratio < 3). For the candidate vaccine group alone, assuming a SD just less 
than 3.5 and 48 evaluable subjects, the CI for the mean log2 titer would be approximately ±1.0 log2. That 
is, if the estimated GMT is 28 (256), the figure indicates the CI would be expected to be approximately (27, 
29), or equivalently (128, 512), on average. If instead the SD is 2.5 with 48 evaluable subjects, the CI would 
be expected to be approximately (27.3, 28.7), or equivalently (158, 416), on average. 
With respect to response rates, for which precision is naturally lower than the continuous measurement 
of serum NAbs: if a true response rate is 50% in each group (maximum variability), then the CI for the 
estimated candidate vaccine response rate would be expected to average ±15%  (±20% for 28 evaluable 
subjects) from the point estimate, and the CI for the difference in response rates would be expected to 
average ±23% (±30% for 28:14)  from the point estimate. 
 
 
Intestinal Immunity, Genetic Stability 
In recognition that previously OPV-vaccinated participants are unlikely to shed vaccine virus in substantial 
quantities, the 30-40 participants for each type with exclusive prior IPV vaccination to be randomized 1:1 
to nOPV or mOPV are included primarily to provide a preliminary indication of intestinal take (shedding 
of virus, indicating replicating infection), as well as to provide samples for potential genetic stability 
analysis of shed virus, including NGS and evaluation in a mouse neurovirulence assay. The relevant 

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neurovirulence assay for comparison to Sabin-strain vaccines is yet to be developed, but it is anticipated 
that a null hypothesis of no difference, vs. an alternative hypothesis of superiority of nOPV to mOPV will 
be evaluated from this model; a defined level of statistical power is not a requirement for this preliminary 
evaluation. It is currently unknown what levels of paralysis may be seen in transgenic mice in such an 
assay as assay development is ongoing but based on preclinical data indicating no paralysis associated 
with passaged candidate vaccine virus, and the known reversion to neurovirulence resulting in frequent 
paralysis of mice inoculated with reverted Sabin-strain vaccines, sufficient discriminatory capability is 
expected to be provided by 15-20 participants per vaccine. 
 Definitions of Populations to be Analyzed 
11.4.1 Enrolled Population 
The Enrolled Population is defined as all participants who provide informed consent, regardless of the 
participant’s randomization and treatment status in the study. 
11.4.2 Safety Population 
The Safety Population is defined as all participants in the Enrolled Population who received a study 
vaccine.  
11.4.3 Full Analysis Population 
The Full Analysis Population (FAP) is defined as all participants in the Enrolled Population who were 
randomized, received a study vaccination, and provided a baseline and at least one post-study vaccination 
evaluable serum sample. 
11.4.4 Per-Protocol Population 
The Per-Protocol (PP) population is defined as all participants in the FAP who correctly received all study 
vaccinations per randomization with no major protocol deviations that are determined to potentially 
interfere with the immunogenicity result of the participant. The PP population will be defined on the time-
point level; that is, a participant may be evaluable in the PP population with their baseline and Day 29 
samples, but not for the Day 57 sample due to a major protocol deviation. For summaries of the PP 
population on the participant level, the PP membership for the Day 29 visit will be used. 
Prior to database lock, the database will be searched for potentially disqualifying deviations. Additionally, 
protocol deviations will be collected from monitoring and medication listings will be reviewed; this 
information will be reviewed in a Data Review Meeting (DRM) attended by representatives from PATH, 
Emmes, and the study sites to determine PP population eligibility. Efforts will be taken to blind participant 
group membership during this review to the extent possible in this observer-blind study. The following 
constitute potential criteria for elimination from the per-protocol population. The list is not exhaustive, 
as unexpected deviations may arise requiring unique consideration. 
• 
Missed vaccinations 
• 
Significant non-compliance with visit windows 
• 
Any eligibility criteria not met 
• 
Receipt of a non-study vaccine  
• 
Receipt of immunosuppressants or immune modulators 
• 
Receipt of study vaccine not stored as per manufacturers approved storage condition 
• 
Incomplete vaccine dose administration or vomiting within 5 minutes of vaccination 

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• 
Serological results unavailability 
• 
Wrong randomization 
• 
Dosed with wrong treatment arm 
 
A DRM report will provide the criteria used for determination, as well as list the participants excluded and 
accompanying rationale. 
11.4.5 Other Populations 
The SAP will define additional subgroup participant populations for specific analyses. 
 Analytical Methodology 
11.5.1 Descriptive Methodology 
All data collected will be summarized and/or listed. Analyses will be performed using SAS® software (SAS 
Institute Inc., Cary, NC, USA) version 9.4 or higher. 
Unless otherwise specified, descriptive statistics include the mean, SD, median, minimum, maximum for 
continuous variables, and the number and proportion in each group for categorical variables. Unless 
otherwise specified here or in the SAP, statistical tests, and confidence intervals (CIs) will be computed 
using a two-sided 5% significance level. Exact (Clopper-Pearson) CIs will be used for univariate summaries 
of dichotomous variables, and Miettinen-Nurminen score-based confidence intervals will be used for rate 
differences. All proportions will use as denominator the number of participants contributing data at the 
specified time point within the specified group and study population. 
Summaries will be presented by group and by time point, where relevant. 
For all summaries outlined below, the SAP will contain additional detailed description of the analyses to 
be conducted. 
11.5.2 Analysis Sequence 
Analysis of immunological endpoints will occur separately for each type, in advance of the completion of 
long-term safety follow-up of participants. Following database lock for long-term safety follow-up and 
completion of stool viral shedding assays, a complete final analysis will be produced and incorporated into 
the clinical study report (CSR). 
11.5.3 Changes in Analysis Plan 
Any deviations or changes from the statistical analyses specified in the protocol will be described and 
justified in the SAP and the CSR. 
11.5.4 Baseline and Demographic Characteristics, and Participant Disposition 
Descriptive statistics will be computed for demographic (e.g., height, weight, race, sex) characteristics in 
both the safety and PP populations, and other initial participant characteristics (e.g., medical and surgical 
history, concomitant diseases) in the safety population. 
Concomitant medications will be coded using the WHO Drug Dictionary. Medical history will be coded 
using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). 

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Participant disposition including dropout and reasons for dropout, as well as study population 
membership will be summarized descriptively, and supported with a CONSORT (Consolidated Standards 
of Reporting Trials) diagram. 
Screening serology will be summarized descriptively, including HIV, HBV, and HCV, pregnancy testing, and 
type-specific anti-polio antibodies among all participants, and in the enrolled population. 
11.5.5  Safety Analysis 
All safety analyses will be conducted in the safety population. Summaries will be computed separately by 
group, and within type across group (i.e., combined Groups 1 and 3 compared to combined Groups 2 and 
4, and combined Groups 5 and 7 compared to combined Groups 6 and 8). 
The extent of exposure will be summarized by tabulating the number of doses of a given vaccine received 
for each participant, as well as descriptive summaries of the time (days) between vaccinations 
11.5.5.1 
Solicited Adverse Events 
Solicited events will be summarized by computing the proportion of participants with observation of any 
event, and any event according to event type, over all vaccinations within groups, and for each vaccination 
individually within group. Additional analyses will summarize the frequency and duration of events 
ongoing at Day 7 post-study vaccine administration. Summaries will be prepared corresponding to 
maximum severity and duration per participant, where relevant. Solicited adverse event rates will be 
accompanied by two-sided exact 95% confidence intervals. Within cohorts (separately for each type), the 
rate of solicited adverse events will be compared using a two-sided Fisher’s exact test for pairwise 
comparisons, both overall and by type following each dose, and overall (across doses); this will be 
repeated for severe and for moderate or greater events. 
11.5.5.2 
Unsolicited Adverse Events 
All unsolicited adverse events will be listed and summarized in tables. Unless an AE is classified as an SAE, 
summaries of unsolicited AEs will be made using only those events recorded with onset within 28 days of 
the prior vaccine dose. Unsolicited adverse events will primarily be summarized on the participant level, 
where a participant contributes once to a given event type under the maximum severity and/or causality, 
as appropriate. Tables will additionally display the number of events of a given type observed within a 
group, regardless of the number of participants from which they originate. 
Unsolicited adverse events will be summarized by severity and by relationship; SAEs will be summarized 
overall, and by reason for seriousness designation. In addition, all AEs, coded with MedDRA, will be 
summarized by System Organ Class (SOC) and Preferred Term (PT), and separate tables by SOC and PT will 
be prepared for severe unsolicited AEs, severe AEs, related AEs, severe related AEs, and SAEs. A table will 
be prepared summarizing all preferred terms occurring in ≥2% of participants. Additional summaries will 
include the rate of participants experiencing an AE leading to withdrawal from vaccinations, or from the 
study. Additional listings will be prepared for severe AEs, related AEs, and SAEs. Within OPV type, the rates 
of participants experiencing severe adverse events, related adverse events, and serious adverse events 
will be compared across groups using a two-sided Fisher’s exact test for pairwise comparisons. 
11.5.5.3 
Safety Labs 
Each continuous hematology and chemistry laboratory test will be evaluated by means of descriptive 
statistics (i.e., number of participants, mean, SD, median, minimum, and maximum) on the actual values, 

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at each assessment time point and by group. Changes from baseline will also be summarized by 
assessment time point and by group. 
Clinical safety laboratory test values will be evaluated according to the table for grading the severity of 
adverse events provided in this protocol or in accordance with the normal ranges of the clinical laboratory 
(below, within, or above normal range) for parameters for which no toxicity grades are defined. 
Clinical laboratory abnormalities will be summarized by group, parameter, time point, and grade, 
including the maximum grade post-baseline abnormality for each participant for each parameter. 
Summaries will include any baseline abnormality across parameters within group, and any post-baseline 
abnormality across visits within parameters, as well as across parameters and visits. Abnormalities will 
also be summarized in a shift table, displaying the frequency of post-baseline abnormalities by grade (with 
separate categories for high and for low values of a given lab, where relevant) cross-tabulated with the 
baseline classification for each time point for each lab. Boxplots will display the raw value by lab parameter 
and study collection day and will include separate symbols to depict values out of range, and those that 
are grade 2 or higher. 
11.5.5.4 
Other Safety Measures 
Vital signs will be summarized descriptively, including change from baseline for continuous measures. 
Vital sign abnormalities will be summarized descriptively. 
Abnormal findings in physical examination will be summarized descriptively. 
11.5.6 Immunogenicity Analysis 
All immunogenicity analyses will be performed in the PP population and select analyses will be repeated 
in the FAP. All descriptive analyses will be conducted across all participants within a group/time point 
combination, and these will be repeated for each site. 
11.5.6.1 
Descriptive Analyses 
At each time point where NAb titers are obtained: 
- 
Median of log2 antibody titers will be computed along with 95% CIs 
- 
GMT with accompanying 95% CIs will be computed. GMTs will be estimated with likelihood-based 
methods (SAS PROC LIFEREG) to accommodate censoring at assay ULOQ and LLOQ. 
- 
The geometric mean fold rise (GMFR) will be computed for each post-baseline time point as the 
reverse-transformed difference between the post-baseline log2 value and the baseline log2 value and 
accompanied by two-sided paired-sample 95% CIs computed using asymptotic methods on the log2 
scale, then reverse-transformed. A subgroup analysis of GMFR will consider only those participants 
with values between the LLOQ and ULOQ (exclusive of the endpoints) for the numerator and 
denominator samples. For post-dose-2 GMFR, this will be computed from baseline, and from the pre-
dose-2 titer. Among these participants, a plot of the log2 fold rise vs the baseline log2 antibody titer 
will be generated. 
- 
Type-specific seroconversion rates with 95% exact CIs will be tabulated for post-vaccination time 
points. Seroconversion rate will be computed among those participants with seroconversion possible 
to observe (within 4-fold of the assay ULOQ). For post-dose-2 seroconversion, seroconversion rates 
will be computed both from baseline and from the pre-dose-2 titer 

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o In addition, the rate of any fold-rise (titer increased from baseline) and a minimum 2-fold 
rise in titer and accompanying CIs will be computed in the same manner 
- 
Type-specific seroprotection rates with 95% exact CIs will be tabulated 
- 
Plots of the reverse cumulative distribution of antibody titers will be generated 
Additional figures will display immunity and changes in immunity over time, by type. Additional subgroup 
computations will be specified and conducted, per the SAP. 
11.5.6.2 
Comparative Analyses 
No specific immunogenicity hypothesis is to be tested. Descriptive comparative evaluation will be 
conducted with multiple endpoints; such evaluations will be conducted for the nOPV-vaccinated groups 
compared to the mOPV-vaccinated control groups within type, and within background vaccination cohort 
(within groups defined by exclusive IPV prior vaccination, and separately among those previously receiving 
OPV). Separately for each pairwise comparison, the NAb GMT ratio (nOPV/mOPV) will be estimated via a 
linear model of the log2 NAb titer as a function of group with a fixed parameter for site and a covariate for 
the log2 NAb titer level. This will be conducted using SAS PROC LIFEREG to account for censoring of the 
dependent variable assuming a Normal error distribution on the log2 scale; baseline values achieving 
ULOQ or LLOQ will be replaced with ULOQ or LLOQ, as appropriate, for the covariate. The log-scale 
difference and its corresponding confidence interval, estimated with SAS LSMEANS, will be reverse-
transformed to obtain the estimated GMT ratio and corresponding 95% confidence interval. Among the 
subset of participants where baseline and post-baseline NAb titers are below the assay ULOQ, the fold-
rise in titer will be computed, and these fold-rises will be compared between nOPV vs mOPV groups within 
background vaccination cohort and type using standard t-distribution methodology. 
Similar comparisons will be made for seroprotection rates, seroconversion rates, and other response rates 
(any fold-rise, 2-fold rise). For these binary variables, two-sided 95% Miettinen and Nurminen confidence 
intervals for the rate difference (nOPV minus mOPV) will be computed, and these will be supplemented 
with a two-sided Fisher exact test p-value. 
Imbalance in baseline immunity between sites will be evaluated via the Kruskal-Wallis test for Nab titers. 
Wherever the global test is significant at two-sided level α = 0.10, pairwise comparisons will be drawn 
from the Wilcoxon test. 
11.5.7 Viral Shedding Analysis 
Only participants receiving a dose will be evaluated for viral shedding in the corresponding post-dose 
period. The SAP will provide detail about participants selected into each analysis. 
11.5.7.1 
Descriptive Analyses 
For each group and time point, viral shedding positivity (PCR) and infectivity (log10 CCID50 per gram) will 
be summarized. Additional summary of infectivity will be conducted only among those PCR-positive for 
(only) the vaccine virus. Positivity will be accompanied by two-sided exact 95% confidence intervals for 
the proportion, and infectivity will be summarized with the median and bootstrap-based 95% CI. All 
samples will be evaluated for the appropriate virus type (1 or 3). Participants PCR-positive for type-specific 
viral shedding of only the appropriate virus but with log10 CCID50 per gram equal to LLOQ will contribute a 
value equal to the LLOQ; participants PCR-negative for viral shedding of the appropriate virus will 
contribute zero. A summary will also be produced for each post-dose period of the proportion of 

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participants contributing any PCR-positive sample, any culture-positive sample (≥2.75 log10 CCID50 per 
gram), and those with log10 CCID50 per gram ≥4.0) 
The Shedding Index Endpoint (SIE) will be computed as the mean of the log10 CCID50 per gram from 
nominal collection days 7, 14, 21, and 28 post-dose (e.g., study days 8, 15, 22, and 29 following the first 
dose). An additional summary table will describe the samples considered to be within-window for 
computation of the Shedding Index Endpoint. Permissible stool sample windows will mirror the visit 
windows defined in this protocol. The SIE will be computed for each participant contributing samples at 
each time point, and will be summarized by group, including the median and its bootstrap-based 95% 
confidence intervals. The SAP will define the AUC computations for each post-dose period, which will be 
summarized similarly. 
Time to cessation of shedding is defined as the time (days) between vaccination and last PCR-positive 
stool prior to 2 consecutive PCR-negative stools (with a minimum 24-hour interval between the 2 negative 
stools). The time to cessation of shedding will be assessed with interval-censored methodology to describe 
and compare the duration of shedding. Similarly, supplementary definitions of shedding negativity 
(culture-negative, defined as the last culture-positive value, and “transmission-negative”, defined as the 
last value with ≥4.0 log10 CCID50 per gram) will be described in the SAP, and evaluated with methods 
accommodating censored data. The methods for considering participants censored will be further defined 
in the SAP. 
Descriptive analysis and plots of the reverse cumulative distribution of the daily infectivity assay results, 
the SIE, and the AUC will be generated. Additional figures will display the shedding of virus over time. 
Additional subgroup analyses may be specified in the SAP. 
11.5.7.2 
Comparative Analyses 
Comparisons of viral shedding data will be made within type and within background vaccination group 
(exclusively IPV and OPV-containing). Rate of shedders (PCR, culture-positive, etc.) will be compared at 
each time point using summary statistics, as well as 95% score-based confidence intervals for the 
difference in proportions at each time point. The log10 CCID50 per gram will be compared between groups 
with a Wilcoxon test for the difference between groups, accompanied by the difference in medians and 
accompanying bootstrap-based 95% confidence interval, both overall and among only those PCR-positive 
for (only) the appropriate virus. The same methods will be used for the SIE and AUC. 
Tests between nOPV and mOPV for time-to-shedding cessation endpoints will be conducted with two-
sided log-rank tests using a Type I error rate of 5%. 
11.5.8 Genetic Stability Analyses 
As an exploratory evaluation, genetic stability of shed vaccine virus may be evaluated for the potential for 
neurovirulence in a transgenic mouse model using select post-vaccination stool samples. Briefly, 
transgenic mice susceptible to poliovirus will be inoculated with virus isolated and cell culture amplified 
from participant stool samples, and the mice will be monitored and scored for presence/absence of 
paralysis. The proportion of mice paralyzed as a function of inoculum dose will be used to describe and 
compare the nOPVs to the corresponding mOPVs, according to OPV type. The assay may include mice 
inoculated with relevant control material, and/or mice inoculated with the clinical trial material, to 
compare to the resultant shed virus from participants. 

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In addition, NGS may be used to explore genetic heterogeneity of shed virus, including reversion at known 
sites of attenuation as well as attenuating modifications introduced to enhance genetic stability. Sequence 
information on shed virus may be compared with the results of neurovirulence testing, if available. Both 
stool suspension and amplified material may be sequenced. 
11.5.9 Handling of Dropouts and Missing Data 
All missing data will be assumed to be missing completely at random, and no imputation will be 
performed. Analysis will, therefore, exclude participants with missing or non-evaluable measurements. If 
an excess of data is missing or if patterns in the missing data are detected, the SAP may specify methods 
to accommodate this. 
 QUALITY ASSURANCE AND QUALITY CONTROL 
Guidance on internal and external processes to assure effective protocol implementation, quality of the 
research conducted and compliance with PATH and applicable regulatory requirements. 
 General Considerations 
The study will be conducted in full compliance with the protocol and ICH GCP to provide public assurance 
that the rights, safety, and well-being of trial participants are protected, and that the clinical trial data are 
credible. To ensure quality and standardization, the site will develop SOPs for key protocol procedures 
and conduct the study guided by the study Manual of Procedures or other written guidelines. The site will 
also develop routine operational checks to verify that critical protocol requirements and procedures are 
executed correctly and completely at the time the work is being performed. Prior to the initiation of the 
study, PATH and Emmes will conduct training for the protocol, including applicable SOPs, for study staff. 
The investigational site will provide direct access to all study related documents, source data/documents, 
and reports for the purpose of monitoring and auditing by PATH, and inspection by local and regulatory 
authorities. 
 Study Monitoring 
PATH, the sponsor of this study is responsible for ensuring that the study is conducted in accordance with 
ICH GCP and regulatory requirements. For this purpose, monitors under contract from PATH or its 
designees will provide external monitoring for this study. A site initiation visit will be conducted prior to 
beginning the study, and monitoring will be conducted during, and at closeout of the study.  During the 
study, the monitors will visit the clinical site at intervals to verify compliance to the protocol, 
completeness, accuracy, and consistency of the data, study vaccine accountability, and adherence to ICH 
GCP and applicable regulations. As needed and when appropriate, the monitors will also provide 
clarifications and additional training to help the site resolve issues identified during the monitoring visit. 
As appropriate and informed by risk assessment, remote centralized monitoring activities may be 
considered in place of or to supplement onsite monitoring. These may include analysis of data quality 
(e.g., missing or inconsistent data, outlier data), and identifying data trends not easily detected by onsite 
monitoring and performance metrics (e.g., screening or withdrawal rates, eligibility violations, timeliness, 
and accuracy of data submission).  
The extent and frequency of the monitoring visits will be described in a separate Study Monitoring Plan 
(SMP) developed prior to study initiation. The investigator will be notified in advance of the scheduled 
monitoring visit. The monitor should have access to all trial related sites, participant medical records, 
study vaccine accountability and other study-related records needed to conduct monitoring activities. 

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PATH is to be notified by the investigator or Emmes in an expedited manner of all detected major protocol 
deviations. PATH and Emmes will share the findings of the monitoring visit, including any corrective 
actions, with the site investigator. The site PI and the monitor must agree to cooperate to ensure that any 
problems detected during these monitoring visits are resolved in a predefined timeframe. 
 Independent Auditing 
PATH or its designee may audit the study to ensure that study procedures and data collected comply with 
the protocol and applicable SOPs at the clinical site and that data are correct and complete. The site PIs 
will permit auditors (employees of PATH or employee of a company designated by PATH) to verify source 
data validation of the regularly monitored clinical study. The auditors will compare the entries in the eCRFs 
with the source data and evaluate the study site for its adherence to the clinical study protocol and GCP 
guidelines and applicable regulatory requirements. 
 Regulatory Agency Auditing 
The site PIs must be aware that regulatory authorities, including IRB/IEC may wish to inspect the site to 
verify the validity and integrity of the study data, and protection of human research participants. The site 
PIs will notify PATH within 24 hours following contact by a regulatory authority. The site PIs must make 
the relevant records available for inspection and will be available to respond to reasonable requests and 
audit queries made by authorized representatives of regulatory agencies. The site PIs will provide PATH 
with copies of all correspondence that may affect the review of the current study or their qualification as 
an investigator in clinical studies conducted by PATH. PATH will provide any needed assistance in 
responding to regulatory audits or correspondence. 
 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) 
 Ethical Standards 
This study will be conducted in accordance with the ethical principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research, as drafted by the US 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and in 
conformity with ICH GCP E6 (R2), 45 CFR Part 46 and 21 CFR 50.  
 Ethical Review 
Each participating institution will be responsible for assuring that this protocol and the associated ICFs 
and study-related documents are reviewed and approved by an IRB/IEC prior to implementation of the 
protocol. Any amendments to the protocol, ICFs, or other study-related documents must be approved by 
the IRB/IEC and PATH prior to implementation. A copy of the protocol, proposed ICF, other written 
participant information, and any proposed advertising material will be submitted to each study site’s 
designated IRB/IEC for written approval. The investigator must submit and obtain, as necessary, approval 
from the IRB/IEC for all subsequent protocol amendments and changes to the ICF. The investigator will 
notify the IRB/IEC of SAEs as noted in the protocol and of protocol deviations according to local regulatory 
authority and IRB/IEC requirements. The study will be conducted in full compliance with the protocol. 
 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout the individual’s study participation. Before any study-related activities and in 
agreement with applicable regulatory requirements, the site PI must ensure that the participant is fully 

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informed about the aims, procedures, potential risks, and potential benefits of the study. The participant 
will be given the written, local IRB/IEC approved ICF, allowed ample time to read the consent form, 
encouraged to ask questions about the study, have the questions answered and then be given time to 
decide if they would like to participate in the study. It will be emphasized that participation is voluntary, 
and that the participant has the right to decline to participate or subsequently withdraw from the study 
at any time without prejudice. 
The site PIs or designees must obtain the participant’s voluntary, signed, and dated ICF before any study-
related procedures are performed. Study staff must document the informed consent process. The original, 
signed ICF must be kept in the site study file. A copy of the informed consent document will be given to 
the participants for their records. 
For each participant, following ICF signature, as further evidence that the comprehension requirement of 
informed consent is fulfilled, an informed consent comprehension assessment will be used in the form of 
an open-ended questionnaire to assess the participant’s recall of information related to study 
investigational procedures and expectations regarding hygiene. 
The informed consent process and the informed consent comprehension assessment may be undertaken 
using electronic systems and processes, provided designated IRB/IEC approval, and provided that there is 
adherence to the guidance provided in the FDA document “Use of Electronic Informed Consent. Questions 
and Answers. Guidance for Institutional Review Boards, Investigators, and Sponsors. December 2016.”  
 Participant Confidentiality  
The investigators, PATH and all staff from organizations involved with the implementation of the trial must 
ensure that the participant’s confidentiality is maintained. Personal identifiers will not be included in any 
study report.  All study records will be kept confidential to the extent provided by national and local laws.  
Medical records containing identifying information may be made available for review when the study is 
monitored by PATH or an authorized regulatory agency. Direct access may include examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the study. 
When appropriate and to the extent possible, study procedures will be conducted to protect participant 
privacy and confidentiality.  
All study-related information will be stored securely at the study site. All participant information will be 
stored in locked file cabinets in areas with access limited to study staff. Data collection, process, and 
administrative forms, laboratory specimens, and other reports will be identified by a coded number only 
to maintain participant confidentiality. All records that contain names or other personal identifiers, such 
as locator forms and ICFs, will be stored separately from study records identified by code number. All local 
databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment 
books, and any other listings that link Participant ID numbers to other identifying information will be 
stored in a separate, locked file in an area with limited access. Participants’ study information will not be 
released without their written permission, except as necessary for monitoring. 
 Reimbursement 
Pending local EC approval, participants will be compensated for their time and effort in this study and be 
reimbursed for travel to study visits. The study ICF will state the plan for reimbursement. Participants will 
not be charged for study vaccinations, research clinic visits, research-related examinations, or research-
related laboratory tests. 

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 Risk and Benefits 
Participants will not derive any direct benefits from their participation in this research study. Participants 
may indirectly benefit from the clinical assessments (medical history, physical examination, and routine 
clinical safety laboratory tests) conducted at screening and during the study. If the participant is found to 
have any newly diagnosed medical condition or infection, the investigator will ensure that the participant 
is provided with appropriate and adequate referrals within the health care system. Participation in this 
study will hopefully contribute to development and eventual deployment of a vaccine to address a global 
public health concern. 
Preclinical testing of the two nOPVs (nOPV1 and nOPV3) to be assessed in this study have not identified 
specific, inherent risks of these products. There are currently no clinical safety data for nOPV1 or nOPV3 
as they have not yet been tested in humans; however, a similar nOPV, against type 2 poliovirus (nOPV2), 
has been assessed in phase 1 and 2 trials in adults in Belgium and in a phase 2 trial in young children and 
infants in Panama, and the vaccine has been well-tolerated and no specific safety concerns have been 
identified.  
As the nOPVs are derived from Sabin OPV, the risks associated with Sabin OPV must be considered 
possible for these products. There are certain symptoms that have commonly been associated with 
immunizations in general, and if they do occur, are usually not severe in intensity and transient in nature. 
Consequently, in early clinical trials of investigational vaccines, these symptoms are typically considered 
as risks and are solicited as potential AEs in the first week following immunization. As with other similar 
vaccines, these events have also been observed following immunization with Sabin OPV; therefore, in this 
study, the AEs that will be actively solicited in the one week following administration of the study vaccines 
include such events, specifically, fever, chills, fatigue, headache, myalgias (muscle aches), arthralgias (joint 
aches), nausea, vomiting, abdominal pain, and diarrhea. 
The most concerning risks for the Sabin OPVs are VAPP and the introduction of VDPV into vulnerable 
populations. VAPP, in which vaccine administered to an individual reverts to virulence (a risk the nOPVs 
are designed to avoid) and results in paralytic polio in that individual, occurs in approximately 1 in every 
2.4 million doses distributed, overall, and approximately 1 case in every 750,000 doses among those 
receiving the first dose. More specifically, participants will have had the full recommended polio 
vaccination series, with confirmation of protective levels of antibodies against types 1 and 3 poliovirus, 
and will also be assessed for immunocompetence, further greatly reducing the prospects of this generally 
very rare risk of Sabin OPV.  And for further risk mitigation, to protect against provocation poliomyelitis, 
participants will be prohibited from the receipt of any intramuscular injection for 30 days, prior to or 
following each study vaccination (except seasonal inactivated influenza and COVID-19 vaccines, which are 
prohibited for 14 days). 
Risks associated with contamination with shed vaccine virus, and potential transmission to others, is to 
be mitigated by emphasis on strict hygienic practices for the vaccine recipient, at least until cessation of 
shedding of vaccine virus by the participant is confirmed. As components of such strict hygienic practices, 
study participants will be counseled to: 
• 
flush toilet with toilet lid closed, and then sanitize the toilet surfaces 
• 
use hygienic techniques to obtain and handle stool specimens 
• 
wash hands after toilet use 
• 
wash hands before handling food 
• 
shower prior to entering public swimming pools and avoid spas and hot tubs  

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Individuals who may be involved with the professional handling of food, catering or food production 
activities during study participation will not be eligible to participate in the study. 
Individuals who during their study participation are likely  to come in direct household or close 
professional contact with those who are either immunocompromised, pregnant, encopretic, less than two 
years of age, or who have not received a full polio vaccine primary immunization series, will be excluded 
from the study, and study participants will be reminded to avoid contact with such people, at least until 
it is confirmed that they have ceased to shed vaccine virus. Close professional contact means that the 
person works in close physical proximity for routine, sustained time periods with the person at risk. 
Study clinics will be requested to schedule participant study visits and their flow through the clinic, insofar 
as is possible, to avoid direct contact between participants participating in this study. Participants in the 
study will be advised to notify their primary caregivers and any health care provider who were to attend 
to the participant about their participation in the study. The contact information for the study will be 
provided to the healthcare provider to allow them to obtain additional information on the study. 
Risks of vaccine virus transmission to study clinic staff will be mitigated by ensuring that all site staff in 
contact with participants or their stool specimens have been fully immunized against polio and they will 
be required to adhere to the relevant CDC guidelines for the prevention of transmission of poliovirus in 
healthcare settings, included under both standard and contact precautions [12]. The site laboratory 
processing the stool specimens must meet BSL-2 requirements. Details as to how stool specimens should 
be collected, managed, and processed on site, as well as the use of personal protective equipment, 
incorporating these precautions, will be provided in the study-specific Laboratory Manual. 
Hypersensitivity reactions may occur following the administration of any vaccine, including licensed 
vaccines, which in rare circumstances may be life-threatening. Investigators are informed in the protocol 
and IB of this possibility following study vaccine administration. All participants shall be informed in the 
ICF and observed for a minimum of 30 minutes following study vaccine administration. As with all 
immunizations, appropriate emergency medical treatment shall be made available in case of severe 
immediate reactions, such as anaphylaxis. Participants with a known hypersensitivity to any component 
of the study vaccines will be excluded from the study, or if hypersensitivity is observed after 
administration of initial vaccination, the participant will be excluded from any further study vaccination. 
Blood drawing and venipuncture associated risks may include minor bleeding or bruising at the venous 
access site, mild discomfort, upset stomach, dizziness, light-headedness, syncope, or very rarely infection. 
Blood samples will only be drawn by trained staff members using aseptic technique and medical assistance 
will be available in case of any complications. Participants will be informed of risks in the ICF and will be 
in a seated or supine position during blood draws. 
The known risks of participation in this study are believed to be outweighed by the value of the 
information to be gained. 
 Reporting to Local Health Department 
Each study site will be required to notify the local health department that oversees their catchment area 
of the proposed implementation of this study, and any further guidance and precautions mandated by 
them will be followed. 
 Compensation for Research Related Injury 
Participants will be instructed that if they experience any illness during the study, they should contact 
study staff as soon as possible. Participants will be encouraged to be evaluated at the study clinic, if 

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possible. If participants seek medical care outside the study clinic, they should inform the health care 
provider(s) of their participation in this study, provide the health care provider(s) with contact information 
for the investigator, and separately contact the investigator to inform the investigator of the medically 
attended illness. There are limited funds available to the study for care of study-related injury, in addition 
to modest no-fault insurance for study-related injury. In addition, both PATH, the Sponsor, and Bio Farma, 
the vaccine manufacturer, will have liability insurance coverage for the trial. Although the investigators 
and PATH will make every effort to cover the costs of any study-related injury, full coverage cannot be 
guaranteed, and uncovered costs may fall on participants and/or their insurers. Participants will be 
reimbursed to the extent possible for costs of medical care necessary for any study-related injury. 
Participants will be informed of the limitations for coverage of study-related care costs and that there is 
the possibility that they may ultimately be responsible for at least some of the cost of care. 
 FINANCING AND INSURANCE 
The trial is supported by a grant from the Bill and Melinda Gates Foundation to PATH. Funding of the sites 
and Emmes’ activities will also be covered by this grant through PATH. Bio Farma will be providing 
pharmaceutical support through the provision of the clinical study vaccines.  
PATH will secure insurance that complies with the applicable regulatory and legal requirements.  
 PUBLICATION POLICY 
According to the policy of the International Committee of Medical Journal Editors (ICMJE) member 
journals, this clinical trial will be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine in accordance with their  requirements under the Food and 
Drug Administration Amendments Act. 
The information generated in this study will be used by PATH in connection with the development of the 
product and therefore may be disclosed to government regulatory agencies in various countries, as well 
as global public health organizations, such as the World Health Organization. PATH (or designee) will 
prepare a CSR according to ICH-E3 guidelines. PATH and Bio Farma recognize the importance of 
communicating study findings and will therefore encourage their publication in reputable scientific 
journals and presentation at seminars or conferences, while protecting the integrity of the ongoing trial. 
Study results will be made publicly available in compliance with the WHO mandated timeframe for public 
disclosure of results from clinical trials. Any publication, lecture, manuscripts of the findings of this study 
by any individual involved with the study will be governed by the procedure outlined in the Clinical Trial 
Agreement. The ICMJE authorship criteria will be strictly followed for publication of any manuscripts 
arising from this trial. Within any presentation or publication, confidentiality of individual participants will 
be maintained, with identification by participant code number and initials, if applicable. 
 
 
 

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 REFERENCES 
 
[1] GPEI-cVDPV-factsheet: http://polioeradication.org/wp-content/uploads/2018/07/GPEI-cVDPV-Fact-
Sheet-20191115.pdf 
[2] WHO. Wkly Epidemiol Rec. No 46, 2019, 94, 525–540 
[3] Yeh MT, Bujaki E, Dolan PT, Smith M, Wahid R, Konz J, et al. Engineering the Live-Attenuated Polio 
Vaccine to Prevent Reversion to Virulence [published online ahead of print, 2020 Apr 10]. Cell Host 
Microbe. 2020; S1931-3128(20)30230-4 
[4] Singer C, Knauert F, Bushar G, Klutch M, Lundquist R, Quinnan GV Jr. Quantitation of poliovirus 
antigens in inactivated viral vaccines by enzyme-linked immunosorbent assay using animal sera and 
monoclonal antibodies. J Biol Stand. 1989; 17:137–50 
[5] Minor P.D., Ferguson M., Katrak K., Wood D., John A., Howlett J., et al. Antigenic structure of 
chimeras of type 1 and type 3 polioviruses involving antigenic sites 2, 3, and 4. J. Gen Virol. 1991 Oct; 
72:2475-81 
[6] Minor P.D., Macadam, A.J. Personal communication on monoclonal antibodies for type 3 available at 
NIBSC 
[7] Ohka S, Igarashi H, Nagata N, Sakai M, Koike S, Nochi T, et al.  Establishment of a poliovirus oral 
infection system in human poliovirus receptor-expressing transgenic mice that are deficient in 
alpha/beta interferon receptor.  J Virol. 2007 Aug; 81(15):7902-12 
[8] Dragunsky EM, Ivanov AP, Wells VR, Ivshina AV, Rezapkin GV, Abe S, et al. Evaluation of 
immunogenicity and protective properties of inactivated poliovirus vaccines: a new surrogate method 
for predicting vaccine efficacy. J Infect Dis. 2004 Oct 15; 190(8):1404-12 
[9] Van Damme P, De Coster I, Bandyopadhyay AS, Revets H, Withanage K, De Smedt P, et al. The safety 
and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in 
healthy adults: a double-blind, single-centre phase 1 study. Lancet. 2019; 394(10193):148-158 
[10] Caceres VM, Sutter RW.  Sabin monovalent oral polio vaccines: review of past experiences and their 
potential use after polio eradication. Clin Infect Dis. 2001 Aug 15; 33(4):531-41 
[11] Eggers M, Terletskaia-Ladwig E, Rabenau HF, Doerr HW, Diedrich S, Enders G, et al. Immunity status 
of adults and children against poliomyelitis virus type 1 strains CHAT and Sabin (LSc-2ab) in Germany. 
BMC Infectious Diseases. 2010 Dec 9; 10:347 
[12] Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices 
Advisory Committee. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious 
Agents in Healthcare Settings https://www.cdc.gov/infectioncontrol/guidelines/isolation/index.html  
 
 

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APPENDICES 
APPENDIX 1:  SCHEDULE OF STUDY VISITS AND EVALUATIONS  
Participants with an Exclusive IPV Vaccination History (Cohorts 1 and 3: Single-dose groups) 
Procedure 
Screen 
Visits 
 
 
 
Visit Name 
00 
01 
01A 
01B 
02 
02A 
02B 
02C 
03 
03A 
03B 
03C 
03D 
04 
Study Day (allowed window days) 
-90 to 1 
1 
3 
5 
8 (+1) 
10  
15 
22 
29 (+2) 
36 
43 
50 
57 
169 
(+14) 
Clinic visits 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Stool collection 
 
 
X 
X 
X# 
X# 
X# 
X# 
X# 
X 
X 
X 
X1 
 
Allowed stool collection window 
(days) 
 
 
±1 
±1 
D8±1 
±1 
±2 
±2 
D29±3 
±1 
±2 
±2 
±3 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X  
 
 
  
 
  
 
  
 
 
 
 
 
Demographic data 
X 
  
 
 
  
 
  
 
  
 
 
 
 
 
Medical history 
X 
  
 
 
  
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X2 
Full physical exam (PE) with VS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (VS) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted PE with VS, if indicated 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X4 
Blood for HIV1/2, HBsAg, HCV Ab, 
total IgG & IgA, pregnancy in FOCP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for CBC & chemistry 
X 
X3 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood for type-specific poliovirus 
neutralizing Ab 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urine pregnancy in FOCP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
  
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Study vaccine 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect solicited AEs 
 
X 
 
Collect unsolicited AEs 
 
X 
 
Collect SAEs 
 
X 
 

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#  – Participants may contribute additional stool samples between study Days 8 and 28, in addition to the nominal study stool sampling days, if 
available. 
X1 – If cessation of vaccine virus shedding not confirmed, collections will continue until cessation confirmed 
X2 – Only those associated with SAEs or COVID-19 vaccinations 
X3 – The results of these laboratory tests are not required for eligibility, but will be used as baseline for analyses 
X4 – Day 169 assessments will be performed via telephone. The participants will only come to the clinical if a physical exam is indicated.  
X5– Randomization can be done prior to Day 1 after confirmation of eligibility.  
 
 

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Participants with an OPV-Containing Vaccination History (Cohorts 2 and 4: Two-dose groups) 
Procedure 
Screen 
Visits 
Visit Name 
00 
01 
02 
02A 
02B 
03 
04 
04A 
04B 
05 
06 
Study Day (allowed window days) 
-90 to 1 
1 
8 (+1) 
15 
22 
29 (+2) 
36 (+1) 
43 
50 
57 (+2) 
169 (+14) 
Clinic visits 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Stool collection 
 
 
X 
X 
X 
X 
X 
X 
X 
X1 
 
Allowed stool collection window 
(days) 
 
 
D8±1 
±2 
±2 
D29±3 
D36±1 
±2 
±2 
D57±3 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X2 
Full physical exam (PE) with VS 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (VS) 
 
X 
 
 
 
X 
 
 
 
 
 
Targeted PE with VS, if indicated 
 
X 
X 
 
 
X 
X 
 
 
X 
X4 
Blood for HIV1/2, HBsAg, HCV Ab, 
total IgG & IgA, pregnancy in FOCP 
X 
 
 
 
 
 
 
 
 
 
 
Blood for CBC & chemistry 
X 
X3 
X 
 
 
 
 
 
 
 
 
Blood for type-specific poliovirus 
neutralizing Ab 
X 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancy in FOCP 
 
X 
 
 
 
X 
 
 
 
 
 
Randomization 
 
X5 
 
 
 
 
 
 
 
 
 
Study vaccine 
 
X 
 
 
 
X 
 
 
 
 
 
Collect solicited AEs 
 
X 
 
X 
 
Collect unsolicited AEs 
 
X 
 
Collect SAEs 
 
X 
 
X1 – If cessation of vaccine virus shedding not confirmed, collections will continue until cessation confirmed 
X2 – Only those associated with SAEs or COVID-19 vaccinations 
X3 – The results of these laboratory tests are not required for eligibility, but will be used as baseline for analyses 
X4 – Day 169 assessments will be performed via telephone. The participants will only come to the clinical if a physical exam is indicated. 
X5 – Randomization can be done prior to Day 1 after confirmation of eligibility.