A Phase I, Multicenter, Randomized, Double-blind, Placebo-controlled Single Dose, Dose-ranging Study to Evaluate the Safety, Tolerability, and Immunogenicity of Orally Administered Bivalent GI.1/GII.4 Norovirus Vaccine in Healthy Lactating Females ≥ 18 Years Old and Their Breast-feeding Infants
Phase: PHASE1
Conditions: Norovirus Infections
Sponsor: Vaxart

Protocol Number: VXA-NVV-108
Official Title: A Phase I, Multicenter, Randomized, Double-blind, Placebo-controlled Single Dose, Dose-
ranging Study to Evaluate the Safety, Tolerability, and Immunogenicity of Orally Administered Bivalent 
GI.1/GII.4 Norovirus Vaccine in Healthy Lactating Females ≥ 18 years Old and Their Breast-feeding Infants
NCT Number: NCT07254728
Document Date: 17 February 2023

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VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
Protocol Title: A phase I, multicenter, randomized, double-blind, placebo-controlled single 
dose, dose-ranging study to evaluate the safety, tolerability, and immunogenicity of orally 
administered bivalent GI.1/GII.4 norovirus vaccine in healthy lactating females ≥ 18 years old 
and their breast-feeding infants 
 
Brief Title: Evaluating Vaxart’s oral bivalent GI.1/GII.4 norovirus vaccine in healthy lactating 
females and their nursing infants 
 
Protocol Number: VXA-NVV-108 
 
Amendment Number: Not applicable 
 
Date of Amendment (Optional): Not applicable 
 
Investigational Product Name:  Bivalent GI.1 and GII.4 vaccines (VXA-G1.1-NN plus VXA 
GII.4-NS) 
 
Phase:  
  
I 
 
Sponsor: 
  
Vaxart, Inc. 
     
 
170 Harbor Way, Suite 300  
      
 
South San Francisco, CA 94080 
 
Funding Sponsor:  
Vaxart, Inc and Bill & Melinda Gates Foundation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________ 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to Investigators, potential Investigators, 
consultants, study staff, and applicable independent ethics committees or institutional review boards. The contents of 
this document shall not be disclosed to others without written permission from Sponsor (or others, as applicable). 
_____________________________________________________________________________________________    

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PPD

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), the ethical principles that have their origin in the Declaration of 
Helsinki and the Code of Federal Regulations on the Protection of Human Participants (45 CFR 
Part 46). The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the Sponsor, funding agency and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial Subjects. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training per country requirements. 
I agree to ensure that all staff members involved in the conduct of this trial are informed about 
their obligations in meeting the above commitments. 
Principal Investigator: _________________________ 
  ___________________ 
     Signature
Date 
Name:
__________________________ 
Address:         
___________________________ 
 ______________________________  
 ______________________________ 
 (Full Address, Landmark, State, Country, Phone: Fax:) 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................................................... 0 
STATEMENT OF COMPLIANCE ............................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................................................ 2 
LIST OF IN-TEXT TABLE ........................................................................................................................................... 5 
LIST OF IN-TEXT FIGURE ......................................................................................................................................... 5 
LIST OF ABBREVIATIONS [AND DEFINITIONS OF TERMS] .............................................................................. 6 
1. 
PROTOCOL SYNOPSIS .................................................................................................................................. 8 
1.1. 
Schedule of Trial Activities .................................................................................................................. 17 
2. 
Introduction ..................................................................................................................................................... 19 
2.1. 
Indication .............................................................................................................................................. 19 
2.2. 
Background .......................................................................................................................................... 19 
2.2.1. 
Background of Disease ..................................................................................................... 19 
2.2.2 
 Non-clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine ............ 19 
2.2.3 
Clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine..................... 19 
2.3 
Trial Rationale ...................................................................................................................................... 20 
2.4 
Risk / Benefit Assessment .................................................................................................................... 21 
2.4.1 
Known Potential Risks to the Subjects ............................................................................. 21 
2.4.2 
Known Potential Benefits to the Subject .......................................................................... 22 
2.4.3 
Overall Benefit Risk Conclusion ...................................................................................... 22 
3. 
Trial Objective and end points ........................................................................................................................ 22 
3.1. 
Objectives ............................................................................................................................................. 22 
3.1.1. 
Primary Objectives ........................................................................................................... 22 
3.1.2. 
Secondary Objectives ....................................................................................................... 23 
3.1.3. 
Exploratory Objectives ..................................................................................................... 23 
3.2. 
End Points ............................................................................................................................................ 23 
3.2.1. 
Primary End Points ........................................................................................................... 23 
3.2.2. 
Secondary End Points ....................................................................................................... 24 
3.2.3. 
Exploratory End Points ..................................................................................................... 25 
4. 
Trial Design ..................................................................................................................................................... 25 
4.1. 
Overall Description of Trial Design ..................................................................................................... 25 
4.2 
Scientific Rationale of Trial Design ..................................................................................................... 28 
4.3 
Justification for Dose Selection ............................................................................................................ 28 
4.4 
End of the Study Definition .................................................................................................................. 28 
4.5 
Premature Termination or Suspension of Trial .................................................................................... 29 
4.6 
Trial and Site Start and Close-Out ........................................................................................................ 29 
4.6.1 
First Act of Recruitment ................................................................................................... 29 
4.6.2 
Study/Site Termination ..................................................................................................... 29 
5. 
Selection of Trial Population ........................................................................................................................... 30 
5.1. 
Inclusion Criteria .................................................................................................................................. 30 
5.2. 
Early Termination/Withdrawal Criteria................................................................................................ 33 
5.3. 
Lost to Follow Up Procedure ............................................................................................................... 34 
5.4. 
Screening Failure .................................................................................................................................. 34 
5.5. 
Classification of Subjects Who Discontinue the Study ........................................................................ 34 
6. 
Trial Intervention ............................................................................................................................................ 35 
6.1. 
Investigational Product Description ..................................................................................................... 35 
6.2. 
Preparation and Dispensing of Investigational Product ........................................................................ 36 

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6.3. 
Dosing and Administration of Investigational Product ........................................................................ 36 
6.4. 
Formulation, Appearance, Packaging, and Labelling ........................................................................... 37 
6.5. 
Product Storage and Stability ............................................................................................................... 38 
6.6. 
Accountability Procedures.................................................................................................................... 38 
6.7. 
Randomization and Blinding ................................................................................................................ 39 
6.7.1. 
Randomization Procedures ............................................................................................... 39 
6.7.2. 
Blinding and Unblinding Procedures ................................................................................ 39 
6.8. 
Treatment Compliance ......................................................................................................................... 40 
6.9. 
Overdose of Treatment ......................................................................................................................... 40 
6.10. 
Concomitant Medications and Other Therapies ................................................................................... 40 
7. 
Schedule of Trial Procedures and Assessments ............................................................................................... 41 
7.1. 
Trial Procedures ................................................................................................................................... 41 
7.1.1. 
Procedure to be followed on Screening Period (Day -45 to Day -1) ................................ 41 
7.1.2. 
Procedure to be followed during Active Study Period (Day 1 to Day 29) ........................ 42 
7.1.3. 
Procedure to be followed during follow-up period (Day 30 to Day 365) ......................... 44 
7.1.4 
Follow-up of Subjects with Related AEs or with AEs that Led to Study Discontinuation
 
45 
7.1.5 
Unscheduled Visit ............................................................................................................. 45 
7.2. 
Management of Blood/Saliva/Nasal/Breastmilk/Infant Fecal Samples ................................................ 46 
7.2.1. 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Collection .......................................................... 46 
7.2.2 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Preparation ........................................................ 46 
7.2.3 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Storage and Shipment ....................................... 46 
7.2.4 
Future Use of Stored Specimens and Data ........................................................................................... 46 
8. 
Trial Assessments and Procedures .................................................................................................................. 46 
8.1 
Safety Assessment ................................................................................................................................ 47 
8.1.1 
Physical Examination ....................................................................................................... 47 
8.1.2 
Vital Signs ........................................................................................................................ 47 
8.1.3 
Clinical Safety Laboratory Tests ...................................................................................... 47 
8.1.4 
Pregnancy Testing ............................................................................................................ 48 
8.2 
Immunogenicity Assessment ................................................................................................................ 48 
8.2.1 
Primary Immunogenicity Assessments: ............................................................................ 48 
8.2.2 
 Immunogenicity Assessments: ........................................................................................ 48 
8.2.3 
Exploratory Immunogenicity Assessments:...................................................................... 49 
9. 
Adverse Events ............................................................................................................................................... 50 
9.1 
Definition of an Adverse Event, Serious Adverse Event, Suspected Unexpected Serious 
Adverse Reaction, Adverse Event of Special Interest and New Onset of Chronic Illness .................................. 50 
9.2 
Grading of Severity of an Adverse Event ......................................................................... 52 
9.3 
Relationship of Adverse Event Following Immunization to Experimental 
Vaccine/Vaccine Adverse Event Causality Assessment ...................................................................................... 52 
9.4 
Monitoring and Follow-up of AEs, NOCIs, and SUSARs during Trial ........................... 53 
9.4.1 
Monitoring and Follow-up of SAEs from Day 1 to Day 29 after Vaccination ................. 53 
9.4.2 
Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE Information .... 54 
9.4.3 
Information for Follow-up of AESIS, NOCIS, and SAEs ................................................ 54 
9.5 
Reporting of AEs, AESIs, NOCIs, SAEs, SUSARs, Pregnancies, and Death Events ...... 55 
9.5.1 
Adverse Event Reporting .................................................................................................. 55 
9.5.2 
Serious Adverse Events Reporting ................................................................................... 56 
9.5.3 
Suspected Unexpected Serious Adverse Reaction Reporting ........................................... 57 
9.5.4 
Pregnancy Reporting ........................................................................................................ 58 
9.5.5  
Death Events ........................................................................................................................................ 58 
10. 
Safety Oversight ........................................................................................................................................... 59 
10.1. 
Internal Sponsor Review ................................................................................................................................. 59 

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10.2. 
Safety Monitoring Committee ......................................................................................................................... 59 
11. 
STATISTICAL CONSIDERATION ............................................................................................................... 59 
11.1 
Sample Size Determination .................................................................................................................. 60 
11.2  
Multiplicity Adjustment ....................................................................................................................... 60 
11.3 
Population for Analysis ........................................................................................................................ 60 
11.4 
Statistical Analysis Plan ....................................................................................................................... 60 
11.4.1 
General Approach ............................................................................................................. 60 
11.4.2 
Analysis of the Primary and Secondary Safety End Points .............................................. 61 
11.4.3 Analysis of Primary, Secondary, and Exploratory Immunogenicity and Endpoints ................................. 61 
11.4.4 Baseline Descriptive Statistics .................................................................................................................. 62 
11.4.5 Tabulation of Individual Subject Data ...................................................................................................... 62 
12. 
Ethical considerations ..................................................................................................................................... 63 
12.1 
Ethical Conduct of the Study ................................................................................................................ 63 
12.2 
Institutional Review Board ................................................................................................................... 63 
12.3 
 Informed Consent Process ................................................................................................................... 63 
12.4 
Insurance Compensation ...................................................................................................................... 64 
12.5 
Stipends/Rewards/Compensation for Participation .............................................................................. 64 
12.6 Subject Confidentiality .................................................................................................................................... 64 
12.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ................................... 65 
13. Data Handling and Record keeping................................................................................................................. 65 
13.1 
Source Documents ................................................................................................................................ 65 
13.2 
Case Report Forms (CRF) .................................................................................................................... 65 
13.3 
Data Collection and Management Responsibility ................................................................................ 66 
13.4 
Record Retention .................................................................................................................................. 66 
13.5 
Property Rights and Data Protection .................................................................................................... 66 
14. Quality Control and Quality Assurance ........................................................................................................... 67 
14.1 
Early Safety Data Review AND/OR Committee .................................................................................. 67 
14.2 
Clinical Trial Site Monitoring .............................................................................................................. 67 
14.3 
Audit and Inspection ............................................................................................................................ 68 
14.4 
Responsibility of Investigator............................................................................................................... 68 
14.5 
Responsibility of Sponsor .................................................................................................................... 69 
14.6 
Protocol Deviation ................................................................................................................................ 69 
15. 
Publication and Data Sharing Policy ......................................................................................................... 69 
16. 
References .................................................................................................................................................... 71 
Appendix 1: Clinical Laboratory Tests ................................................................................................................... 73 
Appendix 2: Country-specific Requirements ......................................................................................................... 73 
Appendix 3: Adverse Events Grading .................................................................................................................... 73 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ............................................. 74 
Definitions 
74 
Collection of Pregnancy Information .............................................................................................................. 75 
Appendix 5: ADVERSE EVENTS OF SPECIAL INTEREST .............................................................................. 76 
PROTOCOL VERSION HISTORY ......................................................................................................................... 78 
VERSION 1.0 .......................................................................................................................................................... 78 
12 OCT 2022 ........................................................................................................................................................... 78 
INITIAL VERSION ................................................................................................................................................ 78 
 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
LIST OF IN-TEXT TABLE 
Table 1: 
Schedule of Activities.......................................................................................................... 18 
Table 2: 
Study Design ....................................................................................................................... 28 
Table 3: 
Study Duration .................................................................................................................... 29 
Table 4: 
Discontinuation Reasons ..................................................................................................... 36 
Table 5:  
Investigational Product Dosing ........................................................................................... 38 
Table 6: 
Study Arm(s) ....................................................................................................................... 37 
Table 7: 
Adverse Event Reporting Timelines to the Sponsor ........................................................... 57 
Table 8: 
Populations for Analyses ..................................................................................................... 62 
Table 9: 
Protocol-Required Laboratory Assessments ....................................................................... 75 
Table 10: 
Grading of Solicited Symptoms of Reactogenicity ............................................................. 76 
Table 11: 
Adverse Events of Special Interest ...................................................................................... 78 
LIST OF IN-TEXT FIGURE 
Figure 1 Study Design ................................................................................................................................ 26 
 
 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
LIST OF ABBREVIATIONS [AND DEFINITIONS OF TERMS] 
Term 
Description 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AEFI 
Adverse events following immunization 
AGE 
Acute gastroenteritis 
ANCA 
Anti-neutrophil cytoplasmic antibody  
ASC 
Antibody secreting cells 
BMI 
Body mass index 
CBER 
Center for Biologics Evaluation and Research – FDA 
DP 
Drug product 
eCRF 
Electronic case report form 
CFR 
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences 
CMP 
Clinical Monitoring Plan 
CSR 
Clinical Study Report 
DCC 
Data Coordinating Center 
EOS 
End of Study 
ET 
Early Termination 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI.1 
Norovirus genogroup I.1 
GII.4 
Norovirus genogroup II.4 
GMP 
Good Manufacturing Practice 
GRAS 
Generally recognized as safe 
HBsAg 
Hepatitis B surface antigen 
HBGA 
Histo-blood group antigen 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed Consent 
ICH 
International Conference on Harmonisation 
IP  
Investigational Product 

Vaxart Inc 
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17 FEB 2023 
 
 
ITT 
Intent to treat 
SMC 
Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IU 
Infectious units 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSD 
Meso Scale Discovery 
NOCI 
New Onset of Chronic Illness 
NoV 
Norovirus   
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral blood mononuclear cells 
PVP 
Polyvinyl pyrrolidone 
PI 
Principal investigator 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities 
SUSAR 
Serious unexpected suspected adverse reaction  
TEAE 
Treatment-emergent adverse event 
VP1 
Viral Protein 1, major capsid protein of norovirus 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
1.
PROTOCOL SYNOPSIS
Title of Study: A phase I, multicenter, randomized, double-blind, placebo-controlled single 
dose, dose-ranging study to evaluate the safety, tolerability, and immunogenicity of orally 
administered bivalent GI.1/GII.4 norovirus vaccine in healthy lactating females ≥ 18 years 
old and their breast-feeding infants. 
Sponsor: Vaxart Biosciences, Inc. 
170 Harbor Way, Suite 300 
South San Francisco, CA 94080 
Contract Research Organization: TBD 
Protocol number: 
VXA-NVV-108 
IND Number: 
Trial Blinding 
scheme: 
Double-Blind 
Phase of the 
study: 
Phase I 
Study Arms: 
A total of 76 healthy lactating female participants will be enrolled and randomized into three 
Arms (medium dose, high dose, and placebo), as described below: 
•
Arm 1: Bivalent GII.4/GI.1 medium dose vaccine (VXA-GII.4-NS plus VXA-
G1.1-NN) 5×1010 tablets; total dose is 1×1011 IU/dose (N=30)
•
Arm 2: Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-
NN) 1×1011 tablets; total dose is 2×1011 IU/dose (N=30)
•
Arm 3: Placebo tablets (N=16)

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
Study Rationale: 
Noroviruses (NoV) are a genetically diverse group of small, non-enveloped, single-stranded 
positive-sense RNA viruses belonging to the Caliciviridae family and currently, it is the main 
viral cause of acute gastroenteritis (AGEs) in most countries worldwide. After adoption of 
the rotavirus vaccine throughout the world, norovirus infection has been one of three major 
causes of infant diarrheal disease.  It was estimated that each year NoVs cause 64,000 
episodes of diarrhea requiring hospitalization and 900,000 clinic visits among children in 
industrialized countries, and up to 200,000 deaths of children <5 years of age in developing 
countries (Patel, et al). Hence, there is an urgent public health need for the rapid development 
of novel interventions to prevent the spread of this disease.  
 
Vaxart’s norovirus oral tablet vaccine uses Vaxart’s non-replicating adenoviral-based oral 
vaccine platform. The platform has been assessed to be well tolerated and safe in over 600 
healthy adult subjects who have been enrolled in studies to evaluate the safety, tolerability, 
and immunogenicity of the platform. Notably, Vaxart’s norovirus oral tablet vaccine is highly 
immunogenic in humans, inducing serum antibodies and potent mucosal responses at both in 
the intestine and in more distal mucosal sites such as the saliva and the nose (Kim, et al, JCI 
Insights, 2018 and unpublished data).  
Norovirus gastroenteritis is a contagious disease that can affect all age groups, and infants 
aged 6 to 23 months have the highest norovirus disease burden in children.  Breastmilk 
antibodies to norovirus have been shown to be inhibitory to severe disease in breast milk fed 
children (Labayo, et al). Vaxart and collaborators Dr. Stephanie Langel and colleagues at 
Duke University have shown that oral immunization of lactating ferrets can provide 
substantial breast milk antibodies to the vaccine candidate (Langel, et al, unpublished data). 
In this study, we will evaluate the immunogenicity effect of orally administered bivalent 
GI.1/GII.4 norovirus vaccine in the breast milk of lactating females and fecal samples in their 
infants.  
This trial is not powered as an efficacy study and any cases of norovirus acute gastroenteritis 
during the study period will be evaluated as exploratory. 
Description of Sites/Facilities: 
This will be a multi-center trial conducted at (approximately) 7 sites in South Africa. The 
name of the Investigators and sites are provided within the “List of Investigators and Centers 
Involved in the Trial” document. 
Description of Investigational Product: 
Name of Vaccine: Bivalent GI.1/GII.4 norovirus vaccine 
• Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective 
Recombinant Adenovirus 5 with dsRNA Adjuvant (VXA-G1.1-NN) 
• Norovirus GII.4 Sydney VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective 
Recombinant Adenovirus 5 with dsRNA Adjuvant (VXA-G2.4-NS) 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
Dose Regimen: 5×1010 IU (medium dose) and 1×1011 IU (high dose) per strain per dose at 
Day 1.  
Route: Oral administration 
Dosage Form: Enteric coated tablet 
Study Design 
This study will investigate the safety, tolerability, and immunogenicity of two distinct 
monovalent norovirus oral vaccine products given together as a single bivalent dose. Both 
vaccine drug products (DP) will be supplied in the form of small white enteric-coated tablets 
containing VXA-G1.1-NN or VXA-G2.4-NS.   
VXA-G1.1-NN and VXA-G2.4-NS are E1/E3-deleted, replication-incompetent, serotype 5 
adenovirus vaccine vectors designed for use as vaccines for the prevention of NoV infection. 
These non-replicating vectors encode for a full-length VP1 gene of either Norwalk virus 
(VXA-G1.1-NN vaccine) or Sydney virus (VXA-G2.4-NS vaccine). In addition to the 
transgene cassette, the rAd5 vector also contains a dsRNA hairpin following a second 
hCMVie promoter, thereby expressing both vaccine antigen and adjuvant in the same cell. 
These rAd5 vectors are designed to deliver both NoV VP1 antigen and adjuvant to the same 
target cells in the intestinal ileum. 
A matching number of placebo tablets will be dispensed to maintain the study blinding. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoints 
• To evaluate the safety and tolerability of 
oral bivalent GI.1/GII.4 norovirus 
vaccine 
administration 
in 
healthy 
lactating female participants.  
 
 
 
 
 
 
• To 
assess 
the 
short-term 
immunogenicity 
of 
oral 
bivalent 
GI.1/GII.4 
norovirus 
vaccine 
administration in healthy lactating 
female participants and its association 
• Frequency, duration, and severity of 
solicited symptoms of reactogenicity 
(local and systemic) for 1 week 
following study drug dose. 
• Frequency, duration, and severity of 
unsolicited treatment-emergent adverse 
events (TEAEs), serious AEs (SAEs), 
adverse events of special interest 
(AESIs), and new onset of chronic 
illness (NOCIs) through the active 
period (4 weeks post dose). 
 
 
• Serum VP1 specific (GI.1 and GII.4) 
IgA on Day 1 (baseline), Day 8, and 
Day 29 (4 weeks post last dose). 
• Breastmilk VPI specific (GI.1 and 
GII.4) IgA on Day 1 (baseline), Day 8, 

Vaxart Inc 
VXA-NVV-108 Version 1.0 
17 FEB 2023 
 
 
with the immunogenicity response in 
breastmilk. 
 
Day 15, and Day 29 (4 weeks post last 
dose). 
Secondary Objective 
Secondary Endpoints 
• 
To assess the long-term safety of 
bivalent GI.1/GII.4 norovirus vaccine 
through 12 months after the last 
vaccination. 
 
• 
To assess the immunogenicity of oral 
bivalent GI.1/GII.4 norovirus vaccine 
administration in healthy lactating 
female participants and its association 
with the immunogenicity response in 
breastmilk.  
 
• Frequency, duration, and severity of all 
SAEs, AESIs, and NOCIs through 12 
months after study drug dose  
 
 
• Serum VP1 specific (GI.1 and GII.4) IgA 
on Day 180 after study drug dose 
• Breastmilk VP1 specific (GI.1 and 
GII.4) IgA on Day 60, Day 120, and Day 
180 after study drug dose 
• Serum VP1 specific (GI.1 and GII.4) IgG 
on Day 1 (baseline), Day 8, Day 29, and 
Day 180 after study drug dose 
• Serum BT50 (GI.1 and GII.4) on D1 
(baseline), on Day 8, Day 29, and Day 
180 after study drug dose 
 
Exploratory Objective 
Exploratory Endpoints 
• 
To assess additional immunogenicity 
parameters of bivalent GI.1/GII.4 
norovirus vaccine including 
immunogenicity response in breastfed 
infants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To assess clinical effects in subjects 
presenting with acute gastroenteritis 
symptoms during the study period 
• Nasal and saliva VP1 specific (GI.1 and 
GII.4) IgA from lactating mother on D1 
(baseline), on Day 8, Day 29, Day 60, 
and Day 180   
• Infant stool VP1 specific (GI.1 and 
GII.4) IgA on Day 1 (baseline), Day 29, 
and Day 60 
• Breastmilk BT50 (GI.1 and GII.4) at 
various, critical timepoints if feasible, 
and with samples that have high 
probability of significant responses 
• Breastmilk Enterocyte culture 
neutralizing antibodies (GI.1 and GII.4) 
at various timepoints, if feasible, and 
with samples that have a high 
probability of significant responses. 
 
 
• Occurrence of norovirus acute 
gastroenteritis  
 

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Study Population:  
76 healthy adult lactating female participants aged 18 years or greater and their breastfed 
infants aged >30 days to 11 months of age   
Planned Number of Subjects: 
A total of 76 healthy lactating female participants aged ≥18 years and their breastfed infants 
aged >30 days to 11 months of age will be enrolled and randomized during this trial.  
Eligibility Criteria: 
Inclusion Criteria: 
To be eligible for this study, participants must meet all the following: 
1. Lactating females aged ≥ 18 years at the time of enrolment and their breastfed 
infants aged >30 days to 11 months of age at the time of the participants’ study 
drug administration. 
2. In stable and good general health, without significant medical illness, based on 
medical history, physical examination (including vital signs), and clinical 
judgment of the investigator. 
3. Lactating females willing and able to provide informed consent which includes 
compliance with the requirements and restrictions listed in the ICF and in the 
protocol. 
4. Lactating females who are willing to provide consent for their breastfed infant.  
5. Negative pregnancy tests at screening and prior to dose on Day 1 
6. Available for all planned visits and tele-health appointments, and ability to 
comply with all study-related evaluations (including but not limited to having 
the ability and willingness to swallow multiple small enteric-coated tablets per 
study dose, express/pump breastmilk, and collect infant stool samples) 
7. Plan to continue breastfeeding as the main source of the infant's nutrition for at 
least 1 month (longer is preferred with goal of 6 months post dose if possible) 
from the time of study drug administration. Exclusive breastfeeding is 
acceptable but not necessary. 
8. The nursing infant is the product of a singleton pregnancy AND does not have 
any of the following: 
a.     Any abnormality that may interfere with breastfeeding or milk 
absorption 
b. Active infection (may be included if the infection resolves and the 
subject is re-assessed during the screening period) 
c. Infant has any other medical condition or abnormality that, in the 
opinion of the investigator, could compromise the infant's appropriate 
inclusion in this study including interference with the interpretation of 
study results (such as malabsorption) 
d. One or more documented brief resolved unexplained events (BRUE) 

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e. Extreme prematurity (infants who were born at less than 28 weeks 
gestation) 
f. 30 days of age or less at the participant's study drug administration OR 
greater than 11 months of age at the participant's study drug 
administration 
g. Prior hospitalization that is not exclusively for hyperbilirubinemia 
requiring phototherapy 
h. Any genetic/metabolic disease 
i. 
Any chronic illness requiring long term medication 
9. Subjects must be willing to use a highly effective form of contraception for 30 
days prior to vaccination and until 60 days after the vaccination. Acceptable 
forms are oral, implantable, intrauterine, transdermal, intravaginal, injectable, 
double barrier or abstinence (subjects using diaphragms must also use condom). 
The form of contraception must be approved by the investigator. 
Subject Exclusion Criteria: 
The participants must be excluded from participating in the study if they meet any of the 
following: 
1. Presence of a fever ≥ 38.0oC measured orally at baseline, on Day 1 prior to 
vaccination. (Assessment may be repeated once during screening period). 
2. Acute disease within 72 hours prior to vaccination, defined as the presence of a 
moderate or severe illness (as determined by the Investigator through medical 
history and physical exam). (Assessment may be repeated once during screening 
period). 
3. Participants who have received antipyretic/analgesic medications within 24 hours 
prior to the intended vaccine administration. 
4. Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV) tests at the screening visit. 
5. History of hypersensitivity or allergic reaction to any component of the 
investigational vaccine, including but not limited to fish gelatin. 
6. History of serious reactions to vaccination such as anaphylaxis, respiratory 
problems, hives, or abdominal pain. 
7. Presence of significant uncontrolled medical or psychiatric illness (acute or 
chronic) including the institution of new medical/surgical treatment or significant 
dose alteration for uncontrolled symptoms or drug toxicity within 3 months of 
screening and reconfirmed at baseline. 
8. History of significant pregnancy-related complications during this pregnancy, 
including but not limited to pre-eclampsia, eclampsia, or gestational diabetes 
unless a full resolution is documented. 
9. Cancer, or treatment for cancer, within the past 3 years (excluding fully treated 
and resolved basal cell carcinoma or squamous cell carcinoma). 

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10. Presence of immunosuppression or medical condition possibly associated with 
impaired immune responsiveness, including diabetes mellitus type 1 or 2. 
11. History of irritable bowel disease or other inflammatory digestive or 
gastrointestinal condition that could affect the distribution/safety evaluation of an 
orally administered vaccine targeting the mucosa of the small intestine. Such 
conditions may include but are not limited to: 
a. Any history of:  
i. 
Malignancy 
ii. 
Malabsorption  
iii. 
Pancreatobiliary disorders 
iv. 
Inflammatory bowel disease 
v. 
Irritable bowel disease 
vi. 
Hiatal hernia 
vii. 
Surgical resection 
b.   History of diagnosis or treatment in past 5 years of: 
i. 
Esophageal or gastric motility disorder 
ii. 
Gastroesophageal reflux disease (GERD) - Will allow for 
subjects with a history of pregnancy-related GERD if fully 
resolved for >3 months and no other history of GERD diagnosis  
iii. 
Peptic ulcer 
iv. 
Cholecystectomy 
12. Any condition that resulted in the absence or removal of the spleen  
13. History of any form of angioedema  
14. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that 
could make blood draws problematic 
15. History of GI bleeding including hematochezia (blood in stool) or melena (black 
stool) 
16. Any significant hospitalization within the last year which in the opinion of the 
investigator or sponsor could interfere with study participation 
17. Any of the following history or conditions that may lead to a higher risk of 
clotting events and/or thrombocytopenia: 
a. Family or personal history of bleeding or thrombosis 
b. History of heparin-related thrombotic events, and/or receiving heparin 
treatments 
c. History of autoimmune or inflammatory disease 
d. Presence of any of the following conditions known to increase the risk of 
thrombosis within 6 months prior to screening: 
 
i. 
Recent surgery other than fully healed cesarean delivery or 
excision/ biopsy of cutaneous lesions  
ii. 
Immobility (confined to bed or wheelchair for 3 or more 
successive days)  

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iii. 
Head trauma with loss of consciousness or documented brain 
injury  
iv. 
Receipt of anticoagulants for prophylaxis of thrombosis 
v. 
Recent clinically significant infection including hospitalization 
for COVID-19 related illness 
18. Any other condition that, in the clinical judgment of the investigator, would 
jeopardize the safety or rights of a participant taking in the study, would render 
the participant unable to comply with the protocol, or would interfere with the 
evaluation of the study endpoints 
19. Receipt of a licensed vaccine (including any COVID-19 vaccines under 
Emergency Use Authorization) within 14 days prior to study drug dose or planned 
administration during the study active period 
20. Use of antibiotics, proton pump inhibitors, H2 blockers, or antacids within 7 days 
prior to study drug administration or planned use during the active study period 
21. Use of medications known to affect the immune function (including but not 
limited to systemic corticosteroids, leukotriene modifiers, and JAK inhibitors) 
within 2 weeks before study drug administration or planned use during the active 
study period 
22. Daily use of nonsteroidal anti-inflammatory drugs within 7 days prior to study 
drug administration or planned use during the active study period  
23. Donation or receipt of blood or blood products within 30 days prior to study drug 
administration or planned donation during the active study period 
24. Participating in any clinical trial with another investigational product within 
30 days prior to the first trial visit or intend to participate in another clinical trial 
at any time during the conduct of this trial 
25. Are first-degree relatives of individuals involved in trial conduct 
26. Positive urine drug screen for drugs of abuse at screening 
27. Positive alcohol test at screening or baseline 
28. History of drug, alcohol, or chemical abuse within 1 year of screening 
 
 
 
 

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Study Duration Criteria for Individual Subject: 
The total duration of the study will be 365 days. 
For each participant, study participation is expected to last as follows: 
Screening period:  
Up to 45 days  
Active study period: 
29 days  
Follow-up period for safety and 
duration of immune response, 
SAEs, AESIs, NOCIs 
12 months (from the study dose at Day 1) 
Total duration: 
12 months from study dose at Day 1 
 
Summary of Statistical Analysis: 
The statistical analysis plan (SAP) will be developed and finalized before database lock for 
any of the planned analyses. It will describe the participant populations to be included in the 
analyses and the procedures for accounting for missing, unused, and spurious data. This 
section provides a summary of the planned statistical analyses of the primary, secondary, and 
tertiary/exploratory endpoints.  
Analyses will be performed for the total population. 
Sample Size Justification:  
Overall, 76 healthy lactating female subjects from 18 years of age or greater and their 
breastfed infants aged >30 days to 11 months of age will be enrolled and randomly 
assigned to the three cohorts. The sample size chosen is based on clinical judgment 
consultation with physicians and a biostatistician, and no formal sample size or power 
calculation was conducted. 
Interim Analysis:  
No interim analysis will be conducted for this study. 
Safety Monitoring Committee: 
A Safety Monitoring Committee (SMC) will be assigned by the Sponsor prior to the 
beginning of the study and will provide oversight of the study throughout the duration of the 
study period (Day 1 through Day 365) as needed. Ad hoc meetings will be convened if any 
predefined stopping rules are met, or any serious vaccine-related events or trends are 
observed. 
Further details regarding data safety monitoring guidelines will be included in the SMC 
Charter, which is the governing document that supersedes this section of the protocol. 
 

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1.1.   Schedule of Trial Activities 
Table 1: Schedule of Activities 
Screening 
Active Study Period 
                                   Follow-up Period 
  Study Day 
Day -45 
to  
Day -1 
Day   
1 
Day 
8 
(ET)f 
Day   
15 
Day 
29 
(ET)f 
Month 2 
Day 60 
Month 4 
Day 120 
Month 6 
Day 180 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Telephone call visit 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
+ 2  
±2 
 
±2 
 
±7 
±7 
±7 
±7 
±7 
±7 
Informed consent 
X 
  
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
  
 
 
 
 
 
 
 
 
 
Medical history 
X 
X  
 
 
 
 
 
 
 
 
 
Serologya 
X 
  
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
  
 
 
 
 
 
 
 
 
 
Alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test b 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
Xc 
 
Xc 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
  
X 
  
 
 
 
 
 
 
 
 
Distribute Solicited Symptom Diary 
  
X 
  
 
 
 
 
 
 
 
 
Review Solicited Symptom Diarye  
  
  
Xf 
 
 
 
 
 
 
 
 
Review prior & concomitant medication 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Query for AEs, SAEs, AESIs and NOCIs 
 
X 
X 
X 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 

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Screening 
Active Study Period 
                                   Follow-up Period 
  Study Day 
Day -45 
to  
Day -1 
Day   
1 
Day 
8 
(ET)f 
Day   
15 
Day 
29 
(ET)f 
Month 2 
Day 60 
Month 4 
Day 120 
Month 6 
Day 180 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Telephone call visit 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
+ 2  
±2 
 
±2 
 
±7 
±7 
±7 
±7 
±7 
±7 
Sample Collection for Immunogenicity Assessments 
 
 
 
 
 
 
 
 
 
 
Serum sample - BT50, VP1 specific IgA and IgG 
 
X 
X 
 
X 
 
 
X 
 
 
 
Nasal Swab (SAMTM Device) - VP1 specific IgA 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Saliva Sample - VP1 specific IgA 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Breastmilk - VP1 specific IgA, Enterocyte 
culture neutralizing antibodies, and BT50h 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Infant Stool - VP1 specific IgA 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Notes:  
Tele-health appointment (by phone)  
a Serology- human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV)  
b Serum pregnancy tests will be done at screening. Point-of-Care urine pregnancy test will be performed before dosing on Day 1 and women found positive with urine pregnancy 
test will not be enrolled during this study.  
c Targeted exam: at a minimum, assessments of the skin, respiratory system, cardiovascular system, and GI (abdomen, liver, and spleen) will be included. 
d Blood pressure, heart rate, and respiratory rate will be measured after the subject has been resting in a sitting position for 5 minutes.  
e At the discretion of PI and/or per subject request to evaluate any of the expected reactogenicity symptoms or any unexpected symptoms of concern, a contact must occur as soon 
as possible between the subject and the Investigator, or a medically qualified member of the study site staff, to assess if an unscheduled visit is required. 
f Early termination assessments. Review of solicited symptoms should be included if the subject drops out before Day 8. Day 29 procedures should be performed if the subject 
drops out before Day 29 on the day of early termination. 
g TEAEs will only be collected during the Active Study period (from time of first dose through 4 weeks post dose). Only SAEs, AESIs and NOCIs will be collected during the 
Follow-up Period.   
h Breastmilk VP1 specific IgA will be tested at the indicated intervals in the table. Breastmilk enterocyte culture neutralizing antibodies and BT50 will be tested at various time 
points if feasible. 

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2. 
INTRODUCTION 
2.1. 
Indication  
Bivalent GI.1 and GII.4 vaccines are being investigated for the prevention of noroviral 
gastroenteritis caused by norovirus GI.1 and GII.4. 
2.2. Background 
2.2.1. Background of Disease 
Norovirus (NoV) infection remains a leading cause of Acute gastroenteritis (AGEs) globally, with 
a prevalence of 16% (Liao et al., 2021). Noroviruses are a genetically diverse group of small, non-
enveloped, single-stranded positive sense (RNA) viruses belonging to the Caliciviridae family 
(Bresee et al., 2002). Genogroups I, II and IV are human-transmitted. Genogroup I and II account 
for the majority of norovirus outbreaks.  Each genogroup is further divided into genotypes based 
on the similarity of the amino acid sequence of the major viral capsid protein, VP1 (Atmar and 
Estes, 2012). Genogroup I and II account for the majority of norovirus outbreaks (Vega et al., 
2014). The classic symptoms of NoV infection include sudden onset of vomiting, abdominal 
cramps, watery diarrhea, and other clinical symptoms such as headache, chills, and myalgias. 
Currently, there is no specific treatment modality for NoV infection. The standard treatment is oral 
rehydration with fluids and electrolytes (Glass et al., 2009). In 2016, the World Health 
Organization (WHO) stated that the development of a NoV vaccine should be considered an 
absolute priority. It is important to develop prevention methods like vaccines considering the 
NoV-associated risk (Esposito and Principi, 2020). Despite a large medical need and years of 
development, no vaccine is licensed for use in any population for NoV infection. 
2.2.2  Non-clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine 
Vaxart has conducted multiple preclinical studies of our norovirus vaccine candidate in mice and 
ferrets, further details are available in the Investigator’s Brochure. The preclinical and clinical data 
on VXA-G1.1-NN and on influenza HA (with the same exact vector backbone) demonstrates a 
29-fold increase in neutralizing antibody responses after single dose enteric-coated tablet 
administration (Liebowitz et al., 2020), confirming that VXA-G1.1-NN and VXA-GII.4-NS are 
capable of eliciting robust antibody responses to VP1 following oral tablet delivery. 
2.2.3 Clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine 
Vaxart has completed four Phase 1 studies in over 200 healthy volunteers with our monovalent 
tableted norovirus GI.1 oral tablet vaccine candidate and one Phase 1b study with our bivalent 
tableted vaccine candidate (co-administration of GI.1 and GII.4 vaccines).  In all studies, the 
primary endpoint was safety, and the secondary endpoint was immunogenicity. In the bivalent 
study, potential interference with co-administration was also evaluated.  These studies indicate that 
the vaccine was safe and generally well tolerated, and there have been no severe adverse events 

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(SAEs) attributed to vaccine. The vaccine has generated robust immune responses including 
systemic and mucosal antibodies as well as immunoglobulin A + (IgA) and immunoglobulin G 
(IgG) + memory B cells. In addition to increase in serum blocking titer fifty assay (BT50) titers, 
vaccine recipients also developed mucosally primed VP1-specific circulating antibody secreting 
cells (ASCs), IgA+ memory B cells expressing gut-homing receptor (α4β7), and fecal IgA, 
indicating substantial and local responses potentially relevant to prevent norovirus infection (Kim 
et al., 2018).  
 
During the Phase 1 dose-ranging study VXA-NVV-104, a total of 65 healthy older adult volunteers 
ages 55-80 (in two age cohorts) were evaluated for immunogenicity, safety, and tolerability at 
three dosing levels of monovalent GI.1-NN: low, medium, and high. Preliminary results of this 
Phase 1 study indicate this oral norovirus vaccine candidate was safe, well-tolerated, and induced 
similar immune responses in this older population compared to previous results in younger 
volunteers.  
 
In an open label Phase 1b boost optimization study (VXA-NVV-105), immunogenicity, safety, 
and tolerability of repeat-dose administration with varying boost schedules were evaluated in 30 
healthy adults (18-55 years). VXA-GI.1 was found to be safe and generally well-tolerated in 4-
week, 8-week and 12-week boost schedules. All solicited symptoms were graded as mild or 
moderate severity, and none required treatment or study discontinuation. During the active period 
there were no related unsolicited AEs and no related SAEs, AESI or NOCIs. There were no SAEs, 
AESIs, or NOCIs reported during the safety follow-up period. There were no deaths during the 
study. Clinical laboratory data, vital signs data, and physical examination findings were within 
normal ranges and those reporting deviations were mild and transient. No clinically significant 
abnormal physical examination findings were noted. 
  
2.3  Trial Rationale 
Noroviruses are a genetically diverse group of small, non-enveloped, single-stranded positive-
sense RNA viruses belonging to the Caliciviridae family, and currently, it is the main viral cause 
of acute gastroenteritis (AGEs) in most countries worldwide. After adoption of the rotavirus 
vaccine throughout the world, norovirus infection has been one of three major causes of infant 
diarrheal disease.  It was estimated that each year NoVs cause 64,000 episodes of diarrhea 
requiring hospitalization and 900,000 clinic visits among children in industrialized countries, and 
up to 200,000 deaths of children <5 years of age in developing countries (Patel, et al). Hence, there 
is an urgent public health need for the rapid development of novel interventions to prevent the 
spread of this disease.  
An effective NoV vaccine must prevent the two most common NoV genotypes, GI.1 and GII.4, 
and Vaxart’s bivalent norovirus vaccine consists of VXA-G1.1-NN and VXA-GII.4-NS. Vaxart’s 
norovirus oral tablet vaccine uses Vaxart’s non-replicating adenoviral-based oral vaccine platform 
(vector adjuvant antigen standard technology (VAAST)), which has been studied to be well 
tolerated and safe in over 600 healthy adult subjects who have been enrolled in studies to evaluate 
the safety, tolerability, and immunogenicity of vaccines built on the VAAST platform. Notably, 
Vaxart’s norovirus oral tablet vaccine is highly immunogenic in humans, inducing serum 
antibodies and potent mucosal responses. 

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A unique and advantageous immune response elicited by oral vaccination is the induction of 
antibodies derived from mucosal cells. Given that the mucosal route of immunization produces 
superior mucosal immunity compared to injected vaccines, it is hypothesized that GI.1/GII.4 
bivalent oral vaccine may enable higher degrees of mucosal protection against infection when 
compared to a parenteral immunization method. 
Presently, norovirus gastroenteritis is a contagious disease that can affect all age groups, and 
infants aged 6 to 23 months have the highest norovirus disease burden in children. A study 
published by Labayo and colleagues demonstrated the passive transfer of IgA in breastfeeding 
moms infected with NoV may inhibit norovirus diarrheal disease in their nursing infants (Labayo 
et al, 2020).  Although several phase 1 norovirus studies have shown a robust immune response in 
healthy subjects when given Vaxart’s norovirus G1.1 and G2.4 monovalent and bivalent vaccines, 
the immune response to orally administered bivalent GI.1/GII.4 norovirus vaccine in healthy, 
lactating females is still unknown.  
 
Unpublished data from Vaxart in collaboration with Stephanie Langel and colleagues show 
promising results for inducible breastmilk immunogenicity after receipt of a Vaxart vaccine 
construct in animal models. Pregnant/postpartum ferrets were orally administered Vaxart influenza 
vaccine and subsequently produced IgG and IgA antibodies to influenza in their breast milk.  
Breast milk from mucosally immunized ferret mothers was found to be capable of neutralizing 
influenza H1N1 by microneutralization assay. The bivalent GI.1/GII.4 norovirus vaccine uses the 
same VAAST platform as Vaxart influenza vaccine, thus there is a potential for lactating women 
to induce immunogenicity towards NoV in their breastmilk.  Besides directly neutralizing 
pathogens, IgA has other functional activity, which may greatly underestimate IgA protective 
responses.   Following immunization of lactating, postpartum mothers with Vaxart’s oral tablet, it 
is hypothesized that nursing infant incidence of norovirus diarrheal disease will be significantly 
lower due to the passive transfer of norovirus breast milk IgA antibodies, which may also reduce 
further viral transmission and thus disease burden within the family. 
 
Therefore, in this phase 1 study, we will evaluate the immunogenicity effect of orally administered 
bivalent GI.1/GII.4 norovirus vaccine in the breast milk of healthy, lactating female volunteers 
and fecal samples (exploratory) in their infants. Additionally, the study will evaluate the safety 
and tolerability of the norovirus bivalent vaccine in lactating females; the dose of the vaccine will 
be 5×1010 IU or 1×1011 IU per strain given as a single bivalent dose. 
 
This trial is not powered as an efficacy study and any cases of norovirus acute gastroenteritis during 
the study period will be evaluated as exploratory. 
2.4 Risk / Benefit Assessment   
2.4.1 Known Potential Risks to the Subjects 
More detailed information about the known and expected risks and reasonably expected adverse 
events of Bivalent GI.1/GII.4 NoV vaccine may be found in the Investigator’s Brochure (IB). 
Below are the expected treatment emergent adverse events (TEAEs) with Grade 1-3 symptoms: 

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1. Diarrhea 
2. Nausea 
3. Abdominal pain 
4. Malaise/fatigue 
5. Headache 
6. Fever 
7. Vomiting 
8. Anorexia 
9. Myalgia (muscle pain) 
2.4.2 Known Potential Benefits to the Subject 
Benefits to individual subjects may include receipt of a potentially efficacious NoV vaccine. 
Clinical data from Phase 1 studies demonstrated that VXA-G1.1-NN and VXA-G2.4-NS generated 
robust immune responses. 
 
Since these are experimental vaccines against NoV, there are no proven benefits to the subjects for 
their participation in this research study. This vaccine may successfully be developed to address a 
common and sometimes serious gastrointestinal infection. 
 
2.4.3 Overall Benefit Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this study, the 
potential risks identified in association with Bivalent GI.1/GII.4 NoV vaccine are justified by the 
anticipated benefits that may be afforded to subjects and potentially their infants with noroviral 
gastroenteritis caused by NoV GI.1 and GII.4. 
3. 
TRIAL OBJECTIVE AND END POINTS 
3.1. Objectives 
3.1.1. Primary Objectives 
• Safety 
o To determine the safety and tolerability of oral bivalent dosing regimen of GI.1 
and GII.4 norovirus vaccine administration in healthy lactating female 
participants. 
 
• Immunogenicity 
o To determine the short-term immunogenicity of oral bivalent GI.1/GII.4 
norovirus vaccine administration in healthy lactating female participants and 
most critically, the association with vaccine specific antibody responses in 
breastmilk.  

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3.1.2. Secondary Objectives 
• Safety 
o To determine the long-term safety of bivalent GI.1/GII.4 norovirus vaccine 
through 12 months after the last vaccination. 
 
• Immunogenicity 
o To assess the immunogenicity of oral bivalent GI.1/GII.4 norovirus vaccine 
administration in healthy lactating female participants and most critically, the 
association with vaccine specific antibody responses in breastmilk.  
3.1.3. Exploratory Objectives 
• Immunogenicity 
o To determine the additional immunogenicity parameters of bivalent GI.1/GII.4 
norovirus vaccine including immunogenicity response in breastfed infants. 
o To determine the clinical effects in subjects presenting with acute gastroenteritis 
symptoms during the study period.  
3.2. End Points 
3.2.1. Primary End Points 
• Safety 
o Frequency, duration, and severity of solicited symptoms of reactogenicity (local, 
systemic) for 1 week following each dose of study drug  
o Frequency, duration, and severity of unsolicited treatment-emergent adverse 
events (TEAEs), serious AEs (SAEs), adverse events of special interest (AESIs), 
and new onset of chronic illness (NOCIs) through the active period (4 weeks post 
last dose). 
 
• Immunogenicity 
o Serum VP1 specific (GI.1 and GII.4) IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by dose level  
▪ Geometric mean concentration (GMC) at Day 1, Day 8 and Day 29  
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 
to Day 29 
o Breastmilk VPI specific (GI.1 and GII.4) IgA through the active period measured 
by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 15, and Day 
29  
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to 
Day 15, and from Day 1 to Day 29   

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o The number of subjects in each dose group that had a 2-fold GMC rise or greater 
in breast milk VP1 specific IgA (GI.1 and GII.4) between Day 1 and any other 
timepoint.  
3.2.2. Secondary End Points 
• Safety 
o Frequency, duration, and severity of all SAEs, AESIs, and NOCIs through 12 
months after last study drug dose 
 
• Immunogenicity                                                 
o Serum VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 180 
o Breastmilk VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug 
dose measured by Meso Scale Discovery (MSD) by dose level 
▪ Geometric mean concentration (GMC) at Day 60, Day 120, and Day 
180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 60, from Day 1 
to Day 120, and from Day 1 to Day 180 
o Serum VP1 specific (GI.1 and GII.4) IgG through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, and 
Day 180   
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to 
Day 29, and from Day 1 to Day 180  
o Serum Blocking titers 50 (BT50) (GI.1 and GII.4) through 6 months after study 
drug dose measured by Histo-blood group antigen (HBGA) assay by dose level 
▪ Geometric mean titer (GMT) at Day 1, Day 8, Day 29, and Day 180   
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to 
Day 29, and from Day 1 to Day 180 
 
 

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3.2.3. Exploratory End Points 
• Efficacy 
o Occurrence of norovirus acute gastroenteritis 
 
• Immunogenicity 
o Saliva VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by 
Enzyme-linked immunosorbent assay (ELISA) by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 
60 and Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 
1 to Day 29, from Day 1 to Day 60, and from Day 1 to Day 180 
o Nasal VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Meso 
Scale Discovery (MSD) by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 
60 and Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 
1 to Day 29, from Day 1 to Day 60, and from Day 1 to Day 180 
o Infant stool VP1 specific (GI.1 and GII.4) IgA measured by Enzyme-linked 
immunosorbent assay (ELISA) by dose level 
▪ Geometric mean concentration (GMC) Day 1, Day 29, and Day 60 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 29 and from 
Day 1 to Day 60 
o Breastmilk Blocking titers 50 (BT50)  (GI.1 and GII.4) measured by Histo-blood 
group antigen (HBGA) assay by dose level 
▪ Individual subject titers on samples and some timepoints that have a 
high likelihood of success, assuming the assay works in breast milk 
samples 
o Breastmilk Enterocyte culture neutralizing antibody titers (GI.1 and GII.4) 
measured by norovirus neutralization in enterocyte culture 
▪ Individual subject titers on samples and some timepoints that have 
a high likelihood of success, under the assumption that the assay works 
in breast milk samples. At the date of this protocol, only serum GII.4 
neutralizing antibodies have been successfully measured. 
 
4. 
TRIAL DESIGN 
4.1. Overall Description of Trial Design  
This is a multi-center, double-blind, randomized, placebo-controlled, single dose, dose ranging 
study in healthy, breastfeeding, female volunteers (≥18 years). The study will randomize 76 
subjects and their breastfed infants aged >30 days to 11 months of age into three arms.  

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After reviewing and signing an informed consent, the subjects will undergo screening assessments 
to determine study eligibility up to a 45-day Screening Period. 
On Day 1 of the randomized portion, subjects will be randomized in a 2:2:1 ratio to one of the 
three treatment arms to receive active vaccine at medium dose or high dose or placebo, as follows 
(Figure 1):  
 
Figure 1 
 
All subjects will be monitored for Solicited Symptoms of Reactogenicity (GI and systemic) for 1 
week following the study drug dose and unsolicited AEs for 28 days post study drug dose (until 
Day 29) during the Active Period. Subjects will then enter the Follow-up period after Day 29 and 
will be monitored for specified unsolicited adverse events (SAEs, AESIs, and NOCIs) through 
Day 365 (Month 12) for safety and durability of immune response. Subjects will have samples 
(nasal, saliva, and serum) collected at the site, and will also self-collect samples (breastmilk and 
infant stool) at home for evaluation of immunogenicity as specified in the SoA (Table 1).  
 
 

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Table 2 Study Design 
Treatment 
Group 
Study Drug 
Per Strain Dose 
(IU) +/- 0.5 log 
Total Dose 
(IU/dose) 
Dosing Schedule 
No of Subjects 
Arm 1 
(n=30) 
Bivalent 
GII.4/GI.1 
vaccine 
5×1010 
1×1011 
Day 1 
30 
Arm 2 
(n=30) 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
Day 1 
30 
Arm 3 
(n=16) 
Placebo 
N/A 
N/A 
Day 1 
16 
Total 
76 
Abbreviations: IU=infectious units 
After vaccination on Day 1, the study will include an Active Study Period that runs through 4 
weeks after administration (Day 29), and a Follow-up Period of one year for safety and duration 
of immune response. Study assessments will be conducted as shown in the SoA (Table 1). In 
addition, subjects will be contacted by phone between site visits to monitor for safety as specified 
in the SoA (Table 1). 
A subject is considered to have completed the study if she completes the study active period at 
Day 29 (End of Study Active Period). Following completion of the Day 29 visit by all subjects the 
database will be cleaned and locked and the study unblinded. The Clinical Study Report (CSR) 
will be written based on the Day 29 dataset. 
 
A subject is considered to have completed the Follow-up Period if she remains in the study through 
Day 365 (Month 12). Following completion of the Day 365 tele-health appointment for all 
subjects, the safety database will be cleaned and locked, and data collected during the Follow-up 
Period will be included in a CSR addendum. 
 
All subjects will be monitored for Solicited Symptoms of Reactogenicity (GI and systemic) for 1 
week following the study drug dose and unsolicited AEs for 28 days post study drug dose (until 
Day 29) during the active period. The subjects will then enter the Follow-Up Period after Day 29 
and will be monitored for SAEs, AESIs, and NOCIs through Day 365 (Month 12) for safety. 
Subjects will also have samples collected for evaluation of immunogenicity and durability of 
immune response as specified in the SoA (Table 1). 
 
Planned Number of Subjects: 
 
A total of 76 healthy, lactating, female subjects aged ≥18 years and their breastfed infants aged 
>30 days to 11 months of age will be randomized and assigned to the three cohorts: placebo, 
medium dose (total 1×1011 IU/dose), or high dose (total 2×1011 IU/dose).  
 

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Study Duration: 
 
For each subject, study participation is expected to last as follows: 
 
Table 3: 
Study Duration 
Screening period:  
Up to 45 days  
Active study period: 
29 days  
Follow-up period for safety and 
duration of immune response, 
SAEs, AESIs, NOCIs 
12 months (from the study dose at Day 1) 
Total duration: 
Approximately 14 months from Screening to 
Month 12/Day 365 post vaccination  
 
4.2 
Scientific Rationale of Trial Design 
This study is designed as a standard double-blind placebo-controlled single administration, dose-
ranging study to evaluate the effect of 2 different doses (high and medium dose) of VXA-GII.4-
NS plus VXA-G1.1-NN in the target population, compared with placebo. 
4.3 
Justification for Dose Selection 
Vaxart has previously completed dose escalation (Protocol VXA-G11-101) and dose optimization 
(Protocol VXA-G11-102) studies in its initial Phase 1 NoV vaccine studies to demonstrate the 
safety, tolerability, and immunogenicity of the VXA-G1.1-NN vaccine candidate. A Phase 1b, 
double-blind, placebo-controlled study (Protocol VXA-NVV-103) with VXA-G1.1-NN and 
VXA-GII.4-NS with monovalent or bivalent dosing have also been completed. Additionally, dose 
ranging studies from 1×108 IU – 1×1011 IU (2 doses) have been studied across multiple studies 
with the same vaccine platform. 
Safety results from these completed oral tablet vaccine studies support investigations of bivalent 
administration of the VXA-G1.1-NN and VXA-GII.4-NS vaccine candidates at single total dose 
of 1×1011 IU per vaccine or 2×1011 IU per administration. 
4.4 
End of the Study Definition 
A subject is considered to have completed the study if he/she completes the study active period at 
Day 29 (End of Study Active Period). Following completion of the Day 29 visit by all subjects the 
database will be cleaned and locked, and the study unblinded. The CSR will be written based on 
the Day 29 dataset. 
A subject is considered to have completed the Safety Follow-up Period if he/she remains in the 
study Day 365 (Month 12). Following completion of the Day 365 tele-health appointment of all 
subjects, the safety database will be cleaned and locked, and data collected during the Follow-Up 
Period will be used to generate a CSR addendum. 

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4.5 
Premature Termination or Suspension of Trial 
The Sponsor or designee reserves the right to terminate the study at any time for any reason at the 
sole discretion of the Sponsor. This trial may be temporarily suspended, or prematurely terminated 
if there is sufficient reasonable cause. Written notification, documenting the reason for trial 
suspension or termination, will be provided by the suspending, or terminating party to study 
subjects, Investigators, funding agency, the Investigational New Drug (IND) Sponsor and 
regulatory authorities. If the study is prematurely terminated or suspended, the site Principal 
Investigator (PI) will promptly inform study subjects, the site Institutional Review Board (IRB) (if 
applicable) and will provide the reason(s) for the termination or suspension. Study subjects will be 
contacted, as applicable, and be informed of changes if any, to the study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB/IEC, Food and Drug Administration (FDA) and/or South 
African Health Products Regulatory Authority. 
4.6 Trial and Site Start and Close-Out  
4.6.1 First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of subjects. 
The first act of recruitment is the first site open and will be the study start date. 
4.6.2 Study/Site Termination 
The Sponsor or designee reserves the right to close the study site at any time for any reason at the 
sole discretion of the Sponsor. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed. 
 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given to Sponsor and subjects in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the Investigator. 

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• Total number of subjects included is achieved earlier than expected. 
The Investigator shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up. 
5. 
SELECTION OF TRIAL POPULATION 
5.1. 
Inclusion Criteria 
To be eligible for this study, subjects must meet all the following: 
Age 
1. 
≥18 years old at the time of signing the Informed Consent Form (ICF) and her infant 
will be aged >30 days to 11 months of age at the time of the participants’ study drug 
administration 
Type of Subjects 
2. 
In stable and good general health, without significant medical illness, based on 
medical history, physical examination (including vital signs), and clinical judgment of 
the investigator. 
3. 
Lactating females willing and able to provide informed consent which includes 
compliance with the requirements and restrictions listed in the ICF and in the 
protocol. 
4. 
Lactating females who are willing to provide consent for their breastfed infant will be 
enrolled in the study 
5. 
Negative pregnancy test prior to dose 
6. 
Available for all planned visits and tele-health appointments, and ability to comply 
with all study-related evaluations (including ability and willingness to swallow 
multiple small enteric-coated tablets per study dose). 
7. 
Plan to continue breastfeeding as the main source of the infant's nutrition for at least 1 
month (longer is preferred with goal of 6 months post dose if possible) from the time 
of study drug administration. Exclusive breastfeeding is acceptable but not necessary. 
8. 
The nursing infant is the product of a singleton pregnancy AND does not have any of 
the following: 
a. Any abnormality that may interfere with breastfeeding or milk 
absorption 
b. Active infection (may be included if the infection resolves and the 
subject is re-assessed during the screening period) 
c. Infant has any other medical condition or abnormality that, in the 
opinion of the investigator, could compromise the infant's appropriate 
inclusion in this study including interference with the interpretation of 
study results (such as malabsorption) 
d. One or more documented brief resolved unexplained events (BRUE) 
e. Extreme prematurity (infants who were born at less than 28 weeks 
gestation) 

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f. 30 days of age or less at the participant's study drug administration OR 
greater than 11 months of age at the participant's study drug 
administration 
g. Prior hospitalization that is not exclusively for hyperbilirubinemia 
requiring phototherapy 
h. Any genetic/metabolic disease 
i. Any chronic illness requiring long term medication 
9. 
Subjects must be willing to use a highly effective form of contraception for 30 days 
prior to vaccination and until 60 days after the vaccination. Acceptable forms are oral, 
implantable, intrauterine, transdermal, intravaginal, injectable, double barrier or 
abstinence (subjects using diaphragms must also use condom). The form of 
contraception must be approved by the investigator. 
Subject Exclusion Criteria: 
The participants must be excluded from participating in the study if they meet any of the 
following: 
1. 
Presence of a fever ≥ 38oC measured orally at baseline, on Day 1 prior to vaccination.  
(Assessment may be repeated once during screening period) 
2. 
Acute disease within 72 hours prior to vaccination is defined as the presence of a 
moderate or severe illness (as determined by the Investigator through medical history 
and physical exam). (Assessment may be repeated once during screening period.) 
3. 
Who have received antipyretic/analgesic medications within 24 hours prior to the 
intended vaccine administration 
4. 
Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), 
or hepatitis C virus (HCV) tests at the screening visit 
5. 
History of hypersensitivity or allergic reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin 
6. 
History of serious reactions to vaccination such as anaphylaxis, respiratory problems, 
hives, or abdominal pain 
7. 
Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) 
including the institution of new medical/surgical treatment or significant dose alteration 
for uncontrolled symptoms or drug toxicity within 3 months of screening and 
reconfirmed at baseline 
8. 
History of significant pregnancy-related complications during this pregnancy, 
including but not limited to pre-eclampsia, eclampsia, or gestational diabetes unless a 
full resolution is documented. 
9. 
Cancer, or treatment for cancer, within the past 3 years (excluding fully treated and 
resolved basal cell carcinoma or squamous cell carcinoma)  
10. 
Presence of immunosuppression or medical condition possibly associated with 
impaired immune responsiveness, including diabetes mellitus  

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11. 
History of irritable bowel disease or other inflammatory digestive or gastrointestinal 
condition that could affect the distribution/safety evaluation of an orally administered 
vaccine targeting the mucosa of the small intestine. Such conditions may include but 
are not limited to: 
a. Any history of:  
i. Malignancy 
ii. Malabsorption  
iii. Pancreatobiliary disorders 
iv. Inflammatory bowel disease 
v. Irritable bowel disease 
vi. Hiatal hernia 
vii. Surgical resection 
b.    History of diagnosis or treatment in past 5 years of: 
v. Esophageal or gastric motility disorder 
vi. GERD (Will allow for subjects with a history of pregnancy-related GERD 
if fully resolved for >3 months and no other history of GERD diagnosis  
vii. Peptic ulcer 
viii. Cholecystectomy 
12. 
Any condition that resulted in the absence or removal of the spleen  
13. 
History of any form of angioedema  
14. 
Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could 
make blood draws problematic 
15. 
History of GI bleeding including hematochezia (blood in stool) or melena (black 
stool) 
16. 
Any significant hospitalization within the last year which in the opinion of the 
investigator or sponsor could interfere with study participation. 
17. 
Any of the following history or conditions that may lead to a higher risk of clotting 
events and/or thrombocytopenia: 
a. Family or personal history of bleeding or thrombosis 
b. History of heparin-related thrombotic events, and/or receiving heparin treatments 
c. History of autoimmune or inflammatory disease 
d. Presence of any of the following conditions known to increase the risk of 
thrombosis within 6 months prior to screening: 
i. Recent surgery other than fully healed cesarean delivery or excision/ 
biopsy of cutaneous lesions  
ii. Immobility (confined to bed or wheelchair for 3 or more successive days)  
iii. Head trauma with loss of consciousness or documented brain injury  
iv. Receipt of anticoagulants for prophylaxis of thrombosis 
v. Recent clinically significant infection 
18. 
Any other condition that in the clinical judgment of the investigator would jeopardize 
the safety or rights of a participant taking in the study, would render the participant 
unable to comply with the protocol, or would interfere with the evaluation of the study 
endpoints 

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19. 
Receipt of a licensed vaccine (including any COVID-19 vaccines under Emergency 
Use Authorization) within 14 days prior to study drug dose or planned administration 
during the study active period. 
20. 
Use of antibiotics, proton pump inhibitors, H2 blockers, or antacids within 7 days prior 
to study drug administration or planned use during the active study period 
21. 
Use of medications known to affect the immune function (including but not limited to 
systemic corticosteroids, leukotriene modifiers, and JAK inhibitors) within 2 weeks 
before study drug administration or planned use during the active study period  
22. 
Daily use of nonsteroidal anti-inflammatory drugs within 7 days prior to study drug 
administration or planned use during the active study period  
23. 
Donation or receipt of blood or blood products within 30 days prior to study drug 
administration or planned donation during the active study period 
24. 
Participants participating in any clinical trial with another investigational product 
30 days prior to the first trial visit or intend to participate in another clinical trial at any 
time during the conduct of this trial 
25. 
Are first-degree relatives of individuals involved in trial conduct. 
26. 
Positive urine drug screen for drugs of abuse at screening 
27. 
Positive alcohol test at screening or baseline 
28. 
History of drug, alcohol, or chemical abuse within 1 year of screening 
5.2. Early Termination/Withdrawal Criteria 
All procedures for Day 8 visit should be completed for Early Termination (ET) assessment, 
including Review Solicited Symptom Diary if ET occurs prior to Day 8 as shown in the SoA 
(Table 1). 
 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A subject may 
discontinue/withdraw study drug for reasons including but not limited to: 
• Adverse event 
• Death 
• Lost to follow-up 
• Physician decision 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject (only for discontinuing study drug, but will remain in study) 
The reason for subject discontinuation from study drug will be recorded in the electronic case 
report form (eCRF). 
At the time of withdrawal from the study, the ET visit should be completed, as shown in the SoA 
(Table 1). 

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If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
5.3. Lost to Follow Up Procedure 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, tele-health 
appointment and, if necessary, a certified or registered letter to the subject’s last 
known mailing address or local equivalent methods). All these contact attempts 
should be documented in the subject’s research record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
5.4. Screening Failure 
Screening failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently entered in the study.  
 
Re-screening outside the screening period will be possible on a case-by-case basis following 
Sponsor approval. Subjects allowed to be re-screened will be assigned a new screening number 
and must undergo all screening procedures again. Subjects cannot re-screen more than once and 
will be determined to be permanent screen failures after the second screening determines a subject 
is ineligible.  Re-assessment of not clinically significant abnormal and/or out of range parameters 
within the screening period is allowed per Investigators’ discretion. 
5.5. Classification of Subjects Who Discontinue the Study 
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the eCRF. Reasons are listed below from the most significant 
to the least significant: 
 
 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 37 of 81 
 
 
Table 5:  
Investigational Product Dosing 
Intervention 
Name 
VXA-G1.1-NN 
VXA-GII.4-NS 
Placebo 
Type 
Biologic 
Biologic 
Matching placebo 
Dose 
Formulation 
Enteric-coated tablets 
Enteric-coated tablets 
Enteric-coated tablets 
Dosing 
Schedule 
Day 1 
Day 1 
Day 1 
Route of 
Administration 
Oral 
Administration 
instructions 
Subjects should fast and refrain from ingesting solid food for at least 4 hours prior to oral dosing. 
A trained member of the site study staff will dispense the tablet(s) constituting their assigned 
dose to the subject. The subjects will swallow the tablets with 360 to 480 mL of water or clear 
fruit juice (acidic, such as cranberry juice) followed by a light snack (e.g., crackers) at time of 
dosage administration to aid in tablet transit out of the stomach. Normal food consumption may 
resume 90 minutes after dosing. For more information refer to the study specific Pharmacy 
Manual. 
Sourcing 
Study drug will be provided to the sites by the Sponsor or designated representative. 
Table 6: 
Study Arm(s) 
Arm Title* 
Arm 1 
Arm 2 
Arm 3 
Arm Type 
Experimental 
Experimental 
Placebo 
Arm Description 
Bivalent GII.4/GI.1 
vaccine 
Bivalent GII.4/GI.1 
vaccine 
Placebo 
Per Strain Dose 
(IU) +/- 0.5 log 
5×1010 
1×1011 
N/A 
Total Dose 
(IU/dose) 
1×1011 
2×1011 
N/A 
6.4. Formulation, Appearance, Packaging, and Labelling 
Formulation: 
Both the VXA-G1.1-NN and VXA-GII.4-NS are formulated as small enteric-coated tablets. 
Packaging and Labelling: 
The tablets are packaged into foil-sealed, high-density polyethylene (HDPE) screw-cap containers 
with 10 tablets per bottle. 
All packaging and labeling operations for study drug will be performed according to Good 
Manufacturing Practices (GMP) for Medicinal Products and the relevant regulatory requirements. 
Label text for the study drug bottle will at a minimum include name of the manufacturer, the 
protocol number, the name of the product, the lot number of the product, the concentration of the 
vaccine, the date of manufacturing or expiration. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
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Secondary packaging of the study drug upon dispensing from the pharmacy to the clinical staff for 
subject dosing will be determined with consideration of the site’ pharmacy standard operating 
procedures and outlined in the study pharmacy manual. 
The final subject use dispensing container (cup or secondary bottle) will be appropriately labeled 
with specific requirements for the country and deemed necessary per the site’s standard operating 
procedures (i.e., subject randomization number, total tablet count, dispensing date and time etc.) 
6.5. Product Storage and Stability 
Storage: 
The Investigator will be personally responsible for product management or will designate a study 
site staff to assume this responsibility.  
Both the VXA-G1.1-NN and VXA-GII.4-NS DP should be stored at 2-8 °C. The DP tablets may 
be kept at room temperature during the dispensation and administration process for a brief period. 
Please refer to the study specific Pharmacy Manual for detailed information. 
Stability: 
Stability studies have been performed on similarly formulated tablets prepared from the same or 
similar adenovirus 5 constructs incorporating different antigens, including, VP1 Norwalk and other 
influenza antigens (e.g., hemagglutinin H1). The 2-8°C data indicate that drug product potency 
will remain within release specification prior to retest.  Additionally, data from accelerated stability 
studies indicate that handling at controlled room temperature or brief exposure to temperatures 
above room temperature (below 37°C) is acceptable for this product. 
6.6. Accountability Procedures 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for study drug received and any discrepancies are reported and resolved 
before use of study drug. 
Only subjects enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All bottles of study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study drug accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
At the end of the study active period, the unblinded monitor will conduct a final drug reconciliation 
for all subjects and the study site overall. All records of study drug administration, accountability 
records and study drug disposition records will be examined and reconciled by the study monitor. 
Further details will be provided in the study specific Pharmacy Manual. 
Further guidance and information for the final disposition of unused study drug are provided in 
the study specific Pharmacy Manual. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 39 of 81 
 
 
6.7. Randomization and Blinding 
6.7.1. Randomization Procedures 
Assignment of a Subject Number: 
New subjects once deemed eligible and enrolled in the study will also receive a randomization 
number and treatment assignment, based on the blinded randomization schedule. The subject 
number will be used as the primary identifier for the complete duration of the study. After the 
subject signed the informed consent form (ICF), the Investigator (or designee) will enter the 
subject into the Screening Log, once randomized or screen failed their data will be entered into the 
eCRF.  
Randomization: 
After signing an informed consent, the subjects will undergo screening assessments to determine 
study eligibility over a 45-day Screening Period. All subjects who sign a study specific informed 
consent form will have data entered into the EDC.  On Day 1, subjects will be randomized in a 
2:2:1 ratio to one of the three treatment arms to receive active vaccine or placebo (Table 6: Study 
Arm(s). 
6.7.2. Blinding and Unblinding Procedures 
Subjects, Investigators, site personnel and the Sponsor (except as described below) will be blinded 
to individual participant treatment assignment. 
Study drug doses will be prepared at the study sites by an unblinded research pharmacist(s) or 
designee who will be provided treatment assignment through a randomization schedule. 
Specifically designated Sponsor representative(s) will also have access to unblinded individual 
subject treatment assignments for the purposes of study-required activities, including management 
of study drug inventory, production of summaries of data for SMC review, and performance of 
bioanalytical analysis. These personnel will not be directly involved in the conduct of the study. 
An SMC may convene to review unblinded overall safety if deemed necessary to ensure the safety 
of study subjects (Section 10.2). 
Instructions for breaking the blind will be provided to the study site in case of a medical 
emergency. The Investigator has the sole responsibility for determining if unblinding of a subject’s 
treatment assignment is warranted. Subject safety must always be the first consideration in making 
such a determination. The Investigator must notify the Sponsor’s Medical Monitor (or designee) 
prior to unblinding a subject’s treatment assignment. The Investigator(s) must document and report 
to the Medical Monitor any breaking of the treatment code but must not disclose the result of 
unblinding. The date and reason that the blind was broken must be recorded in the source 
documentation. 
Appropriate personnel at the Sponsor (or designee) will unblind suspected unexpected serious 
adverse reactions (SUSARs) for the purpose as required per each local regulation. The Sponsor 

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will submit SUSARs to Regulatory Agencies in blinded or unblinded fashion according to local 
law. The Sponsor will submit SUSARs to Investigators in a blinded fashion. 
6.8. Treatment Compliance 
Subjects will receive study drug directly from the Investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and recorded in the electronic case report form (eCRF). The dose of study drug 
and study subject identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study drug. 
6.9. Overdose of Treatment 
Any overdose of intervention should be recorded in the eCRF (including quantity of the excess 
dose and the duration of the overdose). AEs associated with an overdose or incorrect 
administration of study drug should be recorded in the AE eCRF. An overdose will not be 
considered an SAE unless the outcome of the overdose meets seriousness criteria. 
The effects of acute overdose of VXA-G1.1-NN and VXA-GII.4-NS in human are unknown. 
No specific antidote for overdose is known. Study subjects should be managed with appropriate 
supportive care if overdose occurs. 
6.10. Concomitant Medications and Other Therapies 
Concomitant medication is defined as any prescription or over-the-counter preparation. 
Use of concomitant medication from 4 weeks before Day 1 through Day 29 (completion of Active 
Study period) must be recorded onto the eCRF from the subject’s medical file along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Medications for pre-existing medical conditions or required for a medical condition during the 
study are allowed if not considered exclusionary. 
The Sponsor's Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
Prohibited Concomitant Medication: 
Medications specifically prohibited in the exclusion criteria are not allowed during the Active 
Study period (Section 5.2 prior/concurrent therapy), unless deemed medically necessary by the 
Investigator. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
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7. SCHEDULE OF TRIAL PROCEDURES AND ASSESSMENTS 
7.1. Trial Procedures 
A schedule of trial procedures and their timing are summarized in the SoA (Table 1). The day of 
the first investigational product vaccination is considered to be Day 1. 
7.1.1. Procedure to be followed on Screening Period (Day -45 to Day -1) 
Before enrollment and before any study-related procedures are performed, voluntary, written 
study-specific informed consent will be obtained from the subject. Each signature on the ICF must 
be personally dated by the signatory. A copy of the signed and dated ICF must be given to the 
subject. The source data must reflect that the informed consent was obtained before participation 
in the study. 
 
After obtaining signed copy of written informed consent from the subject, the subject will undergo 
screening procedures as mentioned below: 
• The demographic information (i.e., age, ethnic origin, race, height (cm), body weight (kg), 
and body mass index (kg/m2) will be recorded. 
• Obtain history of drug abuse, alcohol abuse, and blood or plasma donation. 
• Obtain any medical history of clinical significance and details of any medications currently 
taken. 
• Measure vital signs, including blood pressure, pulse rate and respiratory rate after resting 
in a sitting position for at least 5 minutes. 
• Measure subject’s temperature (oral). Oral temperature is preferred for all visits. If 
unavailable, it is acceptable for clinical study sites to measure subject’s temperature 
according to site usual standard using tympanic thermometer instead of oral and this should 
be clearly documented. All subjects must use the study-provided thermometer for daily 
oral temperature checks for solicited symptoms in the week following vaccine dose. 
• Perform physical examination evaluating any clinically significant abnormalities within 
the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
cardiovascular; 
respiratory; 
gastrointestinal 
(GI); 
musculoskeletal; 
extremities; 
neurological; and lymph nodes.  
• Perform a serum pregnancy test for all subjects at screening. At screening all women will 
have a negative serum HCG. (Prior to dosing all women will have a negative urine HCG.) 
• Verify understanding of and compliance with protocol requirements for contraception (see 
Appendix 4).  
• Perform an alcohol test. 
• Verify understanding of requirement for breastmilk and infant stool collection. 
• Ensure that all inclusion criteria are met and that none of exclusion criteria are met for the 
subject and her infant.   
• Obtain a urine sample for urine drug screen test. 

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• Collect a blood sample to determine the subject’s Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) status.  
• If the subject and her infant pass all the inclusion and exclusion criteria at the end of the 
screening visit:  
1. Provide a manual breast pump set. Teach the subject how to use a manual breast 
pump properly. 
2. Provide kits with instructions for breastmilk sample collection, storage, and 
return. Teach the subject how to express breastmilk to provide a total of 10 ml 
of breastmilk from the right breast for each sample collection. Instruct the 
subject to consistently collect breastmilk samples from the right breast. Teach 
the subject how to properly freeze her milk after expression each time until all 
samples are collected and shipped. (The subject can use a manual breast pump 
if she does not wish to manually express her breastmilk. If the subject is unable 
to express or pump breastmilk from the right breast, she can collect breastmilk 
from the left breast and must consistently collect breastmilk samples from the 
left breast.)  
3. Provide kits with instructions for infant stool sample collection, storage, and 
return.  Teach the subject how to properly collect the infant stool sample and 
store it until the samples are ready to be shipped. 
4. Timepoints for breastmilk and infant stool sample collection must be 
thoroughly discussed with the subject. The subject must collect breastmilk 
sample and infant stool sample at baseline prior to the first dose (Day -2 to Day 
1). 
7.1.2. Procedure to be followed during Active Study Period (Day 1 to Day 29) 
It is anticipated that the procedures below will be conducted in a stepwise manner; ensuring that 
procedures listed prior to administration of the vaccine are conducted prior to that administration. 
The site does not need to wait the full 45 day screening period to start the active study period for 
the subject. 
• The Principal Investigator will ensure that all inclusion criteria and none of the 
exclusion criteria for the subject and her infant are met on Day1. 
• Ensure the subject collected baseline breastmilk sample (5ml-10ml) and infant stool 
sample between D-2 to D1. Review with the subject how the collection was done and 
if the samples were properly stored, prior to vaccination. If this was not done, the 
subject will need to reschedule the dosing visit ASAP and be reminded to collect 
baseline samples prior to the rescheduled visit. 
• A urine pregnancy test will be done for all subjects; site must confirm negative result 
before dosing. 
• Perform an alcohol test and site must confirm negative result before dosing. 
• Vital signs will be obtained, including temperature, blood pressure, pulse rate and 
respiratory rate after resting in a sitting position for at least 5 minutes. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
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• A targeted, and symptom-directed physical examination will be done for all subjects 
during the active study period visits. At a minimum, assessments of the skin, respiratory 
system, cardiovascular system, and GI (abdomen, liver, and spleen) will be included. 
• The subject’s randomization number will be noted.  
• Collect blood, nasal and saliva samples for Immunogenicity assessment prior to study 
drug administration. 
• Site staff member(s) will dispense/administer the investigational product. Please refer 
to the Pharmacy Manual for further instruction on this process.  
• Prior to study drug administration on Day 1, the subject’s temperature (oral) will be 
measured, and a trained member of the site study staff will dispense the tablet(s) 
constituting the assigned dose to the subject. 
• The site staff must observe the subjects for at least 30 minutes after study drug 
administration for any acute reactions. Any acute reactions are to be recorded in the 
subject’s source documents, on the AE page of the eCRF, as applicable.  
• Subjects will be asked to record symptoms of reactogenicity daily for 1 week after 
study drug administration on Day 1, using the Solicited Symptom Diary; the Solicited 
Symptom Diary will be collected from the subject on Day 8 and reviewed.   
• Subjects will be queried for unsolicited AEs for 28 days following the study drug 
administration and for SAEs, AESIs and NOCIs for 1 year following the study drug 
administration. 
• Subjects will return to the site on Day 8 and Day 29: 
1. Blood, nasal, and saliva samples will be collected for immunogenicity 
assessment on Day 8 and Day 29 as specified in the SoA (Table 1).  
2. Ascertain if the subject is still breastfeeding. Ensure the subject has also 
collected breastmilk sample and infant stool sample during the timepoints 
specified in the SoA (Table 1), if not then remind the subject. Review with the 
subject how the collection was done and if the samples were properly stored. 
3. Verify understanding of and compliance with protocol requirements for 
contraception (see Appendix 4). 
 
• The subject will be asked to contact the site staff or Investigator if an AE (e.g., doctor’s 
visit, emergency room visit) or hospitalization occurs. 
• The subject is to be informed that use of prophylactic antipyretic/pain medication, is 
not permitted on the day of study drug administration. If antipyretic/pain medication is 
used after study drug dosing, and if clinically appropriate in the judgement of the 
Investigator, acetaminophen is preferred over other non-steroidal anti-inflammatory 
drugs.  
• Prior and concomitant medications will be reviewed if the subjects took any during the 
active study period. 
• The subject will be asked to bring the completed Diary to the next visit. 
• The subject will be reminded that study staff may contact them to obtain additional 
information on events entered into the Solicited Symptom Diary. 
• Source documents will be completed. 

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• The Investigator or appropriately qualified designee will review the Diary following 
vaccination, to evaluate subject compliance and as part of the ongoing safety review. 
Daily review is optimal during the active Diary period. Any solicited symptom marked 
as Grade 3 should be specifically reviewed with the subject to ensure they meet the 
detailed solicited AE grading criteria in (Table 10) and to evaluate for potential 
alternative etiology. 
• An appointment will be scheduled for the subject to return for the next study visit. 
• The Investigator or an authorized designee completes the eCRFs and an unblinded 
dispenser/administrator will update the investigational product accountability records. 
• The subjects will be contacted by phone between site visits on Day 15 to monitor for 
safety as specified in the SoA (Table 1) and to remind the subjects to collect and store 
breastmilk samples. If the study personnel are unable to contact the subject with 3 
attempts, the study personnel will follow instructions given in Section 5.4. 
7.1.3. 
Procedure to be followed during follow-up period (Day 30 to Day 365) 
• Verify understanding of and compliance with protocol requirements for contraception 
(see Appendix 4). 
• Subjects will return to the site on Day 60 and Day 180: 
1. A blood sample will be collected for immunogenicity assessment on D180 as 
specified in the SoA (Table 1).  
2. Nasal and saliva samples will be collected for immunogenicity assessment on 
Day 60 and Day 180 as specified in the SoA (Table 1).  
3. Ascertain if the subject is still breastfeeding. If they are then ensure the subject 
has also collected breastmilk sample and infant stool sample during the 
timepoints specified in the SoA (Table 1), if not then remind the subject. 
Review with the subject how the collection was done and if the samples were 
properly stored. 
 
• Collect and record SAEs, AESIs and NOCIs.  
• Complete the source documents.  
• The Investigator or an authorized designee completes the eCRFs.  
• Ask the subject to contact the site staff or Investigator if an adverse event (e.g., doctor’s 
visit, emergency room visit) or hospitalization occurs. 
• The subjects will be contacted by phone between site visits on Day 120, Day 240, Day 
300, and Day 365 to monitor for safety as specified in the SoA (Table 1). For Day 120, 
determine if the subjects are still breastfeeding; if yes then remind the subjects to collect 
and store breastmilk samples. If the study personnel are unable to contact the subject 
with 3 attempts, the study personnel will follow instructions given in Section 5.4. 

Vaxart Inc 
VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 45 of 81 
 
 
7.1.4 Follow-up of Subjects with Related AEs or with AEs that Led to Study 
Discontinuation  
Unless the subject refuses further contact, each subject who experiences an AE (whether serious 
or non-serious) during the study must be followed until the condition resolves, becomes stable, or 
becomes chronic (even after the end of the subject’s participation in the study) if either of the 
following is true. 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study. 
7.1.5 Unscheduled Visit 
At the discretion of PI and/or per subject request to evaluate any of the expected reactogenicity 
symptoms or any unexpected symptoms of concern, a contact must occur as soon as possible 
between the subject and the Investigator, or a medically qualified member of the study site staff, 
to assess if an unscheduled visit is required. 
This contact will be recorded in the subject’s eCRF. If the subject is unable to attend the 
unscheduled visit, any ongoing reactions must be assessed at the next scheduled visit. 
Reactogenicity events should be assessed by the Investigator or a medically qualified member of 
the site staff, such as a study physician or a study nurse, as applicable, to the Investigator’s local 
practice, who will: 
• Measure oral temperature.  
• Measure the subject’s pulse rate (after five minutes of sitting). 
• Measure the subject’s blood pressure (after five minutes of sitting).  
• Assess any events (specify the events of interest) that are present, in accordance with 
the reactogenicity grading scale. 
• Perform a symptom focused physical examination. 
• Ask the subject if she attended an emergency room visit or was hospitalized.  
• Complete the source documents. 
• The Investigator or an authorized designee will complete the eCRF. 
 
The subject will be instructed to contact the site to report any significant illness, AEs, or 
hospitalization that occurs during the study period. 

Vaxart Inc 
VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 46 of 81 
 
 
7.2. Management of Blood/Saliva/Nasal/Breastmilk/Infant Fecal Samples 
7.2.1. Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Collection 
Blood / saliva samples for the assessment of immunogenicity will be collected from the subjects 
as specified in the SoA (Table 1). Sample collection, storage, and shipping information can be 
found in the General and Immunogenicity Laboratory Manuals. 
 
7.2.2 Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the study specific Laboratory Manual provided to the site. 
7.2.3 Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Storage and Shipment 
Detailed instructions on blood sample storage and shipment are contained in the study specific 
Laboratory Manual provided to the site. 
 
 7.2.4 Future Use of Stored Specimens and Data  
 
The current trial is an early phase study in which Vaxart’s goal is to understand the mechanism of 
action of the oral NoV vaccine in the prevention of NoV illness, it is important to have samples 
available for the full characterization of the vaccine. The Sponsor is planning to store blood, saliva, 
nasal, breastmilk, and infant stool samples post the completion of the study for possible future 
testing towards the development of a NoV vaccine. This testing includes evaluation of serum 
antibody titers to NoV and cell-mediated immune responses to NoV. At this time, the exact tests 
are not known but this will help to further understand how the oral NoV vaccine works in the body 
and in the prevention of NoV illness. Other immunological assays may be performed to further 
elucidate the response to our vaccine. These may include cloning the antibodies that are induced 
following immunization. All samples will use subject identifiers that are coded and will not include 
subject initials or demographic information. Only Vaxart staff will have access to the samples and 
data; they will be responsible for providing access to the samples as needed for assays. Samples 
will be stored at Vaxart or Vaxart’s designee in a secured, access-controlled location for at least 
05 years after the last license approval in the relevant market areas has been obtained for the 
vaccine being tested. Samples may be shared with collaborating researchers, but only in 
relationship to the NoV program. Any data developed externally will only be displayed in a 
deidentified form as authorized by Vaxart.  
 
8. TRIAL ASSESSMENTS AND PROCEDURES 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study drug. 
Adherence to the study design requirements, including those specified in the SoA is essential and 
required for study conduct. 

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All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The Investigator will maintain a screening log to record details of all subjects 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Subjects who experience any serious or severe TEAEs, or any event of concern should be 
instructed to contact the study site and be scheduled for a visit for further evaluation. If an 
unscheduled visit occurs, the reason for the visit and data collected during the visit should be 
recorded and entered into the unscheduled eCRF. 
8.1 
Safety Assessment 
The safety of the bivalent GI.1 and GII.4 vaccines will be evaluated through the reporting of 
Solicited Symptoms of Reactogenicity (GI and systemic) for 1 week following the study drug dose 
and through reporting of frequency, duration, and severity of unsolicited AEs for the next 28 days 
following the study drug dose. The subjects will then enter the Follow-Up Period after Day 29 and 
will be monitored for SAEs, AESIs, and NOCIs through Day 365 (Month 12) for safety and 
duration of immune response. Each SAE, AESI, and NOCI occurrence must be assessed for 
causality.  
AESIs are listed in Appendix 5, the occurrence of these events should be reported to the Sponsor 
in an expedited manner, similar to SAEs as described in Section 9.   
Planned time points for all safety assessments are provided in the SoA (Table 1) 
8.1.1 Physical Examination 
A complete physical examination evaluating any clinically significant abnormalities in general 
appearance and within the following body systems: skin; head, eyes, ears, nose, and throat; 
cardiovascular; respiratory; gastrointestinal (GI) (abdomen; liver and spleen) musculoskeletal; 
extremities; neurological; and lymph nodes. Height and weight will also be measured and recorded 
at screening and BMI will be calculated. 
A targeted, symptom-directed physical examination will include, at a minimum, assessments of 
the skin, respiratory system, cardiovascular system, and GI (abdomen, liver, and spleen). 
8.1.2 Vital Signs  
Blood pressure, heart rate, and respiratory rate will be measured after the subject has been resting 
in a sitting position for 5 minutes. Vital signs will be measured prior to any blood draw that occurs 
at the same timepoint. 
8.1.3 Clinical Safety Laboratory Tests 
See APPENDIX 1: Clinical Laboratory Tests for the list of clinical laboratory tests to be performed 
for inclusion and exclusion purposes only. 

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8.1.4 Pregnancy Testing 
• Details of all pregnancies in female subjects, will be tested as outlined in SoA (Table 1). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 9.1.7. 
8.2 
Immunogenicity Assessment 
Immunogenicity will be evaluated using cellular and humoral immune function assays from blood, 
mucosal (saliva and nasal swab), and breastmilk samples from subjects and their infants’ stool 
samples. Samples will be collected from all subjects according to the time points specified in the 
SoA. The following analytes will be measured: 
8.2.1 Primary Immunogenicity Assessments: 
• Serum VP1 specific (GI.1 and GII.4) IgA through the active period measured by Meso 
Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8 and Day 29   
o Geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
29  
• Breastmilk VPI specific (GI.1 and GII.4) IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 15, and Day 29   
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
15, and from Day 1 to Day 29    
• The number of subjects in each dose group that had a 2-fold GMC rise or greater in 
breast milk VP1 specific IgA (GI.1 and GII.4) between Day 1 and any other timepoint. 
8.2.2  Immunogenicity Assessments: 
Serum VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose measured by 
Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 180  
• Breastmilk VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) by dose level 
o Geometric mean concentration (GMC) at Day 60, Day 120, and Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 60, from Day 1 to 
Day 120, and from Day 1 to Day 180  
• Serum VP1 specific (GI.1 and GII.4) IgG through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, and Day 
180    

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o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, and from Day 1 to Day 180   
• Serum Blocking titers 50 (BT50) (GI.1 and GII.4) through 6 months after study drug 
dose measured by Histo-blood group antigen (HBGA) assay by dose level 
o Geometric mean titer (GMT) at Day 1, Day 8, Day 29, and Day 180    
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, and from Day 1 to Day 180   
8.2.3 Exploratory Immunogenicity Assessments: 
• Saliva VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Enzyme-
linked immunosorbent assay (ELISA) by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 60 and 
Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, from Day 1 to Day 60, and from Day 1 to Day 180 
• Nasal VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Meso 
Scale Discovery (MSD) by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 60 and 
Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, from Day 1 to Day 60, and from Day 1 to Day 180  
• Infant stool VP1 specific (GI.1 and GII.4) IgA measured by Enzyme-linked 
immunosorbent assay (ELISA) by dose level: 
o Geometric mean concentration (GMC) Day 1, Day 29, and Day 60  
o Geometric mean fold rise (GMFR) from Day 1 to Day 29 and from Day 1 to 
Day 60  
• Breastmilk Blocking titers 50 (BT50) (GI.1 and GII.4) measured by Histo-blood group 
antigen (HBGA) assay by dose level 
o Individual subject titers on samples and some timepoints that have a high 
likelihood of success, assuming the assay works in breast milk samples 
• Breastmilk Enterocyte culture neutralizing antibody titers (GI.1 and GII.4) measured 
by enterocyte culture 
o Individual subject titers on samples and some timepoints that have a high 
likelihood of success, under the assumption that the assay works in breast milk 
samples. At the date of this protocol, only serum GII.4 neutralizing antibodies 
have been successfully measured 
Additional exploratory immunogenicity assays may also be performed to further evaluate the 
activity of the bivalent GI.1 and GII.4 vaccines. Note that not all sample timepoints may be 
relevant for some of the analysis, so not all assays may be performed at all timepoints.  In 
particular, because it is unclear if the breast milk matrix will inhibit the analysis of neutralizing 
antibodies or BT50, those assays may not be feasible.   

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Sample collection, processing and shipping details are provided within the study specific 
Laboratory Manuals. 
9.  ADVERSE EVENTS  
9.1 Definition of an Adverse Event, Serious Adverse Event, Suspected Unexpected 
Serious Adverse Reaction, Adverse Event of Special Interest and New Onset of 
Chronic Illness 
 Adverse Event Reporting 
Adverse event means any untoward medical occurrence associated with the use of an 
investigational product, whether or not considered intervention related.   
Adverse Events Treatment Emergent Adverse Event  
Treatment emergent adverse event (TEAE) is an AE that began after the start of an investigational 
product or an already present event that worsens either in intensity or frequency following the 
intervention. 
Serious Adverse Event (SAE) 
a. An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the Investigator or Sponsor, it results in any of the following outcomes:  
i. 
Death 
ii. 
A life-threatening adverse event (at the time of the event; not an event that 
hypothetically might have caused death if it were more severe) 
iii. 
Inpatient hospitalization or prolongation of existing hospitalization 
iv. 
A persistent or significant incapacity or disability which results in a substantial 
disruption of the ability to conduct normal life functions 
v. 
A congenital anomaly/birth defect 
vi. 
Important medical events which based upon appropriate medical judgment may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
• Examples of such medical events include but are not limited to allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
b. A preplanned/elective procedure and its associated hospitalization for a pre-existing 
condition that did not worsen from baseline is not considered an AE/SAE. If the 
procedure is performed early due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
 

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Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected Unexpected Serious Adverse Reaction refers to an adverse event which is assessed by 
the sponsor and or study investigator as being unexpected, serious, and as having a reasonable 
possibility of a causal relationship with the investigational product. 
Adverse Event of Special Interest (AESIs) 
An adverse event of special interest (serious or nonserious) is one of scientific and medical concern 
specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate.  For this study, AESIs are 
serious or non-serious adverse events of scientific and medical concern with potential immune-
mediated medical conditions as well as events associated with thrombosis and thrombocytopenia 
as listed in but not limited to Table 11. 
New Onset of Chronic Illness (NOCIs) 
New Onset of Chronic Illness is defined as diagnosis post-enrollment and vaccination of a new 
medical condition, which is chronic in nature, including those potentially controllable by 
medication (e.g., diabetes, asthma).  
Adverse Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse reactions (AR). (The phrase “responses to an investigational product” means 
that a causal relationship between a medicinal product and an AE is at least a reasonable 
possibility.) 
Additional Sponsor Definition 
a.   Solicited Adverse Events- 
i. 
Solicited adverse events (AEs) are predefined signs and symptoms of 
reactogenicity for which the subject is specifically questioned, and which are noted 
by the subject in their Solicited Symptom Diary, including: 
• fever (any temperature 100°F or higher) 
• headache 
• myalgia (muscle pain) 
• abdominal pain 
• anorexia (defined and not eating) 
• nausea 
• vomiting 
• diarrhea 
• malaise/fatigue 

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ii. 
Subjects will utilize a Solicited Symptom Diary issued on the day of the vaccination 
to record solicited any TEAE daily for the one week following that administration. 
b.   Unsolicited Adverse Events  
i. 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted 
in the eCRF in terms of diagnosis and/or onset window post-vaccination; this also 
includes progression of chronic diseases. Unsolicited AEs includes both serious 
(SAEs) and non-serious unsolicited AE. 
9.2 Grading of Severity of an Adverse Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity: 
• Mild – Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe – Events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. Of note, the term “severe” does not necessarily 
equate to “serious.” 
9.3 
Relationship of Adverse Event Following Immunization to Experimental 
Vaccine/Vaccine Adverse Event Causality Assessment 
The principal investigator will use his or her clinical judgment to assess each and every occurrence 
of an AE/SAE for causality. A 'reasonable possibility' means there is evidence to suggest a causal 
relationship between the study drug and the adverse event, and the AE is more likely to be 
explained by the study drug than by another cause. 
The investigator is obligated to consider and investigate alternative causes including underlying 
disease(s), concomitant therapy, and other risk factors, in addition to the temporal sequence of the 
adverse event to the administration of the study drug.  
The investigator will determine biological plausibility and strength of association by consulting 
the IB and comparators if applicable in his/her assessment. The investigator will also evaluate the 
course of event including the reproducibility of the adverse event with subsequent study drug 
administration (in subjects who are allowed to continue with the study). 
For more details refer to Causality Assessment of an Adverse Event Following Immunization 
(AEFI): User Manual for the Revised WHO Classification Second Edition, 2019 Update link: 
https://www.who.int/publications/i/item/9789241516990. 

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All adverse events following immunization (AEFIs) must have their relationship to study drug 
assessed by the Investigator. The degree of certainty about causality will be graded using the 
categories below.  
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study drug administration 
and cannot be explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the study drug should be clinically plausible.  
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study drug, is unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the study drug) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant 
treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
In situations where an SAE has occurred with minimal information available to the investigator, 
the investigator is still required to make an assessment of causality for the event with the 
transmission of the initial report to the sponsor. If the investigator is uncertain about causality, the 
adverse event will initially be handled as “related to study intervention” for reporting purposes. 
Once more clinical information is obtained, the investigator can modify the causality assessment 
to reflect this new knowledge by sending an SAE follow-up report with the updated assessment. 
9.4 
Monitoring and Follow-up of AEs, NOCIs, and SUSARs during Trial 
9.4.1 Monitoring and Follow-up of SAEs from Day 1 to Day 29 after Vaccination 
Following AEs/SAEs, could appear during the entire course of the trial after vaccination. The 
following symptoms will be captured via Solicited Symptoms during Day 1 to Day 8. After Day 8 
they will be captured as unsolicited adverse events. SAEs are captured from the first dose of study 
product.  

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• Fever/pyrexia 
• Diarrhea 
• Nausea 
• Vomiting 
• Abdominal pain 
• Malaise/fatigue 
• Anorexia 
• Headache 
• Myalgia (muscle pain) 
9.4.2 Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE 
Information 
All TEAEs, SAEs, AESIs, and NOCIs will be collected from the time of study drug dose until 
the follow up visit at the timepoints specified in the SoA (Table 1).  TEAEs will be collected 
through Day 29.  SAEs, AESIs, and NOCIs will be collected through Day 365. 
Medical occurrences that begin before the start of study drug but after obtaining informed consent 
will be recorded as medical history/current medical conditions, not as AEs if they do not have a 
causal relationship with study participation.  There are two situations to note as below:  
 
• If the medical occurrence causes the subject to be excluded from the study, then it must 
be reported by the investigator. This event will then need to be classified as an "AE not 
related to the study drug.”   
• If the medical occurrence is the result of a protocol-specified intervention (prior to 
study drug dose), including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure then these must be reported appropriately as an AE 
(solicited and unsolicited), SAE, AESI, NOCI, and other reportable safety events by 
the Investigator. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of being available. The Investigator will submit any 
updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and the Investigator considers the event 
to be reasonably related to the study drug or study participation, the Investigator must promptly 
notify the Sponsor. 
9.4.3 
Information for Follow-up of AESIS, NOCIS, and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 5.4).  

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The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, AESIs, 
NOCIs or SAEs as fully as possible. This may include laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
New or updated information will be recorded in the originally submitted documents. 
 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
9.5 
Reporting of AEs, AESIs, NOCIs, SAEs, SUSARs, Pregnancies, and Death Events 
All AEs (solicited and unsolicited), AESIs, NOCIs, SAEs and other reportable safety events that 
occur after the consent form is signed but before study product administration must be reported by 
the Investigator if the event causes the subject to be excluded from the study (these will be reported 
as “AE not related to the study drug”) or is the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
 
Table 7 below summarizes the different reporting timelines for TEAEs (unsolicited and solicited), 
AESIs, NOCIs, SAEs, and SUSAR. 
 
Table 7 Adverse Event Reporting Timelines to the Sponsor 
Type of 
Event 
TEAE 
(unsolicited) 
TEAE (solicited) 
AESI/NOCIs 
SAE / SUSAR 
Reporting 
period 
From first dose 
until 4 weeks after 
last dose of study 
drug 
1 week after each 
study drug 
administration 
From first dose 
until EOS 
From first dose 
until EOS 
Reporting 
Timelines 
to the 
Sponsor  
Entered into the 
clinical database 
on an ongoing 
basis  
Entered into the 
clinical database 
on an ongoing 
basis 
Within 24 hours 
Within 24 hours  
Reporting 
Method 
AE page of eCRF 
Solicited 
Symptom Diary 
AE page of eCRF AE page of eCRF 
Abbreviations: AE = adverse event; eCRF = electronic Case Report Form; EOS = end of study; AESI = Adverse 
Event of Special Interest; NOCI= New Onset Chronic Illness; SAE = serious adverse event; SUSAR = suspected 
unexpected serious adverse reaction; TEAE = treatment-emergent adverse event 
 
9.5.1 Adverse Event Reporting 
All subjects experiencing AEs after the first dose of study drug, until Day 29 (Active Period), 
whether considered causally related with the use of the investigational vaccine or not, must be 

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monitored until symptoms subside, or until there is a satisfactory explanation for the changes 
observed, or until death, in which case a full pathologist’s report should be supplied, if possible. 
All findings must be reported on an adverse event page of eCRF and on the SAE form, if 
applicable. All findings in subjects experiencing AEs must also be documented in the subject’s 
clinical research records.  
The following information will be documented for each event:  
• Reported term for the AE.  
• Start and end date.  
• Serious (Y/N)? If yes, appropriate seriousness criteria must be selected on eCRF and 
SAE Form. 
• Severity.  
• Investigator’s opinion of the causality (relationship) between the event and 
administration of investigational vaccine(s) (“related” or “not related”).  
• Investigator’s opinion of the causality (relationship) to trial procedure(s), including the 
details of the suspected procedure.  
• Action taken with study treatment (investigational vaccine).,  
• Outcome of event. 
• For Death cases provide all applicable details (e.g., date and cause of death etc., 
including autopsy results if available). 
 
9.5.2 Serious Adverse Events Reporting 
The Investigator or designee will within 24 hours report to the Sponsor any serious adverse event, 
whether or not considered study drug related, including those listed in the protocol or Investigator 
Brochure and must include an assessment of whether there is a reasonable possibility that the study 
drug caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) 
must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study drug and the event (e.g., death from anaphylaxis). In that case, the 
Investigator must within 24 hours report the event to the Sponsor. 
 
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the event 
to be chronic or the subject is stable. Other supporting documentation of the event may be 
requested by the Data Coordinating Center (DCC)/study Sponsor and should be provided as soon 
as possible. 
 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours and under no 
circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to 

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the Sponsor within 24 hours of it being available.  The information should be completed as fully 
as possible and contain the following information at the minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
 
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
submit it within 24 hours of receipt. The timelines and procedure for follow-up reports are the 
same as those for the initial report. 
 
9.5.3 Suspected Unexpected Serious Adverse Reaction Reporting 
Suspected unexpected serious adverse reactions (SUSARs) are subject to expedited reporting. The 
study Sponsor will be responsible for notifying both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation including 
the Food and Drug Administration (FDA of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible, but in no case later than 7 calendar days after the Sponsor's 
initial receipt of the information. In addition, the Sponsor must notify FDA and all participating 
Investigators in an Investigational New Drug (IND safety report of potential serious risks, from 

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clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days 
after the Sponsor determines that the information qualifies for reporting. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
  
An investigator who receives SUSARs or other specific safety information (e.g., summary or 
listing of SAEs) from the sponsor will review and then file it along with the IB for the study and 
will notify the IRB/EC, if appropriate according to local requirements. 
 
9.5.4 Pregnancy Reporting 
Details of all pregnancies in female subjects will be collected after the start of study drug as per 
SoA (Table 1).  
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form (pregnancy form) and submit it to the Sponsor within 24 hours of 
learning of the female subject pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate up to one 
month post-partum, and the information will be forwarded to the Sponsor. 
• Any post study pregnancy-related SAE considered reasonably related to the study drug 
by the Investigator will be reported to the Sponsor. While the Investigator is not 
obligated to actively seek this information in former (study subjects) beyond the 
resolution of the pregnancy, he or she may learn of an SAE through spontaneous 
reporting. 
Should a female subject become pregnant during the course of the study after dosing, she will 
continue to be followed for safety and pregnancy outcomes. Subjects who have a positive 
pregnancy test at Day 1, prior to randomization, will be considered screen failures. 
 
If a subject is found pregnant post study drug administration, the subject will only be monitored 
for safety. 
 
9.5.5  Death Events   
Events resulting in death will be an SAE regardless of association to study drug. Death is an 
outcome and should not be reported as an event term. The event that leads to the death should be 
reported as the SAE term. 

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10.     SAFETY OVERSIGHT 
10.1. Internal Sponsor Review 
Safety data will be monitored on an ongoing basis by the Investigator (or medically qualified 
designee) and the Sponsor’s Medical Monitor (or designee) in order to promptly identify and flag 
any event that potentially contributes to a Stopping Rule. 
 
The lead Medical Monitor will be a physician experienced in the conduct of research clinical 
studies whose primary responsibility will be to monitor subject safety. The Medical Monitor will 
be responsible for reviewing the cumulative safety data, including a review of safety laboratory 
test results and adverse event reporting. The Medical Monitor will be familiar with study-specific 
data as well as relevant background information about the disease, investigational drug, and target 
population under study. The Medical Monitor(s) will be empowered to request a SMC safety 
review which can suspend the study, recommend amendments to the protocol, and/or to request 
further information. 
10.2. Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will be created to provide oversight of the conduct of the 
trial to ensure the safety of subjects. The committee will consist of independent physicians and/or 
scientists with vaccine clinical trials experience or expertise, and the Medical Monitor, who does 
not enroll subjects into the study.  
The SMC will be assigned by the Sponsor prior to the beginning of the study and will provide 
oversight of the study throughout the duration of the study period (Day 1 through Day 365) as 
needed. Ad hoc meetings will be convened if any predefined stopping rules are met, or any 
serious vaccine-related events or trends are observed. 
 
The SMC will function in accordance with the following provisions: (1) United States (US) Code 
of Federal Regulations (CFR) applicable to clinical studies (21 CFR Part 50, 21 CFR Part 54, 21 
CFR Part 312.55 and 312.56. (2) ICH E6 and 62 Federal Register 25691 (1997): Good Clinical 
Practice (GCP) Consolidated Guideline. 
Further details regarding data safety monitoring guidelines will be included in the SMC Charter, 
which is the governing document that supersedes this section of the protocol. 
11. 
STATISTICAL CONSIDERATION 
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentation and analyses will be provided in SAP. 
 
Additional statistical analyses other than these described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report (CSR). 

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11.1 
Sample Size Determination 
A sample size of 76 randomized subjects (30 each in medium and high dose levels and 16 in 
placebo) is not based on formal statistical testing but rather based on clinical judgement and 
predicted to yield meaningful safety and immunogenicity results. Placebo was added for safety 
comparison.  
 
11.2  Multiplicity Adjustment 
No multiplicity adjustment will be implemented for this study. 
11.3 
Population for Analysis 
For purposes of analysis, the following analysis sets are defined: 
Table 8: 
Populations for Analyses 
Analysis 
Population 
Description 
Screened 
All subjects who enter screening (assigned a screening number) 
Intent to Treat (ITT)  All subjects who are randomized. The analyses using ITT will be based 
upon the randomization group allocated. 
Per Protocol 
 All subjects in the ITT set who receive one dose and who have not 
violated any inclusion/exclusion criteria and / or deviated in a way that 
could influence their Immunogenicity assessments. 
Safety 
All randomized subjects who receive at least 1 dose of the study drug. 
Subjects will be analyzed according to the treatment (vaccine) they 
actually received. All safety analyses will be conducted based on the 
Safety set. 
Immunogenicity 
All randomized subjects who receive at least 1 dose of the study drug 
and have at least one valid immunogenicity result after Day 1. Subjects 
will be analyzed according to the treatment (vaccine) they actually 
received. All immunogenicity analyses will be conducted based on the 
Immunogenicity set. 
11.4 Statistical Analysis Plan 
11.4.1 General Approach 
The SAP will be developed and finalized before database lock and breaking the blind for any of 
the planned analyses. It will describe the subject sets to be included in the analyses and the 
procedures for accounting for missing, unused, and spurious data. This section provides a summary 
of the planned statistical analyses of the primary endpoints.  
 

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11.4.2 Analysis of the Primary and Secondary Safety End Points 
Safety will be summarized for the safety set (active vs. placebo). Solicited Symptoms of 
Reactogenicity, unsolicited AEs, SAEs, physical examination, and vital signs will be summarized 
descriptively by treatment group and study visit. 
 
Analyses will be performed for the total set (active vs. placebo). All results will be presented 
descriptively and summarized by treatment groups. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
(measured 
from Day 1 
through 
Day 29) 
Frequency, duration, and severity of Solicited Symptoms of Reactogenicity 
(local, systemic) measured daily for 1 week following vaccination. 
Frequency, duration, and severity of unsolicited AEs, and SAEs through the 
active period (4 weeks post dose). 
Descriptive statistics will be provided for each reactogenicity endpoint for each 
dose. Local reactions and systemic events from Day 1 through Day 8 after each 
dose will be presented by severity and cumulatively across severity levels. 
Descriptive summary statistics will include counts and percentages of subjects 
with the indicated endpoint and the associated Clopper-Pearson 95% CIs. 
AEs will be categorized according to the Medical Dictionary for Regulatory 
Activities (MedDRA®) terms. Descriptive summary statistics (counts, 
percentages, and associated Clopper-Pearson 95% CIs) will be provided for 
any TEAEs for each vaccine group as well as the placebo group. SAEs will be 
categorized according to MedDRA® terms. The safety analyses are based on 
the safety set. Subjects will be summarized by vaccine group and placebo 
according to the study drug they actually received. Missing reactogenicity 
Diary data will not be imputed; missing TEAE dates will be handled according 
to the rules determined in the SAP. 
Secondary 
(measured 
through 
Day 365) 
Frequency, duration, and severity of SAEs, AESIs and NOCIs for 1 year 
following the study drug dose. 
 
11.4.3 Analysis of Primary, Secondary, and Exploratory Immunogenicity and 
Endpoints 
Immunogenicity will be summarized according to the treatment group to which the subject was 
randomized. 
 
Immunogenicity samples will be drawn for all subjects and their infants. Immunogenicity analyses 
will be based upon results from appropriately sized subsets of samples, according to the purpose. 

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The statistical analysis of immunogenicity results will be primarily based on the evaluable 
immunogenicity sets.  
 
An additional analysis will be performed based on the all-available sets if there is a large enough 
difference in sample size between the all-available immunogenicity set and the evaluable 
immunogenicity set.  
 
Immunogenicity will be summarized by the total set (active vs. placebo). For all endpoints, all 
measures will be analyzed comparing the two active vaccine groups. The immunogenicity set 
will be used for this analysis. All results will be presented descriptively and summarized by 
treatment groups. 
Endpoint 
Statistical Analysis Methods 
Primary (Key 
Immunogenicity 
Endpoints 
measured from 
Day 1 through 
Day 29) 
Serum and breastmilk VP1 specific IgA for both GI.1 and GII.4 by Meso 
Scale Discovery will be summarized descriptively through the active period 
(4 weeks post dose). 
Secondary 
(measured 
through Day 
180) 
Serum VP1 specific IgA and IgG for both GI.1 and GII.4 by Meso Scale 
Discovery will be summarized descriptively through 6 months post dose. 
Serum Blocking titers 50 (BT50) (GI.1 and GII.4) by Histo-blood group 
antigen (HBGA) assay will be summarized descriptively through 6 months 
post dose. 
Breastmilk VP1 specific IgA for both GI.1 and GII.4 by Meso Scale 
Discovery will be summarized descriptively through 6 months post dose. 
Exploratory 
For specific exploratory immunogenicity endpoints please refer to Section 
8.2-Immunogenicity Assessments- Exploratory Immunogenicity 
Assessments. 
11.4.4 Baseline Descriptive Statistics 
Demographic data, baseline characteristics, physical examination, concomitant medications, 
medical history data and study medication exposure will be summarized by treatment group.  
 
11.4.5 Tabulation of Individual Subject Data 
By subjects listing will be produced for each variable by treatment group and study visit. 

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12. 
ETHICAL CONSIDERATIONS 
12.1 
Ethical Conduct of the Study   
The study will be conducted in accordance with the protocol, legal and regulatory requirements, 
and the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences [CIOMS] 
2002), ICH Guideline for Good Clinical Practice, and the Declaration of Helsinki. 
12.2 
Institutional Review Board  
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/EC 
should be retained in the Investigator file. 
 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/IEC and Sponsor in writing immediately after the 
implementation. 
 
They should also be informed of any event likely to affect the safety of the subjects or the continued 
conduct of the clinical study, in particular any change in safety. All updates to the IB will be sent 
to the IRB/IEC and to Health Authorities (Competent Regulatory Authority), as required by local 
regulation. A progress report is sent to the IRB/IEC at least annually and a summary of the study’s 
outcome at the end of the clinical study. 
 
12.3 
 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the subject will be asked to read and review the 
document. The Investigator will explain the research study to the subject and answer any questions 
that may arise. A verbal explanation will be provided in terms suited to the subject’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research subjects. Subjects will have the opportunity to carefully review the written consent form 
and ask questions prior to signing.  
 
The subjects should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The subject will sign the informed consent documents 
for herself and her infant prior to any procedures being done specifically for the study. Subjects 
must be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the informed consent document will be given to the subjects 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the forms signed, before the subject undergoes any study-
specific procedures. The rights and welfare of the subjects will be protected by emphasizing to 

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them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
If the trial is involving vulnerable population, video recording of entire informed consent process 
should be ensured depending on the norms of respective country’s regulatory authorities.  
12.4 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRB/IEC or regulatory authorities in countries requiring this document. 
 
12.5 
Stipends/Rewards/Compensation for Participation 
 
Subjects may be provided with a stipend according to local practice to compensate for the time 
and travel required for study visits and procedures. Participating subjects will be given a manual 
breast pump set. 
 
12.6 Subject Confidentiality 
 
Subject confidentiality and privacy will be strictly held in trust by the participating Investigators, 
their staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to subjects. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the Sponsor. All research activities will be conducted 
in as private a setting as possible. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the Subjects in this study. The clinical study site will permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 
 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at sponsors designated vendor. This will not include the subject’s 
contact or identifying information. Rather, individual Subjects and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by designated vendor research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived. 
 

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12.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new information 
that might influence the evaluation of the benefits and risks of the investigational product, Sponsor 
should be informed immediately.  
 
In addition, the Investigator will inform Sponsor immediately of any urgent safety measures taken 
by the Investigator to protect the study subjects against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the Investigator becomes aware of. 
13. DATA HANDLING AND RECORD KEEPING 
13.1 
Source Documents 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for validation of the clinical data. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or 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, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. All information on the CRF will 
be traceable to these source documents, which are generally maintained in the subject’s study file. 
 
The source documents will include a copy of the signed Informed Consent/ Health Insurance 
Portability and Accountability Act (HIPAA) authorization. The source document data collection 
forms for screening. Outpatient visits and AEs will also serve as CRF data collection instruments. 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. Source documents are maintained for recording data for each subject enrolled 
in this clinical trial. Study subjects’ data collected on the CRF during the trial will only be 
identified by subject number. If, as an exception, it is necessary for safety or regulatory reasons to 
identify the subject, both the Sponsor and the Investigator are bound to keep this information 
confidential. 
 
13.2 
Case Report Forms (CRF)  
 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this trial.  
 
A CRF is required and should be completed for each included subject. The completed original 
CRFs are the sole property of Vaxart and should not be made available in any form to third parties, 
except for authorized representatives of Vaxart or appropriate regulatory authorities, without 
written permission from Vaxart.  
 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 

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and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring, and available when required. 
 
The CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.  
 
13.3 Data Collection and Management Responsibility 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Hardcopies of the study visit worksheets will be provided for use as source 
document worksheets for recording data for each subject enrolled in the study.  
 
Data recorded in the eCRF/CRF derived from source documents should be consistent with the data 
recorded on the source documents. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a data capture system that is 21 CFR Part 11-compliant. 
The data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
13.4 
Record Retention 
 
Study documents should be retained for a minimum of 10 years after the last approval of a 
marketing application in an International Conference on Harminosation (ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 10 
years have elapsed since the formal discontinuation of clinical development of the study drug.  
 
These documents should be retained for a longer period, however, if required by local regulations. 
No records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the Investigator when these documents no longer need to 
be retained. 
 
13.5 
Property Rights and Data Protection 
 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
 
The subject must be informed that their personal study-related data will be used by the Sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 

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subject who will be required to give consent for their data to be used as described in the informed 
consent. 
  
The subject must be informed that their medical records may be examined by clinical quality 
assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
All information, data and documents including results and investigational products provided by 
the Sponsor or its designee are and remain the sole property of the Sponsor. 
 
The Sponsor may use or exploit all the results at its own discretion. 
 
14. QUALITY CONTROL AND QUALITY ASSURANCE 
 
14.1 
Early Safety Data Review AND/OR Committee 
 
Subject safety will be continuously monitored by the Sponsor or designee, which includes safety 
signal detection during the study. 
 
All safety data collected will be summarized and reviewed by the sponsor’s internal/external safety 
monitoring committee for agreement of next steps. 
 
In particular, data will be reviewed by the sponsor for identification of the following events that 
would potentially contribute to a requirement to [pause/stop] the study.  
• One or more subjects experiences a treatment-related serious adverse event (SAE) of 
any grade  
• Two or more subjects experience the same treatment-related grade ≥3 solicited 
symptom within one week following vaccination. 
• Two or more subjects experience the same treatment-related unsolicited grade ≥3 AE 
between Day 1 and Day 29 (Active Period). 
Enrollment will be paused during the review. If a pausing/stopping rule is met, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to resume. If no 
dose-related toxicities are observed, and upon the recommendation of the SMC following review 
of safety data, enrollment of the remaining subjects will be initiated.     
14.2 
Clinical Trial Site Monitoring 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP, and with applicable regulatory 
requirement(s). 
• Monitoring for this study will be performed by the Sponsor or designee 

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• Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
• If needed, independent audits will be conducted to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the 
CMP. 
14.3 
Audit and Inspection 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. 
For the purpose of ensuring compliance with the clinical study protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on behalf of the Sponsor 
and inspection by regulatory authorities. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities. 
 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
 
The confidentiality of the data verified, and the protection of the subjects should be respected 
during these inspections. 
 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
 
The Investigator shall take appropriate measures required by the Sponsor to take corrective actions 
for all problems found during the audit or inspections. 
14.4 
Responsibility of Investigator 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all trial procedures provided by the Sponsor (including security rules).  
 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, discrepancy resolution form, or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct access 
to source documents to the Sponsor representatives.  
 

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If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the subject’s data to be transferred. The Investigator may appoint such other individuals as he/she 
may deem appropriate as Sub-investigators to assist in the conduct of the clinical study in 
accordance with the clinical trial protocol.  
 
All Sub-investigators shall be appointed and listed in a timely manner. The Sub-investigators will 
be supervised by and work under the responsibility of the Investigator. The Investigator will 
provide them with a copy of the clinical trial protocol and all necessary information. 
 
To providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
 
To notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
 
Signed copy of Investigator’s undertaking should be provided as an appendix. 
14.5 
Responsibility of Sponsor 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical study as regards ethics, clinical study protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical study. 
 
At regular intervals during the clinical study, the site will be contacted, through monitoring visits, 
letters, or electronically, by a representative of the monitoring team to review study progress, 
Investigator and subject compliance with clinical study protocol requirements, and any emergent 
problems. 
 
These monitoring visits will include but not be limited to review of the following aspects: subject’s 
informed consent, subject recruitment and follow-up, SAE documentation and reporting, AE 
documentation, IP allocation, IP accountability, concomitant therapy use, and quality of data. 
 
14.6 
Protocol Deviation 
 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual 
of Procedures (MOP) requirements. The noncompliance may be either on the part of the subject, 
the Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. Details can be found in the study specific 
Protocol Deviation Plan or the Clinical Monitoring Plan. 
 
15. 
PUBLICATION AND DATA SHARING POLICY 
 

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The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. Requests for publication of site-specific data 
should be presented to the Sponsor for review and approval at least 90 days prior to submission 
for publication. 
 

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16. 
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Sanchez G.J., Cornejo, A.T., Bern, C., Dapat, C., Nochi, T., Parra, G.I., Oshitani, H., Saito, M. 
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McIlwain, D.R., Tucker, S.N., 2020. Efficacy, immunogenicity, and safety of an oral influenza 
vaccine: a placebo-controlled and active-controlled phase 2 human challenge study. The Lancet 
Infectious Diseases 20, 435–444.  
McGuire, MK., Seppo A., Goga A., et al.  2021. Best Practices for Human Milk Collection for 
COVID-19 Research.  Breastfeeding Medicine. Vol 16, 29-38 
Narayanaswamy, V., Pentecost BT., Schoen, CN., et al. Neutralizing Antibodies and Cytokines 
in Breast Milk after coronavirus disease 2019 (covid-19) mRNA vaccination. Obsterics & 
Gynecology. vol 139, 181-191 
Patel MM, Widdowson MA, Glass RI, Akazawa K, Vinjé J, Parashar UD. Systematic literature 
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Vega, E., Barclay, L., Gregoricus, N., Shirley, S.H., Lee, D., Vinjé, J., 2014. Genotypic and 
Epidemiologic Trends of Norovirus Outbreaks in the United States, 2009 to 2013. J Clin 
Microbiol 52, 147–155.  
 
 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 73 of 81 
 
 
Appendix 1: Clinical Laboratory Tests 
• The tests detailed in Table 9 will be performed by the local laboratory, unless 
otherwise specified. 
• Protocol-specific requirements for inclusion or exclusion of subject are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 9 
Protocol-Required Laboratory Assessments 
Urine drug screen 
amphetamines, methamphetamines, methadone, barbiturates, benzodiazepines, 
cocaine, opiates, methylenedioxymethamphetamine, phencyclidine, 
tetrahydrocannabinol 
Other laboratory 
assessments 
Hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency 
virus antibody types 1 and 2 (Screening only) 
Female subjects serum pregnancy tests at screening 
Female subjects Point-of-Care urine pregnancy tests prior to dosing at Day 1 
Alcohol test at screening and prior to dosing on Day 1 
 
Appendix 2: Country-specific Requirements 
Not applicable. 
Appendix 3: Adverse Events Grading 
Grading of Solicited Adverse Events 
Subjects should be instructed to rate Solicited Symptoms of Reactogenicity that are collected 
within their Solicited Symptom Diary based on the severity scale presented in Table 10. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 74 of 81 
 
 
Table 10 
Grading of Solicited Symptoms of Reactogenicity 
 
Symptom 
Grading 
Normal 
Mild 
Moderate 
Severe 
Life Threatening 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever 
(oral temp) 
< 
100.4°F 
(< 38.0°C)
100.4 – 101.1°F 
(38.0 – 38.4°C) 
101.2 – 102.0°F 
(38.5 – 38.9°C) 
102.1 – 104°F 
(39.0 – 40°C) 
> 104.0°F 
(>40°C) 
Headache 
None 
No interference with 
activity 
Repeated use of 
nonnarcotic pain 
reliever > 24 hours or 
some interference 
with activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
(muscle 
pain) 
None 
AE easily tolerated, 
causing minimal 
discomfort and does 
not interfere with 
everyday activitiesa 
Adverse event 
sufficiently 
discomforting to 
interfere with 
everyday activities 
Adverse event 
prevents normal 
everyday activities or 
requires medical 
advice 
ER visit or 
hospitalization 
Abdominal 
Pain 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Anorexia 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Nausea 
None 
No interference with 
activity or 1 to 2 
episodes 
Some interference 
with activity or >2 
episodes 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Vomiting 
None 
No interference with 
activity or 24 hours 
Some interference 
with activity or 24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
None 
2 to 3 loose stools or 
< 400 gms/24 hours 
4–5 stools or 400 
to 800 gms/24 hours 
6 or more watery 
stools or > 800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Malaise/ 
Fatigue 
None 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
a Everyday activity include attendance at work, school, and usual habits of the subjects. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions 
Postmenopausal female: 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 75 of 81 
 
 
−  A negative pregnancy test will be required for all female subjects prior to study 
drug administration, as outlined in the SoA (Table 1). 
Collection of Pregnancy Information 
Female subjects or Male subjects with partners who become pregnant: 
• 
The investigator will attempt to collect pregnancy information on any female subjects or 
male subject’s female partner who becomes pregnant while the male subject is in this study. 
After obtaining the necessary signed ICF from the pregnant female subject or male subject’s 
female partner directly, the investigator will record pregnancy information on the appropriate form 
and submit it to the Sponsor within 24 hours of learning of the pregnancy. The Sponsor will attempt 
to follow the female subject or female partner to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. The Sponsor 
will follow the female subject or female partner until birth or termination of pregnancy when 
possible. Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
 

Vaxart Inc 
VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 76 of 81 
 
 
Appendix 5: ADVERSE EVENTS OF SPECIAL INTEREST 
An Adverse event of special interest (AESI) is a serious or non-serious adverse events of scientific 
and medical concern for which ongoing monitoring and rapid communication by the Investigator 
to the Sponsor is indicated. The following adverse events (AEs) for potential immune-mediated 
medical conditions as well as events associated with thrombosis and thrombocytopenia are AEs of 
special interest (AESIs) and include new onset of chronic illness (NOCIs). These events should be 
monitored for actively and reported to the Sponsor in an expedited manner as outlined in Section 
9. 
Table 11: 
Adverse Events of Special Interest 
Gastrointestinal disorders: 
Liver disorders: 
• 
Celiac disease 
• 
Autoimmune cholangitis 
• 
Crohn’s disease 
• 
Autoimmune Hepatitis 
• 
Ulcerative colitis 
• 
Primary biliary cirrhosis 
• 
Ulcerative proctitis 
• 
Primary sclerosing cholangitis 
Metabolic diseases: 
• 
Addison’s disease 
• 
Diabetes mellitus type 1 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave’s or Basedow’s disease 
Coagulopathy: 
• 
Acquired amegakaryocytic 
thrombocytopenia 
• 
Amegakaryocytic thrombocytopenia 
• 
Axillary vein thrombosis 
• 
Cavernous sinus thrombosis 
• 
Cerebral venous thrombosis 
• 
Deep vein thrombosis 
• 
Disseminated intravascular coagulation 
• 
Embolism venous 
• 
Hepatic vein thrombosis 
• 
Immune thrombocytopenia 
• 
Intracranial venous sinus thrombosis 
• 
Mesenteric vein thrombosis 
• 
Portal vein thrombosis 
• 
Pulmonary embolism 
• 
Pulmonary thrombosis 
• 
Pulmonary venous thrombosis 
• 
Severe fever with thrombocytopenia 
syndrome 
• 
Subclavian vein thrombosis 
• 
Thrombocytopenia 
• 
Thrombocytopenia purpura 
• 
Thrombotic thrombocytopenia purpura 
• 
Thrombosis 
• 
Transverse sinus thrombosis 
• 
Vena cava embolism 
• 
Vena cava thrombosis 
• 
Venous thrombosis 
Musculoskeletal disorders: 
• 
Antisynthetase syndrome 
• 
Polymyalgia rheumatic 
• 
Dermatomyosotis 
• 
Polymyositis 
• 
Juvenile chronic arthritis (including Still’s 
disease) 
• 
Psoriatic arthropathy 
• 
Mixed connective tissue disorder 
• 
Relapsing polychondritis 
• 
Scleroderma, including diffuse systemic 
form and CREST Syndrome 
• 
Rheumatoid arthritis 

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VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 77 of 81 
 
 
• 
Systemic lupus erythematous  
• 
Systemic sclerosis  
• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) and 
undifferentiated spondyloarthritis. 
Neuroinflammatory disorders: 
• 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non-infections encephalitis, 
encephalomyelitis, myelitis, myeloradiculomyelitis)  
• 
Immune related peripheral neuropathies and plexopathies, including chronic inflammatory demyelinating 
polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal 
gammopathy 
• 
Cranial nerve disorders, including 
paralysis/paresis (e.g., Bell’s palsy) 
• 
Guillain-Barre syndrome, including Miller Fisher 
syndrome and other variants 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse Myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders: 
• 
Autoimmune bullous skin diseases 
(including pemphigus, pemphigoid and 
dermatitis herpetiformis 
• 
Rosacea 
• 
Alopecia aerate 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Psoriasis 
• 
Morphoea 
• 
Sweet’s syndrome 
• 
Lichen planus 
• 
Vitiligo 
Vasculitis: 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and temporal arteritis 
• 
Medium sized/and or small vessels vasculitis including: polyarthritis nodosa, Kawasaki’s disease, 
microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome (allergic granulomatous 
angititis), Buerger’s disease thromboangitis obliterans), nerotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet’s 
syndrome, leulocytoclassic vasculitis 
Others: 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, membranaoprolifative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune hemolytic anemia 
• 
Raynaud’ phenomenon 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Autoimmune thrombocytopenia 
• 
Sjogren’s syndrome 
• 
Goodpasture syndrome 
• 
Stevens-Johnson Syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Uveitis 

Vaxart Inc 
VXA-NVV-108 Version 1.0                                                                                                                            17 FEB 2023 
CONFIDENTIAL                                                                                                                                                            Page 78 of 81 
 
 
PROTOCOL VERSION HISTORY 
Name of the Document with 
Version Number 
Date 
Summary of Changes and 
Rationale 
VERSION 1.0 
12 OCT 2022 
INITIAL VERSION 
 
 
 
 

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Vaxart Inc 
VXA-NVV-108 Version 2.0 
25 Jul 2023 
 
 
Protocol Title: A phase I, multicenter, randomized, double-blind, placebo-controlled single 
dose, dose-ranging study to evaluate the safety, tolerability, and immunogenicity of orally 
administered bivalent GI.1/GII.4 norovirus vaccine in healthy lactating females ≥ 18 years old 
and their breast-feeding infants 
 
Brief Title: Evaluating Vaxart’s oral bivalent GI.1/GII.4 norovirus vaccine in healthy lactating 
females and their nursing infants 
 
Protocol Number: VXA-NVV-108 
 
Amendment Number: Not applicable 
 
Date of Amendment (Optional): Not applicable 
 
Investigational Product Name:  Bivalent GI.1 and GII.4 vaccines (VXA-G1.1-NN plus VXA 
GII.4-NS) 
 
Phase:  
  
I 
 
Sponsor: 
  
Vaxart, Inc. 
     
 
170 Harbor Way, Suite 300  
      
 
South San Francisco, CA 94080 
 
Funding Sponsor:  
Vaxart, Inc and Bill & Melinda Gates Foundation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________ 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to Investigators, potential Investigators, 
consultants, study staff, and applicable independent ethics committees or institutional review boards. The contents of 
this document shall not be disclosed to others without written permission from Sponsor (or others, as applicable). 
_____________________________________________________________________________________________    
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

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Vaxart Inc 
VXA-NVV-108 Version 2.0 
25 Jul 2023 
CONFIDENTIAL    
 
Page 1 of 88 
 
STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), the ethical principles that have their origin in the Declaration of 
Helsinki and the Code of Federal Regulations on the Protection of Human Participants (45 CFR 
Part 46). The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the Sponsor, funding agency and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial Subjects. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training per country requirements. 
 
I agree to ensure that all staff members involved in the conduct of this trial are informed about 
their obligations in meeting the above commitments. 
 
 
 
Principal Investigator: _________________________                                        ___________________ 
                             Signature                                                                   Date 
 
 
Name:                         __________________________ 
 
 
Address:                    ___________________________ 
 
                                                       
                                          ______________________________                                                                                                            
 
 
                                         ______________________________ 
                                          (Full Address, Landmark, State, Country, Phone: Fax:)  
 
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Vaxart Inc 
VXA-NVV-108 Version 2.0 
25 Jul 2023 
CONFIDENTIAL    
 
Page 2 of 88 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................................................... 0 
STATEMENT OF COMPLIANCE ............................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................................................ 2 
LIST OF IN-TEXT TABLE ........................................................................................................................................... 5 
LIST OF IN-TEXT FIGURE ......................................................................................................................................... 5 
LIST OF ABBREVIATIONS [AND DEFINITIONS OF TERMS] .............................................................................. 6 
1. 
PROTOCOL SYNOPSIS .................................................................................................................................. 8 
1.1. 
Schedule of Trial Activities ................................................................................................................ 17 
2. 
Introduction ..................................................................................................................................................... 19 
2.1. 
Indication ............................................................................................................................................ 19 
2.2. 
Background ......................................................................................................................................... 19 
2.2.1. 
Background of Disease ................................................................................................... 19 
2.2.2 
 Non-clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine ...... 19 
2.2.3 
Clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine .............. 19 
2.3 
Trial Rationale .................................................................................................................................... 20 
2.4 
Risk / Benefit Assessment .................................................................................................................. 21 
2.4.1 
Known Potential Risks to the Subjects ......................................................................... 21 
2.4.2 
Known Potential Benefits to the Subject....................................................................... 22 
2.4.3 
Overall Benefit Risk Conclusion.................................................................................... 22 
3. 
Trial Objective and end points ........................................................................................................................ 22 
3.1. 
Objectives ............................................................................................................................................ 22 
3.1.1. 
Primary Objectives ......................................................................................................... 22 
3.1.2. 
Secondary Objectives ..................................................................................................... 23 
3.1.3. 
Exploratory Objectives................................................................................................... 23 
3.2. 
End Points ........................................................................................................................................... 23 
3.2.1. 
Primary End Points ........................................................................................................ 23 
3.2.2. 
Secondary End Points ..................................................................................................... 24 
3.2.3. 
Exploratory End Points .................................................................................................. 25 
4. 
Trial Design ..................................................................................................................................................... 25 
4.1. 
Overall Description of Trial Design .................................................................................................. 25 
4.2 
Scientific Rationale of Trial Design .................................................................................................. 28 
4.3 
Justification for Dose Selection ......................................................................................................... 28 
4.4 
End of the Study Definition ............................................................................................................... 28 
4.5 
Premature Termination or Suspension of Trial .............................................................................. 29 
4.6 
Trial and Site Start and Close-Out ................................................................................................... 29 
4.6.1 
First Act of Recruitment ................................................................................................ 29 
4.6.2 
Study/Site Termination .................................................................................................. 29 
5. 
Selection of Trial Population ........................................................................................................................... 30 
5.1. 
Inclusion Criteria ............................................................................................................................... 30 
5.2. 
Early Termination/Withdrawal Criteria .......................................................................................... 33 
5.3. 
Lost to Follow Up Procedure ............................................................................................................. 34 
5.4. 
Screening Failure ................................................................................................................................ 34 
5.5. 
Classification of Subjects Who Discontinue the Study .................................................................... 35 
6. 
Trial Intervention ............................................................................................................................................ 36 
6.1. 
Investigational Product Description ................................................................................................. 36 
6.2. 
Preparation and Dispensing of Investigational Product ................................................................. 37 
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6.3. 
Dosing and Administration of Investigational Product................................................................... 37 
6.4. 
Formulation, Appearance, Packaging, and Labelling ..................................................................... 38 
6.5. 
Product Storage and Stability ........................................................................................................... 39 
6.6. 
Accountability Procedures ................................................................................................................. 39 
6.7. 
Randomization and Blinding ............................................................................................................. 40 
6.7.1. 
Randomization Procedures ............................................................................................ 40 
6.7.2. 
Blinding and Unblinding Procedures ............................................................................ 40 
6.8. 
Treatment Compliance ...................................................................................................................... 41 
6.9. 
Overdose of Treatment ...................................................................................................................... 41 
6.10. 
Concomitant Medications and Other Therapies ............................................................................. 41 
7. 
Schedule of Trial Procedures and Assessments ............................................................................................... 42 
7.1. 
Trial Procedures ................................................................................................................................. 42 
7.1.1. 
Procedure to be followed on Screening Period (Day -45 to Day -1) ............................ 42 
7.1.2. 
Procedure to be followed during Active Study Period (Day 1 to Day 29) .................. 43 
7.1.3. 
Procedure to be followed during follow-up period (Day 30 to Day 365) .................... 45 
7.1.4 
Follow-up of Subjects with Related AEs or with AEs that Led to Study 
Discontinuation 
45 
7.1.5 
Unscheduled Visit ........................................................................................................... 46 
7.2. 
Management of Blood/Saliva/Nasal/Breastmilk/Infant Fecal Samples.......................................... 46 
7.2.1. 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Collection .................................................... 46 
7.2.2 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Preparation ........................................................ 47 
7.2.3 
Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Storage and Shipment ....................................... 47 
7.2.4 
Future Use of Stored Specimens and Data ........................................................................................... 47 
8. 
Trial Assessments and Procedures .................................................................................................................. 47 
8.1 
Safety Assessment ................................................................................................................................ 48 
8.1.1 
Physical Examination ..................................................................................................... 48 
8.1.2 
Vital Signs ........................................................................................................................ 48 
8.1.3 
Clinical Safety Laboratory Tests ................................................................................... 48 
8.1.4 
Pregnancy Testing .......................................................................................................... 48 
8.2 
Immunogenicity Assessment ................................................................................................................ 49 
8.2.1 
Primary Immunogenicity Assessments: ........................................................................ 49 
8.2.2 
 Secondary Immunogenicity Assessments: ................................................................... 49 
8.2.3 
Exploratory Immunogenicity Assessments: ................................................................. 50 
9. 
Adverse Events ............................................................................................................................................... 51 
9.1 
Definition of an Adverse Event, Serious Adverse Event, Suspected Unexpected 
Serious Adverse Reaction, Adverse Event of Special Interest and New Onset of Chronic Illness ............. 51 
9.2 
Grading of Severity of an Adverse Event ..................................................................... 53 
9.3 
Relationship of Adverse Event Following Immunization to Experimental 
Vaccine/Vaccine Adverse Event Causality Assessment .................................................................................. 53 
9.4 
Monitoring and Follow-up of AEs, NOCIs, and SUSARs during Trial ..................... 54 
9.4.1 
Monitoring and Follow-up of SAEs from Day 1 to Day 29 after Vaccination ........... 54 
9.4.2 
Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE Information
 
55 
9.4.3 
Information for Follow-up of AESIS, NOCIS, and SAEs ........................................... 55 
9.5 
Reporting of AEs, AESIs, NOCIs, SAEs, SUSARs, Pregnancies, and Death Events 56 
9.5.1 
Adverse Event Reporting ............................................................................................... 56 
9.5.2 
Serious Adverse Events Reporting ................................................................................ 57 
9.5.3 
Suspected Unexpected Serious Adverse Reaction Reporting ...................................... 58 
9.5.4 
Pregnancy Reporting ...................................................................................................... 59 
9.5.5  
Death Events ........................................................................................................................................ 59 
10. 
Safety Oversight ........................................................................................................................................... 60 
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25 Jul 2023 
CONFIDENTIAL    
 
Page 4 of 88 
 
10.1. 
Internal Sponsor Review ................................................................................................................................. 60 
10.2. 
Safety Monitoring Committee ......................................................................................................................... 60 
11. 
STATISTICAL CONSIDERATION ............................................................................................................... 60 
11.1 
Sample Size Determination .................................................................................................................. 61 
11.2  
Multiplicity Adjustment ....................................................................................................................... 61 
11.3 
Population for Analysis ........................................................................................................................ 61 
11.4 
Statistical Analysis Plan ....................................................................................................................... 61 
11.4.1 
General Approach .......................................................................................................... 61 
11.4.2 
Analysis of the Primary and Secondary Safety End Points ........................................ 62 
11.4.3 Analysis of Primary, Secondary, and Exploratory Immunogenicity and Endpoints ........................ 62 
11.4.4 Baseline Descriptive Statistics ................................................................................................................ 63 
11.4.5 Tabulation of Individual Subject Data ................................................................................................. 63 
12. 
Ethical considerations ..................................................................................................................................... 64 
12.1 
Ethical Conduct of the Study ................................................................................................................ 64 
12.2 
Institutional Review Board ................................................................................................................... 64 
12.3 
 Informed Consent Process ................................................................................................................... 64 
12.4 
Insurance Compensation ...................................................................................................................... 65 
12.5 
Stipends/Rewards/Compensation for Participation .............................................................................. 65 
12.6 Subject Confidentiality .................................................................................................................................... 65 
12.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ................................... 66 
13. Data Handling and Record keeping................................................................................................................. 66 
13.1 
Source Documents ................................................................................................................................ 66 
13.2 
Case Report Forms (CRF) .................................................................................................................... 66 
13.3 
Data Collection and Management Responsibility ................................................................................ 67 
13.4 
Record Retention .................................................................................................................................. 67 
13.5 
Property Rights and Data Protection .................................................................................................... 67 
14. Quality Control and Quality Assurance ........................................................................................................... 68 
14.1 
Early Safety Data Review AND/OR Committee .................................................................................. 68 
14.2 
Clinical Trial Site Monitoring .............................................................................................................. 68 
14.3 
Audit and Inspection ............................................................................................................................ 69 
14.4 
Responsibility of Investigator............................................................................................................... 69 
14.5 
Responsibility of Sponsor .................................................................................................................... 70 
14.6 
Protocol Deviation ................................................................................................................................ 70 
15. 
Publication and Data Sharing Policy ......................................................................................................... 70 
16. 
References .................................................................................................................................................... 72 
Appendix 1: Clinical Laboratory Tests ................................................................................................................... 74 
Appendix 2: Country-specific Requirements ......................................................................................................... 74 
Appendix 3: Adverse Events Grading .................................................................................................................... 74 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ............................................. 75 
Definitions 
75 
Collection of Pregnancy Information .............................................................................................................. 76 
Appendix 5: ADVERSE EVENTS OF SPECIAL INTEREST .............................................................................. 77 
APPENDIX 6:  SUMMARY OF CHANGES TO PROTOCOL ............................................................................. 78 
VERSION 1.0 .......................................................................................................................................................... 79 
17 FEB 2023 .......................................................................................................................................................... 79 
INITIAL VERSION ................................................................................................................................................ 79 
VERSION 2.0 ........................................................................................................................................................ 79 
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25 JUL 2023 ............................................................................................................................................................ 79 
 
LIST OF IN-TEXT TABLE 
Table 1: 
Schedule of Activities.......................................................................................................... 18 
Table 2: 
Study Design ....................................................................................................................... 28 
Table 3: 
Study Duration .................................................................................................................... 29 
Table 4: 
Discontinuation Reasons ..................................................................................................... 36 
Table 5:  
Investigational Product Dosing ........................................................................................... 38 
Table 6: 
Study Arm(s) ....................................................................................................................... 37 
Table 7: 
Adverse Event Reporting Timelines to the Sponsor ........................................................... 57 
Table 8: 
Populations for Analyses ..................................................................................................... 62 
Table 9: 
Protocol-Required Laboratory Assessments ....................................................................... 75 
Table 10: 
Grading of Solicited Symptoms of Reactogenicity ............................................................. 76 
Table 11: 
Adverse Events of Special Interest ...................................................................................... 78 
LIST OF IN-TEXT FIGURE 
Figure 1 Study Design ................................................................................................................................ 26 
 
 
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LIST OF ABBREVIATIONS [AND DEFINITIONS OF TERMS] 
Term 
Description 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AEFI 
Adverse events following immunization 
AGE 
Acute gastroenteritis 
ANCA 
Anti-neutrophil cytoplasmic antibody  
ASC 
Antibody secreting cells 
BMI 
Body mass index 
CBER 
Center for Biologics Evaluation and Research – FDA 
DP 
Drug product 
eCRF 
Electronic case report form 
CFR 
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences 
CMP 
Clinical Monitoring Plan 
CSR 
Clinical Study Report 
DCC 
Data Coordinating Center 
EOS 
End of Study 
ET 
Early Termination 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI.1 
Norovirus genogroup I.1 
GII.4 
Norovirus genogroup II.4 
GMP 
Good Manufacturing Practice 
GRAS 
Generally recognized as safe 
HBsAg 
Hepatitis B surface antigen 
HBGA 
Histo-blood group antigen 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed Consent 
ICH 
International Conference on Harmonisation 
IP  
Investigational Product 
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ITT 
Intent to treat 
SMC 
Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IU 
Infectious units 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSD 
Meso Scale Discovery 
NOCI 
New Onset of Chronic Illness 
NoV 
Norovirus   
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral blood mononuclear cells 
PVP 
Polyvinyl pyrrolidone 
PI 
Principal investigator 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities 
SUSAR 
Serious unexpected suspected adverse reaction  
TEAE 
Treatment-emergent adverse event 
VP1 
Viral Protein 1, major capsid protein of norovirus 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
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Study Rationale: 
Noroviruses (NoV) are a genetically diverse group of small, non-enveloped, single-stranded 
positive-sense RNA viruses belonging to the Caliciviridae family and currently, it is the main 
viral cause of acute gastroenteritis (AGEs) in most countries worldwide. After adoption of 
the rotavirus vaccine throughout the world, norovirus infection has been one of three major 
causes of infant diarrheal disease.  It was estimated that each year NoVs cause 64,000 
episodes of diarrhea requiring hospitalization and 900,000 clinic visits among children in 
industrialized countries, and up to 200,000 deaths of children <5 years of age in developing 
countries (Patel, et al). Hence, there is an urgent public health need for the rapid development 
of novel interventions to prevent the spread of this disease.  
 
Vaxart’s norovirus oral tablet vaccine uses Vaxart’s non-replicating adenoviral-based oral 
vaccine platform. The platform has been assessed to be well tolerated and safe in over 600 
healthy adult subjects who have been enrolled in studies to evaluate the safety, tolerability, 
and immunogenicity of the platform. Notably, Vaxart’s norovirus oral tablet vaccine is highly 
immunogenic in humans, inducing serum antibodies and potent mucosal responses at both in 
the intestine and in more distal mucosal sites such as the saliva and the nose (Kim, et al, JCI 
Insights, 2018 and unpublished data).  
Norovirus gastroenteritis is a contagious disease that can affect all age groups, and infants 
aged 6 to 23 months have the highest norovirus disease burden in children.  Breastmilk 
antibodies to norovirus have been shown to be inhibitory to severe disease in breast milk fed 
children (Labayo, et al). Vaxart and collaborators Dr. Stephanie Langel and colleagues at 
Duke University have shown that oral immunization of lactating ferrets can provide 
substantial breast milk antibodies to the vaccine candidate (Langel, et al, unpublished data). 
In this study, we will evaluate the immunogenicity effect of orally administered bivalent 
GI.1/GII.4 norovirus vaccine in the breast milk of lactating females and fecal samples in their 
infants.  
This trial is not powered as an efficacy study and any cases of norovirus acute gastroenteritis 
during the study period will be evaluated as exploratory. 
Description of Sites/Facilities: 
This will be a multi-center trial conducted at (approximately) 7 sites in South Africa. The 
name of the Investigators and sites are provided within the “List of Investigators and Centers 
Involved in the Trial” document. 
Description of Investigational Product: 
Name of Vaccine: Bivalent GI.1/GII.4 norovirus vaccine 
• Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective 
Recombinant Adenovirus 5 with dsRNA Adjuvant (VXA-G1.1-NN) 
• Norovirus GII.4 Sydney VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective 
Recombinant Adenovirus 5 with dsRNA Adjuvant (VXA-G2.4-NS) 
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Dose Regimen: 5×1010 IU (medium dose) and 1×1011 IU (high dose) per strain per dose at 
Day 1.  
Route: Oral administration 
Dosage Form: Enteric coated tablet 
Study Design 
This study will investigate the safety, tolerability, and immunogenicity of two distinct 
monovalent norovirus oral vaccine products given together as a single bivalent dose. Both 
vaccine drug products (DP) will be supplied in the form of small white enteric-coated tablets 
containing VXA-G1.1-NN or VXA-G2.4-NS.   
VXA-G1.1-NN and VXA-G2.4-NS are E1/E3-deleted, replication-incompetent, serotype 5 
adenovirus vaccine vectors designed for use as vaccines for the prevention of NoV infection. 
These non-replicating vectors encode for a full-length VP1 gene of either Norwalk virus 
(VXA-G1.1-NN vaccine) or Sydney virus (VXA-G2.4-NS vaccine). In addition to the 
transgene cassette, the rAd5 vector also contains a dsRNA hairpin following a second 
hCMVie promoter, thereby expressing both vaccine antigen and adjuvant in the same cell. 
These rAd5 vectors are designed to deliver both NoV VP1 antigen and adjuvant to the same 
target cells in the intestinal ileum. 
A matching number of placebo tablets will be dispensed to maintain the study blinding. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoints 
• To evaluate the safety and tolerability of 
oral bivalent GI.1/GII.4 norovirus 
vaccine 
administration 
in 
healthy 
lactating female participants.  
 
 
 
 
 
 
• To 
assess 
the 
short-term 
immunogenicity 
of 
oral 
bivalent 
GI.1/GII.4 
norovirus 
vaccine 
administration in healthy lactating 
female participants and its association 
• Frequency, duration, and severity of 
solicited symptoms of reactogenicity 
(local and systemic) for 1 week 
following study drug dose. 
• Frequency, duration, and severity of 
unsolicited treatment-emergent adverse 
events (TEAEs), serious AEs (SAEs), 
adverse events of special interest 
(AESIs), and new onset of chronic 
illness (NOCIs) through the active 
period (4 weeks post dose). 
 
 
• Serum VP1 specific (GI.1 and GII.4) 
IgA on Day 1 (baseline), Day 8, and 
Day 29 (4 weeks post last dose). 
• Breastmilk VPI specific (GI.1 and 
GII.4) IgA on Day 1 (baseline), Day 8, 
, and Day 29 (4 weeks post last dose). 
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with the immunogenicity response in 
breastmilk. 
 
Secondary Objective 
Secondary Endpoints 
• 
To assess the long-term safety of 
bivalent GI.1/GII.4 norovirus vaccine 
through 12 months after the last 
vaccination. 
 
• 
To assess the immunogenicity of oral 
bivalent GI.1/GII.4 norovirus vaccine 
administration in healthy lactating 
female participants and its association 
with the immunogenicity response in 
breastmilk.  
 
• Frequency, duration, and severity of all 
SAEs, AESIs, and NOCIs through 12 
months after study drug dose  
 
 
• Serum VP1 specific (GI.1 and GII.4) IgA 
on Day 180 after study drug dose 
• Breastmilk VP1 specific (GI.1 and 
GII.4) IgA on Day 60, , and Day 180 
after study drug dose 
• Serum VP1 specific (GI.1 and GII.4) IgG 
on Day 1 (baseline), Day 8, Day 29, and 
Day 180 after study drug dose 
• Serum BT50 (GI.1 and GII.4) on D1 
(baseline), on Day 8, Day 29, and Day 
180 after study drug dose 
 
Exploratory Objective 
Exploratory Endpoints 
• 
To assess additional immunogenicity 
parameters of bivalent GI.1/GII.4 
norovirus vaccine including 
immunogenicity response in breastfed 
infants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To assess clinical effects in subjects 
presenting with acute gastroenteritis 
symptoms during the study period 
• Nasal and saliva VP1 specific (GI.1 and 
GII.4) IgA from lactating mother on D1 
(baseline), on Day 8, Day 29, Day 60, 
and Day 180   
• Infant stool VP1 specific (GI.1 and 
GII.4) IgA on Day 1 (baseline), Day 29, 
and Day 60 
• Breastmilk BT50 (GI.1 and GII.4) at 
various, critical timepoints if feasible, 
and with samples that have high 
probability of significant responses 
• Breastmilk Enterocyte culture 
neutralizing antibodies (GI.1 and GII.4) 
at various timepoints, if feasible, and 
with samples that have a high 
probability of significant responses. 
 
 
• Occurrence of norovirus acute 
gastroenteritis  
 
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Study Population:  
76 healthy adult lactating female participants aged 18 years or greater and their breastfed 
infants aged >30 days to 11 months of age   
Planned Number of Subjects: 
A total of 76 healthy lactating female participants aged ≥18 years and their breastfed infants 
aged >30 days to 11 months of age will be enrolled and randomized during this trial.  
Eligibility Criteria: 
Inclusion Criteria: 
To be eligible for this study, participants must meet all the following: 
1. Lactating females aged ≥ 18 years at the time of enrolment and their breastfed 
infants aged >30 days to 11 months of age at the time of the participants’ study 
drug administration. 
2. In stable and good general health, without significant medical illness, based on 
medical history, physical examination (including vital signs), and clinical 
judgment of the investigator. 
3. Lactating females willing and able to provide informed consent which includes 
compliance with the requirements and restrictions listed in the ICF and in the 
protocol. 
4. Lactating females who are willing to provide consent for their breastfed infant.  
5. Negative pregnancy tests at screening and prior to dose on Day 1 
6. Available for all planned visits and tele-health appointments, and ability to 
comply with all study-related evaluations (including but not limited to having 
the ability and willingness to swallow multiple small enteric-coated tablets per 
study dose, express/pump breastmilk, and collect infant stool samples) 
7. Plan to continue breastfeeding as the main source of the infant's nutrition for at 
least 1 month (longer is preferred with goal of 6 months post dose if possible) 
from the time of study drug administration. Exclusive breastfeeding is 
acceptable but not necessary. 
8. The nursing infant is the product of a singleton pregnancy AND does not have 
any of the following (therefore, subjects must be willing to provide the infant’s 
medical record at screening and Day 1 and the infant’s updated vaccine record 
at Day 60 or later): 
a.     Any abnormality that may interfere with breastfeeding or milk 
absorption 
b. Active infection (may be included if the infection resolves and the 
subject is re-assessed during the screening period) 
c. Infant has any other medical condition or abnormality that, in the 
opinion of the investigator, could compromise the infant's appropriate 
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inclusion in this study including interference with the interpretation of 
study results (such as malabsorption) 
d. One or more documented brief resolved unexplained events (BRUE) 
e. Extreme prematurity (infants who were born at less than 28 weeks 
gestation) 
f. 30 days of age or less at the participant's study drug administration OR 
greater than 11 months of age at the participant's study drug 
administration 
g. Prior hospitalization that is not exclusively for hyperbilirubinemia 
requiring phototherapy 
h. Any genetic/metabolic disease 
i. 
Any chronic illness requiring long term medication 
9. Subjects must be willing to use a highly effective form of contraception for 30 
days prior to vaccination and until 60 days after the vaccination. Acceptable 
forms are oral, implantable, intrauterine, transdermal, intravaginal, injectable, 
double barrier or abstinence (subjects using diaphragms must also use condom). 
The form of contraception must be approved by the investigator. 
Subject reac Criteria: 
The participants must be excluded from participating in the study if they meet any of the 
following: 
1. Presence of a fever ≥ 38.0oC measured orally at baseline, on Day 1 prior to 
vaccination. (Assessment may be repeated once during screening period). 
2. Acute disease within 72 hours prior to vaccination, defined as the presence of a 
moderate or severe illness (as determined by the Investigator through medical 
history and physical exam). (Assessment may be repeated once during screening 
period). 
3. Participants who have received antipyretic/analgesic medications within 24 hours 
prior to the intended vaccine administration. 
4. Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV) tests at the screening visit. 
5. History of hypersensitivity or allergic reaction to any component of the 
investigational vaccine, including but not limited to fish gelatin. 
6. History of serious reactions to vaccination such as anaphylaxis, respiratory 
problems, hives, or abdominal pain. 
7. Presence of significant uncontrolled medical or psychiatric illness (acute or 
chronic) including the institution of new medical/surgical treatment or significant 
dose alteration for uncontrolled symptoms or drug toxicity within 3 months of 
screening and reconfirmed at baseline. 
8. History of significant pregnancy-related complications during this pregnancy, 
including but not limited to pre-eclampsia, eclampsia, or gestational diabetes 
unless a full resolution is documented. 
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9. Cancer, or treatment for cancer, within the past 3 years (excluding fully treated 
and resolved basal cell carcinoma or squamous cell carcinoma). 
10. Presence of immunosuppression or medical condition possibly associated with 
impaired immune responsiveness, including diabetes mellitus type 1 or 2. 
11. History of irritable bowel disease or other inflammatory digestive or 
gastrointestinal condition that could affect the distribution/safety evaluation of an 
orally administered vaccine targeting the mucosa of the small intestine. Such 
conditions may include but are not limited to: 
a. Any history of:  
i. 
Malignancy 
ii. 
Malabsorption  
iii. 
Pancreatobiliary disorders 
iv. 
Inflammatory bowel disease 
v. 
Irritable bowel disease 
vi. 
Hiatal hernia 
vii. 
Surgical resection 
b.   History of diagnosis or treatment in past 5 years of: 
i. 
Esophageal or gastric motility disorder 
ii. 
Gastroesophageal reflux disease (GERD) - Will allow for 
subjects with a history of pregnancy-related GERD if fully 
resolved for >3 months and no other history of GERD diagnosis  
iii. 
Peptic ulcer 
iv. 
Cholecystectomy 
12. Any condition that resulted in the absence or removal of the spleen  
13. History of any form of angioedema  
14. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that 
could make blood draws problematic 
15. History of GI bleeding including hematochezia (blood in stool) or melena (black 
stool) 
16. Any significant hospitalization within the last year which in the opinion of the 
investigator or sponsor could interfere with study participation 
17. Any of the following history or conditions that may lead to a higher risk of 
clotting events and/or thrombocytopenia: 
a. Family or personal history of bleeding or thrombosis 
b. History of heparin-related thrombotic events, and/or receiving heparin 
treatments 
c. History of autoimmune or inflammatory disease 
d. Presence of any of the following conditions known to increase the risk of 
thrombosis within 6 months prior to screening: 
 
i. 
Recent surgery other than fully healed cesarean delivery or 
excision/ biopsy of cutaneous lesions  
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ii. 
Immobility (confined to bed or wheelchair for 3 or more 
successive days)  
iii. 
Head trauma with loss of consciousness or documented brain 
injury  
iv. 
Receipt of anticoagulants for prophylaxis of thrombosis 
v. 
Recent clinically significant infection including hospitalization 
for COVID-19 related illness 
18. Any other condition that, in the clinical judgment of the investigator, would 
jeopardize the safety or rights of a participant taking in the study, would render 
the participant unable to comply with the protocol, or would interfere with the 
evaluation of the study endpoints 
19. Receipt of a licensed vaccine (including any COVID-19 vaccines under 
Emergency Use Authorization) within 14 days prior to study drug dose or planned 
administration during the study active period 
20. Use of antibiotics, proton pump inhibitors, H2 blockers, or antacids within 7 days 
prior to study drug administration or planned use during the active study period 
21. Use of medications known to affect the immune function (including but not 
limited to systemic corticosteroids, leukotriene modifiers, and JAK inhibitors) 
within 2 weeks before study drug administration or planned use during the active 
study period. Ophthalmic, inhaled, and intranasal steroids should follow these 
restrictions. 
22. Daily use of nonsteroidal anti-inflammatory drugs within 7 days prior to study 
drug administration or planned use during the active study period  
23. Donation or receipt of blood or blood products within 30 days prior to study drug 
administration or planned donation during the active study period 
24. Participating in any clinical trial with another investigational product within 
30 days prior to the first trial visit or intend to participate in another clinical trial 
at any time during the conduct of this trial 
25. Are first-degree relatives of individuals involved in trial conduct 
26. Positive urine drug screen for drugs of abuse at screening 
27. Positive alcohol test at screening or baseline 
28. History of drug, alcohol, or chemical abuse within 1 year of screening 
 
 
 
 
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Study Duration Criteria for Individual Subject: 
The total duration of the study will be 365 days. 
For each participant, study participation is expected to last as follows: 
Screening period:  
Up to 45 days  
Active study period: 
29 days  
Follow-up period for safety and 
duration of immune response, 
SAEs, AESIs, NOCIs 
12 months (from the study dose at Day 1) 
Total duration: 
12 months from study dose at Day 1 
 
Summary of Statistical Analysis: 
The statistical analysis plan (SAP) will be developed and finalized before database lock for 
any of the planned analyses. It will describe the participant populations to be included in the 
analyses and the procedures for accounting for missing, unused, and spurious data. This 
section provides a summary of the planned statistical analyses of the primary, secondary, and 
tertiary/exploratory endpoints.  
Analyses will be performed for the total population. 
Sample Size Justification:  
Overall, 76 healthy lactating female subjects from 18 years of age or greater and their 
breastfed infants aged >30 days to 11 months of age will be enrolled and randomly 
assigned to the three cohorts. The sample size chosen is based on clinical judgment 
consultation with physicians and a biostatistician, and no formal sample size or power 
calculation was conducted. 
Interim Analysis:  
No interim analysis will be conducted for this study. 
Safety Monitoring Committee: 
A Safety Monitoring Committee (SMC) will be assigned by the Sponsor prior to the 
beginning of the study and will provide oversight of the study throughout the duration of the 
study period (Day 1 through Day 365) as needed. Ad hoc meetings will be convened if any 
predefined stopping rules are met, or any serious vaccine-related events or trends are 
observed. 
Further details regarding data safety monitoring guidelines will be included in the SMC 
Charter, which is the governing document that supersedes this section of the protocol. 
 
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1.1.   Schedule of Trial Activities 
Table 1: Schedule of Activities 
Screening 
Active Study Period 
                                   Follow-up Period 
  Study Day 
Day -45 
to  
Day -1 
Day   
1 
Day 
8 
(ET)f 
Day   
15 
Day 
29 
(ET)f 
Month 2 
Day 60* 
Month 4 
Day 120 
Month 6 
Day 180 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Telephone call visit 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
+ 2  
±2 
 
±2 
 
±7 
±7 
±7 
±7 
±7 
±7 
Informed consent 
X 
  
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
  
 
 
 
 
 
 
 
 
 
Medical history* 
X 
X  
 
 
 
 
 
 
 
 
 
Serologya 
X 
  
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
  
 
 
 
 
 
 
 
 
 
Alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test b 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Xc 
Xc 
 
Xc 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
  
X 
  
 
 
 
 
 
 
 
 
Distribute Solicited Symptom Diary 
  
X 
  
 
 
 
 
 
 
 
 
Review Solicited Symptom Diarye  
  
  
Xf 
 
 
 
 
 
 
 
 
Review prior & concomitant medication 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Query for AEs, SAEs, AESIs and NOCIs 
 
X 
X 
X 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
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Screening 
Active Study Period 
                                   Follow-up Period 
  Study Day 
Day -45 
to  
Day -1 
Day   
1 
Day 
8 
(ET)f 
Day   
15 
Day 
29 
(ET)f 
Month 2 
Day 60* 
Month 4 
Day 120 
Month 6 
Day 180 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Telephone call visit 
 
 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
 
 
+ 2  
±2 
 
±2 
 
±7 
±7 
±7 
±7 
±7 
±7 
Sample Collection for Immunogenicity Assessments 
 
 
 
 
 
 
 
 
 
 
Serum sample - BT50, VP1 specific IgA and IgG 
 
X 
X 
 
X 
 
 
X 
 
 
 
Nasal Swab (SAMTM Device) - VP1 specific IgA 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Saliva Sample - VP1 specific IgA 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Breastmilk - VP1 specific IgA, Enterocyte 
culture neutralizing antibodies, and BT50h 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Infant Stool - VP1 specific IgA 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Notes:  
Tele-health appointment (by phone)  
a F- human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV)  
b Serum pregnancy tests will be done at screening. Point-of-Care urine pregnancy test will be performed before dosing on Day 1 and women found positive with urine pregnancy 
test will not be enrolled during this study.  
c Targeted exam: at a minimum, assessments of the skin, respiratory system, cardiovascular system, and GI (abdomen, liver, and spleen) will be included. 
d Blood pressure, heart rate, and respiratory rate will be measured after the subject has been resting in a sitting position for 5 minutes.  
e At the discretion of PI and/or per subject request to evaluate any of the expected reactogenicity symptoms or any unexpected symptoms of concern, a contact must occur as soon 
as possible between the subject and the Investigator, or a medically qualified member of the study site staff, to assess if an unscheduled visit is required. 
f Early termination assessments. Review of solicited symptoms should be included if the subject drops out before Day 8. Day 29 procedures should be performed if the subject 
drops out before Day 29 on the day of early termination. 
g TEAEs will only be collected during the Active Study period (from time of first dose through 4 weeks post dose). Only SAEs, AESIs and NOCIs will be collected during the 
Follow-up Period.   
h Breastmilk VP1 specific IgA will be tested at the indicated intervals in the table. Breastmilk enterocyte culture neutralizing antibodies and BT50 will be tested at various time 
points if feasible. 
* Also collect the infant’s medical record at screening and day 1 and the infant’s updated vaccine record at D60 or later 
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2. 
INTRODUCTION 
2.1. 
Indication  
Bivalent GI.1 and GII.4 vaccines are being investigated for the prevention of noroviral 
gastroenteritis caused by norovirus GI.1 and GII.4. 
2.2. Background 
2.2.1. Background of Disease 
Norovirus (NoV) infection remains a leading cause of Acute gastroenteritis (AGEs) globally, with 
a prevalence of 16% (Liao et al., 2021). Noroviruses are a genetically diverse group of small, non-
enveloped, single-stranded positive sense (RNA) viruses belonging to the Caliciviridae family 
(Bresee et al., 2002). Genogroups I, II and IV are human-transmitted. Genogroup I and II account 
for the majority of norovirus outbreaks.  Each genogroup is further divided into genotypes based 
on the similarity of the amino acid sequence of the major viral capsid protein, VP1 (Atmar and 
Estes, 2012). Genogroup I and II account for the majority of norovirus outbreaks (Vega et al., 
2014). The classic symptoms of NoV infection include sudden onset of vomiting, abdominal 
cramps, watery diarrhea, and other clinical symptoms such as headache, chills, and myalgias. 
Currently, there is no specific treatment modality for NoV infection. The standard treatment is oral 
rehydration with fluids and electrolytes (Glass et al., 2009). In 2016, the World Health 
Organization (WHO) stated that the development of a NoV vaccine should be considered an 
absolute priority. It is important to develop prevention methods like vaccines considering the 
NoV-associated risk (Esposito and Principi, 2020). Despite a large medical need and years of 
development, no vaccine is licensed for use in any population for NoV infection. 
2.2.2  Non-clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine 
Vaxart has conducted multiple preclinical studies of our norovirus vaccine candidate in mice and 
ferrets, further details are available in the Investigator’s Brochure. The preclinical and clinical data 
on VXA-G1.1-NN and on influenza HA (with the same exact vector backbone) demonstrates a 
29-fold increase in neutralizing antibody responses after single dose enteric-coated tablet 
administration (Liebowitz et al., 2020), confirming that VXA-G1.1-NN and VXA-GII.4-NS are 
capable of eliciting robust antibody responses to VP1 following oral tablet delivery. 
2.2.3 Clinical experience with Monovalent and Bivalent GI.1 and GII.4 vaccine 
Vaxart has completed four Phase 1 studies in over 200 healthy volunteers with our monovalent 
tableted norovirus GI.1 oral tablet vaccine candidate and one Phase 1b study with our bivalent 
tableted vaccine candidate (co-administration of GI.1 and GII.4 vaccines).  In all studies, the 
primary endpoint was safety, and the secondary endpoint was immunogenicity. In the bivalent 
study, potential interference with co-administration was also evaluated.  These studies indicate that 
the vaccine was safe and generally well tolerated, and there have been no severe adverse events 
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(SAEs) attributed to vaccine. The vaccine has generated robust immune responses including 
systemic and mucosal antibodies as well as immunoglobulin A + (IgA) and immunoglobulin G 
(IgG) + memory B cells. In addition to increase in serum blocking titer fifty assay (BT50) titers, 
vaccine recipients also developed mucosally primed VP1-specific circulating antibody secreting 
cells (ASCs), IgA+ memory B cells expressing gut-homing receptor (α4β7), and fecal IgA, 
indicating substantial and local responses potentially relevant to prevent norovirus infection (Kim 
et al., 2018).  
 
During the Phase 1 dose-ranging study VXA-NVV-104, a total of 65 healthy older adult volunteers 
ages 55-80 (in two age cohorts) were evaluated for immunogenicity, safety, and tolerability at 
three dosing levels of monovalent GI.1-NN: low, medium, and high. Preliminary results of this 
Phase 1 study indicate this oral norovirus vaccine candidate was safe, well-tolerated, and induced 
similar immune responses in this older population compared to previous results in younger 
volunteers.  
 
In an open label Phase 1b boost optimization study (VXA-NVV-105), immunogenicity, safety, 
and tolerability of repeat-dose administration with varying boost schedules were evaluated in 30 
healthy adults (18-55 years). VXA-GI.1 was found to be safe and generally well-tolerated in 4-
week, 8-week and 12-week boost schedules. All solicited symptoms were graded as mild or 
moderate severity, and none required treatment or study discontinuation. During the active period 
there were no related unsolicited AEs and no related SAEs, AESI or NOCIs. There were no SAEs, 
AESIs, or NOCIs reported during the safety follow-up period. There were no deaths during the 
study. Clinical laboratory data, vital signs data, and physical examination findings were within 
normal ranges and those reporting deviations were mild and transient. No clinically significant 
abnormal physical examination findings were noted. 
  
2.3  Trial Rationale 
Noroviruses are a genetically diverse group of small, non-enveloped, single-stranded positive-
sense RNA viruses belonging to the Caliciviridae family, and currently, it is the main viral cause 
of acute gastroenteritis (AGEs) in most countries worldwide. After adoption of the rotavirus 
vaccine throughout the world, norovirus infection has been one of three major causes of infant 
diarrheal disease.  It was estimated that each year NoVs cause 64,000 episodes of diarrhea 
requiring hospitalization and 900,000 clinic visits among children in industrialized countries, and 
up to 200,000 deaths of children <5 years of age in developing countries (Patel, et al). Hence, there 
is an urgent public health need for the rapid development of novel interventions to prevent the 
spread of this disease.  
An effective NoV vaccine must prevent the two most common NoV genotypes, GI.1 and GII.4, 
and Vaxart’s bivalent norovirus vaccine consists of VXA-G1.1-NN and VXA-GII.4-NS. Vaxart’s 
norovirus oral tablet vaccine uses Vaxart’s non-replicating adenoviral-based oral vaccine platform 
(vector adjuvant antigen standard technology (VAAST)), which has been studied to be well 
tolerated and safe in over 600 healthy adult subjects who have been enrolled in studies to evaluate 
the safety, tolerability, and immunogenicity of vaccines built on the VAAST platform. Notably, 
Vaxart’s norovirus oral tablet vaccine is highly immunogenic in humans, inducing serum 
antibodies and potent mucosal responses. 
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A unique and advantageous immune response elicited by oral vaccination is the induction of 
antibodies derived from mucosal cells. Given that the mucosal route of immunization produces 
superior mucosal immunity compared to injected vaccines, it is hypothesized that GI.1/GII.4 
bivalent oral vaccine may enable higher degrees of mucosal protection against infection when 
compared to a parenteral immunization method. 
Presently, norovirus gastroenteritis is a contagious disease that can affect all age groups, and 
infants aged 6 to 23 months have the highest norovirus disease burden in children. A study 
published by Labayo and colleagues demonstrated the passive transfer of IgA in breastfeeding 
moms infected with NoV may inhibit norovirus diarrheal disease in their nursing infants (Labayo 
et al, 2020).  Although several phase 1 norovirus studies have shown a robust immune response in 
healthy subjects when given Vaxart’s norovirus G1.1 and G2.4 monovalent and bivalent vaccines, 
the immune response to orally administered bivalent GI.1/GII.4 norovirus vaccine in healthy, 
lactating females is still unknown.  
 
Unpublished data from Vaxart in collaboration with Stephanie Langel and colleagues show 
promising results for inducible breastmilk immunogenicity after receipt of a Vaxart vaccine 
construct in animal models. Pregnant/postpartum ferrets were orally administered Vaxart influenza 
vaccine and subsequently produced IgG and IgA antibodies to influenza in their breast milk.  
Breast milk from mucosally immunized ferret mothers was found to be capable of neutralizing 
influenza H1N1 by microneutralization assay. The bivalent GI.1/GII.4 norovirus vaccine uses the 
same VAAST platform as Vaxart influenza vaccine, thus there is a potential for lactating women 
to induce immunogenicity towards NoV in their breastmilk.  Besides directly neutralizing 
pathogens, IgA has other functional activity, which may greatly underestimate IgA protective 
responses.   Following immunization of lactating, postpartum mothers with Vaxart’s oral tablet, it 
is hypothesized that nursing infant incidence of norovirus diarrheal disease will be significantly 
lower due to the passive transfer of norovirus breast milk IgA antibodies, which may also reduce 
further viral transmission and thus disease burden within the family. 
 
Therefore, in this phase 1 study, we will evaluate the immunogenicity effect of orally administered 
bivalent GI.1/GII.4 norovirus vaccine in the breast milk of healthy, lactating female volunteers 
and fecal samples (exploratory) in their infants. Additionally, the study will evaluate the safety 
and tolerability of the norovirus bivalent vaccine in lactating females; the dose of the vaccine will 
be 5×1010 IU or 1×1011 IU per strain given as a single bivalent dose. 
 
This trial is not powered as an efficacy study and any cases of norovirus acute gastroenteritis during 
the study period will be evaluated as exploratory. 
2.4 Risk / Benefit Assessment   
2.4.1 Known Potential Risks to the Subjects 
More detailed information about the known and expected risks and reasonably expected adverse 
events of Bivalent GI.1/GII.4 NoV vaccine may be found in the Investigator’s Brochure (IB). 
Below are the expected treatment emergent adverse events (TEAEs) with Grade 1-3 symptoms: 
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1. Diarrhea 
2. Nausea 
3. Abdominal pain 
4. Malaise/fatigue 
5. Headache 
6. Fever 
7. Vomiting 
8. Anorexia 
9. Myalgia (muscle pain) 
2.4.2 Known Potential Benefits to the Subject 
Benefits to individual subjects may include receipt of a potentially efficacious NoV vaccine. 
Clinical data from Phase 1 studies demonstrated that VXA-G1.1-NN and VXA-G2.4-NS generated 
robust immune responses. 
 
Since these are experimental vaccines against NoV, there are no proven benefits to the subjects for 
their participation in this research study. This vaccine may successfully be developed to address a 
common and sometimes serious gastrointestinal infection. 
 
2.4.3 Overall Benefit Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this study, the 
potential risks identified in association with Bivalent GI.1/GII.4 NoV vaccine are justified by the 
anticipated benefits that may be afforded to subjects and potentially their infants with noroviral 
gastroenteritis caused by NoV GI.1 and GII.4. 
3. 
TRIAL OBJECTIVE AND END POINTS 
3.1. Objectives 
3.1.1. Primary Objectives 
• Safety 
o To determine the safety and tolerability of oral bivalent dosing regimen of GI.1 
and GII.4 norovirus vaccine administration in healthy lactating female 
participants. 
 
• Immunogenicity 
o To determine the short-term immunogenicity of oral bivalent GI.1/GII.4 
norovirus vaccine administration in healthy lactating female participants and 
most critically, the association with vaccine specific antibody responses in 
breastmilk.  
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3.1.2. Secondary Objectives 
• Safety 
o To determine the long-term safety of bivalent GI.1/GII.4 norovirus vaccine 
through 12 months after the last vaccination. 
 
• Immunogenicity 
o To assess the immunogenicity of oral bivalent GI.1/GII.4 norovirus vaccine 
administration in healthy lactating female participants and most critically, the 
association with vaccine specific antibody responses in breastmilk.  
3.1.3. Exploratory Objectives 
• Immunogenicity 
o To determine the additional immunogenicity parameters of bivalent GI.1/GII.4 
norovirus vaccine including immunogenicity response in breastfed infants. 
o To determine the clinical effects in subjects presenting with acute gastroenteritis 
symptoms during the study period.  
3.2. End Points 
3.2.1. Primary End Points 
• Safety 
o Frequency, duration, and severity of solicited symptoms of reactogenicity (local, 
systemic) for 1 week following each dose of study drug  
o Frequency, duration, and severity of unsolicited treatment-emergent adverse 
events (TEAEs), serious AEs (SAEs), adverse events of special interest (AESIs), 
and new onset of chronic illness (NOCIs) through the active period (4 weeks post 
last dose). 
 
• Immunogenicity 
o Serum VP1 specific (GI.1 and GII.4) IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by dose level  
▪ Geometric mean concentration (GMC) at Day 1, Day 8 and Day 29  
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 
to Day 29 
o Breastmilk VPI specific (GI.1 and GII.4) IgA through the active period measured 
by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, and Day 29  
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 
to Day 29   
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o The number of subjects in each dose group that had a 2-fold GMC rise or greater 
in breast milk VP1 specific IgA (GI.1 and GII.4) between Day 1 and any other 
timepoint.  
3.2.2. Secondary End Points 
• Safety 
o Frequency, duration, and severity of all SAEs, AESIs, and NOCIs through 12 
months after last study drug dose 
 
• Immunogenicity                                                 
o Serum VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 180 
o Breastmilk VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug 
dose measured by Meso Scale Discovery (MSD) by dose level 
▪ Geometric mean concentration (GMC) at Day 60 and Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 60 and from Day 
1 to Day 180 
o Serum VP1 specific (GI.1 and GII.4) IgG through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, and 
Day 180   
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to 
Day 29, and from Day 1 to Day 180  
o Serum Blocking titers 50 (BT50) (GI.1 and GII.4) through 6 months after study 
drug dose measured by Histo-blood group antigen (HBGA) assay by dose level 
▪ Geometric mean titer (GMT) at Day 1, Day 8, Day 29, and Day 180   
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to 
Day 29, and from Day 1 to Day 180 
 
 
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3.2.3. Exploratory End Points 
• Efficacy 
o Occurrence of norovirus acute gastroenteritis 
 
• Immunogenicity 
o Saliva VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by 
Enzyme-linked immunosorbent assay (ELISA) by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 
60 and Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 
1 to Day 29, from Day 1 to Day 60, and from Day 1 to Day 180 
o Nasal VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Meso 
Scale Discovery (MSD) by dose level 
▪ Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 
60 and Day 180 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 
1 to Day 29, from Day 1 to Day 60, and from Day 1 to Day 180 
o Infant stool VP1 specific (GI.1 and GII.4) IgA measured by Enzyme-linked 
immunosorbent assay (ELISA) by dose level 
▪ Geometric mean concentration (GMC) Day 1, Day 29, and Day 60 
▪ Geometric mean fold rise (GMFR) from Day 1 to Day 29 and from 
Day 1 to Day 60 
o Breastmilk Blocking titers 50 (BT50)  (GI.1 and GII.4) measured by Histo-blood 
group antigen (HBGA) assay by dose level 
▪ Individual subject titers on samples and some timepoints that have a 
high likelihood of success, assuming the assay works in breast milk 
samples 
o Breastmilk Enterocyte culture neutralizing antibody titers (GI.1 and GII.4) 
measured by norovirus neutralization in enterocyte culture 
▪ Individual subject titers on samples and some timepoints that have 
a high likelihood of success, under the assumption that the assay works 
in breast milk samples. At the date of this protocol, only serum GII.4 
neutralizing antibodies have been successfully measured. 
 
4. 
TRIAL DESIGN 
4.1. Overall Description of Trial Design  
This is a multi-center, double-blind, randomized, placebo-controlled, single dose, dose ranging 
study in healthy, breastfeeding, female volunteers (≥18 years). The study will randomize 76 
subjects and their breastfed infants aged >30 days to 11 months of age into three arms.  
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After reviewing and signing an informed consent, the subjects will undergo screening assessments 
to determine study eligibility up to a 45-day Screening Period. 
On Day 1 of the randomized portion, subjects will be randomized in a 2:2:1 ratio to one of the 
three treatment arms to receive active vaccine at medium dose or high dose or placebo, as follows 
(Figure 1):  
 
Figure 1 
 
All subjects will be monitored for Solicited Symptoms of Reactogenicity (GI and systemic) for 1 
week following the study drug dose and unsolicited AEs for 28 days post study drug dose (until 
Day 29) during the Active Period. Subjects will then enter the Follow-up period after Day 29 and 
will be monitored for specified unsolicited adverse events (SAEs, AESIs, and NOCIs) through 
Day 365 (Month 12) for safety and durability of immune response. Subjects will have samples 
(nasal, saliva, and serum) collected at the site, and will also self-collect samples (breastmilk and 
infant stool) at home for evaluation of immunogenicity as specified in the SoA (Table 1).  
 
 
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Table 2 Study Design 
Treatment 
Group 
Study Drug 
Per Strain Dose 
(IU) +/- 0.5 log 
Total Dose 
(IU/dose) 
Dosing Schedule 
No of Subjects 
Arm 1 
(n=30) 
Bivalent 
GII.4/GI.1 
vaccine 
5×1010 
1×1011 
Day 1 
30 
Arm 2 
(n=30) 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
Day 1 
30 
Arm 3 
(n=16) 
Placebo 
N/A 
N/A 
Day 1 
16 
Total 
76 
Abbreviations: IU=infectious units 
After vaccination on Day 1, the study will include an Active Study Period that runs through 4 
weeks after administration (Day 29), and a Follow-up Period of one year for safety and duration 
of immune response. Study assessments will be conducted as shown in the SoA (Table 1). In 
addition, subjects will be contacted by phone between site visits to monitor for safety as specified 
in the SoA (Table 1). 
A subject is considered to have completed the study if she completes the study active period at 
Day 29 (End of Study Active Period). Following completion of the Day 29 visit by all subjects the 
database will be cleaned and locked and the study unblinded. The Clinical Study Report (CSR) 
will be written based on the Day 29 dataset. 
 
A subject is considered to have completed the Follow-up Period if she remains in the study through 
Day 365 (Month 12). Following completion of the Day 365 tele-health appointment for all 
subjects, the safety database will be cleaned and locked, and data collected during the Follow-up 
Period will be included in a CSR addendum. 
 
All subjects will be monitored for Solicited Symptoms of Reactogenicity (GI and systemic) for 1 
week following the study drug dose and unsolicited AEs for 28 days post study drug dose (until 
Day 29) during the active period. The subjects will then enter the Follow-Up Period after Day 29 
and will be monitored for SAEs, AESIs, and NOCIs through Day 365 (Month 12) for safety. 
Subjects will also have samples collected for evaluation of immunogenicity and durability of 
immune response as specified in the SoA (Table 1). 
 
Planned Number of Subjects: 
 
A total of 76 healthy, lactating, female subjects aged ≥18 years and their breastfed infants aged 
>30 days to 11 months of age will be randomized and assigned to the three cohorts: placebo, 
medium dose (total 1×1011 IU/dose), or high dose (total 2×1011 IU/dose).  
 
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Study Duration: 
 
For each subject, study participation is expected to last as follows: 
 
Table 3: 
Study Duration 
Screening period:  
Up to 45 days  
Active study period: 
29 days  
Follow-up period for safety and 
duration of immune response, 
SAEs, AESIs, NOCIs 
12 months (from the study dose at Day 1) 
Total duration: 
Approximately 14 months from Screening to 
Month 12/Day 365 post vaccination  
 
4.2 
Scientific Rationale of Trial Design 
This study is designed as a standard double-blind placebo-controlled single administration, dose-
ranging study to evaluate the effect of 2 different doses (high and medium dose) of VXA-GII.4-
NS plus VXA-G1.1-NN in the target population, compared with placebo. 
4.3 
Justification for Dose Selection 
Vaxart has previously completed dose escalation (Protocol VXA-G11-101) and dose optimization 
(Protocol VXA-G11-102) studies in its initial Phase 1 NoV vaccine studies to demonstrate the 
safety, tolerability, and immunogenicity of the VXA-G1.1-NN vaccine candidate. A Phase 1b, 
double-blind, placebo-controlled study (Protocol VXA-NVV-103) with VXA-G1.1-NN and 
VXA-GII.4-NS with monovalent or bivalent dosing have also been completed. Additionally, dose 
ranging studies from 1×108 IU – 1×1011 IU (2 doses) have been studied across multiple studies 
with the same vaccine platform. 
Safety results from these completed oral tablet vaccine studies support investigations of bivalent 
administration of the VXA-G1.1-NN and VXA-GII.4-NS vaccine candidates at single total dose 
of 1×1011 IU per vaccine or 2×1011 IU per administration. 
4.4 
End of the Study Definition 
A subject is considered to have completed the study if he/she completes the study active period at 
Day 29 (End of Study Active Period). Following completion of the Day 29 visit by all subjects the 
database will be cleaned and locked, and the study unblinded. The CSR will be written based on 
the Day 29 dataset. 
A subject is considered to have completed the Safety Follow-up Period if he/she remains in the 
study Day 365 (Month 12). Following completion of the Day 365 tele-health appointment of all 
subjects, the safety database will be cleaned and locked, and data collected during the Follow-Up 
Period will be used to generate a CSR addendum. 
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4.5 
Premature Termination or Suspension of Trial 
The Sponsor or designee reserves the right to terminate the study at any time for any reason at the 
sole discretion of the Sponsor. This trial may be temporarily suspended, or prematurely terminated 
if there is sufficient reasonable cause. Written notification, documenting the reason for trial 
suspension or termination, will be provided by the suspending, or terminating party to study 
subjects, Investigators, funding agency, the Investigational New Drug (IND) Sponsor and 
regulatory authorities. If the study is prematurely terminated or suspended, the site Principal 
Investigator (PI) will promptly inform study subjects, the site Institutional Review Board (IRB) (if 
applicable) and will provide the reason(s) for the termination or suspension. Study subjects will be 
contacted, as applicable, and be informed of changes if any, to the study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB/IEC, Food and Drug Administration (FDA) and/or South 
African Health Products Regulatory Authority. 
4.6 Trial and Site Start and Close-Out  
4.6.1 First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of subjects. 
The first act of recruitment is the first site open and will be the study start date. 
4.6.2 Study/Site Termination 
The Sponsor or designee reserves the right to close the study site at any time for any reason at the 
sole discretion of the Sponsor. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed. 
 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given to Sponsor and subjects in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the Investigator. 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 30 of 88 
 
 
• Total number of subjects included is achieved earlier than expected. 
The Investigator shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up. 
5. 
SELECTION OF TRIAL POPULATION 
5.1. 
Inclusion Criteria 
To be eligible for this study, subjects must meet all the following: 
Age 
1. 
≥18 years old at the time of signing the Informed Consent Form (ICF) and her infant 
will be aged >30 days to 11 months of age at the time of the participants’ study drug 
administration 
Type of Subjects 
2. 
In stable and good general health, without significant medical illness, based on 
medical history, physical examination (including vital signs), and clinical judgment of 
the investigator. 
3. 
Lactating females willing and able to provide informed consent which includes 
compliance with the requirements and restrictions listed in the ICF and in the 
protocol. 
4. 
Lactating females who are willing to provide consent for their breastfed infant will be 
enrolled in the study 
5. 
Negative pregnancy test prior to dose 
6. 
Available for all planned visits and tele-health appointments, and ability to comply 
with all study-related evaluations (including ability and willingness to swallow 
multiple small enteric-coated tablets per study dose). 
7. 
Plan to continue breastfeeding as the main source of the infant's nutrition for at least 1 
month (longer is preferred with goal of 6 months post dose if possible) from the time 
of study drug administration. Exclusive breastfeeding is acceptable but not necessary. 
8. 
The nursing infant is the product of a singleton pregnancy AND does not have any of 
the following (therefore, subjects must be willing to provide the infant’s medical 
record at screening and Day 1 and the infant’s updated vaccine record at Day 60 or 
later): 
a. Any abnormality that may interfere with breastfeeding or milk 
absorption 
b. Active infection (may be included if the infection resolves and the 
subject is re-assessed during the screening period) 
c. Infant has any other medical condition or abnormality that, in the 
opinion of the investigator, could compromise the infant's appropriate 
inclusion in this study including interference with the interpretation of 
study results (such as malabsorption) 
d. One or more documented brief resolved unexplained events (BRUE) 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 31 of 88 
 
 
e. Extreme prematurity (infants who were born at less than 28 weeks 
gestation) 
f. 30 days of age or less at the participant's study drug administration OR 
greater than 11 months of age at the participant's study drug 
administration 
g. Prior hospitalization that is not exclusively for hyperbilirubinemia 
requiring phototherapy 
h. Any genetic/metabolic disease 
i. Any chronic illness requiring long term medication 
9. 
Subjects must be willing to use a highly effective form of contraception for 30 days 
prior to vaccination and until 60 days after the vaccination. Acceptable forms are oral, 
implantable, intrauterine, transdermal, intravaginal, injectable, double barrier or 
abstinence (subjects using diaphragms must also use condom). The form of 
contraception must be approved by the investigator. 
Subject Exclusion Criteria: 
The participants must be excluded from participating in the study if they meet any of the 
following: 
1. 
Presence of a fever ≥ 38oC measured orally at baseline, on Day 1 prior to vaccination.  
(Assessment may be repeated once during screening period) 
2. 
Acute disease within 72 hours prior to vaccination is defined as the presence of a 
moderate or severe illness (as determined by the Investigator through medical history 
and physical exam). (Assessment may be repeated once during screening period.) 
3. 
Who have received antipyretic/analgesic medications within 24 hours prior to the 
intended vaccine administration 
4. 
Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), 
or hepatitis C virus (HCV) tests at the screening visit 
5. 
History of hypersensitivity or allergic reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin 
6. 
History of serious reactions to vaccination such as anaphylaxis, respiratory problems, 
hives, or abdominal pain 
7. 
Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) 
including the institution of new medical/surgical treatment or significant dose alteration 
for uncontrolled symptoms or drug toxicity within 3 months of screening and 
reconfirmed at baseline 
8. 
History of significant pregnancy-related complications during this pregnancy, 
including but not limited to pre-eclampsia, eclampsia, or gestational diabetes unless a 
full resolution is documented. 
9. 
Cancer, or treatment for cancer, within the past 3 years (excluding fully treated and 
resolved basal cell carcinoma or squamous cell carcinoma)  
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 32 of 88 
 
 
10. 
Presence of immunosuppression or medical condition possibly associated with 
impaired immune responsiveness, including diabetes mellitus  
11. 
History of irritable bowel disease or other inflammatory digestive or gastrointestinal 
condition that could affect the distribution/safety evaluation of an orally administered 
vaccine targeting the mucosa of the small intestine. Such conditions may include but 
are not limited to: 
a. Any history of:  
i. Malignancy 
ii. Malabsorption  
iii. Pancreatobiliary disorders 
iv. Inflammatory bowel disease 
v. Irritable bowel disease 
vi. Hiatal hernia 
vii. Surgical resection 
b.    History of diagnosis or treatment in past 5 years of: 
v. Esophageal or gastric motility disorder 
vi. GERD (Will allow for subjects with a history of pregnancy-related GERD 
if fully resolved for >3 months and no other history of GERD diagnosis  
vii. Peptic ulcer 
viii. Cholecystectomy 
12. 
Any condition that resulted in the absence or removal of the spleen  
13. 
History of any form of angioedema  
14. 
Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could 
make blood draws problematic 
15. 
History of GI bleeding including hematochezia (blood in stool) or melena (black 
stool) 
16. 
Any significant hospitalization within the last year which in the opinion of the 
investigator or sponsor could interfere with study participation. 
17. 
Any of the following history or conditions that may lead to a higher risk of clotting 
events and/or thrombocytopenia: 
a. Family or personal history of bleeding or thrombosis 
b. History of heparin-related thrombotic events, and/or receiving heparin treatments 
c. History of autoimmune or inflammatory disease 
d. Presence of any of the following conditions known to increase the risk of 
thrombosis within 6 months prior to screening: 
i. Recent surgery other than fully healed cesarean delivery or excision/ 
biopsy of cutaneous lesions  
ii. Immobility (confined to bed or wheelchair for 3 or more successive days)  
iii. Head trauma with loss of consciousness or documented brain injury  
iv. Receipt of anticoagulants for prophylaxis of thrombosis 
v. Recent clinically significant infection 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 33 of 88 
 
 
18. 
Any other condition that in the clinical judgment of the investigator would jeopardize 
the safety or rights of a participant taking in the study, would render the participant 
unable to comply with the protocol, or would interfere with the evaluation of the study 
endpoints 
19. 
Receipt of a licensed vaccine (including any COVID-19 vaccines under Emergency 
Use Authorization) within 14 days prior to study drug dose or planned administration 
during the study active period. 
20. 
Use of antibiotics, proton pump inhibitors, H2 blockers, or antacids within 7 days prior 
to study drug administration or planned use during the active study period 
21. 
Use of medications known to affect the immune function (including but not limited to 
systemic corticosteroids, leukotriene modifiers, and JAK inhibitors) within 2 weeks 
before study drug administration or planned use during the active study period.  
Ophthalmic, inhaled, and intranasal steroids should follow these restrictions.   
22. 
Daily use of nonsteroidal anti-inflammatory drugs within 7 days prior to study drug 
administration or planned use during the active study period  
23. 
Donation or receipt of blood or blood products within 30 days prior to study drug 
administration or planned donation during the active study period 
24. 
Participants participating in any clinical trial with another investigational product 
30 days prior to the first trial visit or intend to participate in another clinical trial at any 
time during the conduct of this trial 
25. 
Are first-degree relatives of individuals involved in trial conduct. 
26. 
Positive urine drug screen for drugs of abuse at screening 
27. 
Positive alcohol test at screening or baseline 
28. 
History of drug, alcohol, or chemical abuse within 1 year of screening 
5.2. Early Termination/Withdrawal Criteria 
All procedures for Day 8 visit should be completed for Early Termination (ET) assessment, 
including Review Solicited Symptom Diary if ET occurs prior to Day 8 as shown in the SoA 
(Table 1). 
 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A subject may 
discontinue/withdraw study drug for reasons including but not limited to: 
• Adverse event 
• Death 
• Lost to follow-up 
• Physician decision 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject (only for discontinuing study drug, but will remain in study) 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 34 of 88 
 
 
The reason for subject discontinuation from study drug will be recorded in the electronic case 
report form (eCRF). 
At the time of withdrawal from the study, the ET visit should be completed, as shown in the SoA 
(Table 1). 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
5.3. Lost to Follow Up Procedure 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, tele-health 
appointment and, if necessary, a certified or registered letter to the subject’s last 
known mailing address or local equivalent methods). All these contact attempts 
should be documented in the subject’s research record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
5.4. Screening Failure 
Screening failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently entered in the study.  
 
Re-screening outside the screening period will be possible on a case-by-case basis following 
Sponsor approval. Subjects allowed to be re-screened will be assigned a new screening number 
and must undergo all screening procedures again. Subjects cannot re-screen more than once and 
will be determined to be permanent screen failures after the second screening determines a subject 
is ineligible.  Re-assessment of not clinically significant abnormal and/or out of range parameters 
within the screening period is allowed per Investigators’ discretion. 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 35 of 88 
 
 
5.5. Classification of Subjects Who Discontinue the Study 
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the eCRF. Reasons are listed below from the most significant 
to the least significant: 
 
 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

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Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 38 of 88 
 
 
Table 5:  
Investigational Product Dosing 
Intervention 
Name 
VXA-G1.1-NN 
VXA-GII.4-NS 
Placebo 
Type 
Biologic 
Biologic 
Matching placebo 
Dose 
Formulation 
Enteric-coated tablets 
Enteric-coated tablets 
Enteric-coated tablets 
Dosing 
Schedule 
Day 1 
Day 1 
Day 1 
Route of 
Administration 
Oral 
Administration 
instructions 
Subjects should fast and refrain from ingesting solid food for at least 4 hours prior to oral dosing. 
A trained member of the site study staff will dispense the tablet(s) constituting their assigned 
dose to the subject. The subjects will swallow the tablets with 360 to 480 mL of water or clear 
fruit juice (acidic, such as cranberry juice) followed by a light snack (e.g., crackers) at time of 
dosage administration to aid in tablet transit out of the stomach. Normal food consumption may 
resume 90 minutes after dosing. For more information refer to the study specific Pharmacy 
Manual. 
Sourcing 
Study drug will be provided to the sites by the Sponsor or designated representative. 
Table 6: 
Study Arm(s) 
Arm Title* 
Arm 1 
Arm 2 
Arm 3 
Arm Type 
Experimental 
Experimental 
Placebo 
Arm Description 
Bivalent GII.4/GI.1 
vaccine 
Bivalent GII.4/GI.1 
vaccine 
Placebo 
Per Strain Dose 
(IU) +/- 0.5 log 
5×1010 
1×1011 
N/A 
Total Dose 
(IU/dose) 
1×1011 
2×1011 
N/A 
6.4. Formulation, Appearance, Packaging, and Labelling 
Formulation: 
Both the VXA-G1.1-NN and VXA-GII.4-NS are formulated as small enteric-coated tablets. 
Packaging and Labelling: 
The tablets are packaged into foil-sealed, high-density polyethylene (HDPE) screw-cap containers 
with 10 tablets per bottle. 
All packaging and labeling operations for study drug will be performed according to Good 
Manufacturing Practices (GMP) for Medicinal Products and the relevant regulatory requirements. 
Label text for the study drug bottle will at a minimum include name of the manufacturer, the 
protocol number, the name of the product, the lot number of the product, the concentration of the 
vaccine, the date of manufacturing or expiration. 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 39 of 88 
 
 
Secondary packaging of the study drug upon dispensing from the pharmacy to the clinical staff for 
subject dosing will be determined with consideration of the site’ pharmacy standard operating 
procedures and outlined in the study pharmacy manual. 
The final subject use dispensing container (cup or secondary bottle) will be appropriately labeled 
with specific requirements for the country and deemed necessary per the site’s standard operating 
procedures (i.e., subject randomization number, total tablet count, dispensing date and time etc.) 
6.5. Product Storage and Stability 
Storage: 
The Investigator will be personally responsible for product management or will designate a study 
site staff to assume this responsibility.  
Both the VXA-G1.1-NN and VXA-GII.4-NS DP should be stored at 2-8 °C. The DP tablets may 
be kept at room temperature during the dispensation and administration process for a brief period. 
Please refer to the study specific Pharmacy Manual for detailed information. 
Stability: 
Stability studies have been performed on similarly formulated tablets prepared from the same or 
similar adenovirus 5 constructs incorporating different antigens, including, VP1 Norwalk and other 
influenza antigens (e.g., hemagglutinin H1). The 2-8°C data indicate that drug product potency 
will remain within release specification prior to retest.  Additionally, data from accelerated stability 
studies indicate that handling at controlled room temperature or brief exposure to temperatures 
above room temperature (below 37°C) is acceptable for this product. 
6.6. Accountability Procedures 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for study drug received and any discrepancies are reported and resolved 
before use of study drug. 
Only subjects enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All bottles of study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study drug accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
At the end of the study active period, the unblinded monitor will conduct a final drug reconciliation 
for all subjects and the study site overall. All records of study drug administration, accountability 
records and study drug disposition records will be examined and reconciled by the study monitor. 
Further details will be provided in the study specific Pharmacy Manual. 
Further guidance and information for the final disposition of unused study drug are provided in 
the study specific Pharmacy Manual. 
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6.7. Randomization and Blinding 
6.7.1. Randomization Procedures 
Assignment of a Subject Number: 
New subjects once deemed eligible and enrolled in the study will also receive a randomization 
number and treatment assignment, based on the blinded randomization schedule. The subject 
number will be used as the primary identifier for the complete duration of the study. After the 
subject signed the informed consent form (ICF), the Investigator (or designee) will enter the 
subject into the Screening Log, once randomized or screen failed their data will be entered into the 
eCRF.  
Randomization: 
After signing an informed consent, the subjects will undergo screening assessments to determine 
study eligibility over a 45-day Screening Period. All subjects who sign a study specific informed 
consent form will have data entered into the EDC.  On Day 1, subjects will be randomized in a 
2:2:1 ratio to one of the three treatment arms to receive active vaccine or placebo (Table 6: Study 
Arm(s). 
6.7.2. Blinding and Unblinding Procedures 
Subjects, Investigators, site personnel and the Sponsor (except as described below) will be blinded 
to individual participant treatment assignment. 
Study drug doses will be prepared at the study sites by an unblinded research pharmacist(s) or 
designee who will be provided treatment assignment through a randomization schedule. 
Specifically designated Sponsor representative(s) will also have access to unblinded individual 
subject treatment assignments for the purposes of study-required activities, including management 
of study drug inventory, production of summaries of data for SMC review, and performance of 
bioanalytical analysis. These personnel will not be directly involved in the conduct of the study. 
An SMC may convene to review unblinded overall safety if deemed necessary to ensure the safety 
of study subjects (Section 10.2). 
Instructions for breaking the blind will be provided to the study site in case of a medical 
emergency. The Investigator has the sole responsibility for determining if unblinding of a subject’s 
treatment assignment is warranted. Subject safety must always be the first consideration in making 
such a determination. The Investigator must notify the Sponsor’s Medical Monitor (or designee) 
prior to unblinding a subject’s treatment assignment. The Investigator(s) must document and report 
to the Medical Monitor any breaking of the treatment code but must not disclose the result of 
unblinding. The date and reason that the blind was broken must be recorded in the source 
documentation. 
Appropriate personnel at the Sponsor (or designee) will unblind suspected unexpected serious 
adverse reactions (SUSARs) for the purpose as required per each local regulation. The Sponsor 
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will submit SUSARs to Regulatory Agencies in blinded or unblinded fashion according to local 
law. The Sponsor will submit SUSARs to Investigators in a blinded fashion. 
6.8. Treatment Compliance 
Subjects will receive study drug directly from the Investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and recorded in the electronic case report form (eCRF). The dose of study drug 
and study subject identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study drug. 
6.9. Overdose of Treatment 
Any overdose of intervention should be recorded in the eCRF (including quantity of the excess 
dose and the duration of the overdose). AEs associated with an overdose or incorrect 
administration of study drug should be recorded in the AE eCRF. An overdose will not be 
considered an SAE unless the outcome of the overdose meets seriousness criteria. 
The effects of acute overdose of VXA-G1.1-NN and VXA-GII.4-NS in human are unknown. 
No specific antidote for overdose is known. Study subjects should be managed with appropriate 
supportive care if overdose occurs. 
6.10. Concomitant Medications and Other Therapies 
Concomitant medication is defined as any prescription or over-the-counter preparation. 
Use of concomitant medication from 4 weeks before Day 1 through Day 29 (completion of Active 
Study period) must be recorded onto the eCRF from the subject’s medical file along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Medications for pre-existing medical conditions or required for a medical condition during the 
study are allowed if not considered exclusionary. 
The Sponsor's Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
Prohibited Concomitant Medication: 
Medications specifically prohibited in the exclusion criteria are not allowed during the Active 
Study period (Section 5.2 prior/concurrent therapy), unless deemed medically necessary by the 
Investigator. 
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7. SCHEDULE OF TRIAL PROCEDURES AND ASSESSMENTS 
7.1. Trial Procedures 
A schedule of trial procedures and their timing are summarized in the SoA (Table 1). The day of 
the first investigational product vaccination is considered to be Day 1. 
7.1.1. Procedure to be followed on Screening Period (Day -45 to Day -1) 
Before enrollment and before any study-related procedures are performed, voluntary, written 
study-specific informed consent will be obtained from the subject. Each signature on the ICF must 
be personally dated by the signatory. A copy of the signed and dated ICF must be given to the 
subject. The source data must reflect that the informed consent was obtained before participation 
in the study. 
 
After obtaining signed copy of written informed consent from the subject, the subject will undergo 
screening procedures as mentioned below: 
• The demographic information (i.e., age, ethnic origin, race, height (cm), body weight (kg), 
and body mass index (kg/m2) will be recorded. 
• Obtain history of drug abuse, alcohol abuse, and blood or plasma donation. 
• Obtain any medical history of clinical significance and details of any medications currently 
taken. 
• Measure vital signs, including blood pressure, pulse rate and respiratory rate after resting 
in a sitting position for at least 5 minutes. 
• Measure subject’s temperature (oral). Oral temperature is preferred for all visits. If 
unavailable, it is acceptable for clinical study sites to measure subject’s temperature 
according to site usual standard using tympanic thermometer instead of oral and this should 
be clearly documented. All subjects must use the study-provided thermometer for daily 
oral temperature checks for solicited symptoms in the week following vaccine dose. 
• Perform physical examination evaluating any clinically significant abnormalities within 
the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
cardiovascular; 
respiratory; 
gastrointestinal 
(GI); 
musculoskeletal; 
extremities; 
neurological; and lymph nodes.  
• Perform a serum pregnancy test for all subjects at screening. At screening all women will 
have a negative serum HCG. (Prior to dosing all women will have a negative urine HCG.) 
• Verify understanding of and compliance with protocol requirements for contraception (see 
Appendix 4).  
• Perform an alcohol test. 
• Verify understanding of requirement for breastmilk and infant stool collection. 
• Ensure that all inclusion criteria are met and that none of exclusion criteria are met for the 
subject and her infant.   
• Obtain a urine sample for urine drug screen test. 
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• Collect a blood sample to determine the subject’s Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) status.  
• If the subject and her infant pass all the inclusion and exclusion criteria at the end of the 
screening visit:  
1. Provide a manual breast pump set. Teach the subject how to use a manual breast 
pump properly. 
2. Provide kits with instructions for breastmilk sample collection, storage, and 
return. Teach the subject how to express breastmilk to provide a total of 10 ml 
of breastmilk from the right breast for each sample collection. Instruct the 
subject to consistently collect breastmilk samples from the right breast. (The 
subject can use a manual or electric breast pump if she does not wish to 
manually express her breastmilk. If the subject is unable to express or pump 
breastmilk from the right breast, she can collect breastmilk from the left breast 
and must consistently collect breastmilk samples from the left breast.)  
3. Provide kits with instructions for infant stool sample collection, storage, and 
return.  Teach the subject how to properly collect the infant stool sample and 
store it until the samples are ready to be shipped.  
4. Timepoints for breastmilk and infant stool sample collection must be 
thoroughly discussed with the subject. The subject must collect breastmilk 
sample and infant stool sample (15ml) at baseline prior to the first dose (Day -
2 to Day 1). 
7.1.2. Procedure to be followed during Active Study Period (Day 1 to Day 29) 
It is anticipated that the procedures below will be conducted in a stepwise manner; ensuring that 
procedures listed prior to administration of the vaccine are conducted prior to that administration. 
The site does not need to wait the full 45 day screening period to start the active study period for 
the subject. 
• The Principal Investigator will ensure that all inclusion criteria and none of the 
exclusion criteria for the subject and her infant are met on Day1. 
• Ensure the subject collected baseline breastmilk sample (10ml) and infant stool sample 
between D-2 to D1. Review with the subject how the collection was done and if the 
samples were properly stored, prior to vaccination. If this was not done, the subject will 
need to reschedule the dosing visit ASAP and be reminded to collect baseline samples 
prior to the rescheduled visit. 
• A urine pregnancy test will be done for all subjects; site must confirm negative result 
before dosing. 
• Perform an alcohol test and site must confirm negative result before dosing. 
• Vital signs will be obtained, including temperature, blood pressure, pulse rate and 
respiratory rate after resting in a sitting position for at least 5 minutes. 
• A targeted, and symptom-directed physical examination will be done for all subjects 
during the active study period visits. At a minimum, assessments of the skin, respiratory 
system, cardiovascular system, and GI (abdomen, liver, and spleen) will be included. 
• The subject’s randomization number will be noted.  
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• Collect blood, nasal and saliva samples for Immunogenicity assessment prior to study 
drug administration. 
• Site staff member(s) will dispense/administer the investigational product. Please refer 
to the Pharmacy Manual for further instruction on this process.  
• Prior to study drug administration on Day 1, the subject’s temperature (oral) will be 
measured, and a trained member of the site study staff will dispense the tablet(s) 
constituting the assigned dose to the subject. 
• The site staff must observe the subjects for at least 30 minutes after study drug 
administration for any acute reactions. Any acute reactions are to be recorded in the 
subject’s source documents, on the AE page of the eCRF, as applicable.  
• Subjects will be asked to record symptoms of reactogenicity daily for 1 week after 
study drug administration on Day 1, using the Solicited Symptom Diary; the Solicited 
Symptom Diary will be collected from the subject on Day 8 and reviewed.   
• Subjects will be queried for unsolicited AEs for 28 days following the study drug 
administration and for SAEs, AESIs and NOCIs for 1 year following the study drug 
administration. 
• Subjects will return to the site on Day 8 and Day 29: 
1. Blood, nasal, and saliva samples will be collected for immunogenicity 
assessment on Day 8 and Day 29 as specified in the SoA (Table 1).  
2. Ascertain if the subject is still breastfeeding. Ensure the subject has also 
collected breastmilk sample and infant stool sample during the timepoints 
specified in the SoA (Table 1), if not then remind the subject. Review with the 
subject how the collection was done and if the samples were properly stored. 
3. Verify understanding of and compliance with protocol requirements for 
contraception (see Appendix 4). 
 
• The subject will be asked to contact the site staff or Investigator if an AE (e.g., doctor’s 
visit, emergency room visit) or hospitalization occurs. 
• The subject is to be informed that use of prophylactic antipyretic/pain medication, is 
not permitted on the day of study drug administration. If antipyretic/pain medication is 
used after study drug dosing, and if clinically appropriate in the judgement of the 
Investigator, acetaminophen is preferred over other non-steroidal anti-inflammatory 
drugs.  
• Prior and concomitant medications will be reviewed if the subjects took any during the 
active study period. 
• The subject will be asked to bring the completed Diary to the next visit. 
• The subject will be reminded that study staff may contact them to obtain additional 
information on events entered into the Solicited Symptom Diary. 
• Source documents will be completed. 
• The Investigator or appropriately qualified designee will review the Diary following 
vaccination, to evaluate subject compliance and as part of the ongoing safety review. 
Daily review is optimal during the active Diary period. Any solicited symptom marked 
as Grade 3 should be specifically reviewed with the subject to ensure they meet the 
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detailed solicited AE grading criteria in (Table 10) and to evaluate for potential 
alternative etiology. 
• An appointment will be scheduled for the subject to return for the next study visit. 
• The Investigator or an authorized designee completes the eCRFs and an unblinded 
dispenser/administrator will update the investigational product accountability records. 
• The subjects will be contacted by phone between site visits on Day 15 to monitor for 
safety as specified in the SoA (Table 1). If the study personnel are unable to contact 
the subject with 3 attempts, the study personnel will follow instructions given in 
Section 5.4. 
7.1.3. 
Procedure to be followed during follow-up period (Day 30 to Day 365) 
• Verify understanding of and compliance with protocol requirements for contraception 
(see Appendix 4). 
• Subjects will return to the site on Day 60 and Day 180: 
1. A blood sample will be collected for immunogenicity assessment on D180 as 
specified in the SoA (Table 1).  
2. Nasal and saliva samples will be collected for immunogenicity assessment on 
Day 60 and Day 180 as specified in the SoA (Table 1).  
3. Ascertain if the subject is still breastfeeding. If they are then ensure the subject 
has also collected breastmilk sample and infant stool sample during the 
timepoints specified in the SoA (Table 1), if not then remind the subject. 
Review with the subject how the collection was done and if the samples were 
properly stored. 
4. Collect the most current infant vaccine record on Day 60 or any time after. 
 
• Collect and record SAEs, AESIs and NOCIs.  
• Complete the source documents.  
• The Investigator or an authorized designee completes the eCRFs.  
• Ask the subject to contact the site staff or Investigator if an adverse event (e.g., doctor’s 
visit, emergency room visit) or hospitalization occurs. 
• The subjects will be contacted by phone between site visits on Day 120, Day 240, Day 
300, and Day 365 to monitor for safety as specified in the SoA (Table 1). If the study 
personnel are unable to contact the subject with 3 attempts, the study personnel will 
follow instructions given in Section 5.4. 
7.1.4 Follow-up of Subjects with Related AEs or with AEs that Led to Study 
Discontinuation  
Unless the subject refuses further contact, each subject who experiences an AE (whether serious 
or non-serious) during the study must be followed until the condition resolves, becomes stable, or 
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becomes chronic (even after the end of the subject’s participation in the study) if either of the 
following is true. 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study. 
7.1.5 Unscheduled Visit 
At the discretion of PI and/or per subject request to evaluate any of the expected reactogenicity 
symptoms or any unexpected symptoms of concern, a contact must occur as soon as possible 
between the subject and the Investigator, or a medically qualified member of the study site staff, 
to assess if an unscheduled visit is required. 
This contact will be recorded in the subject’s eCRF. If the subject is unable to attend the 
unscheduled visit, any ongoing reactions must be assessed at the next scheduled visit. 
Reactogenicity events should be assessed by the Investigator or a medically qualified member of 
the site staff, such as a study physician or a study nurse, as applicable, to the Investigator’s local 
practice, who will: 
• Measure oral temperature.  
• Measure the subject’s pulse rate (after five minutes of sitting). 
• Measure the subject’s blood pressure (after five minutes of sitting).  
• Assess any events (specify the events of interest) that are present, in accordance with 
the reactogenicity grading scale. 
• Perform a symptom focused physical examination. 
• Ask the subject if she attended an emergency room visit or was hospitalized.  
• Complete the source documents. 
• The Investigator or an authorized designee will complete the eCRF. 
 
The subject will be instructed to contact the site to report any significant illness, AEs, or 
hospitalization that occurs during the study period. 
7.2. Management of Blood/Saliva/Nasal/Breastmilk/Infant Fecal Samples 
7.2.1. Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Collection 
Blood / saliva samples for the assessment of immunogenicity will be collected from the subjects 
as specified in the SoA (Table 1). Sample collection, storage, and shipping information can be 
found in the General and Immunogenicity Laboratory Manuals. 
 
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7.2.2 Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the study specific Laboratory Manual provided to the site. 
7.2.3 Blood/Saliva/Nasal/Breastmilk/Infant Fecal Sample Storage and Shipment 
Detailed instructions on blood sample storage and shipment are contained in the study specific 
Laboratory Manual provided to the site. 
 
 7.2.4 Future Use of Stored Specimens and Data  
 
The current trial is an early phase study in which Vaxart’s goal is to understand the mechanism of 
action of the oral NoV vaccine in the prevention of NoV illness, it is important to have samples 
available for the full characterization of the vaccine. The Sponsor is planning to store blood, saliva, 
nasal, breastmilk, and infant stool samples post the completion of the study for possible future 
testing towards the development of a NoV vaccine. This testing includes evaluation of serum 
antibody titers to NoV and cell-mediated immune responses to NoV. At this time, the exact tests 
are not known but this will help to further understand how the oral NoV vaccine works in the body 
and in the prevention of NoV illness. Other immunological assays may be performed to further 
elucidate the response to our vaccine. These may include cloning the antibodies that are induced 
following immunization. All samples will use subject identifiers that are coded and will not include 
subject initials or demographic information. Only Vaxart staff will have access to the samples and 
data; they will be responsible for providing access to the samples as needed for assays. Samples 
will be stored at Vaxart or Vaxart’s designee in a secured, access-controlled location for at least 
05 years after the last license approval in the relevant market areas has been obtained for the 
vaccine being tested. Samples may be shared with collaborating researchers, but only in 
relationship to the NoV program. Any data developed externally will only be displayed in a 
deidentified form as authorized by Vaxart.  
 
8. TRIAL ASSESSMENTS AND PROCEDURES 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study drug. 
Adherence to the study design requirements, including those specified in the SoA is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The Investigator will maintain a screening log to record details of all subjects 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Subjects who experience any serious or severe TEAEs, or any event of concern should be 
instructed to contact the study site and be scheduled for a visit for further evaluation. If an 
unscheduled visit occurs, the reason for the visit and data collected during the visit should be 
recorded and entered into the unscheduled eCRF. 
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8.1 
Safety Assessment 
The safety of the bivalent GI.1 and GII.4 vaccines will be evaluated through the reporting of 
Solicited Symptoms of Reactogenicity (GI and systemic) for 1 week following the study drug dose 
and through reporting of frequency, duration, and severity of unsolicited AEs for the next 28 days 
following the study drug dose. The subjects will then enter the Follow-Up Period after Day 29 and 
will be monitored for SAEs, AESIs, and NOCIs through Day 365 (Month 12) for safety and 
duration of immune response. Each SAE, AESI, and NOCI occurrence must be assessed for 
causality.  
AESIs are listed in Appendix 5, the occurrence of these events should be reported to the Sponsor 
in an expedited manner, similar to SAEs as described in Section 9.   
Planned time points for all safety assessments are provided in the SoA (Table 1) 
8.1.1 Physical Examination 
A complete physical examination evaluating any clinically significant abnormalities in general 
appearance and within the following body systems: skin; head, eyes, ears, nose, and throat; 
cardiovascular; respiratory; gastrointestinal (GI) (abdomen; liver and spleen) musculoskeletal; 
extremities; neurological; and lymph nodes. Height and weight will also be measured and recorded 
at screening and BMI will be calculated. 
A targeted, symptom-directed physical examination will include, at a minimum, assessments of 
the skin, respiratory system, cardiovascular system, and GI (abdomen, liver, and spleen). 
8.1.2 Vital Signs  
Blood pressure, heart rate, and respiratory rate will be measured after the subject has been resting 
in a sitting position for 5 minutes. Vital signs will be measured prior to any blood draw that occurs 
at the same timepoint. 
8.1.3 Clinical Safety Laboratory Tests 
See APPENDIX 1: Clinical Laboratory Tests for the list of clinical laboratory tests to be performed 
for inclusion and exclusion purposes only. 
8.1.4 Pregnancy Testing 
• Details of all pregnancies in female subjects, will be tested as outlined in SoA (Table 1). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 9.5.4. 
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8.2 
Immunogenicity Assessment 
Immunogenicity will be evaluated using cellular and humoral immune function assays from blood, 
mucosal (saliva and nasal swab), and breastmilk samples from subjects and their infants’ stool 
samples. Samples will be collected from all subjects according to the time points specified in the 
SoA. The following analytes will be measured: 
8.2.1 Primary Immunogenicity Assessments: 
• Serum VP1 specific (GI.1 and GII.4) IgA through the active period measured by Meso 
Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8 and Day 29   
o Geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
29  
• Breastmilk VPI specific (GI.1 and GII.4) IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, , and Day 29   
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, to, and from Day 1 to 
Day 29    
• The number of subjects in each dose group that had a 2-fold GMC rise or greater in 
breast milk VP1 specific IgA (GI.1 and GII.4) between Day 1 and any other timepoint. 
8.2.2  Secondary Immunogenicity Assessments: 
Serum VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose measured by 
Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 180  
• Breastmilk VP1 specific (GI.1 and GII.4) IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) by dose level 
o Geometric mean concentration (GMC) at Day 60 and Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 60 and from Day 1 
to Day 180  
• Serum VP1 specific (GI.1 and GII.4) IgG through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) assay by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, and Day 
180    
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, and from Day 1 to Day 180   
• Serum Blocking titers 50 (BT50) (GI.1 and GII.4) through 6 months after study drug 
dose measured by Histo-blood group antigen (HBGA) assay by dose level 
o Geometric mean titer (GMT) at Day 1, Day 8, Day 29, and Day 180    
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, and from Day 1 to Day 180   
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8.2.3 Exploratory Immunogenicity Assessments: 
• Saliva VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Enzyme-
linked immunosorbent assay (ELISA) by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 60 and 
Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, from Day 1 to Day 60, and from Day 1 to Day 180 
• Nasal VP1 specific (GI.1 and GII.4) IgA from lactating mother measured by Meso 
Scale Discovery (MSD) by dose level 
o Geometric mean concentration (GMC) at Day 1, Day 8, Day 29, Day 60 and 
Day 180  
o Geometric mean fold rise (GMFR) from Day 1 to Day 8, from Day 1 to Day 
29, from Day 1 to Day 60, and from Day 1 to Day 180  
• Infant stool VP1 specific (GI.1 and GII.4) IgA measured by Enzyme-linked 
immunosorbent assay (ELISA) by dose level: 
o Geometric mean concentration (GMC) Day 1, Day 29, and Day 60  
o Geometric mean fold rise (GMFR) from Day 1 to Day 29 and from Day 1 to 
Day 60  
• Breastmilk Blocking titers 50 (BT50) (GI.1 and GII.4) measured by Histo-blood group 
antigen (HBGA) assay by dose level 
o Individual subject titers on samples and some timepoints that have a high 
likelihood of success, assuming the assay works in breast milk samples 
• Breastmilk Enterocyte culture neutralizing antibody titers (GI.1 and GII.4) measured 
by enterocyte culture 
o Individual subject titers on samples and some timepoints that have a high 
likelihood of success, under the assumption that the assay works in breast milk 
samples. At the date of this protocol, only serum GII.4 neutralizing antibodies 
have been successfully measured 
Additional exploratory immunogenicity assays may also be performed to further evaluate the 
activity of the bivalent GI.1 and GII.4 vaccines. Note that not all sample timepoints may be 
relevant for some of the analysis, so not all assays may be performed at all timepoints.  In 
particular, because it is unclear if the breast milk matrix will inhibit the analysis of neutralizing 
antibodies or BT50, those assays may not be feasible.   
Sample collection, processing and shipping details are provided within the study specific 
Laboratory Manuals. 
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9.  ADVERSE EVENTS  
9.1 Definition of an Adverse Event, Serious Adverse Event, Suspected Unexpected 
Serious Adverse Reaction, Adverse Event of Special Interest and New Onset of 
Chronic Illness 
 Adverse Event Reporting 
Adverse event means any untoward medical occurrence associated with the use of an 
investigational product, whether or not considered intervention related.   
Adverse Events Treatment Emergent Adverse Event  
Treatment emergent adverse event (TEAE) is an AE that began after the start of an investigational 
product or an already present event that worsens either in intensity or frequency following the 
intervention. 
Serious Adverse Event (SAE) 
a. An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the Investigator or Sponsor, it results in any of the following outcomes:  
i. 
Death 
ii. 
A life-threatening adverse event (at the time of the event; not an event that 
hypothetically might have caused death if it were more severe) 
iii. 
Inpatient hospitalization or prolongation of existing hospitalization 
iv. 
A persistent or significant incapacity or disability which results in a substantial 
disruption of the ability to conduct normal life functions 
v. 
A congenital anomaly/birth defect 
vi. 
Important medical events which based upon appropriate medical judgment may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
• Examples of such medical events include but are not limited to allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
b. A preplanned/elective procedure and its associated hospitalization for a pre-existing 
condition that did not worsen from baseline is not considered an AE/SAE. If the 
procedure is performed early due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
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Suspected Unexpected Serious Adverse Reaction refers to an adverse event which is assessed by 
the sponsor and or study investigator as being unexpected, serious, and as having a reasonable 
possibility of a causal relationship with the investigational product. 
Adverse Event of Special Interest (AESIs) 
An adverse event of special interest (serious or nonserious) is one of scientific and medical concern 
specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate.  For this study, AESIs are 
serious or non-serious adverse events of scientific and medical concern with potential immune-
mediated medical conditions as well as events associated with thrombosis and thrombocytopenia 
as listed in but not limited to Table 11. 
New Onset of Chronic Illness (NOCIs) 
New Onset of Chronic Illness is defined as diagnosis post-enrollment and vaccination of a new 
medical condition, which is chronic in nature, including those potentially controllable by 
medication (e.g., diabetes, asthma).  
Adverse Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse reactions (AR). (The phrase “responses to an investigational product” means 
that a causal relationship between a medicinal product and an AE is at least a reasonable 
possibility.) 
Additional Sponsor Definition 
a.   Solicited Adverse Events- 
i. 
Solicited adverse events (AEs) are predefined signs and symptoms of 
reactogenicity for which the subject is specifically questioned, and which are noted 
by the subject in their Solicited Symptom Diary, including: 
• fever (any temperature 100°F or higher) 
• headache 
• myalgia (muscle pain) 
• abdominal pain 
• anorexia (defined and not eating) 
• nausea 
• vomiting 
• diarrhea 
• malaise/fatigue 
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ii. 
Subjects will utilize a Solicited Symptom Diary issued on the day of the vaccination 
to record solicited any TEAE daily for the one week following that administration. 
b.   Unsolicited Adverse Events  
i. 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted 
in the eCRF in terms of diagnosis and/or onset window post-vaccination; this also 
includes progression of chronic diseases. Unsolicited AEs includes both serious 
(SAEs) and non-serious unsolicited AE. 
9.2 Grading of Severity of an Adverse Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity: 
• Mild – Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe – Events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. Of note, the term “severe” does not necessarily 
equate to “serious.” 
9.3 
Relationship of Adverse Event Following Immunization to Experimental 
Vaccine/Vaccine Adverse Event Causality Assessment 
The principal investigator will use his or her clinical judgment to assess each and every occurrence 
of an AE/SAE for causality. A 'reasonable possibility' means there is evidence to suggest a causal 
relationship between the study drug and the adverse event, and the AE is more likely to be 
explained by the study drug than by another cause. 
The investigator is obligated to consider and investigate alternative causes including underlying 
disease(s), concomitant therapy, and other risk factors, in addition to the temporal sequence of the 
adverse event to the administration of the study drug.  
The investigator will determine biological plausibility and strength of association by consulting 
the IB and comparators if applicable in his/her assessment. The investigator will also evaluate the 
course of event including the reproducibility of the adverse event with subsequent study drug 
administration (in subjects who are allowed to continue with the study). 
For more details refer to Causality Assessment of an Adverse Event Following Immunization 
(AEFI): User Manual for the Revised WHO Classification Second Edition, 2019 Update link: 
https://www.who.int/publications/i/item/9789241516990. 
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All adverse events following immunization (AEFIs) must have their relationship to study drug 
assessed by the Investigator. The degree of certainty about causality will be graded using the 
categories below.  
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study drug administration 
and cannot be explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the study drug should be clinically plausible.  
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study drug, is unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the study drug) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant 
treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
In situations where an SAE has occurred with minimal information available to the investigator, 
the investigator is still required to make an assessment of causality for the event with the 
transmission of the initial report to the sponsor. If the investigator is uncertain about causality, the 
adverse event will initially be handled as “related to study intervention” for reporting purposes. 
Once more clinical information is obtained, the investigator can modify the causality assessment 
to reflect this new knowledge by sending an SAE follow-up report with the updated assessment. 
9.4 
Monitoring and Follow-up of AEs, NOCIs, and SUSARs during Trial 
9.4.1 Monitoring and Follow-up of SAEs from Day 1 to Day 29 after Vaccination 
Following AEs/SAEs, could appear during the entire course of the trial after vaccination. The 
following symptoms will be captured via Solicited Symptoms during Day 1 to Day 8. After Day 8 
they will be captured as unsolicited adverse events. SAEs are captured from the first dose of study 
product.  
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• Fever/pyrexia 
• Diarrhea 
• Nausea 
• Vomiting 
• Abdominal pain 
• Malaise/fatigue 
• Anorexia 
• Headache 
• Myalgia (muscle pain) 
9.4.2 Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE 
Information 
All TEAEs, SAEs, AESIs, and NOCIs will be collected from the time of study drug dose until 
the follow up visit at the timepoints specified in the SoA (Table 1).  TEAEs will be collected 
through Day 29.  SAEs, AESIs, and NOCIs will be collected through Day 365. 
Medical occurrences that begin before the start of study drug but after obtaining informed consent 
will be recorded as medical history/current medical conditions, not as AEs if they do not have a 
causal relationship with study participation.  There are two situations to note as below:  
 
• If the medical occurrence causes the subject to be excluded from the study, then it must 
be reported by the investigator. This event will then need to be classified as an "AE not 
related to the study drug.”   
• If the medical occurrence is the result of a protocol-specified intervention (prior to 
study drug dose), including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure then these must be reported appropriately as an AE 
(solicited and unsolicited), SAE, AESI, NOCI, and other reportable safety events by 
the Investigator. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of being available. The Investigator will submit any 
updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and the Investigator considers the event 
to be reasonably related to the study drug or study participation, the Investigator must promptly 
notify the Sponsor. 
9.4.3 
Information for Follow-up of AESIS, NOCIS, and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 5.4).  
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The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, AESIs, 
NOCIs or SAEs as fully as possible. This may include laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
New or updated information will be recorded in the originally submitted documents. 
 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
9.5 
Reporting of AEs, AESIs, NOCIs, SAEs, SUSARs, Pregnancies, and Death Events 
All AEs (solicited and unsolicited), AESIs, NOCIs, SAEs and other reportable safety events that 
occur after the consent form is signed but before study product administration must be reported by 
the Investigator if the event causes the subject to be excluded from the study (these will be reported 
as “AE not related to the study drug”) or is the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
 
Table 7 below summarizes the different reporting timelines for TEAEs (unsolicited and solicited), 
AESIs, NOCIs, SAEs, and SUSAR. 
 
Table 7 Adverse Event Reporting Timelines to the Sponsor 
Type of 
Event 
TEAE 
(unsolicited) 
TEAE (solicited) 
AESI/NOCIs 
SAE / SUSAR 
Reporting 
period 
From first dose 
until 4 weeks after 
last dose of study 
drug 
1 week after each 
study drug 
administration 
From first dose 
until EOS 
From first dose 
until EOS 
Reporting 
Timelines 
to the 
Sponsor  
Entered into the 
clinical database 
on an ongoing 
basis  
Entered into the 
clinical database 
on an ongoing 
basis 
Within 24 hours 
Within 24 hours  
Reporting 
Method 
AE page of eCRF 
Solicited 
Symptom Diary 
AE page of eCRF AE page of eCRF 
Abbreviations: AE = adverse event; eCRF = electronic Case Report Form; EOS = end of study; AESI = Adverse 
Event of Special Interest; NOCI= New Onset Chronic Illness; SAE = serious adverse event; SUSAR = suspected 
unexpected serious adverse reaction; TEAE = treatment-emergent adverse event 
 
9.5.1 Adverse Event Reporting 
All subjects experiencing AEs after the first dose of study drug, until Day 29 (Active Period), 
whether considered causally related with the use of the investigational vaccine or not, must be 
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monitored until symptoms subside, or until there is a satisfactory explanation for the changes 
observed, or until death, in which case a full pathologist’s report should be supplied, if possible. 
All findings must be reported on an adverse event page of eCRF and on the SAE form, if 
applicable. All findings in subjects experiencing AEs must also be documented in the subject’s 
clinical research records.  
The following information will be documented for each event:  
• Reported term for the AE.  
• Start and end date.  
• Serious (Y/N)? If yes, appropriate seriousness criteria must be selected on eCRF and 
SAE Form. 
• Severity.  
• Investigator’s opinion of the causality (relationship) between the event and 
administration of investigational vaccine(s) (“related” or “not related”).  
• Investigator’s opinion of the causality (relationship) to trial procedure(s), including the 
details of the suspected procedure.  
• Action taken with study treatment (investigational vaccine).,  
• Outcome of event. 
• For Death cases provide all applicable details (e.g., date and cause of death etc., 
including autopsy results if available). 
 
9.5.2 Serious Adverse Events Reporting 
The Investigator or designee will within 24 hours report to the Sponsor any serious adverse event, 
whether or not considered study drug related, including those listed in the protocol or Investigator 
Brochure and must include an assessment of whether there is a reasonable possibility that the study 
drug caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) 
must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study drug and the event (e.g., death from anaphylaxis). In that case, the 
Investigator must within 24 hours report the event to the Sponsor. 
 
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the event 
to be chronic or the subject is stable. Other supporting documentation of the event may be 
requested by the Data Coordinating Center (DCC)/study Sponsor and should be provided as soon 
as possible. 
 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours and under no 
circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to 
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the Sponsor within 24 hours of it being available.  The information should be completed as fully 
as possible and contain the following information at the minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
 
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
submit it within 24 hours of receipt. The timelines and procedure for follow-up reports are the 
same as those for the initial report. 
 
9.5.3 Suspected Unexpected Serious Adverse Reaction Reporting 
Suspected unexpected serious adverse reactions (SUSARs) are subject to expedited reporting. The 
study Sponsor will be responsible for notifying both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation including 
the Food and Drug Administration (FDA of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible, but in no case later than 7 calendar days after the Sponsor's 
initial receipt of the information. In addition, the Sponsor must notify FDA and all participating 
Investigators in an Investigational New Drug (IND safety report of potential serious risks, from 
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clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days 
after the Sponsor determines that the information qualifies for reporting. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
  
An investigator who receives SUSARs or other specific safety information (e.g., summary or 
listing of SAEs) from the sponsor will review and then file it along with the IB for the study and 
will notify the IRB/EC, if appropriate according to local requirements. 
 
9.5.4 Pregnancy Reporting 
Details of all pregnancies in female subjects will be collected after the start of study drug as per 
SoA (Table 1).  
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form (pregnancy form) and submit it to the Sponsor within 24 hours of 
learning of the female subject pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate up to one 
month post-partum, and the information will be forwarded to the Sponsor. 
• Any post study pregnancy-related SAE considered reasonably related to the study drug 
by the Investigator will be reported to the Sponsor. While the Investigator is not 
obligated to actively seek this information in former (study subjects) beyond the 
resolution of the pregnancy, he or she may learn of an SAE through spontaneous 
reporting. 
Should a female subject become pregnant during the course of the study after dosing, she will 
continue to be followed for safety and pregnancy outcomes. Subjects who have a positive 
pregnancy test at Day 1, prior to randomization, will be considered screen failures. 
 
If a subject is found pregnant post study drug administration, the subject will only be monitored 
for safety. 
 
9.5.5  Death Events   
Events resulting in death will be an SAE regardless of association to study drug. Death is an 
outcome and should not be reported as an event term. The event that leads to the death should be 
reported as the SAE term. 
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10.     SAFETY OVERSIGHT 
10.1. Internal Sponsor Review 
Safety data will be monitored on an ongoing basis by the Investigator (or medically qualified 
designee) and the Sponsor’s Medical Monitor (or designee) in order to promptly identify and flag 
any event that potentially contributes to a Stopping Rule. 
 
The lead Medical Monitor will be a physician experienced in the conduct of research clinical 
studies whose primary responsibility will be to monitor subject safety. The Medical Monitor will 
be responsible for reviewing the cumulative safety data, including a review of safety laboratory 
test results and adverse event reporting. The Medical Monitor will be familiar with study-specific 
data as well as relevant background information about the disease, investigational drug, and target 
population under study. The Medical Monitor(s) will be empowered to request a SMC safety 
review which can suspend the study, recommend amendments to the protocol, and/or to request 
further information. 
10.2. Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will be created to provide oversight of the conduct of the 
trial to ensure the safety of subjects. The committee will consist of independent physicians and/or 
scientists with vaccine clinical trials experience or expertise, and the Medical Monitor, who does 
not enroll subjects into the study.  
The SMC will be assigned by the Sponsor prior to the beginning of the study and will provide 
oversight of the study throughout the duration of the study period (Day 1 through Day 365) as 
needed. Ad hoc meetings will be convened if any predefined stopping rules are met, or any 
serious vaccine-related events or trends are observed. 
 
The SMC will function in accordance with the following provisions: (1) United States (US) Code 
of Federal Regulations (CFR) applicable to clinical studies (21 CFR Part 50, 21 CFR Part 54, 21 
CFR Part 312.55 and 312.56. (2) ICH E6 and 62 Federal Register 25691 (1997): Good Clinical 
Practice (GCP) Consolidated Guideline. 
Further details regarding data safety monitoring guidelines will be included in the SMC Charter, 
which is the governing document that supersedes this section of the protocol. 
11. 
STATISTICAL CONSIDERATION 
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentation and analyses will be provided in SAP. 
 
Additional statistical analyses other than these described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report (CSR). 
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11.1 
Sample Size Determination 
A sample size of 76 randomized subjects (30 each in medium and high dose levels and 16 in 
placebo) is not based on formal statistical testing but rather based on clinical judgement and 
predicted to yield meaningful safety and immunogenicity results. Placebo was added for safety 
comparison.  
 
11.2  Multiplicity Adjustment 
No multiplicity adjustment will be implemented for this study. 
11.3 
Population for Analysis 
For purposes of analysis, the following analysis sets are defined: 
Table 8: 
Populations for Analyses 
Analysis 
Population 
Description 
Screened 
All subjects who enter screening (assigned a screening number) 
Intent to Treat (ITT)  All subjects who are randomized. The analyses using ITT will be based 
upon the randomization group allocated. 
Per Protocol 
 All subjects in the ITT set who receive one dose and who have not 
violated any inclusion/exclusion criteria and / or deviated in a way that 
could influence their Immunogenicity assessments. 
Safety 
All randomized subjects who receive at least 1 dose of the study drug. 
Subjects will be analyzed according to the treatment (vaccine) they 
actually received. All safety analyses will be conducted based on the 
Safety set. 
Immunogenicity 
All randomized subjects who receive at least 1 dose of the study drug 
and have at least one valid immunogenicity result after Day 1. Subjects 
will be analyzed according to the treatment (vaccine) they actually 
received. All immunogenicity analyses will be conducted based on the 
Immunogenicity set. 
11.4 Statistical Analysis Plan 
11.4.1 General Approach 
The SAP will be developed and finalized before database lock and breaking the blind for any of 
the planned analyses. It will describe the subject sets to be included in the analyses and the 
procedures for accounting for missing, unused, and spurious data. This section provides a summary 
of the planned statistical analyses of the primary endpoints.  
 
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11.4.2 Analysis of the Primary and Secondary Safety End Points 
Safety will be summarized for the safety set (active vs. placebo). Solicited Symptoms of 
Reactogenicity, unsolicited AEs, SAEs, physical examination, and vital signs will be summarized 
descriptively by treatment group and study visit. 
 
Analyses will be performed for the total set (active vs. placebo). All results will be presented 
descriptively and summarized by treatment groups. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
(measured 
from Day 1 
through 
Day 29) 
Frequency, duration, and severity of Solicited Symptoms of Reactogenicity 
(local, systemic) measured daily for 1 week following vaccination. 
Frequency, duration, and severity of unsolicited AEs, and SAEs through the 
active period (4 weeks post dose). 
Descriptive statistics will be provided for each reactogenicity endpoint for each 
dose. Local reactions and systemic events from Day 1 through Day 8 after each 
dose will be presented by severity and cumulatively across severity levels. 
Descriptive summary statistics will include counts and percentages of subjects 
with the indicated endpoint and the associated Clopper-Pearson 95% CIs. 
AEs will be categorized according to the Medical Dictionary for Regulatory 
Activities (MedDRA®) terms. Descriptive summary statistics (counts, 
percentages, and associated Clopper-Pearson 95% CIs) will be provided for 
any TEAEs for each vaccine group as well as the placebo group. SAEs will be 
categorized according to MedDRA® terms. The safety analyses are based on 
the safety set. Subjects will be summarized by vaccine group and placebo 
according to the study drug they actually received. Missing reactogenicity 
Diary data will not be imputed; missing TEAE dates will be handled according 
to the rules determined in the SAP. 
Secondary 
(measured 
through 
Day 365) 
Frequency, duration, and severity of SAEs, AESIs and NOCIs for 1 year 
following the study drug dose. 
 
11.4.3 Analysis of Primary, Secondary, and Exploratory Immunogenicity and 
Endpoints 
Immunogenicity will be summarized according to the treatment group to which the subject was 
randomized. 
 
Immunogenicity samples will be drawn for all subjects. Immunogenicity analyses will be based 
upon results from appropriately sized subsets of samples, according to the purpose. The statistical 
analysis of immunogenicity results will be primarily based on the evaluable immunogenicity sets.  
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An additional analysis will be performed based on the all-available sets if there is a large enough 
difference in sample size between the all-available immunogenicity set and the evaluable 
immunogenicity set.  
 
Immunogenicity will be summarized by the total set (active vs. placebo). For all endpoints, all 
measures will be analyzed comparing the two active vaccine groups. The immunogenicity set 
will be used for this analysis. All results will be presented descriptively and summarized by 
treatment groups. 
Endpoint 
Statistical Analysis Methods 
Primary (Key 
Immunogenicity 
Endpoints 
measured from 
Day 1 through 
Day 29) 
Serum and breastmilk VP1 specific IgA for both GI.1 and GII.4 by Meso 
Scale Discovery will be summarized descriptively through the active period 
(4 weeks post dose). 
Secondary 
(measured 
through Day 
180) 
Serum VP1 specific IgA and IgG for both GI.1 and GII.4 by Meso Scale 
Discovery will be summarized descriptively through 6 months post dose. 
Serum Blocking titers 50 (BT50) (GI.1 and GII.4) by Histo-blood group 
antigen (HBGA) assay will be summarized descriptively through 6 months 
post dose. 
Breastmilk VP1 specific IgA for both GI.1 and GII.4 by Meso Scale 
Discovery will be summarized descriptively through 6 months post dose. 
Exploratory 
For specific exploratory immunogenicity endpoints please refer to Section 
8.2-Immunogenicity Assessments- Exploratory Immunogenicity 
Assessments. 
11.4.4 Baseline Descriptive Statistics 
Demographic data, baseline characteristics, physical examination, concomitant medications, 
medical history data and study medication exposure will be summarized by treatment group.  
 
11.4.5 Tabulation of Individual Subject Data 
By subjects listing will be produced for each variable by treatment group and study visit. 
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12. 
ETHICAL CONSIDERATIONS 
12.1 
Ethical Conduct of the Study   
The study will be conducted in accordance with the protocol, legal and regulatory requirements, 
and the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences [CIOMS] 
2002), ICH Guideline for Good Clinical Practice, and the Declaration of Helsinki. 
12.2 
Institutional Review Board  
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/EC 
should be retained in the Investigator file. 
 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/IEC and Sponsor in writing immediately after the 
implementation. 
 
They should also be informed of any event likely to affect the safety of the subjects or the continued 
conduct of the clinical study, in particular any change in safety. All updates to the IB will be sent 
to the IRB/IEC and to Health Authorities (Competent Regulatory Authority), as required by local 
regulation. A progress report is sent to the IRB/IEC at least annually and a summary of the study’s 
outcome at the end of the clinical study. 
 
12.3 
 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the subject will be asked to read and review the 
document. The Investigator will explain the research study to the subject and answer any questions 
that may arise. A verbal explanation will be provided in terms suited to the subject’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research subjects. Subjects will have the opportunity to carefully review the written consent form 
and ask questions prior to signing.  
 
The subjects should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The subject will sign the informed consent documents 
for herself and her infant prior to any procedures being done specifically for the study. Subjects 
must be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the informed consent document will be given to the subjects 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the forms signed, before the subject undergoes any study-
specific procedures. The rights and welfare of the subjects will be protected by emphasizing to 
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them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
If the trial is involving vulnerable population, video recording of entire informed consent process 
should be ensured depending on the norms of respective country’s regulatory authorities.  
12.4 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRB/IEC or regulatory authorities in countries requiring this document. 
 
12.5 
Stipends/Rewards/Compensation for Participation 
 
Subjects may be provided with a stipend according to local practice to compensate for the time 
and travel required for study visits and procedures. Participating subjects will be given a manual 
breast pump set. 
 
12.6 Subject Confidentiality 
 
Subject confidentiality and privacy will be strictly held in trust by the participating Investigators, 
their staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to subjects. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the Sponsor. All research activities will be conducted 
in as private a setting as possible. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the Subjects in this study. The clinical study site will permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 
 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at sponsors designated vendor. This will not include the subject’s 
contact or identifying information. Rather, individual Subjects and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by designated vendor research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived. 
 
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12.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new information 
that might influence the evaluation of the benefits and risks of the investigational product, Sponsor 
should be informed immediately.  
 
In addition, the Investigator will inform Sponsor immediately of any urgent safety measures taken 
by the Investigator to protect the study subjects against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the Investigator becomes aware of. 
13. DATA HANDLING AND RECORD KEEPING 
13.1 
Source Documents 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for validation of the clinical data. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or 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, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. All information on the CRF will 
be traceable to these source documents, which are generally maintained in the subject’s study file. 
 
The source documents will include a copy of the signed Informed Consent/ Health Insurance 
Portability and Accountability Act (HIPAA) authorization. The source document data collection 
forms for screening. Outpatient visits and AEs will also serve as CRF data collection instruments. 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. Source documents are maintained for recording data for each subject enrolled 
in this clinical trial. Study subjects’ data collected on the CRF during the trial will only be 
identified by subject number. If, as an exception, it is necessary for safety or regulatory reasons to 
identify the subject, both the Sponsor and the Investigator are bound to keep this information 
confidential. 
 
13.2 
Case Report Forms (CRF)  
 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this trial.  
 
A CRF is required and should be completed for each included subject. The completed original 
CRFs are the sole property of Vaxart and should not be made available in any form to third parties, 
except for authorized representatives of Vaxart or appropriate regulatory authorities, without 
written permission from Vaxart.  
 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
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and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring, and available when required. 
 
The CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.  
 
13.3 Data Collection and Management Responsibility 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Hardcopies of the study visit worksheets will be provided for use as source 
document worksheets for recording data for each subject enrolled in the study.  
 
Data recorded in the eCRF/CRF derived from source documents should be consistent with the data 
recorded on the source documents. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a data capture system that is 21 CFR Part 11-compliant. 
The data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
13.4 
Record Retention 
 
Study documents should be retained for a minimum of 10 years after the last approval of a 
marketing application in an International Conference on Harminosation (ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 10 
years have elapsed since the formal discontinuation of clinical development of the study drug.  
 
These documents should be retained for a longer period, however, if required by local regulations. 
No records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the Investigator when these documents no longer need to 
be retained. 
 
13.5 
Property Rights and Data Protection 
 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
 
The subject must be informed that their personal study-related data will be used by the Sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 
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subject who will be required to give consent for their data to be used as described in the informed 
consent. 
  
The subject must be informed that their medical records may be examined by clinical quality 
assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
All information, data and documents including results and investigational products provided by 
the Sponsor or its designee are and remain the sole property of the Sponsor. 
 
The Sponsor may use or exploit all the results at its own discretion. 
 
14. QUALITY CONTROL AND QUALITY ASSURANCE 
 
14.1 
Early Safety Data Review AND/OR Committee 
 
Subject safety will be continuously monitored by the Sponsor or designee, which includes safety 
signal detection during the study. 
 
All safety data collected will be summarized and reviewed by the sponsor’s internal/external safety 
monitoring committee for agreement of next steps. 
 
In particular, data will be reviewed by the sponsor for identification of the following events that 
would potentially contribute to a requirement to [pause/stop] the study.  
• One or more subjects experiences a treatment-related serious adverse event (SAE) of 
any grade  
• Two or more subjects experience the same treatment-related grade ≥3 solicited 
symptom within one week following vaccination. 
• Two or more subjects experience the same treatment-related unsolicited grade “severe” 
AE between Day 1 and Day 29 (Active Period). 
Enrollment will be paused during the review. If a pausing/stopping rule is met, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to resume. If no 
dose-related toxicities are observed, and upon the recommendation of the SMC following review 
of safety data, enrollment of the remaining subjects will be initiated.     
14.2 
Clinical Trial Site Monitoring 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP, and with applicable regulatory 
requirement(s). 
• Monitoring for this study will be performed by the Sponsor or designee 
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• Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
• If needed, independent audits will be conducted to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the 
CMP. 
14.3 
Audit and Inspection 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. 
For the purpose of ensuring compliance with the clinical study protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on behalf of the Sponsor 
and inspection by regulatory authorities. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities. 
 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
 
The confidentiality of the data verified, and the protection of the subjects should be respected 
during these inspections. 
 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
 
The Investigator shall take appropriate measures required by the Sponsor to take corrective actions 
for all problems found during the audit or inspections. 
14.4 
Responsibility of Investigator 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all trial procedures provided by the Sponsor (including security rules).  
 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, discrepancy resolution form, or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct access 
to source documents to the Sponsor representatives.  
 
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If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the subject’s data to be transferred. The Investigator may appoint such other individuals as he/she 
may deem appropriate as Sub-investigators to assist in the conduct of the clinical study in 
accordance with the clinical trial protocol.  
 
All Sub-investigators shall be appointed and listed in a timely manner. The Sub-investigators will 
be supervised by and work under the responsibility of the Investigator. The Investigator will 
provide them with a copy of the clinical trial protocol and all necessary information. 
 
To providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
 
To notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
 
Signed copy of Investigator’s undertaking should be provided as an appendix. 
14.5 
Responsibility of Sponsor 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical study as regards ethics, clinical study protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical study. 
 
At regular intervals during the clinical study, the site will be contacted, through monitoring visits, 
letters, or electronically, by a representative of the monitoring team to review study progress, 
Investigator and subject compliance with clinical study protocol requirements, and any emergent 
problems. 
 
These monitoring visits will include but not be limited to review of the following aspects: subject’s 
informed consent, subject recruitment and follow-up, SAE documentation and reporting, AE 
documentation, IP allocation, IP accountability, concomitant therapy use, and quality of data. 
 
14.6 
Protocol Deviation 
 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual 
of Procedures (MOP) requirements. The noncompliance may be either on the part of the subject, 
the Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. Details can be found in the study specific 
Protocol Deviation Plan or the Clinical Monitoring Plan. 
 
15. 
PUBLICATION AND DATA SHARING POLICY 
 
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The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. Requests for publication of site-specific data 
should be presented to the Sponsor for review and approval at least 90 days prior to submission 
for publication. 
 
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16. 
REFERENCES 
Norovirus Vaccine Development –Next Steps. Expert Rev 
Vaccines 11, 1023–1025. 
Bresee, J.S., Widdowson, M., Monroe, S.S., Glass, R.I., 2002. Foodborne Viral Gastroenteritis: 
Challenges and Opportunities. 
Protecting Breastfeeding during the COVID-19 
Pandemic. Am J Perinatol 40:260-266  
Esposito, S., Principi, N., 2020. Norovirus Vaccine: Priorities for Future Research and 
Development. 
Glass, R.I., Parashar, U.D., Estes, M.K., 2009. Norovirus Gastroenteritis. N Engl J Med 361, 
10.1056/NEJMra0804575.  
Kim, L., Liebowitz, D., Lin, K., Kasparek, K., Pasetti, M.F., Garg, S.J., Gottlieb, K., Trager, G., 
Tucker, S.N., 2018. Safety and immunogenicity of an oral tablet norovirus vaccine, a phase I 
randomized, placebo-controlled trial. JCI Insight 3, e121077.  
Labayo, H.K., Pajuelo M.J., Tohma K., Ford-Siltz, L.A., Gilman, R.H., Cabrera L., Mayta H., 
Sanchez G.J., Cornejo, A.T., Bern, C., Dapat, C., Nochi, T., Parra, G.I., Oshitani, H., Saito, M. 
Norovirus-specific immunoglobulin A in breast milk for protection against norovirus-associated 
diarrhea among infants. E Clinical Medicine. 2020 Oct 5;27:100561. doi: 
10.1016/j.eclinm.2020.100561. PMID: 33043286; PMCID: PMC7536734.   
Langel SN, Paim FC, Alhamo MA, Buckley A, Van Geelen A, Lager KM, Vlasova AN and Saif 
LJ (2019) Stage of Gestation at Porcine Epidemic Diarrhea Virus Infection of Pregnant Swine 
Impacts Maternal Immunity and Lactogenic Immune Protection of Neonatal Suckling Piglets. 
Front. Immunol. 
Liao, Y., Hong, X., Wu, A., Jiang, Y., Liang, Y., Gao, J., Xue, L., Kou, X., 2021. Global 
prevalence of norovirus in cases of acute gastroenteritis from 1997 to 2021: An updated 
systematic review and meta-analysis. Microbial Pathogenesis 161, 105259.  
Liebowitz, D., Gottlieb, K., Kolhatkar, N.S., Garg, S.J., Asher, J.M., Nazareno, J., Kim, K., 
McIlwain, D.R., Tucker, S.N., 2020. Efficacy, immunogenicity, and safety of an oral influenza 
vaccine: a placebo-controlled and active-controlled phase 2 human challenge study. The Lancet 
Infectious Diseases 20, 435–444.  
McGuire, MK., Seppo A., Goga A., et al.  2021. Best Practices for Human Milk Collection for 
COVID-19 Research.  Breastfeeding Medicine. Vol 16, 29-38 
Narayanaswamy, V., Pentecost BT., Schoen, CN., et al. Neutralizing Antibodies and Cytokines 
in Breast Milk after coronavirus disease 2019 (covid-19) mRNA vaccination. Obsterics & 
Gynecology. vol 139, 181-191 
Patel MM, Widdowson MA, Glass RI, Akazawa K, Vinjé J, Parashar UD. Systematic literature 
review of role of noroviruses in sporadic gastroenteritis. Emerg Infect Dis. 2008 
Aug;14(8):1224-31. doi: 10.3201/eid1408.071114. PMID: 18680645; PMCID: PMC2600393. 
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Vega, E., Barclay, L., Gregoricus, N., Shirley, S.H., Lee, D., Vinjé, J., 2014. Genotypic and 
Epidemiologic Trends of Norovirus Outbreaks in the United States, 2009 to 2013. J Clin 
Microbiol 52, 147–155.  
 
 
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Appendix 1: Clinical Laboratory Tests 
• The tests detailed in Table 9 will be performed by the local laboratory, unless 
otherwise specified. 
• Protocol-specific requirements for inclusion or exclusion of subject are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 9 
Protocol-Required Laboratory Assessments 
Urine drug screen 
amphetamines, methamphetamines, methadone, barbiturates, benzodiazepines, 
cocaine, opiates, methylenedioxymethamphetamine, phencyclidine, 
tetrahydrocannabinol 
Other laboratory 
assessments 
Hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency 
virus antibody types 1 and 2 (Screening only) 
Female subjects serum pregnancy tests at screening 
Female subjects Point-of-Care urine pregnancy tests prior to dosing at Day 1 
Alcohol test at screening and prior to dosing on Day 1 
 
Appendix 2: Country-specific Requirements 
Not applicable. 
Appendix 3: Adverse Events Grading 
Grading of Solicited Adverse Events 
Subjects should be instructed to rate Solicited Symptoms of Reactogenicity that are collected 
within their Solicited Symptom Diary based on the severity scale presented in Table 10. 
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Table 10 
Grading of Solicited Symptoms of Reactogenicity 
 
Symptom 
Grading 
Normal 
Mild 
Moderate 
Severe 
Life Threatening 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever 
(oral temp) 
< 
100.4°F 
(< 38.0°C)
100.4 – 101.1°F 
(38.0 – 38.4°C) 
101.2 – 102.0°F 
(38.5 – 38.9°C) 
102.1 – 104°F 
(39.0 – 40°C) 
> 104.0°F 
(>40°C) 
Headache 
None 
No interference with 
activity 
Repeated use of 
nonnarcotic pain 
reliever > 24 hours or 
some interference 
with activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
(muscle 
pain) 
None 
AE easily tolerated, 
causing minimal 
discomfort and does 
not interfere with 
everyday activitiesa 
Adverse event 
sufficiently 
discomforting to 
interfere with 
everyday activities 
Adverse event 
prevents normal 
everyday activities or 
requires medical 
advice 
ER visit or 
hospitalization 
Abdominal 
Pain 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Anorexia 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Nausea 
None 
No interference with 
activity or 1 to 2 
episodes 
Some interference 
with activity or >2 
episodes 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Vomiting 
None 
No interference with 
activity or 24 hours 
Some interference 
with activity or 24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
None 
2 to 3 loose stools or 
< 400 gms/24 hours 
4–5 stools or 400 
to 800 gms/24 hours 
6 or more watery 
stools or > 800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Malaise/ 
Fatigue 
None 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
a Everyday activity include attendance at work, school, and usual habits of the subjects. 
 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions 
Postmenopausal female: 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
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Contraceptive Guidance 
• Contraceptive use by women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. Subjects must be willing to 
use a highly effective form of contraception for 30 days prior to vaccination and until 60 
days after the vaccination. Acceptable forms are oral, implantable, intrauterine, transdermal, 
intravaginal, injectable, double barrier or abstinence (subjects using diaphragms must also 
use condom). A reliable form of contraception must be approved by the Investigator.  
• While abstinence is allowed, periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
• A negative pregnancy test will be required for all female subjects prior to study drug 
administration, as outlined in the SoA (Table 1). 
 
Collection of Pregnancy Information 
Female subjects who become pregnant: 
• 
The investigator will attempt to collect pregnancy information on any female subjects. 
After obtaining the necessary signed ICF from the pregnant female subject, the investigator will 
record pregnancy information on the appropriate form and submit it to the Sponsor within 24 hours 
of learning of the pregnancy. The Sponsor will attempt to follow the female subject to determine 
the outcome of the pregnancy. Information on the status of the mother and child will be forwarded 
to the Sponsor. The Sponsor will follow the female subject until birth or termination of pregnancy 
when possible. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 
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Appendix 5: ADVERSE EVENTS OF SPECIAL INTEREST 
An Adverse event of special interest (AESI) is a serious or non-serious adverse events of scientific 
and medical concern for which ongoing monitoring and rapid communication by the Investigator 
to the Sponsor is indicated. The following adverse events (AEs) for potential immune-mediated 
medical conditions as well as events associated with thrombosis and thrombocytopenia are AEs of 
special interest (AESIs) and include new onset of chronic illness (NOCIs). These events should be 
monitored for actively and reported to the Sponsor in an expedited manner as outlined in Section 
9. 
Table 11: 
Adverse Events of Special Interest 
Gastrointestinal disorders: 
Liver disorders: 
• 
Celiac disease 
• 
Autoimmune cholangitis 
• 
Crohn’s disease 
• 
Autoimmune Hepatitis 
• 
Ulcerative colitis 
• 
Primary biliary cirrhosis 
• 
Ulcerative proctitis 
• 
Primary sclerosing cholangitis 
Metabolic diseases: 
• 
Addison’s disease 
• 
Diabetes mellitus type 1 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave’s or Basedow’s disease 
Coagulopathy: 
• 
Acquired amegakaryocytic 
thrombocytopenia 
• 
Amegakaryocytic thrombocytopenia 
• 
Axillary vein thrombosis 
• 
Cavernous sinus thrombosis 
• 
Cerebral venous thrombosis 
• 
Deep vein thrombosis 
• 
Disseminated intravascular coagulation 
• 
Embolism venous 
• 
Hepatic vein thrombosis 
• 
Immune thrombocytopenia 
• 
Intracranial venous sinus thrombosis 
• 
Mesenteric vein thrombosis 
• 
Portal vein thrombosis 
• 
Pulmonary embolism 
• 
Pulmonary thrombosis 
• 
Pulmonary venous thrombosis 
• 
Severe fever with thrombocytopenia 
syndrome 
• 
Subclavian vein thrombosis 
• 
Thrombocytopenia 
• 
Thrombocytopenia purpura 
• 
Thrombotic thrombocytopenia purpura 
• 
Thrombosis 
• 
Transverse sinus thrombosis 
• 
Vena cava embolism 
• 
Vena cava thrombosis 
• 
Venous thrombosis 
Musculoskeletal disorders: 
• 
Antisynthetase syndrome 
• 
Polymyalgia rheumatic 
• 
Dermatomyosotis 
• 
Polymyositis 
• 
Juvenile chronic arthritis (including Still’s 
disease) 
• 
Psoriatic arthropathy 
• 
Mixed connective tissue disorder 
• 
Relapsing polychondritis 
• 
Scleroderma, including diffuse systemic 
form and CREST Syndrome 
• 
Rheumatoid arthritis 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 78 of 88 
 
 
• 
Systemic lupus erythematous  
• 
Systemic sclerosis  
• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) and 
undifferentiated spondyloarthritis. 
Neuroinflammatory disorders: 
• 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non-infections encephalitis, 
encephalomyelitis, myelitis, myeloradiculomyelitis)  
• 
Immune related peripheral neuropathies and plexopathies, including chronic inflammatory demyelinating 
polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal 
gammopathy 
• 
Cranial nerve disorders, including 
paralysis/paresis (e.g., Bell’s palsy) 
• 
Guillain-Barre syndrome, including Miller Fisher 
syndrome and other variants 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse Myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders: 
• 
Autoimmune bullous skin diseases 
(including pemphigus, pemphigoid and 
dermatitis herpetiformis 
• 
Rosacea 
• 
Alopecia aerate 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Psoriasis 
• 
Morphoea 
• 
Sweet’s syndrome 
• 
Lichen planus 
• 
Vitiligo 
Vasculitis: 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and temporal arteritis 
• 
Medium sized/and or small vessels vasculitis including: polyarthritis nodosa, Kawasaki’s disease, 
microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome (allergic granulomatous 
angititis), Buerger’s disease thromboangitis obliterans), nerotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet’s 
syndrome, leulocytoclassic vasculitis 
Others: 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, membranaoprolifative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune hemolytic anemia 
• 
Raynaud’ phenomenon 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Autoimmune thrombocytopenia 
• 
Sjogren’s syndrome 
• 
Goodpasture syndrome 
• 
Stevens-Johnson Syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Uveitis 
APPENDIX 6:  SUMMARY OF CHANGES TO PROTOCOL 
PROTOCOL VXA-NVV-108 HISTORY 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 79 of 88 
 
 
Name of the Document with 
Version Number 
Date 
Summary of Changes and 
Rationale 
VERSION 1.0 
17 FEB 2023 
INITIAL VERSION 
VERSION 2.0 
25 JUL 2023 
 
 
VXA-NVV-108 Protocol Amendment 1, Version 2.0 <DATE> 
 
 Protocol Amendment 1 (Version 2.0) of this phase 1 Norovirus GI.1/G2.4 bivalent protocol (VXA-NVV-
108) was finalized on 17 Feb 2023, approved by the regulatory authority, South African Health Products 
Regulatory Authority, on 19 May 2023 and by the independent ethics committees which also serve as 
central ethics committees, Pharma Ethics Independent Research Ethics Committee  on 14 June 2023 and 
the University of the Witwatersrand’s Human Research Ethics Committee on 27 June 2023.  It is being 
amended to clarify visit procedures, update language on contraception, update language on 
immunogenicity assessment,  administrative updates throughout the protocol and correct other minor 
typographical errors. A description of the changes along with a brief rationale for each change is 
presented in the table below. 
 
 
 
Section No.  
& Title 
Description of Change  
Brief Rationale 
footer 
Updated all footers-page numbers 
Correct typos and pagination errors 
Cover Page and 
headers and 
Signature Page 
Updated Protocol Version and Date 
Correct Protocol Version and date 
Protocol Version 
History 
Original Text:  
 
12 Oct 2022 Page 78 
 
Updated Text:  
 
17 Feb 2023 Page 78  
Updated typographical error 
Table of Contents 
Updated Table of Contents  
Added Appendix 6 -Summary of 
Changes to the Protocol  
Protocol Synopsis 
Current Text:  
 
TBD CRO 
 
Updated Text: 
 
 
 
Administrative detail updated 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

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Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 81 of 88 
 
 
Removed the following procedure from 
the SOA grid: 
 
Remove breast milk from D15, Month 4 
 
Section 3.2.1 
Primary Endpoints 
 Immunogenicity  
Breastmilk VPI specific (GI.1 and GII.4) 
IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by 
dose level 
Removed Day 15 from GMC and removed  
Day 1 to Day 15 GMFR 
 
Section 3.2.2 
Secondary 
Endpoints 
Immunogenicity 
Breastmilk VP1 specific (GI.1 and GII.4) 
IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) 
by dose level 
 
Removed Day 120 from GMC and 
removed  Day 1 to Day 120 GMFR 
 
Section 7.1.1. 
Procedure to be 
followed on 
Screening Period 
(Day -45 to Day -1) 
Current Text 
 
The subject can use a manual breast pump if 
she does not wish to manually express her 
breastmilk. 
Timepoints for breastmilk and infant stool 
sample collection must be thoroughly 
discussed with the subject. The subject must 
collect breastmilk sample and infant stool 
sample at baseline prior to the first dose 
(Day -2 to Day 1). 
Updated Text: 
The subject can use a manual or electric 
breast pump if she does not wish to 
manually express her breastmilk. 
Timepoints for breastmilk and infant stool 
sample collection must be thoroughly 
discussed with the subject. The subject must 
collect breastmilk sample and infant stool 
sample (15ml) at baseline prior to the first 
dose (Day -2 to Day 1). 
Removed text: 
Teach the subject how to properly freeze her 
milk after expression each time until all 
samples are collected and shipped. 
Allow more flexibility for methods 
subject can use to provide breastmilk 
samples 
 
Breastmilk will be collected on site 
instead of home due to difficulty 
collecting and storing breastmilk 
properly and difficulty with transport of 
home collection to site in the required 
timeframe 
 
Provided volume of stool sample 
required. 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 82 of 88 
 
 
7.1.2  Procedure to 
be followed during 
Active Study Period 
(Day 1 to Day 29) 
Current Text: 
 
…breastmilk sample (5ml-10ml) 
…and to remind the subjects to collect and 
store breastmilk samples 
Updated Text: 
Ensure the subject collected baseline 
breastmilk sample (10ml) and infant stool 
sample between D-2 to D1. 
Removed Text:  
deleted "5ml"  
deleted "and to remind the subjects to 
collect and store breastmilk samples."  
 
Subjects not required to collect 
breastmilk samples at home due to 
logistics as mentioned previously 
7.1.3 Procedure to 
be followed during 
follow-up period 
(Day 30 to Day 365) 
Updated Text (added number 4)  
 
4. Collect the most current infant vaccine 
record on Day 60 or any time after. 
Removed Text (bullet 7): 
For Day 120, determine if the subjects are 
still breastfeeding; if yes then remind the 
subjects to collect and store breastmilk 
samples 
Required for inclusion criterium 8c 
assessment. 
 
Breastmilk will not be collected at home 
due to difficulty collecting and storing 
breastmilk properly and difficulty with 
transport of home collection to site in 
the required timeframe 
8.1.4 Pregnancy 
Testing 
Current Text: 
 
If a pregnancy is reported, the Investigator 
should inform the Sponsor within 24 hours 
of learning of the pregnancy and should 
follow the procedures outlined in Section 
9.1.7. 
 
Updated Text: 
 
If a pregnancy is reported, the Investigator 
should inform the Sponsor within 24 hours 
Correct section specified with link 
retained for 9.5.4 (page 48). Edited for 
accuracy. 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 83 of 88 
 
 
of learning of the pregnancy and should 
follow the procedures outlined in Section 
9.5.4. 
 
8.2.1 Primary 
Immunogenicity 
Assessments: 
Current Text: 
 
Breastmilk VPI specific (GI.1 and GII.4) 
IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by 
dose level 
Geometric mean concentration (GMC) at 
Day 1, Day 8, Day 15 and Day 29   
Geometric mean fold rise (GMFR) from 
Day 1 to Day 8, from Day 1 to Day 15, and 
from Day 1 to Day 29 
 
Current Text: 
 
Breastmilk VPI specific (GI.1 and GII.4) 
IgA through the active period measured by 
Meso Scale Discovery (MSD) assay by 
dose level 
Geometric mean concentration (GMC) at 
Day 1, Day 8 and Day 29   
Geometric mean fold rise (GMFR) from 
Day 1 to Day 8 and from Day 1 to Day 29    
    
Align with Schedule of Activities and 
intended immunogenicity analysis 
8.2.2  
Immunogenicity 
Assessments: 
Current Text: 
 
Immunogenicity Endpoints 
 
Updated Text: 
 
Secondary Immunogenicity Endpoints 
 
Current Text: 
Breastmilk VP1 specific (GI.1 and GII.4) 
IgA through 6 months after study drug dose 
measured by Meso Scale Discovery (MSD) 
by dose level 
Added "Secondary" to Immunogenicity 
Assessments to categorize objectives 
more clearly and appropriately. 
 
Align with Schedule of Activities and 
intended immunogenicity analysis 
DocuSign Envelope ID: 94ED443F-ABB4-452E-AB38-D94D8A0EEF63

Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 84 of 88 
 
 
Geometric mean concentration (GMC) at 
Day 60, Day 120 , and Day 180  
Geometric mean fold rise (GMFR) from 
Day 1 to Day 60, from Day 1 to Day 120, 
and from Day 1 to Day 180 
 
 
Updated Text: 
 
Breastmilk VP1 specific (GI.1 and GII.4) 
IgA through 6 months after study drug 
dose measured by Meso Scale Discovery 
(MSD) by dose level 
 
Geometric mean concentration (GMC) at 
Day 60 and Day 180  
Geometric mean fold rise (GMFR) from 
Day 1 to Day 60, and from Day 1 to Day 
180  
 
11.4.3 Analysis of 
Primary, Secondary, 
and Exploratory 
Immunogenicity and 
Endpoints 
Current Text: 
 
Immunogenicity samples will be drawn for 
all subjects and their infants. 
Immunogenicity analyses will be based 
upon results from appropriately sized 
subsets of samples, according to the 
purpose. 
 
 
Updated Text:  
 
Immunogenicity samples will be drawn for 
all subjects. Immunogenicity analyses will 
be based upon results from appropriately 
sized subsets of samples, according to the 
purpose. 
 
Deleted "and their infants." Clarified we 
will not be collecting serum from 
infants 
14.1 
Early Safety 
Data Review 
AND/OR Committee 
 
Current Text: 
 
Two or more subjects experience the same 
treatment-related unsolicited grade  ≥3  AE 
between Day 1 and Day 29 (Active Period). 
 
Updated Text: 
 
There is no numerical grade for 
unsolicited AEs. 
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Vaxart Inc 
VXA-NVV-108 Version 2.0 25 Jul 2023 
CONFIDENTIAL                                                                                                                                                            Page 85 of 88 
 
 
Two or more subjects experience the same 
treatment-related unsolicited grade 
“severe” AE between Day 1 and Day 29 
(Active Period). 
Appendix 4: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Updated Text (added): 
 
Contraceptive Guidance 
Contraceptive use by women should be 
consistent with local regulations regarding 
the use of contraceptive methods for those 
participating in clinical studies. Subjects 
must be willing to use a highly effective 
form of contraception for 30 days prior to 
vaccination and until 60 days after the 
vaccination. Acceptable forms are oral, 
implantable, intrauterine, transdermal, 
intravaginal, injectable, double barrier or 
abstinence (subjects using diaphragms must 
also use condom). A reliable form of 
contraception must be approved by the 
Investigator.  
While abstinence is allowed, periodic 
abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods 
of contraception. 
A negative pregnancy test will be required 
for all female subjects prior to study drug 
administration, as outlined in the SoA 
(Table 1). 
Added to emphasize which 
contraceptive method is allowed and to 
clarify that periodic abstinence is not 
allowed   
 
Contraceptive Guidance. Moved to 
correct section 
 
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