Clinical trial NCT05626803
Conditions: Norovirus Infections
Sponsor: Vaxart
Start date: 2023-01-26; Completion date: 2023-10-16
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the safety and immunogenicity of two monovalent Norovirus (NoV) oral tableted vaccine candidates, VXA-G1.1-NN and VXA-GII.4-NS co-administered (bivalent delivery) against a matching placebo arm. Bivalent GI.1 and GII.4 vaccines are being investigated for the prevention of noroviral gastroenteritis caused by norovirus GI.1 and GII.4.

Detailed description:
Norovirus infections are a leading cause of sporadic and epidemic gastroenteritis across all age groups worldwide. This study is designed as a standard double-blind placebo-controlled single administration, dose ranging study to evaluate the safety and immunogenicity of 2 different doses of VXA-GII.4-NS plus VXA-G1.1-NN (high and medium dose administered orally for the prevention of Norovirus infection), compared with a placebo.

This study will enroll a total of 135 subjects with10 sentinel subjects in an open label period (dosing staggered to not-more-than 2 subjects per 24 hours) and randomize 125 subjects in three arms.

The first 10 sentinel subjects will receive the open label high dose of active vaccine. If no dose-related toxicities are observed, and upon the recommendation of the SMC following review of safety data, subjects will be randomized in a 2:2:1 ratio to one of the 3 study arms to receive active vaccine or placebo. 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.

Arms: arm 1: Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets total dose is 2×10 to the power 11 IU/dose (sentinel n=10) arm 2: Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 medium dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 5×10 to the power 10 tablets total dose is 1×10 to the power 11 IU/dose (N=50) arm 3: Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets total dose is 2×10 to the power 11 IU/dose (N=50) arm 4: Placebo tablets (N= 25)
Interventions: intervention 1: Open label Bivalent GII.4/GI.1 high dose vaccine 2×10 to the power 11 IU/dose intervention 2: Bivalent GII.4/GI.1 high dose vaccine 2×10 to the power 11 IU/dose intervention 3: Bivalent GII.4/GI.1 medium dose vaccine 1×10 to the power 11 IU/dose intervention 4: Placebo
Intervention descriptions: intervention 1: The first 10 sentinel subjects will receive open label high dose of active vaccine. Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets; total dose is 2×10 to the power 11 IU/dose intervention 2: 50 subjects will receive high dose of active vaccine. Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets; total dose is 2×10 to the power 11 IU/dose intervention 3: 50 subjects will receive Bivalent GII.4/GI.1 medium dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 5×10 to the power 10 tablets; total dose is 1×10 to the power 11 IU/dose intervention 4: 25 subjects will receive matching placebo

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number: VXA-NVV-202 
 
Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Single Dose, 
Dose-ranging Study to Determine the Safety and Immunogenicity of Bivalent GI.1 and GII.4 
Vaccine Administered Orally to Healthy Volunteers Aged ≥ 18 Years and ≤ 80 Years Old 
 
NCT Number: NCT05626803 
 
Document Date: 22 February 2023 


Vaxart Inc 
VXA-NVV-202 Version 2.0 
 09 Feb 2023 
 
Clinical Study Protocol 
Protocol Title: 
A phase 2, multicenter, randomized, double-blind, placebo-controlled, 
single dose, dose-ranging study to determine the safety and immunogenicity 
of bivalent GI.1 and GII.4 vaccine administered orally to healthy volunteers 
aged ≥ 18 years and ≤ 80 years old. 
Protocol Number: 
VXA-NVV-202 
IND Numbers: 
BB-IND 16796 
Product Names: 
 
Bivalent GI.1 and GII.4 vaccines (VXA-G1.1-NN plus VXA GII.4-NS) 
Indication: 
Prevention of Norovirus Infection 
Sponsor 
 
Vaxart, Inc. 
170 Harbor Way, Suite 300 
South San Francisco, CA 94080 
 
 
Sponsor Contact 
 
 
 
Ph: 
; Email: 
 
 
 
 
Medical Monitor 
 
 
 
Ph: 
 Email: 
 
 
 
 
Ph: 
;  
Email:
 
Protocol Version and 
Version Date 
 
2.0  09 Feb 2023 
DocuSign Envelope ID: 


Vaxart Inc 
VXA-NVV-202 Version 2.0 
 09 Feb 2023 
 
Prior Version 
 
1.0 13-Oct-2022 
Protocol Title: A phase 2, multicenter, randomized, double-blind, placebo-controlled, single dose, dose-
ranging study to determine the safety and immunogenicity of bivalent GI.1 and GII.4 vaccine administered 
orally to healthy volunteers ≥ 18 years and ≤ 80 years old. 
 
Protocol Number: VXA-NVV-202 
 
Amendment Number: 2.0 
 
Date of Amendment (Optional): .09 Feb 2023 
 
IND Number: BB-IND 16796 
 
Investigational Product Name: Bivalent GI.1 and GII.4 vaccines (VXA-G1.1-NN plus 
VXA-GII.4-NS) 
 
 
Phase:  
  
II 
 
Sponsor: 
  
Vaxart, Inc. 
     
 
170 Harbor Way, Suite 300  
      
 
South San Francisco, CA 94080 
 
Funding Sponsor:  
Vaxart, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________ 
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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CONFIDENTIAL                                                                                                                                                                   Page 3 of 106 
 
SIGNATURE 
 
PROTOCOL TITLE: A phase 2, multicenter, randomized, double-blind, placebo-controlled, 
single dose, dose-ranging study to determine the safety and immunogenicity of bivalent GI.1 and 
GII.4 vaccine administered orally to healthy volunteers ≥ 18 years and ≤ 80 years old. 
PROTOCOL NUMBER: VXA-NVV-202 
PROTOCOL VERSION (Amendment): Not applicable 
 
Signature of Sponsor’s authorized representative(s): 
 
 
 
 
                ________________ 
 
 
 
 
 
 
 
Date 
                                                                                    
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 
2/22/2023


Vaxart I
VXA-NVV-202 Version 2.0 
 09 Feb 2023 
CONFIDENTIAL                                                                                                                                                                   Page 4 of 106 
 
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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TABLE OF CONTENTS 
SIGNATURE ....................................................................................................................... 3 
STATEMENT OF COMPLIANCE ........................................................................................ 4 
TABLE OF CONTENTS ...................................................................................................... 5 
LIST OF IN-TEXT TABLE .................................................................................................. 8 
LIST OF IN-TEXT FIGURE ................................................................................................ 8 
LIST OF ABBREVIATIONS [AND DEFINITIONS OF TERMS] ............................................ 9 
1. 
Protocol synopsis ...................................................................................................... 11 
1.1 
Schedule of Trial Activities ......................................................................................................................... 21 
2. 
Introduction .............................................................................................................24 
2.1 
Indication ..................................................................................................................................................... 24 
2.2 
Background .................................................................................................................................................. 24 
2.2.1 
Background of disease ......................................................................................................................... 24 
2.2.2 
Non-clinical experience with Bivalent GI.1 and GII.4 vaccine ......................................................... 24 
2.2.3 
Clinical experience with Bivalent GI.1 and GII.4 vaccine ................................................................ 25 
2.3 
Trial Rationale ............................................................................................................................................. 26 
2.4 
Risk / Benefit Assessment ........................................................................................................................... 26 
2.4.1 
Known Potential Risks to the Subjects ............................................................................................... 26 
2.4.2 
Known Potential Benefits to the subject ............................................................................................. 27 
2.4.3 
Overall Benefit Risk Conclusion ......................................................................................................... 27 
3. 
Trial Objective and end points ..................................................................................27 
3.1 
Objectives ..................................................................................................................................................... 27 
3.1.1 
Primary Objectives 
 .......................................................................................................................... 27 
3.2 
End Points .................................................................................................................................................... 27 
3.2.1 
Primary End Points  .......................................................................................................................... 27 
3.2.2 
Exploratory End Points ....................................................................................................................... 28 
4. 
Trial Design ..............................................................................................................29 
4.1 
Overall Description of Trial Design ........................................................................................................... 29 
4.2 
Scientific Rationale of Trial Design ........................................................................................................... 32 
4.3 
Justification for dose selection .................................................................................................................... 32 
4.4 
End of the study definition ......................................................................................................................... 33 
4.5 
Premature Termination or Suspension of Trial ....................................................................................... 33 
4.6 
Trial and Site Start and Close-Out ............................................................................................................ 34 
4.6.1 
First Act of Recruitment ...................................................................................................................... 34 
4.6.2 
Study/Site Termination ........................................................................................................................ 34 
5. 
Selection of Trial Population .....................................................................................34 
5.1 
Inclusion Criteria ........................................................................................................................................ 34 
5.2 
Early Termination/ Withdrawal criteria ................................................................................................... 38 
5.3 
Lost to follow up Procedure ....................................................................................................................... 39 
5.4 
Screening Failure ......................................................................................................................................... 39 
5.5 
Classification of Subjects Who Discontinue the Study ............................................................................. 39 
6. 
Trial Intervention .....................................................................................................41 
6.1 
Investigational Product Description .......................................................................................................... 41 
6.2 
Preparation and Dispensing of Investigational Product .......................................................................... 42 
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6.3 
Dosing and Administration of Investigational Product ........................................................................... 42 
6.4 
Formulation, Appearance, Packaging, and Labelling .............................................................................. 43 
6.5 
Product Storage and Stability .................................................................................................................... 43 
6.6 
Accountability Procedures .......................................................................................................................... 44 
6.7 
Randomization and Blinding ...................................................................................................................... 44 
6.7.1 
Randomization Procedures ................................................................................................................. 44 
6.7.2 
Blinding Procedures  .......................................................................................................................... 45 
6.8 
Treatment Compliance ............................................................................................................................... 46 
6.9 
Overdose of Treatment ............................................................................................................................... 46 
6.10 Concomitant Medications and Other Therapies ...................................................................................... 46 
7. 
Schedule of Trial Procedures and Assessments ...........................................................47 
7.1 
Trial Procedures .......................................................................................................................................... 47 
7.1.1 
Procedure to be followed on screening Day -45 to Day -1) ............................................................... 47 
7.1.2 
Procedure to be followed during Active Study Period (Day 1 to Day 29) ....................................... 48 
7.1.3 
Procedure to be followed during follow-up period (Day 30 to Day 365) ......................................... 49 
7.1.4 
Unscheduled Visit 
 .......................................................................................................................... 50 
7.2 
Management of Blood / Saliva / Nasal Samples ........................................................................................ 51 
7.2.1 Blood / Saliva/Nasal Sample Collection ..................................................................................................... 51 
7.2.2 Blood/ Saliva/Nasal Sample Preparation ................................................................................................... 51 
7.2.3 Blood/ Saliva/Nasal Sample Storage and Shipment ................................................................................. 51 
7.2.4 Future use of stored specimens and data ................................................................................................... 51 
8. 
Trial Assessments and Procedures .............................................................................52 
8.1 
Safety Assessment ........................................................................................................................................ 52 
8.1.1 
Physical Examination  .......................................................................................................................... 53 
8.1.2 
Vital Signs 
 .......................................................................................................................... 53 
8.1.3 
Clinical Safety Laboratory Tests ........................................................................................................ 53 
8.1.4 
Pregnancy Testing 
 .......................................................................................................................... 53 
8.2 
Immunogenicity Assessments ..................................................................................................................... 53 
9. 
Adverse Events .........................................................................................................55 
9.1.1 
Definition of an Adverse Event, Serious Adverse Event, Adverse Event of Special Interest, New 
Onset of Chronic Illness, and Unanticipated problems .................................................................................. 55 
9.1.2 
Grading of Severity of an Adverse Event ........................................................................................... 57 
9.1.3 
Relationship of Adverse Event Following Immunization to Experimental Vaccine /Vaccine 
Adverse Event Causality Assessment ............................................................................................................... 58 
9.1.4 
Monitoring of Adverse Events during Trial ...................................................................................... 59 
9.1.4.1   Monitoring of AE/SAEs from Day 1 to Day 29 after vaccination ........................................................ 59 
9.1.5 
Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE Information ................. 59 
9.1.6 
Follow-up of AEs, AESIs, NOCIs and SAEs ...................................................................................... 60 
9.1.7 
Reporting of Adverse Event, Adverse Event of Special Interest, New Onset of Chronic Illness, 
Serious Adverse Events and Unanticipated problems .................................................................................... 60 
9.1.8 
Pregnancy 
 .......................................................................................................................... 62 
10. 
Safety Oversight .......................................................................................................63 
10.1 Internal Sponsor Review ............................................................................................................................. 63 
10.2 Safety Monitoring Committee .................................................................................................................... 64 
11. 
Statistical Consideration ...........................................................................................65 
11.1 Hypothesis .................................................................................................................................................... 65 
11.2 Sample Size Determination ......................................................................................................................... 65 
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11.3 Multiplicity Adjustment .............................................................................................................................. 65 
11.4 Population for Analysis ............................................................................................................................... 65 
11.5 Statistical Analysis Plan .............................................................................................................................. 66 
11.5.1 General Approach 
 .......................................................................................................................... 66 
11.5.2 Analysis of the Primary Safety End Points ........................................................................................ 66 
11.5.3 Analysis of Primary and Exploratory Immunogenicity End Points ................................................ 67 
11.5.4 Baseline descriptive Statistics .............................................................................................................. 68 
11.5.5 Sub-group Analysis  .......................................................................................................................... 68 
11.5.6 Tabulation of Individual Subject Data ............................................................................................... 68 
12. 
Ethical Consideration ...............................................................................................69 
12.1 Ethical Conduct of the Study ..................................................................................................................... 69 
12.2 Institutional Review Board ......................................................................................................................... 69 
12.3 Inform Consent Process .............................................................................................................................. 69 
12.4 Insurance Compensation ............................................................................................................................ 70 
12.5 Stipends/Rewards/Compensation for Participation ................................................................................. 70 
12.6 Subject Confidentiality ............................................................................................................................... 70 
12.7 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ..................................... 71 
13. 
Data Handling and Record Keeping ..........................................................................71 
13.1 Source Documents ....................................................................................................................................... 71 
13.2 Case Report Forms (CRF) .......................................................................................................................... 72 
13.3 Data Collection and Management Responsibility ..................................................................................... 72 
13.4 Record Retention ......................................................................................................................................... 73 
13.5 Property Rights and Data Protection ........................................................................................................ 73 
14. 
Quality Control and Quality Assurance .....................................................................74 
14.1 Early Safety Data Review AND/OR Committee ....................................................................................... 74 
14.2 Clinical Trial Site Monitoring .................................................................................................................... 74 
14.3 Audit and Inspection ................................................................................................................................... 75 
14.4 Responsibility of Investigator ..................................................................................................................... 75 
14.5 Responsibility of Sponsor ........................................................................................................................... 76 
14.6 Protocol Deviation ....................................................................................................................................... 76 
15. 
Publication and Data Sharing Policy .........................................................................77 
16. 
References ................................................................................................................78 
Appendix 1: Clinical Laboratory Tests ................................................................................79 
Appendix 2: Country-specific Requirements .......................................................................79 
Appendix 3: Adverse Events Grading ..................................................................................79 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ...................81 
Definitions 
 .......................................................................................................................... 81 
Contraception Guidance 
 .......................................................................................................................... 81 
Collection of Pregnancy Information ............................................................................................................... 81 
Appendix 5: Adverse Events of Special Interest ...................................................................82 
Appendix 6.0 Protocol Version History ...............................................................................84 
VERSION 1.0 ......................................................................................................................................................... 84 
12 OCT 2022 ........................................................................................................................................................... 84 
INITIAL VERSION............................................................................................................................................... 84 
VERSION 2.0 ` ....................................................................................................................................................... 84 
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09 FEB 2023 ........................................................................................................................................................... 84 
AMENDMENT 1.0 ................................................................................................................................................ 84 
 
LIST OF IN-TEXT TABLE 
Table 1: 
Schedule of Activities ....................................................................................................................... 21 
Table 2:  
Sentinel Subjects .............................................................................................................................. 30 
Table 3: 
Study Design ..................................................................................................................................... 30 
Table 4: 
Study Duration ................................................................................................................................. 32 
Table 5: 
Discontinuation Reasons ................................................................................................................. 40 
Table 6:  
Investigational Product Dosing ....................................................................................................... 42 
Table 7: 
Study Arm(s) .................................................................................................................................... 43 
Table 8: 
Adverse Event Reporting Timelines to the Sponsor ..................................................................... 61 
Table 9: 
Populations for Analyses ................................................................................................................. 65 
Table 10 
Protocol-Required Laboratory Assessments ................................................................................. 79 
Table 11 
Grading of Solicited Symptoms of Reactogenicity ........................................................................ 80 
Table 12: 
Adverse Events of Special Interest ................................................................................................. 82 
 
LIST OF IN-TEXT FIGURE 
Figure 1 Study Design ............................................................................................................................................... 16 
 
 
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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 
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IP  
Investigational Product 
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 
International units 
LAR 
Legally Accepted Representative 
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 
Vaccine Protein 1, major capsid protein of norovirus 
WHO 
World Health Organization 
 
 
 
 
 
 
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1. Protocol synopsis 
Trial Title: A phase 2, multicenter, randomized, double-blind, placebo-controlled, single dose, dose-ranging 
study to determine the safety and immunogenicity of bivalent GI.1 and GII.4 vaccine administered orally to 
healthy volunteers aged ≥ 18 years and ≤ 80 years old. 
Sponsor: Vaxart, Inc. 
                 170 Harbor Way, Suite 300  
                 South San Francisco, CA 94080 
Contract Research Organization:    
 
  
 
 
  
 
Protocol number 
VXA-NVV-202 
IND Number 
BB-IND 16796 
Trial Blinding scheme 
Double-blind 
Phase of study 
2 
Trial Arms:  
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=50) 
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=50) (sentinel n=10) 
Arm 3: Placebo tablets (n= 25) 
Description of Investigational Product: 
Name of Vaccine: Bivalent GI.1 and GII.4 vaccines (VXA-G1.1-NN plus VXA-GII.4-NS) 
• 
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-GII.4-NS) 
Dose Regimen: 5×1010 IU and 1×1011 IU per strain per dose 
Route: Oral 
Dosage Form: Tablet 
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This study will investigate the safety and immunogenicity of two monovalent Norovirus (NoV) oral tableted 
vaccine candidates co-administered (bivalent delivery) against a matching placebo arm. All lots of Drug 
Product (DP) will be provided as small white enteric-coated tablets.   
VXA-G1.1-NN and VXA-GII.4-NS are E1/E3-deleted, replication-incompetent, adenovirus 5 vaccine vectors 
designed for use as vaccines for prevention of  NoV infection. The vaccine vectors encode for a full-length 
VP1 gene of either Norwalk virus (VXA-G1.1-NN vaccine) or Sydney virus (VXA-GII.4-NS vaccine). In 
addition to the transgene cassette, a second hCMVie promoter is also present in the vaccine constructs which 
is used to express a ribonucleic acid (RNA) sequence that acts as an adjuvant. The adjuvant is a short hairpin 
RNA expressed off a promoter such that only target cells in the intestine that express antigen will also express 
the adjuvant. This is likely to result in a tight association of antigen with adjuvant in vivo. 
Multiple tablets of study intervention will be dispensed to allow delivery of the intended vaccine dose. A 
matching number of placebo tablets will be dispensed to maintain the study blinding. 
Subject Population:  
Ten (10) sentinel healthy adult male and female subjects aged ≥ 18 years and ≤ 80 years will be enrolled into 
an open label portion of the study. 
One hundred and twenty -five (125) healthy adult male and female subjects aged ≥ 18 years and ≤ 80 years 
will be enrolled in a double-blind randomized portion of the study. 
Objectives: 
Primary Objective:  
To determine the safety and immunogenicity of a bivalent dosing regimen of GI.1 and GII.4, to select the 
dose level with which to safely proceed into Phase 3 development. 
Endpoints: 
Primary Endpoints:  
Safety: 
• 
Frequency, duration, and severity of Solicited Symptoms of Reactogenicity (GI and systemic) 
for 1 week following study intervention dose 
• 
Frequency, duration, and severity of unsolicited adverse events (AEs) for 28 days following the 
study intervention dose 
Immunogenicity: 
• 
Serum - Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA by Meso Scale Discovery (MSD) assay by 
dose level  
o 
geometric mean concentration (GMC) at Day 1 and Day 29  
o 
geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
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• 
Serum - Anti-VP1 GI.1 IgG and Anti-VP1 GII.4 IgG by Meso Scale Discovery (MSD) assay by 
dose level 
o 
geometric mean concentration (GMC) at Day 1 and Day 29  
o 
geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
• 
Serum - Antibody BT50 titers for both GI.1 and GII.4 by Histo-blood group antigen (HBGA) 
Assay   
o 
geometric mean titer (GMT) Day 1 and Day 29  
o 
geometric mean fold rise (GMFR) from Day 1 to Day 29  
Exploratory Endpoints: 
Safety: 
• 
Frequency, duration, and severity of serious adverse event (SAEs), adverse event of special 
interest (AESIs) and New Onset of Chronic Illness (NOCIs) for 1 year following the study drug 
dose 
Immunogenicity: 
• 
Serum - Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA by Meso Scale Discovery (MSD) assay by 
dose level 
o 
geometric mean concentration (GMC) at Day 8 and Day 180 
o 
geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 180 
 
• 
Serum - Anti-VP1 GI.1 IgG and Anti-VP1 GII.4 IgG by Meso Scale Discovery (MSD) assay by 
dose level 
o 
geometric mean concentration (GMC) at Day 8 and Day 180 
o 
geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 180 
 
• 
Serum - Antibody BT50 titers for both GI.1 and GII.4 by Histo-blood group antigen (HBGA) 
Assay   
o 
geometric mean titer (GMT) Day 8 and Day 180  
o 
geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 180 
 
• 
Nasal Swab – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and from Day 
1 to Day 180 
 
• 
Saliva – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and from Day 
1 to Day 180 
 
• 
Fixed Whole Blood (required for blood draw, optional for testing) 
o 
B-cell immunophenotyping at Day 1 and Day 8  
 
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CONFIDENTIAL                                                                                                                                                                   Page 14 of 106 
 
Trial Rationale 
An effective NoV vaccine must prevent the two most common NoV genotypes, GI.1 and GII.4. This vaccine 
consists of VXA-G1.1-NN and VXA-GII.4-NS; the dose of the vaccine is 5×1010 IU and 1×1011 IU per strain 
per dose. GI.1/GII.4 bivalent vaccine is used to prevent illness from NoV. 
Noroviruses are a genetically diverse group of small, non-enveloped, single-stranded positive sense 
Ribonucleic acid (RNA) viruses belonging to the Caliciviridae family. Norovirus infections are a leading 
cause of sporadic and epidemic gastroenteritis across all age groups worldwide. There is an urgent public 
health need for rapid development of novel interventions to prevent the spread of this disease, including 
prophylactic measures, such as vaccines. 
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  
The current Phase 2 dose confirmation study is designed to assess the safety and immunogenicity of 
GI.1/GII.4 bivalent vaccine with a single vaccine dose in healthy volunteers (≥18 years and ≤80 years). 
Description of Sites/Facilities 
This will be a multi-center trial conducted  in the United States of America. The name of Investigators and 
sites are provided on the site -specific Form FDA 1572 document. 
 
 
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CONFIDENTIAL                                                                                                                                                                   Page 15 of 106 
 
Trial design 
This is a multi-center, double-blind, randomized, placebo-controlled, single dose regimen, dose ranging study in 
healthy volunteers (≥18 years and ≤80 years). The study will enroll 10 sentinel subjects in an open label period and 
randomize 125 subjects in three double-blind arms.  
After reviewing and signing an informed consent, the subjects will undergo screening assessments to determine study 
eligibility up to a 45-day Screening Period.  
The first 10 sentinel subjects will receive open label high dose of active vaccine (2×1011 IU). If no dose-related 
toxicities are observed, and upon the recommendation of the Safety Monitoring Committee (SMC) following review 
of Day 1 through Day 8 safety data, enrollment of the remaining subjects will be initiated. The sentinel subjects will 
be enrolled in a staggered design, in which no more than two (2) subjects are dosed per 24-hours. All sentinel subjects 
will be observed on site, for safety at least 2 hours post dose. After the ten (10) sentinel subjects have completed Day 
8 post dose, and if no dose-related toxicities are observed, and upon the recommendation of the Safety Monitoring 
Committee (SMC) following review of safety data up to one week post dose, enrollment of the randomized double-
blind study will be initiated. While ten (10) subjects will be dosed in the sentinel group, to allow for dropouts, eight 
(8) subjects with complete safety data (defined as Day 1 to Day 8) will be enough to convene the SMC. 
If pre-established stopping rules are met, enrollment of subsequent subjects  will be halted until the SMC has 
completed the review of all available safety data and provides recommendation for further study conduct. 
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 or placebo, as follows (Figure 1): 
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Figure 1 Study Design   
 
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 or 
app between site visits to monitor for safety as specified in the SoA (Table 1). 
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 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 he/she remains in the study through Day 365 
(Month 12). Following completion of the Day 365 a tele-health appointment will be conducted 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 both) for 1 week 
following the study drug dose (until Day 8 (+2 days )-scheduled site visit (the sentinel subjects do not have a Day 8 
(+2) window)).  and unsolicited AEs for 28 days post study drug dose (until Day 29-scheduled site visit)) 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 and duration of immune response. Subjects will also 
have samples collected for evaluation of  immunogenicity as specified in the SoA (Table 1).  
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Planned Number of Subjects: 
A total of 10 healthy adult male and female subjects aged ≥18 years and ≤80 years will be enrolled to the high dose 
investigational vaccine during the open label portion of this study. 
A total of 125 healthy adult male and female subjects aged ≥18 years and ≤80 years will be, randomized, in a 2:2:1 
fashion, to receive the investigational vaccine or placebo during this study. 
Eligibility Criteria 
Inclusion Criteria: 
To be eligible for this study, subjects must meet all the following: 
Age 
1. 
≥18 to ≤80 years old inclusive at the time of signing the Informed Consent Form (ICF). - 
Type of Subjects 
2. 
In stable and good general health, without significant medical illness, based on medical history, 
physical examination, and vital signs at screening based on investigator judgement.  
3. 
Body mass index (BMI) > 17.0 and < 35.0 kg/m2 at screening.  
4. 
Available for all planned visits and tele-health appointments, and willing to complete all protocol-
defined procedures and assessments (including ability and willingness to swallow multiple small 
enteric-coated tablets per study dose). 
Gender and Reproductive Considerations 
5. Male or female subjects 
a. 
Female subjects must not be breastfeeding and must provide a negative pregnancy test at screening and 
pre-dose.  
b. Female subjects must fulfill one of the following criteria: 
i. 
At least 1 year post-menopausal (defined as amenorrhea for ≥ 12 consecutive months prior to 
screening without alternative medical cause) or surgically sterile. 
ii. 
Female subjects of childbearing potential must be willing to use a highly effective form of 
contraception for 30 days prior to initial vaccination and until 60 days after last 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.  
iii. 
Male subjects must agree to refrain from donating sperm and practice abstinence from all 
intercourse or to use an effective method of double barrier birth control or condom as noted 
above from first vaccination to 60 days after last vaccination. 
Informed Consent 
6. 
Capable of understanding and giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in the protocol. 
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Exclusion Criteria: 
The subjects must be excluded from participating in the study if they meet any of the following: 
1. Known clotting/bleeding issues and/or personal and family history with increased risk of bleeding or 
clotting. 
2. Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) including institution of 
new medical/surgical treatment or significant dose alteration for uncontrolled symptoms or drug toxicity 
within 3 months prior to screening and reconfirmed at baseline. 
3. Cancer, or treatment for cancer or any procedure or preventive medication for cancer or to prevent 
recurrence within past 3 years (excluding fully treated and resolved basal cell carcinoma or squamous cell 
carcinoma). 
4. Presence of immunosuppression or medical condition possibly associated with impaired immune 
responsiveness, including diabetes mellitus- type 1 and 2. 
5. Left blank intentionally. 
6. 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. GI 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 disorder  
iii. peptic ulcer 
iv. cholecystectomy 
7. History of any form of angioedema. 
8. History of serious reactions to vaccination such as anaphylaxis, respiratory problems, hives or abdominal 
pain. 
9. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make blood draws 
problematic. 
10. Any condition that resulted in the absence or removal of the spleen. 
11. 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). 
12. Presence of a fever ≥38.0 °C measured orally at baseline.  
13. Any significant hospitalization within the last year which in the opinion of the investigator or sponsor could 
interfere with study participation. 
14. Any of the following history or conditions that may lead to 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 risk of thrombosis within 6 months 
prior to screening: 
i. 
Recent surgery other than removal/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 infection. 
15. Any other condition that in the clinical judgement of the investigator would jeopardize the safety or rights 
of a subject taking the study drug, would render the subject unable to comply within the protocol or would 
interfere with the evaluation of the study endpoints diagnostic assessments. 
16. Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or Hepatitis C virus 
(HCV) tests at the screening visit. 
17. History of GI bleeding including hematochezia (blood in stool) or melena (black stool). 
18. Positive urine drug screen for drugs of abuse at screening (positive test for marijuana is not exclusionary; 
however concurrent use of marijuana during the study Active period through Day 29 is prohibited). 
19. Positive breath or urine alcohol test at screening and baseline. 
Prior/Concurrent Therapy 
20. Receipt of a licensed vaccine (including any COVID-19 vaccines under Emergency Use Authorization) 
within 14 days prior to baseline vaccination or planned administration during the study active period 
(Day 29). 
21. 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 (Day 29). 
22. 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 (Day 29). 
23. Daily use of nonsteroidal anti-inflammatory drugs within7 days prior to study drug administration or 
planned use during the active study period (Day 29). Low dose daily ASA ≤ 100 mg for cardio-protection 
is not exclusionary. 
24. Administration of any investigational vaccine, drug or device within 8 weeks preceding study drug 
administration, or planned use within the duration of the study. 
25. Previous participation in a Vaxart Clinical Trial or other norovirus vaccine trial unless confirmed receipt of 
placebo  
Other Exclusions 
26. Donation or use of blood or blood products within 30 days prior to study drug administration or planned 
donation during the active study period (Day29). 
27. History of drug, alcohol, or chemical abuse within 1 year of screening. 
28. History of hypersensitivity or allergic reaction to any component of the investigational vaccine, including 
but not limited to fish gelatin allergy. 
 
Study Duration: 
For each subject, study participation is expected to last as follows: 
Open Label Period (for sentinel subjects) 
8 days (staggered dosing and collection of Solicited 
Symptoms) and then continue through Active and 
Follow Up Period enrolled in an open label portion. 
Screening period:  
Up to 45 days  
Active study period for reactogenicity, 
safety, and immunogenicity 
29 days  
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Follow Up Period for safety and duration 
of immune response, SAEs, AESIs, NOCIs 
12 months (from last study dose at Day 365) 
Total duration: 
12 months 
 
Statistical Method: 
The statistical analysis plan (SAP) will be developed and finalized before database lock for any of the planned 
analyses. It will describe the subject 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 endpoints.  
Sample Size Justification 
A sample size of 125  randomized subjects (50 each in medium and high dose levels and 25 in placebo) in addition 
to 10 sentinel subjects are 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.  
The numbers of subjects per dose group are predicted to yield meaningful safety and immunogenicity results.  
Interim Analysis   
No interim analysis will be conducted for this study. 
Safety Monitoring Committee: 
A safety monitoring committee will be assigned by the Sponsor prior to the beginning of the study and will provide 
ongoing oversight of the study.  
Unblinded data may be provided to the SMC if required during the double-blind period. Further details regarding 
data safety monitoring guidelines will be included in the SMC Charter.  
 
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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 
(+2 
Days)g 
Day 29/ 
Early 
Termination 
Month 2 
Day 60 
Month 4 
Day 120 
Month 6 
Day 180g 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Tele-health Appointment  
X 
 
 
 
 
 
 
 
 
 
Visit Window (days) 
X 
X 
 
±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 
 
 
 
 
 
 
 
 
 
Breath or urine alcohol 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy Test b 
X 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X* 
X* 
X*d 
 
 
 
 
 
 
Vital Signsc 
X 
X 
X 
Xd 
 
 
 
 
 
 
COVID-19 Vaccination Status 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administrationg 
 
X 
 
 
 
 
 
 
 
 
Access to Solicited Symptom Diary 
/App 
 
X 
 
 
 
 
 
 
 
 
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Review Solicited Symptom Diary 
/Appf  
 
 
Xd 
Xd 
 
 
 
 
 
 
Review prior & concomitant 
medication 
X 
X 
X 
Xd 
 
 
 
 
 
 
Query for AEs, SAEs, AESIs and 
NOCIs 
 
X 
X 
Xd 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
Sample Collection for Immunogenicity Assessments – All Subjects 
Study Day 
Day -45 
to Day -1 
Day 1 
Day 8 
Day 29/ 
Early 
Termination 
Month 2 
Day 60 
Month 4 
Day 120 
Month 6 
Day 180g 
Month 8 
Day 240 
Month 10 
Day 300 
Month 12 
Day 365 
Serum blood sample  
 
X 
Xg 
Xd 
 
 
X 
 
 
 
Nasal Swab 
 
X 
Xg 
Xd 
 
 
X 
 
 
 
Saliva Sample  
 
X 
Xg 
Xd 
 
 
X 
 
 
 
Fixed whole blood sample (required 
for blood draw, optional for testing) 
 
X 
Xg 
 
 
 
 
 
 
 
Abbreviations: Ab, Antibody; AE, adverse events; AESI, adverse event of special interest; ASC, Antibody secreting cells; BT50, serum blocking antibody titers; 
EOS, End of Study (Active Period); ET, Early Termination; HBGA, histo-blood group antigen;  HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; HIV, Human 
Immunodeficiency Virus; IgA, immunoglobulin A; IgG, immunoglobulin G; MSD, Meso Scale Discovery; NOCI, new onset chronic illness; SAE, serious 
adverse event; VP1, Vaccine Protein 1 
Notes: 
 Tele-health appointment (by app or by phone)    
*Targeted  
a Serology- Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV) 
b Serum pregnancy tests will be done at screening on all women. Point-of-Care urine pregnancy test will be performed before dosing on Day 1 on all women, and 
women found positive with urine pregnancy test will not be enrolled during this study.  
c Temperature, blood pressure, heart rate, and respiratory rate will be measured after the subject has been resting for 5 minutes 
d Early termination assessments (Solicited Symptoms are to be captured if ET occurs prior to Day 8) 
e TEAEs will only be collected during the Active Study period (from time of first dose through 4 weeks post last dose). Only SAEs, AESIs and NOCIs will be 
collected during the Follow-up Period. 
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f 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 
g Open label subjects will continue through the active period and into the Follow-up Period and have the same procedures as the randomized population with the 
exception of the Day 8 bio-samples. The Day 8 bio-sampling is not applicable for sentinel subjects. The Day 8 window (Day 8 (+2) is not applicable to the 
sentinel subjects. The sentinel subjects will not have a Day 180 bio sample collected. As such the sentinel subjects will have a phone call visit to collect safety 
data. 
 
  
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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 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.  
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2.2.3 Clinical experience with 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 
(SAEs) attributed to vaccine. The vaccine has generated robust immune responses including 
systemic and mucosal antibodies as well asimmunoglobulin 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 adult volunteers ages 
55-80 (in two age cohorts) were evaluated for  immunogenicity, safety, and tolerability at three 
dosing levels: low, medium or 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 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. 
The Phase 2 (VXA-NVV-201) is an ongoing norovirus challenge monovalent GI.1 vaccine trial 
being conducted in healthy volunteers. Preliminary results obtained to date during this study 
indicate vaccine safety comparable to previous trials.. 
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2.3 Trial Rationale 
An effective NoV vaccine must prevent the two most common NoV genotypes, GI.1 and GII.4. 
This vaccine consists of VXA-G1.1-NN and VXA-GII.4-NS;the dose of the vaccine is 5×1010 IU 
and 1×1011 IU per strain per dose. GI.1/GII.4 bivalent vaccine is used to prevent illness from NoV. 
Noroviruses are a genetically diverse group of small, non-enveloped, single-stranded positive 
sense RNA viruses belonging to the Caliciviridae family. Norovirus infections are a leading cause 
of sporadic and epidemic gastroenteritis across all age groups worldwide. There is an urgent public 
health need for rapid development of novel interventions to prevent the spread of this disease, 
including prophylactic measures, such as vaccines. 
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. 
The current Phase 2 dose confirmation study is designed to assess the safety and immunogenicity 
of medium and high dose levels of GI.1/GII.4 bivalent vaccine with a single dose vaccination 
schedule in healthy volunteers (≥18 years and ≤80 years). 
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 TEAEs with Grade 1-3 symptoms: 
1. Diarrhea 
2. Nausea 
3. Abdominal pain 
4. Malaise/fatigue 
5. Headache 
6. Fever 
7. Vomiting 
8. Anorexia 
9. Myalgia (muscle pain) 
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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 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 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 
To determine the safety and immunogenicity of a bivalent dosing regimen of GI.1 and GII.4, to 
select the dose level and regimen with which to safely proceed into Phase 3 development. 
3.2 End Points 
3.2.1 Primary End Points 
Safety: 
• Frequency, duration, and severity of Solicited Symptoms of Reactogenicity (GI and 
systemic) for 1 week following each study drug dose. 
• Frequency, duration, and severity of unsolicited adverse events (AEs) for 28 days 
following last study drug dose. 
 
 
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Immunogenicity: 
• Serum - Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA by Meso Scale Discovery (MSD) 
assay by dose level  
o geometric mean concentration (GMC) at Day 1 and Day 29  
o geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
• Serum - Anti-VP1 GI.1 IgG and Anti-VP1 GII.4 IgG by Meso Scale Discovery (MSD) 
assay by dose level 
o geometric mean concentration (GMC) at Day 1 and Day 29  
o geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
• Serum - Antibody BT50 titers for both GI.1 and GII.4 by Histo-blood group antigen 
(HBGA) Assay   
o geometric mean titer (GMT) Day 1 and Day 29  
o geometric mean fold rise (GMFR) from Day 1 to Day 29  
3.2.2 Exploratory End Points 
Safety: 
• Frequency, duration, and severity of SAEs, AESIs and NOCIs for 1 year 
following last study drug dose. 
 
Immunogenicity: 
• Serum - Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA by Meso Scale Discovery (MSD) 
assay by dose level 
o geometric mean concentration (GMC) at Day 8 and Day 180 
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Serum - Anti-VP1 GI.1 IgG and Anti-VP1 GII.4 IgG by Meso Scale Discovery (MSD) 
assay by dose level 
o geometric mean concentration (GMC) at Day 8 and Day 180 
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Serum - Antibody BT50 titers for both GI.1 and GII.4 by Histo-blood group antigen 
(HBGA) Assay   
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o geometric mean titer (GMT) Day 8 and Day 180  
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Nasal Swab – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and 
from Day 1 to Day 180 
 
• Saliva – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and 
from Day 1 to Day 180 
 
• Fixed Whole Blood (required for blood draw, optional for testing) 
o B-cell immunophenotyping at Day 1 and Day 8  
 
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 volunteers (≥18 years and ≤80 years). The study will enroll 10 sentinel subjects 
in an open label period and randomize 125  subjects in three arms.  
After reviewing and signing an informed consent, the subjects will undergo screening assessments 
to determine study eligibility up to a 45-day Screening Period.  
The first 10 sentinel subjects, in a staggered manner of up to 2 subjects per 24-hour period, will 
receive the open label high dose of bi-valent active vaccine (2×1011) shown in Table 2. If no dose-
related toxicities are observed, and upon the recommendation of the SMC following review of safety 
data, enrollment of the randomized double-blind study will be initiated.  
 
 
 
 
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Table 2:  
Sentinel Subjects 
Treatment 
Group 
Study 
drug 
Per Strain Dose 
(IU) 
Total Dose 
(IU/dose) 
Dosing 
Schedule 
No of 
Subjects 
Open label 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
Day 1 
2 
Open label 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
* 
3-10 
*Two (2) subjects can be dosed in a staggered manner, at least 24 hours from the dosing date of the 
last 2 subjects 
If pre-established stopping rules are met, enrollment of subsequent subjects will be halted until the 
SMC has completed the review of all available safety data and provides recommendation for 
further study conduct. 
On Day 1 of the double-blind portion, subjects will be randomized in a 2:2:1 ratio to one of the 3 
study arms to receive active vaccine or placebo, as follows (Table 3): 
Table 3: 
Study Design 
Treatment 
Group 
Study drug  
Per Strain Dose 
(IU) 
Total 
Dose 
(IU/dose) 
Dosing Schedule 
No of Subjects 
Sentinel 
Open Label 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
Day 1 
10 
Arm 1 
Bivalent 
GII.4/GI.1 
vaccine 
5×1010 
1×1011  
Day 1 
50 
Arm 2 
Bivalent 
GII.4/GI.1 
vaccine 
1×1011 
2×1011 
Day 1 
50 
Arm 3 
Placebo 
N/A 
N/A 
Day 1 
25 
Total 
135 
Abbreviations: IU=infectious units; N/A=not applicable 
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 
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addition, subjects will be contacted by phone or app between site visits to monitor for safety as 
specified in the SoA (Table 1). 
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 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 he/she remains in the study 
through Day 365 (Month 12). Following completion of the Day 365 a tele-health appointment 
phone contact will be conducted 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 both) 
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 serious adverse events (SAEs), AEs of special interest (AESIs), 
and new onset of chronic illness (NOCIs) through Day 365 (Month 12) for safety. Subjects will 
also have samples collected for evaluation of immunogenicity and duration of immune response 
as specified in the SoA (Table 1). 
Planned Number of Subjects: 
A total of 10 healthy adult male and female subjects aged ≥18 years and ≤80 years will be enrolled 
to the high dose investigational vaccine during the open label sentinel, first portion of this study. 
A total of 125 healthy adult male and female subjects aged ≥18 years and ≤80 years are planned 
to be randomized in one of three study arms, post SMC assessment of safety is complete, and the 
decision post SMC is favorable towards starting the randomized, second portion of this study to 
investigational vaccine  or placebo during this study. 
Study Duration: 
For each subject, study participation is expected to last as follows: 
 
 
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Table 4: 
Study Duration 
Screening period:  
Up to 45 days  
Open Label Period (for 10 sentinel subjects) 
8 days (staggered dosing and collection of Solicited 
Symptoms and continue through Active and Follow 
Up Period) 
Randomized Period (for 125 randomized subjects 
8 days (dosing and collection of Solicited 
Symptoms) and continue through Active (Day 29 ) 
and Follow Up Period (Day 30-Day 365) 
 
 
Active study period for primary immunogenicity and 
safety 
29 days  
Follow Up Period for safety and duration of immune 
response 
12 months (from study dose at Day 1) 
Total duration: 
12 months 
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 in subjects up to age 80 
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. 
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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. 
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 
• Demonstration of efficacy that would warrant stopping 
• 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 New 
Zealand Medicines and Medical Devices Safety Authority. 
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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. 
• Total number of subjects included is archived 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 to ≤80 years old inclusive at the time of signing the Informed Consent Form 
(ICF). 
 
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Type of Subjects 
2. 
In stable and good general health, without significant medical illness, based on 
medical history, physical examination, and vital signs at screening based on 
investigator judgement.  
3. 
Body mass index (BMI) > 17.0 and < 35.0 kg/m2 at screening . 
4. 
Available for all planned visits and tele-health appointment, and willing to complete 
all protocol-defined procedures and assessments (including ability and willingness to 
swallow multiple small enteric-coated tablets per study dose). 
Gender and Reproductive Considerations 
6. Male or female subjects 
a. Female subjects must not be breastfeeding and must provide a negative pregnancy 
test at screening and pre-dose.  
b. Female subjects must fulfill one of the following criteria: 
i. 
At least 1 year post-menopausal (defined as amenorrhea for ≥ 12 consecutive 
months prior to screening without alternative medical cause) or surgically 
sterile. 
ii. 
Female subjects of childbearing potential must be willing to use a highly 
effective form of contraception for 30 days prior to initial vaccination and 
until 60 days after last 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.  
iii. 
Male subjects must agree to practice abstinence from heterosexual intercourse 
or to use an effective method of birth control as noted above from first 
vaccination to 60 days after last vaccination. Male subjects must agree to 
refrain from donating sperm and practice abstinence from all intercourse or to 
use an effective method of double barrier birth control or condom as noted 
above from first vaccination to 60 days after last vaccination. 
Informed Consent 
6. Capable of understanding and giving signed informed consent which includes compliance 
with the requirements and restrictions listed in the ICF and in the protocol. 
 
 
 
 
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Exclusion Criteria 
The subjects must be excluded from participating in the study if they meet any of the following: 
1. Known clotting/bleeding issues and/or personal and family history with increased risk of 
bleeding or clotting. - 
2. Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) 
including institution of new medical/surgical treatment or significant dose alteration for 
uncontrolled symptoms or drug toxicity within 3 months prior to screening and 
reconfirmed at baseline. 
3. Cancer, or treatment for cancer or any procedure or preventive medication for cancer or 
to prevent recurrence, within past 3 years (excluding fully treated and resolved basal cell 
carcinoma or squamous cell carcinoma) 
4. Presence of immunosuppression or medical condition possibly associated with impaired 
immune responsiveness, including diabetes mellitus- type 1 and 2 
5. Left blank intentionally. 
6. 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. GI 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. gastro esophageal reflux disorder  
iii. peptic ulcer 
iv. cholecystectomy 
7. History of any form of angioedema 
8. History of serious reactions to vaccination such as anaphylaxis, respiratory problems, 
hives or abdominal pain 
9. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could 
make blood draws problematic 
10. Any condition that resulted in the absence or removal of the spleen 
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11. 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) 
12. Presence of a fever ≥38.0°C measured orally at baseline.  
13. Any significant hospitalization within the last year which in the opinion of the 
investigator or sponsor could interfere with study participation. 
14. Any of the following history or conditions that may lead to 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 risk of thrombosis 
within 6 months prior to screening: 
i. 
Recent surgery other than removal/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, including hospitalization for 
COVID-19 infection. 
15. Any other condition that in the clinical judgement of the investigator would jeopardize 
the safety or rights of a subject taking the study drug, would render the subject unable to 
comply within the protocol or would interfere with the evaluation of the study endpoints 
diagnostic assessments. 
16. Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or 
Hepatitis C virus (HCV) tests at the screening visit. 
17. History of GI bleeding including hematochezia (blood in stool) or melena (black stool) 
18. Positive urine drug screen for drugs of abuse at screening (positive test for marijuana is 
not exclusionary; however concurrent use of marijuana during the study Active period 
through Day 29 is prohibited). 
19. Positive breath or urine alcohol test at screening and baseline. 
Prior/Concurrent Therapy 
20. Receipt of a licensed vaccine (including any COVID-19 vaccines under emergency use 
authorization) within 14 days prior to baseline vaccination or planned administration 
during the study active period (Day 29). 
21. 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 (Day 29). 
22. Use of medications known to affect the immune function (e.g., 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 (Day 29). 
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23. Daily use of nonsteroidal anti-inflammatory drugs within7 days prior to study drug 
administration or planned use during the active study period (Day 29). Low dose daily 
ASA ≤ 100 mg for cardio-protection is not exclusionary. 
24. Administration of any investigational vaccine, drug or device within 8 weeks preceding 
study drug administration, or planned use within the duration of the study 
25. Previous participation in a Vaxart Clinical Trial or other NoV vaccine trial unless 
confirmed receipt of placebo. 
Other Exclusions 
26. Donation or use of blood or blood products within 30 days prior to study drug 
administration or planned donation during the active study period (Day 29). 
27. History of drug, alcohol, or chemical abuse within 1 year of screening.  
28. History of hypersensitivity or allergic reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin allergy. 
5.2 Early Termination/ Withdrawal criteria 
In case of Early Termination (ET) prior to Day 8, all procedures marked as ‘early termination 
assessments’ should be completed 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). 
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. 
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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 medical 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. Screen failure data will be captured in EDC. 
Re-screening/re-assessment 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 such subjects will be determined to be permanent screen failures after the second screening 
determines a subject is ineligible. 
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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Table 5: 
Discontinuation Reasons 
Adverse Event 
To be used when the subject is permanently terminated from the study because 
of an AE (including an SAE), as defined in Section 9.1.1 
Lost to Follow-up 
To be used when the subject cannot be found or contacted in spite of efforts to 
locate him/her before the date of his/her planned last visit, as outlined in Section 
5.3. 
Protocol Deviation 
To be used in case of significant noncompliance with the protocol (e.g., deviation 
of the Inclusion/Exclusion criteria, non-compliance with time windows, blood 
sampling or vaccination refusal, missed injection/treatment, or error in the 
vaccine/treatment administration).  
Withdrawal by Subject 
•
When the subject indicates unwillingness to continue in the study
•
When the subject made the decision to discontinue participation in the
study for any personal reason other than an SAE/AE (e.g., subject is
relocating, inform consent withdrawal, etc.)
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6. TRIAL INTERVENTION 
6.1 Investigational Product Description 
This study will investigate the safety and immunogenicity of bivalent GI.1 and GII.4 vaccine, 
administered orally at total doses of 1×1011 IU/dose and 2×1011 IU/dose, for the prevention of NoV 
infection.  
• 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-GII.4-NS) 
VXA-G1.1-NN and VXA-GII.4-NS are E1/E3-deleted, replication-incompetent, adenovirus 5 
vaccine vectors designed for use as vaccines for prevention of  NoV infection. The vaccine vectors 
encode for a full-length VP1 gene of either Norwalk virus (VXA-G1.1-NN vaccine) or Sydney 
virus (VXA-GII.4-NS vaccine). In addition to the transgene cassette, a second hCMVie promoter 
is also present in the vaccine constructs which is used to express a ribonucleic acid (RNA) 
sequence that acts as an adjuvant. The adjuvant is a short hairpin RNA expressed off a promoter 
such that only target cells in the intestine that express antigen will also express the adjuvant. This 
is likely to result in a tight association of antigen with adjuvant in vivo. 
 
The VXA-G1.1-NN and VXA-GII.4-NS vaccines are produced in tablet form. The drug substance 
is formulated as compressed powdered solid material containing API, tromethamine, sucrose, 
arginine, hydrolyzed fish gelatin (type A), and polyvinyl pyrrolidone (PVP-grade K90). The 
formulated and dried drug substance is blended with tableting excipients consisting of: 
microcrystalline cellulose, pre-gelatinized starch, magnesium stearate, and hydrophobic colloidal 
silica. All inactive ingredients incorporated into the drug product are generally recognized as safe 
(GRAS) and all are included in currently approved, US-licensed oral drug products currently listed 
in the FDA Inactive Ingredients Database. The formulated drug substance is compressed into 
tablets and enteric coated with an acetone-based solution of methacrylate polymer and talc. 
The placebo for this study is manufactured similarly to the active Drug Product (DP) tablets, but 
without the active drug substance. The placebo tablets are indistinguishable in appearance from 
the active DP tablets. The number of placebo tablets dispensed to the subject will be matched to 
the active treatment groups. The placebo will be dispensed by the site’s in-house pharmacy in a 
manner indistinguishable from the active treatment groups. 
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6.2 Preparation and Dispensing of Investigational Product 
Investigational product 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.  
A trained member of the site study staff will dispense the tablet(s) constituting their assigned dose 
to the subject. 
See the Pharmacy manual for instructions on how to prepare VXA-G1.1-NN and VXA-GII.4-NS 
vaccines and placebo for administration. 
6.3 Dosing and Administration of Investigational Product 
This study will investigate the safety and immunogenicity of two monovalent NoV oral tableted 
vaccine candidates (VXA-G1.1-NN and VXA-GII.4-NS) co-administered (bivalent delivery) 
against a matching placebo arm. All lots of DP will be provided as small white enteric-coated 
tablets for oral route of administration.   
Multiple tablets of study drug will be dispensed to allow delivery of the intended vaccine dose. A 
matching number of placebo tablets will be dispensed to maintain the study blinding. 
Table 6:  
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. 
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Table 7: 
Study Arm(s) 
Arm Title* 
Open Label 
Sentinel 
Arm 1 
Arm 2 
Arm 3 
Arm Type 
Experimental 
Experimental 
Experimental 
Placebo 
Arm Description 
Bivalent GII.4/GI.1 
vaccine 
Bivalent GII.4/GI.1 
vaccine 
Bivalent GII.4/GI.1 
vaccine 
Placebo 
Per Strain Dose 
(IU) 
1×1011 
5×1010 
1×1011 
N/A 
Total Dose 
(IU/dose) 
2×1011 
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. 
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. 
 
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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. 
6.7 Randomization and Blinding 
6.7.1 Randomization Procedures 
Assignment of a Subject Number: 
Each subject who signs informed consent will be assigned a subject number. Only the first 10 
sentinel subjects will receive open label high dose of active vaccine (2×1011 IU). Following SMC 
recommendation on review of sentinel safety data up to  and including Day 8, 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 signs the informed 
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consent form (ICF), the Investigator (or designee) will enter the subject into the sites Screening 
Log. All screen failed and randomized subjects will have data entered in the study specific EDC.  
After signing an informed consent, the subjects in the randomized double blind portion of the study 
will undergo screening assessments to determine study eligibility up to 45-day for 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, as follows (Table 7). 
6.7.2 
Blinding Procedures 
The first 10 sentinel subjects will be enrolled and receive the high dose of active vaccine in an 
open label manner for a safety evaluation. 
If pre-established stopping rules are met, enrollment of subsequent subjects will be halted until the 
study SMC has completed the review of all available safety data and provides guidance regarding 
continuation of study. 
For remaining subjects, Investigators, site personnel and the Sponsor (except as described below) 
will be blinded to individual subject 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 periodically convene to review unblinded overall safety as 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 
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. 
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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 5.1 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 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/subject’s legally Accepted 
Representative (LAR). 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 / subject’s LAR, the 
subject will be undergone for screening procedure 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 sitting blood pressure, pulse rate and respiratory rate after at 
least 5 minutes of rest to the subject. 
• 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; pulmonary; gastrointestinal (GI); musculoskeletal; extremities; neurological; 
and lymph nodes.  
• Perform a serum pregnancy test for all female subjects at screening. At screening all women 
will have a negative serum HCG. Prior to dosing all women will have a negative urine HCG. 
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• Verify understanding of and compliance with protocol requirements for contraception (see 
Appendix 4).  
• Ensure that all inclusion criteria are met and that none of exclusion criteria are met.  
• Obtain a urine sample for urine drug screen test. 
• Collect a blood sample to determine the subject’s Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) status. 
• Obtain COVID-19 vaccination status. 
• Complete the source documents.  
• The Investigator or an authorized designee completes the eCRFs. 
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 
for both the open label and randomized groups of the study. 
• The Principal Investigator will ensure that all inclusion criteria and none of the exclusion 
criteria are met on Day1, prior to vaccination. 
• A urine pregnancy test will be done for all female subjects prior to dosing. 
• 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. 
• Vital signs will be obtained, including temperature, sitting blood pressure, pulse rate and 
respiratory rate after at least 5 minutes of rest to the subject during the active study period. 
• The subject’s number (open label) or randomization number will be noted.  
• 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. 
• For the subjects enrolled into the open label sentinel study arm, the site staff must observe 
the subjects at the site, in the ≥18 to ≤80 years old age group, for at least 2 hours 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, and on a serious adverse event 
(SAE) form, as applicable. 
• For the subjects enrolled into the randomized double blind portion study arm, the site staff 
must observe the subjects at the site, in the ≥18 to ≤80 years old age group for at least 30 
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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, and on a serious 
adverse event (SAE) form, 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 (as specified in SOA) and a blood, nasal and saliva samples
will be collected for immunogenicity assessment.
•
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, while
permitted, is not recommended on the day of study drug administration (before or after
vaccination). If prophylactic antipyretic/pain medication is used, 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 data online
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 11) and 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.
7.1.3 Procedure to be followed during follow-up period (Day 30 to Day 365) 
•
Ensure that the subject meets none of the withdrawal criteria as described in Section 5.2. 
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•
Verify understanding of and compliance with protocol requirements for contraception (see 
Appendix 4).
•
Collect a blood sample for Immunogenicity assessment as noted in the SoA (Table 1).
•
Review the subject’s Diary data with the subject and collect the Diary. Collect stop dates of 
any Diary events ongoing on the last day that the Diary was completed and record stop dates 
in the eCRF if required.
•
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 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 5.3. 
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.
7.1.4 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.
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• Measure the subject’s pulse rate (after five minutes of sitting). 
• Measure the subject’s blood pressure (after five minutes of sitting).  
• Assess any systemic events (specify the events of interest) that are present, in accordance with 
the reactogenicity grading scale. 
• Ask the subject if he/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 Samples 
7.2.1 Blood / Saliva/Nasal Sample Collection 
Blood / saliva/nasal 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 study specific Laboratory Manuals. 
7.2.2 Blood/ Saliva/Nasal 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 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 
and nasal 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 
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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 
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers or 
exemptions are not allowed. 
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. 
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. 
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). 
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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; pulmonary; 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 
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 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 9.1.8. 
8.2 Immunogenicity Assessments 
Immunogenicity will be evaluated using cellular and humoral immune function assays from blood 
and mucosal (saliva and nasal swab) samples. Samples will be collected from all subjects 
according to the time points specified in the SoA. The following analytes will be measured: 
Primary Immunogenicity Assessments: 
• Serum –Anti IgA for both GI.1 and GII.4 by Meso Scale Discovery (MSD) assay by 
dose level 
o geometric mean concentration (GMC) at Day 1 and Day 29 
o geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
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• Serum-Antibody titers for both GI.1 and GII.4 by Histo-blood group antigen (HBGA)-
Blocking Assay (BT50) –  
o geometric mean titer (GMT) Day 1 and Day 29  
o  geometric mean fold rise (GMFR) from Day 1 to Day 29  
 
• Serum Anti- IgG for both GI.1 and GII.4 by MSD assay  
o geometric mean concentration (GMC) at Day 1 and Day 29  
o geometric mean fold rise (GMFR) from Day 1 to Day 29  
Exploratory Immunogenicity Assessments: 
• Serum - Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA by Meso Scale Discovery (MSD) 
assay by dose level 
o geometric mean concentration (GMC) at Day 8 and Day 180 
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Serum - Anti-VP1 GI.1 IgG and Anti-VP1 GII.4 IgG by Meso Scale Discovery (MSD) 
assay by dose level 
o geometric mean concentration (GMC) at Day 8 and Day 180 
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Serum - Antibody BT50 titers for both GI.1 and GII.4 by Histo-blood group antigen 
(HBGA) Assay   
o geometric mean titer (GMT) Day 8 and Day 180  
o geometric mean fold rise (GMFR) from Day 1 to Day 8 and from Day 1 to Day 
180 
 
• Nasal Swab – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and 
from Day 1 to Day 180 
 
• Saliva – Anti-VP1 GI.1 IgA and Anti-VP1 GII.4 IgA 
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, Day 1 to Day 29 and 
from Day 1 to Day 180 
 
 
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• Fixed Whole Blood (required for blood draw, optional for testing) 
o B-cell immunophenotyping at Day 1 and Day 8  
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. 
Sample collection, processing and shipping details are provided within the study specific 
Laboratory Manual. 
9. ADVERSE EVENTS 
9.1.1 Definition of an Adverse Event, Serious Adverse Event, Adverse Event of Special 
Interest, New Onset of Chronic Illness, and Unanticipated problems 
Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention related. 
Serious Adverse Event 
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: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Note: Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE/SAE. 
Adverse Event of Special Interest 
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 Table 12. 
 
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New Onset of Chronic Illness 
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 events of special interest and NOCIs will be collected 
and reported for all participants from the moment of first study drug administration until the end 
of the Safety -Follow-up Period through Day 365. 
Unanticipated problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility.) 
The following additional definitions are being used by the Sponsor.  
Solicited Adverse Events: 
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 
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• myalgia (muscle pain) 
• abdominal pain 
• anorexia (defined and not eating) 
• nausea 
• vomiting 
• diarrhoea 
• malaise/fatigue 
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. 
Unsolicited AE: 
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. Unsolicited AEs includes both serious 
(SAEs) and non-serious unsolicited AE. 
Sentinel subjects will be kept at the site under observation for 2 hours after vaccination to ensure 
their safety. If there are no safety concerns during this period then randomized subjects will be 
kept under observation for 30 minutes after vaccination to ensure their safety. The post-vaccination 
observation period should be documented (including the actual time of observation) in the source 
document.  
9.1.2 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”. 
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9.1.3 Relationship of Adverse Event Following Immunization to Experimental Vaccine 
/Vaccine Adverse Event Causality Assessment 
There are five principles that underpin the causality assessment for vaccine adverse events: 
1. Biological plausibility  
2. Temporal relation  
3. Consistency  
4. Specificity  
5. Strength of association  
For more details, refer to the 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 
All adverse events following immunization (AEFIs) must have their relationship to study drug 
assessed by the Investigator (clinician who examines and evaluates the subject based on temporal 
relationship and his/her clinical judgment). The degree of certainty about causality will be graded 
using the categories below. In a clinical trial, the study product must always be suspect. 
• 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). 
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• 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. 
9.1.4 Monitoring of Adverse Events during Trial 
9.1.4.1 
Monitoring of AE/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.  
• Fever/pyrexia 
• Diarrhea 
• Nausea 
• Vomiting 
• Abdominal pain 
• Malaise/fatigue 
• Anorexia 
• Headache 
• Myalgia (muscle pain) 
9.1.5 Time Period and Frequency for Collecting AE, AESI, NOCIs, and SAE 
Information 
All AEs AESIs and NOCIs will be collected from the first dose of study product until the follow-up 
visit at the timepoints specified in the SoA (Table 1). 
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 it does not have a 
causal relationship with study participation.  There are two situations to note as below. 
1. 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.”   
2. 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. 
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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. 
9.1.6 Follow-up of AEs, 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 5.3).  
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 
9.1.7 Reporting of Adverse Event, Adverse Event of Special Interest, New Onset of 
Chronic Illness, Serious Adverse Events and Unanticipated problems 
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 cause 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 8 below summarizes the different reporting timelines for TEAEs (unsolicited and solicited), 
AESIs, NOCIs, SAEs, and SUSAR. 
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Table 8 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 
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 
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). 
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Serious Adverse Events Reporting 
The Investigator or designee will immediately 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 immediately 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. 
The study Sponsor will be responsible for notifying 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 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. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to 
the Sponsor within 24 hours of it being available. 
9.1.8 Pregnancy 
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 or female partner of male subject (after obtaining the 
necessary signed informed consent from the female partner) 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 (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
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• The subject/pregnant female partner will be followed to determine the outcome of the 
pregnancy. If the subject/pregnant female partner (after consent is obtained to follow 
the pregnancy) delivers an infant, the subject/pregnant female partner and the infant 
will be followed up to one month post-delivery. The Investigator will collect follow-
up information on the subject/pregnant female partner and the neonate 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/pregnant female 
partner) beyond the resolution of the pregnancy, he or she may learn of an SAE 
through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study  may request continuation of 
study drug. 
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.  
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. 
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. 
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10.2 Safety Monitoring Committee 
The first 10 sentinel subjects will receive open label high dose of active vaccine (2×1011) in a 
staggered manner, no more than two (2) subjects dosed in a 24-hour period. All subjects dosed 
will be observed for a minimum of 2 hours post dose. While ten (10) subjects will be dosed in 
the sentinel group, to allow for dropouts, eight (8) subjects with complete safety data (defined as 
Day 1 to Day 8) will be enough to convene the SMC. If no dose-related toxicities are observed, 
and upon consideration of the SMC recommendations following review of safety data, 
enrollment of the randomized double-blind study  will be initiated. 
Alternatively, if pre-established stopping rules are met, enrollment of subsequent subjects will be 
halted until the study SMC has completed a review of all available safety data and offers 
a recommendation to proceed. 
If any of the events described below are met during the overall conduct of the study (open label 
and randomized phase), the study will be halted, and no new randomization/vaccinations will be 
allowed pending an SMC safety review 
•
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).
The SMC will provide study oversight throughout the duration of the trial active and safety 
follow-up periods (Day 1 through Day 365 post-vaccination).  
The IRB, US FDA-CBER will be notified if the study is halted for safety concerns. 
A SMC will be created to provide oversight of the conduct of the trial to ensure the safety of 
subjects and the validity and integrity of study data. 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. Please refer to the study specific SMC for 
details.   
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 of the composition, pre-specified meetings and objectives of the SMC will be 
outlined in the SMC Charter. 
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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). 
11.1 Hypothesis 
No hypothesis testing is planned for this study. 
11.2 Sample Size Determination 
A sample size of 125 randomized subjects (50 each in medium and high dose levels and 25 in 
placebo) in addition to 10 sentinel subjects 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. 
11.3 Multiplicity Adjustment 
No multiplicity adjustment will be implemented for this study. 
11.4  Population for Analysis 
For purposes of analysis, the following analysis sets are defined: 
Table 9: 
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. 
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Analysis 
Population 
Description 
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. 
11.5 Statistical Analysis Plan 
11.5.1 
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.  
11.5.2 Analysis of the Primary 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). 
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 last 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. 
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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. 
Exploratory 
(measured 
from Day 30 
through Day 
365) 
Frequency, duration, and severity of SAEs, AESIs and NOCIs for 1 year 
following the study drug dose. 
11.5.3 Analysis of Primary and Exploratory Immunogenicity End Points 
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. 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). 
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Endpoint 
Statistical Analysis Methods 
Primary (Key 
Immunogenicity 
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.  
.For specific primary immunogenicity endpoints please refer to Section 8.2-
Immunogenicity Assessments- Primary Immunogenicity Assessments: 
Exploratory 
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. The analysis 
of these bio samples is optional. 
For specific exploratory immunogenicity endpoints please refer to Section 
8.2-Immunogenicity Assessments- Exploratory Immunogenicity 
Assessments 
11.5.4 Baseline descriptive Statistics 
Demographic data, baseline characteristics, physical examination, concomitant medications, 
medical history data and study medication exposure will be summarized by treatment group.  
11.5.5 Sub-group Analysis 
The primary endpoint will be summarized and analyzed by the following subgroups using the 
ITT set: 
The primary endpoint will be summarized and analyzed by the following subgroups using the 
ITT set: 
• Age 
o Up to and including age 65 years 
o Age 66 years and older 
• Sex  
• Race 
11.5.6 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 CONSIDERATION  
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  Inform 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.  
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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 document 
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 form signed, before the subject undergoes any study-specific 
procedures. The rights and welfare of the subjects will be protected by emphasizing to 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. 
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. 
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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 
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 
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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) 
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. 
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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 adverse events (AEs, concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into an 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 
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. 
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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. 
An initial safety review for this study is planned for the first 10 sentinel subjects who will receive 
the high dose and provide safety data after administration of 2×1011 dose level in a staggered 
manner, no more than two (2) subjects dosed in a 24-hour period. All subjects dosed will be 
observed for a minimum of 2 hours post dose. All safety data collected will be summarized and 
reviewed by the (Sponsor’s internal/external safety monitoring committee) for agreement of next 
steps. 
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 
• 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. 
 
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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.  
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.  
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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 tele-health appointment, 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. 
 
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15. PUBLICATION AND DATA SHARING POLICY 
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 
Atmar, R.L., Estes, M.K., 2012. 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. CLIN INFECT DIS 35, 748–753.  
Esposito, S., Principi, N., 2020. Norovirus Vaccine: Priorities for Future Research and 
Development. Front Immunol 11, 1383.  
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.  
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.  
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 10 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 10 
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 
 
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 11. 
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Table 11 
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. 
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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. 
−  A negative pregnancy test will be required for all female subjects prior to study 
drug administration, as outlined in the SoA (Table 1). 
Contraception Guidance 
Male Subjects: 
Male subjects are eligible to participate if they agree to the following from informed consent 
through 60 days after the last dose of study drug: 
• 
Refrain from donating sperm. 
       PLUS: 
• 
Be abstinent from intercourse as their preferred and usual lifestyle (abstinent on a long term 
and persistent basis) and agree to remain abstinent. 
            OR 
• 
Must agree to use contraception/barrier (a male condom). 
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. 
 
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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 12: 
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 
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• 
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 
• 
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 
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•
Goodpasture syndrome
•
Stevens-Johnson Syndrome
•
Idiopathic pulmonary fibrosis
•
Uveitis
Appendix 6.0 Protocol Version History 
Name of the Document with 
Version Number 
Date 
Summary of Changes and 
Rationale 
VERSION 1.0 
12 OCT 2022 
INITIAL VERSION 
VERSION 2.0 ` 
09 FEB 2023 
AMENDMENT 1.0 
VXA-NVV-202 Protocol Amendment 1 (Version. 2.0), 09 Feb 2023 
Overall Rationale for the Amendment: 
The original version of this phase 2 Norovirus protocol (VXA-NVV-2022) was finalized in October 
2022 and submitted for CBER (US FDA), MedSafe (New Zealand Regulatory Authority) and IRB 
review.  Although approvals were obtained, the study design was modified to a US only study to include 
10 open label sentinel subjects receiving the high dose. After SMC review of the sentinel safety data 1 
week after dosing, a 125 subject double blind randomization portion of the study will follow. 
The table below summarizes the changes incorporated into Amendment 1 as well as a brief rationale for 
each modification. 
Section No. 
& Title 
Description of Change 
Brief Rationale 
All headers 
Updated to date of amendment 
All headers have been updated to 
match the date of the Amendment 1 
Cover page 
Update information for protocol version and date and 
prior version 
To provide accurate information 
Protocol Title 
Page 
Amendment No: 2 and Date of Amendment-09 Feb 
2023 
To provide accurate information 
Entire protocol Removed any referenced to subjects Legally 
Authorized Representative  
This study is enrolling health 
volunteers  
Protocol 
Synopsis 
Contract Research Organization:   
 
 
. 
Updated to: 
 
 
 
To provide accurate information 
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Protocol 
Synopsis trial 
Arms 
Changed sample for the randomized double-blind 
portion of the study: Trial Arms:  
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=50) 
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 (n50) and (sentinel n=10) 
Arm 3: Placebo tablets (n=25) 
To provide accurate information and 
reflect changes to the design of the 
study 
Protocol 
Synopsis Subject 
Population 
Removed 613 sample size and replaced with 125 
sample size 
Changed study design and sample 
size of the study 
Endpoints: 
Immunogenicity 
Added Day 8 to Serum anti IgA for both GI.1 and 
GII.4, Serum BT50 
Updated bio sample assays at Day 8 
Endpoints: 
Immunogenicity 
Removed: PBMC: Anti- IgA Antibody Secreting Cells 
(ASC) for both GI.1 and GII.4 by ELISpot at Day 8 
PBMC samples will not be collected 
in this study 
Protocol 
Synopsis : 
Description of 
Sites/Facilities 
Removed the country of New Zealand. This study will 
be a single country study. 
Single country study-USA only. 
Protocol 
Synopsis-trial 
design 
Changed sample size from 613 to 125 and added the 
following text for the sentinel subjects: The sentinel 
subjects will be enrolled in a staggered design, in which 
no more than two (2) subjects are dosed per 24-hours. 
All sentinel subjects will be observed for safety at least 
2 hours post dose. After the ten (10) sentinel subjects 
have been enrolled, and if no dose-related toxicities are 
observed, and upon the recommendation of the Safety 
Monitoring Committee (SMC) following review of 
safety data up to one week post dose, enrollment of the 
randomized double-blind study will be initiated. 
a. Sample size modification to 
accurately reflect current study.  
b. The original version of the 
protocol allowed for enrollment 
of the 10 sentinel subjects 
without limitations. This 
amendment limits sentinel 
dosing to 2 subjects per 24-hour 
period and extends the sentinel 
observation period to 2 hours 
post dose. These parameters 
were added in response to 
MedSafe (New Zealand 
Regulatory Authority) request, 
and not due to any new safety 
findings or concerns. Although 
the study will no longer include 
sites in New Zealand after 
modification of the study design 
and size, Vaxart has decided to 
keep the increased sentinel safety 
oversight . 
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Protocol 
Synopsis-Figure 
1-Study Design 
Arm 2 is the High Dose arm. Both the High and 
Medium dose arms are labelled as Arm 1 in the study 
design schematic in error. 
a. Schematic updated and replaced. 
Protocol 
Synopsis-
Planned Number 
of Subjects 
Updated sample size to 125: A total of 125 healthy 
adult male and female subjects aged ≥18 years and ≤80 
years will be , randomized and assigned to 
investigational vaccine during this study. 
To accurately reflect the study design 
sample size 
Protocol 
Synopsis-
Exclusion 
Criteria 
Exclusion #5: Removed History of Gilberts Syndrome.  
Left blank intentionally to ensure exclusion criteria 
numbers reconcile with the EDC. 
Exclusion #14, d: Presence of any of the following 
conditions known to increase risk of thrombosis within 
6 months prior to screening: letter “v”: Recent 
clinically significant infection. 
Gilbert’s syndrome is a common 
inherited condition where the liver 
doesn’t properly process bilirubin, 
leading to harmless elevated bilirubin 
lab results. Gilbert’s has not been an 
exclusion in any previous protocols 
for our vaccines and was added in 
error in the earlier version of NVV 
202 before the decision was made 
not to require chemistry labs during 
this trial. The intent was to avoid 
potential confounding of safety labs 
in subjects with known Gilbert’s. 
There have been no safety signals or 
concerns with Vaxart’s oral vaccine 
platform with regard to liver 
enzymes or bilirubin. 
Severe covid infection is known to 
be associated with risk of 
thrombosis. Since we are not 
screening specifically for covid 
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added the following: v. Including hospitalization for 
COVID-19 infection 
infection, this is a way to exclude 
severe covid infections. 
Protocol 
Synopsis-Other 
Exclusions 
Exclusion #28: History of hypersensitivity or allergic 
reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin 
allergy.  
Added the word “gelatin” as this was 
omitted in error in last protocol 
version. 
Protocol 
Synopsis- Study 
Duration 
Open Label Period (for sentinel subjects): 
8 days (dosing and collection of Solicited 
Symptoms and continue through Active and 
Follow Up Period) 
Added “staggered to the previous text: 
8 days (staggered dosing and collection of 
Solicited Symptoms and continue through Active 
and Follow Up Period) 
Accurate reflection of the dosing 
schedule for the sentinels 
Protocol 
Synopsis : 
Sample Size 
Justification 
Sample Size Justification:  
A sample size of 613 randomized subjects (245 each in 
medium and high dose levels and 123 in placebo) are 
required to achieve 80% power, at the 7% significance 
level (one-sided) using a 2-group fisher exact test with 
equal allocation to each dose level. Calculation 
assumes a difference of 10.2% in MSD IgA fold rise 
between the two dose groups (72.7 % Vs. 62.5%). 
Placebo was added for safety comparison. 
Updated to: 
A sample size of 125 randomized subjects (50 each in 
medium and high dose levels and 25 in placebo) in 
addition to 10 sentinel subjects are 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. 
Accurately reflect sample size 
change and impact on statistics 
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Protocol 
Synopsis : Table 
1 : Schedule of 
Activities 
Updated SOA to align with modifications to protocol 
dated 13 Oct 2022. 
1. Updated immunogenicity testing. 
2. Remove PBMC visits. 
3. Added a Day 8 serum and whole blood sample 
collection. 
4. Added a Day 180 serum, nasal and saliva sample 
collection. 
5. Made Day 180 an in person visit at the clinic. 
6. Added a SOA grid for Sample Collection for 
immunogenicity Assessments-all subjects.  
7. Added clarification of procedures for Early 
Termination subjects 
8. Updated legend and superscripts in the SOA grid 
9. Added temperature to Vital Signs-legend “c” Now 
reads: temperature, blood pressure, heart rate, and 
respiratory rate will be measured after the subject 
has been resting for 5 minutes 
Provide accurate information specific 
to the SOA  
Protocol 
Synopsis : Trial 
Rationale 
Last paragraph: 
Original text: 
The current Phase 2 dose confirmation study is 
designed to assess the safety and immunogenicity of 
GI.1/GII.4 bivalent vaccine with a 1-dose vaccination 
schedule in healthy volunteers (≥18 years and ≤80 
years).  
Updated text: 
The current Phase 2 dose confirmation study is 
designed to assess the safety and immunogenicity of 
GI.1/GII.4 bivalent vaccine with a single vaccine dose 
in healthy volunteers (≥18 years and ≤80 years). 
Provide accurate information specific 
to the study design 
 
2.2.3 Clinical 
experience with 
Updated non clinical experience  
Provide accurate information specific 
to the study design and updates 
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Bivalent GI.1 
and GII.4 
vaccine 
Removed VXA-NVV-106 text since it was specific to 
the low titer/high tablet lot and was not included in the 
IB 
2.3 
Trial 
Rationale 
Original text: 
The current Phase 2 dose confirmation study is 
designed to assess the safety and immunogenicity of 
GI.1/GII.4 bivalent vaccine with a 2-dose vaccination 
schedule in healthy volunteers (≥18 years and ≤80 
years). 
Updated to:  
The current Phase 2 dose confirmation study is 
designed to assess the safety and immunogenicity of 
medium and high dose levels of GI.1/GII.4 bivalent 
vaccine with a single 2-dose vaccination schedule in 
healthy volunteers (≥18 years and ≤80 years). 
Provide accurate information specific 
to the study design  
3.2.1 Primary 
End Points 
Added Day 8 to the following calculation.  
• 
Geometric mean concentration (GMC) at Day 
8 and Day 29 
• 
Geometric mean fold rise (GMFR) from Day 1 
to Day 8 to Day 29 
Provide accurate information specific 
to the modified study design and bio-
sample analysis for serum samples 
 
The current Phase 2 dose confirmation study is 
designed to assess the safety and immunogenicity of 
medium and high dose levels of GI.1/GII.4 bivalent 
vaccine with a single dose2-dose vaccination schedule 
in healthy volunteers (≥18 years and ≤80 years). 
3.2.2 
Exploratory-End 
Points-
Immunogenicity 
Added Day 8 to the following: 
• 
Serum: 
• 
Antibody titers for both GI.1 and GII.4 by 
Histo-blood group antigen (HBGA)-Blocking 
Assay (BT50) - geometric mean titer (GMT) 
and GMFR at Day 8, Day 29 and Day 180 
• 
Anti- IgG for both GI.1 and GII.4 by MSD 
assay -GMC and GMFR at Day 8, Day 29 and 
Day 180 
• 
Anti- IgA for both GI.1 and GII.4 by MSD 
assay - GMC and GMFR at Day 8 Day 180 
Removed PBMC sampling and analysis 
Provide accurate information specific 
to the modified study design and bio-
sample analysis for serum, nasal, 
saliva and whole blood sampling 
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• 
Nasal Swab: 
• 
Anti- IgA for both GI.1 and GII.4 - GMC and 
GMFI at Day 8, Day 29 and Day 180 
• 
Saliva: 
• 
Anti- IgA for both GI.1 and GII.4 - GMC and 
GMFI at Day 8, Day 29 and Day 180 
Added Day 1 and Day 8 collection to the following:  
• 
Fixed Whole Blood (required for blood draw, 
optional for testing) 
• 
B-cell immunophenotyping - Day 1, Day 8 and 
Day 29 
4.1 Overall 
Description of 
Trial Design 
Original text: 
This is a multi-center, double-blind, randomized, 
placebo-controlled, single dose, dose ranging study in 
healthy volunteers (≥18 years and ≤80 years). The 
study will enroll 10 sentinel subjects in an open label 
period and randomize 613 subjects in three arms. 
Updated text: 
This is a multi-center, double-blind, randomized, 
placebo-controlled, single dose, dose ranging study in 
healthy volunteers (≥18 years and ≤80 years). The 
study will enroll 10 sentinel subjects in an open label 
period and randomize 125 subjects in three arms. 
Original Text: 
The first 10 sentinel subjects will receive the open label 
high dose of active vaccine (2×1011) shown in Table 2. 
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. 
Updated Text: 
The first 10 sentinel subjects, in a staggered manner of 
up to 2 subjects per 24-hour period, will receive the 
open label high dose of bi-valent active vaccine 
(2×1011) shown in Table 2. If no dose-related toxicities 
are observed, and upon the recommendation of the 
Accurately reflect sample size 
change from 613 to 125 for the 
double-blind randomized portion of 
the study 
The original version of the protocol 
allowed for enrollment of the 10 
sentinel subjects without limitations. 
This amendment limits sentinel 
dosing to 2 subjects per 24-hour 
period and extends the sentinel 
observation period to 2 hours post 
dose.  
 
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SMC following review of safety data, enrollment of the 
randomized double-blind study will be initiated. 
Table 2 Sentinel Subjects deleted. 
Updated Table 2: Sentinel Subjects 
Updated Table 2 accurately reflects 
the study design modifications for 
the sentinel subjects 
4.1 4.1 Overall 
Description of 
Trial Design 
Table 3: Study Design 
1. Updated the table to reflect the new sample size
and sample size per arm. 
2. Added a row for the sentinels to Table 3 
Abbreviations: IU: International Units,  
Corrected to: Infectious Units (IU) 
Provide accurate information specific 
to the modified study design 
Table 4 : 
 
Original text: 
Open Label Period (for 10 sentinel subjects)-8 days ( 
dosing and collection of Solicited Symptoms and 
continue through Active and Follow Up Period) 
Updated to:  
Provide accurate information specific 
to the modified study design 
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Added “staggered” 
Open Label Period (for 10 sentinel subjects) 
8 days 
(staggered dosing and collection of Solicited Symptoms 
and continue through Active and Follow Up Period) 
5.1 Inclusion 
Criteria 
Inclusion #3:  
Original text: 
3. Body mass index (BMI) between 17.0 and 35.0 
kg/m2 at screening SNG. 
Updated text: 
Removed SNG-erroneous text and clarify range: 
3. Body mass index (BMI) > 17.0 and < 35.0 kg/m2 at
screening 
Correct a text error 
Section 5.1 
Inclusion 
Criteria-
Exclusion 
Criteria 
Exclusion #14: 
Original Text 
14. 
Any of the following history or conditions that 
may lead to higher risk of clotting events and/or 
thrombocytopenia: 
e. 
Family or personal history of bleeding or 
thrombosis. 
f. 
History of heparin-related thrombotic events, 
and/or receiving heparin treatments. 
g. 
History of autoimmune or inflammatory 
disease. 
h. Presence of any of the following conditions known 
to increase risk of thrombosis within 6 months prior to 
screening: 
i. Recent surgery other than removal/biopsy of 
cutaneous lesions 
ii. Immobility (confined to bed or wheelchair for 3 or 
more successive days) 
No change to actual text for 
Exclusion 14,h. Changed 
classification (i to a, ii to b, etc.) 
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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 
Updated text: 
14. 
Any of the following history or conditions that 
may lead to 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 risk of thrombosis within 6 
months prior to screening: 
i. Recent surgery other than removal/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 
Section 5.1 
Inclusion 
Criteria-
Exclusion 
Criteria 
Exclusion #28 
Original text: 
29. History of hypersensitivity or allergic reaction to 
any component of the investigational vaccine, 
including but not limited to fish allergy. 
Updated text: 
Added “gelatin” 
Corrected exclusion criteria 
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28. 
History of hypersensitivity or allergic reaction 
to any component of the investigational vaccine, 
including but not limited to fish gelatin allergy. 
6.1Investigation
al Product 
Description 
Original Text: 
VXA-G1.1-NN and VXA-GII.4-NS are E1/E3-deleted, 
replication-incompetent, adenovirus 5 vaccine vectors 
designed for use as vaccines for prevention of NoV 
infection. The vaccine vectors encode for a full-length 
VP1 gene of either Norwalk virus (VXA-G1.1-NN 
vaccine) or Sydney virus (VXA-GII.4-NS vaccine). In 
addition to the transgene cassette, a second hCMVie 
promoter is also present in the vaccine construct which 
is used to express an RNA sequence that acts as an 
adjuvant. The adjuvant is a short hairpin RNA 
expressed off a promoter such that only target cells in 
the intestine that express antigen will also express the 
adjuvant. This is likely to result in a tight association of 
antigen with adjuvant in vivo. 
Updated text: 
VXA-G1.1-NN and VXA-GII.4-NS are E1/E3-deleted, 
replication-incompetent, adenovirus 5 vaccine vectors 
designed for use as vaccines for prevention of  NoV 
infection. The vaccine vectors encode for a full-length 
VP1 gene of either Norwalk virus (VXA-G1.1-NN 
vaccine) or Sydney virus (VXA-GII.4-NS vaccine). In 
addition to the transgene cassette, a second hCMVie 
promoter is also present in the vaccine constructs which 
is used to express a ribonucleic acid (RNA) sequence 
that acts as an adjuvant. The adjuvant is a short hairpin 
RNA expressed off a promoter such that only target 
cells in the intestine that express antigen will also 
express the adjuvant. This is likely to result in a tight 
association of antigen with adjuvant in vivo. 
Provide accurate information specific 
to the Investigational Product 
6.7.1 
Randomization 
procedures 
Original text: 
After signing an informed consent, the subjects will 
undergo screening assessments to determine study 
eligibility over a 45-day Screening Period. On Day 1, 
subjects will be randomized in a 2:2:1 ratio to one of 
Provide accurate information specific 
to how screen failed subjects will be 
captured in the EDC (reason for 
screen failure) 
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the three treatment arms to receive active vaccine or 
placebo, as follows (Table 6). 
Updated Text: 
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, as 
follows (Table 6). 
7.1.Procedure to 
be followed on 
screening (Day -
45 to Day -1) 
Original text-bullet 5: 
•Measure subject’s temperature (oral). 
Updated text: 
•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. 
Original text-bullet 7 
•Perform a urine pregnancy test for all female subjects 
at screening.  
Updated text: 
•Perform a urine pregnancy test for all female subjects 
at screening. At screening all women will have a 
negative serum HCG. Prior to dosing all women will 
have a negative urine HCG. 
Allow alternatives to oral 
temperatures and clarify the 
preferred use of the sponsor provided 
thermometers for reporting daily 
diary specific temperatures. 
Clarify that all subjects must have a 
negative pregnancy test (serum) at 
screening and a negative pregnancy 
test (urine) prior to dosing. 
7.1.2
 
Procedur
e to be followed 
Procedures to be followed during the Active Study 
Period (Day 1 to Day 29): Subjects will return the site 
Provide accurate information specific 
to the original intent of the study 
procedures 
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during Active 
Study Period 
(Day 1 to Day 
29) 
(as specified in SOA) and a blood sample will be 
collected for immunogenicity assessment. 
Update to: Subjects will return to the site (as specified 
in SOA) and blood, nasal and saliva samples will be 
collected for immunogenicity assessment. 
Added: 
For the subjects enrolled into the open label sentinel 
study arm, the site staff must observe the subjects at the 
site, in the ≥18 to ≤80 years old age group, for at least 2 
hours 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, and on a serious adverse event (SAE) form, as 
applicable. 
Original text: 
The Investigator or appropriately qualified designee 
will review the Diary data online 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). 
Updated test: 
The Investigator or appropriately qualified designee 
will review the Diary data online 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 
evaluate for potential alternative etiology. 
Provide clarification on the post dose 
observation period for the sentinel 
subjects 
To clarify if ≥ Grade 3 Solicited 
Adverse Events are related to study 
drug or other etiology 
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7.2 Management 
of Blood / Saliva 
/ Nasal Samples 
Added text to be consistent about bio samples 
collection, preparation, storage, and shipment 
Provide clarification 
7.2.4 Future 
use of stored 
specimens and 
data 
Removed the following text: 
In addition to the research, you are consenting to under 
this research study, Vaxart, would like to store your 
samples for future development of a NoV vaccine. At 
this time, the exact tests are not known but this will 
help to further understand the how the oral NoV 
vaccine works in the body and in the prevention of 
NoV illness. If you agree to permit your samples to be 
analyzed, the results on your particular sample will not 
be provided to you, because it will not be known which 
samples belong to you. 
Removed subject facing language 
from the protocol. 
8.2 
Immunogenicity 
Assessments 
Updated to match the SOA-Immunogenicity 
Assessments and testing. 
Original text: 
Primary Immunogenicity Assessments: 
•Serum: 
oAnti IgA for both GI.1 and GII.4 by Meso Scale 
Discovery (MSD) assay by dose level-geometric mean 
concentration (GMC) at Day 29 and geometric mean 
fold rise (GMFR) from Day 1 to Day 29. 
Exploratory Immunogenicity Assessments: 
•Serum: 
oAntibody titers for both GI.1 and GII.4 by Histo-blood 
group antigen (HBGA)-Blocking Assay (BT50) - 
geometric mean titer (GMT) and GMFR at Day 29 and 
Day 180 
oAnti- IgG for both GI.1 and GII.4 by MSD assay -
GMC and GMFR at Day 29 and Day 180 
oAnti- IgA for both GI.1 and GII.4 by MSD assay - 
GMC and GMFR at Day 180 
Updated to accurately reflect the 
SOA 
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•PBMC: Anti- IgA Antibody Secreting Cells (ASC) for 
both GI.1 and GII.4 by ELISpot at Day 8 
•Nasal Swab: 
oAnti- IgA for both GI.1 and GII.4 - GMC and GMFI 
at Day 29 and Day 180 
•Saliva: 
oAnti- IgA for both GI.1 and GII.4 - GMC and GMFI 
at Day 29 and Day 180 
•Fixed Whole Blood (required for blood draw, optional 
for testing) 
oB-cell immunophenotyping - Day 8 
Updated text: 
Primary Immunogenicity Assessments: 
•Serum: 
oAnti IgA for both GI.1 and GII.4 by Meso Scale 
Discovery (MSD) assay by dose level-geometric mean 
concentration (GMC) at Day 8 and Day 29 and 
geometric mean fold rise (GMFR) from Day 1 to Day 8 
to Day 29. 
Exploratory Immunogenicity Assessments: 
•Serum: 
oAntibody titers for both GI.1 and GII.4 by Histo-blood 
group antigen (HBGA)-Blocking Assay (BT50) - 
geometric mean titer (GMT) and GMFR at Day 8 and 
Day 29, and Day 180 
oAnti- IgG for both GI.1 and GII.4 by MSD assay -
GMC and GMFR at Day 8, Day 29 and Day 180 
oAnti- IgA for both GI.1 and GII.4 by MSD assay - 
GMC and GMFR at Day 8, Day 29 and Day 180 
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•Nasal Swab:
oAnti- IgA for both GI.1 and GII.4 - GMC and GMFI 
at Day 1, Day 8, Day 29 and Day 180 
•Saliva:
oAnti- IgA for both GI.1 and GII.4 - GMC and GMFI 
at Day 1, Day 8, Day 29 and Day 180 
•Fixed Whole Blood (required for blood draw, optional
for testing)
oB-cell immunophenotyping -– Day 1, Day 8, Day 29 
and Day 180 
9.1.1 Definition 
of an Adverse 
Event, Serious 
Adverse Event, 
Adverse Event 
of Special 
Interest, New 
Onset of 
Chronic Illness, 
and 
Unanticipated 
problems 
Adverse Event of Special Interest 
Original text: 
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. 
Updated text: 
Updated text (addition): 
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, an AESI is a 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 Table 12. 
Unsolicited Adverse Events: 
Original text:  
If there are no safety concerns during this period 
then randomized Subjects will be kept under 
Clarify Adverse Event of Special 
Interest (AESI) 
Clarify sentinel post dose 
observation period 
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observation for 30 minutes after vaccination to 
ensure their safety. The post-vaccination 
observation period should be documented 
(including the actual time of observation) in the 
source document. 
Updated text: 
Sentinel subjects will be kept at the site under 
observation for 2 hours after vaccination to 
ensure their safety. If there are no safety 
concerns during this period then randomized 
Subjects will be kept under observation for 30 
minutes after vaccination to ensure their safety. 
The post-vaccination observation period should be 
documented (including the actual time of 
observation) in the source document. 
9.1.3 
Relationship of 
Adverse Event 
Following 
Immunization to 
Experimental 
Vaccine 
/Vaccine 
Adverse Event 
Causality 
Assessment 
Original text: 
For more details refer to 
https://www.who.int/publications/i/item/causality-
assessment-aefi-user-manual-2019.  
Updated text: 
For more details, refer to the 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/978924151699
0 
Provide updated information 
9.1.5 Time 
Period and 
Frequency for 
Collecting AE, 
AESI, NOCIs, 
and SAE 
Information 
Original text: 
All AEs AESIs and NOCIs will be collected from the 
first dose of study product until the follow-up visit at 
the timepoints specified in the SoA (Table 1). 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. 
Updated text: 
Medical occurrences that begin before the start of study 
drug but after obtaining informed consent will be 
recorded as medical history/current medical conditions, 
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not as AEs if it does not have a causal relationship 
with study participation.  There are two situations 
to note as below. 
1. 
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.”   
2. 
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. 
9.1.7 Reporting 
of Adverse 
Event, Adverse 
Event of Special 
Interest, New 
Onset of 
Chronic Illness, 
Serious Adverse 
Events and 
Unanticipated 
problems 
Original text: 
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 cause the subject to be excluded from the 
study or is the result of a protocol-specified 
intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
Updated text: 
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 cause 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. 
Provide clarification on reporting of 
AEs 
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10.2 Safety 
Monitoring 
Committee 
Original text: 
The first 10 randomized subjects will receive open 
label high dose of active vaccine (2×1011). After Day 8 
is completed for the 10 sentinel subjects, enrollment 
will be paused for a safety review of Solicited 
Symptoms and unsolicited adverse events. If no dose-
related toxicities are observed, and upon consideration 
of the SMC recommendations following review of 
safety data, enrollment of the remaining subjects will 
be initiated. 
Updated text: 
The first 10 sentinel subjects will receive open label 
high dose of active vaccine (2×1011) in a staggered 
manner, no more than two (2) subjects dosed in a 
24-hour period. All subjects dosed will be observed 
for a minimum of 2 hours post dose. While ten (10) 
subjects will be dosed in the sentinel group, to allow 
for dropouts, eight (8) subjects with complete safety 
data (defined as Day 1 to Day 8) will be enough to 
convene the SMC. If no dose-related toxicities are 
observed, and upon consideration of the SMC 
recommendations following review of safety data, 
enrollment of the randomized double-blind study will 
be initiated.  
Provide clarification on the open 
label-sentinel dosing portion of the 
study 
11.1 Hypothesis Original text: 
The following hypotheses will be tested using MSD 
IgA fold rise as the endpoint of interest. 
Null Hypothesis: H0: P1 - P2 ≤ 0. 
Alternative Hypothesis: Ha: P1 – P2 > 0. 
Where p1 is the percentage of MSD IgA fold rise for 
the low dose level and P2 for the high dose level. 
All statistical tests will be performed at the 7% level of 
significance and confidence intervals will also be 
presented. 
Updated text: 
No hypothesis testing is planned for this study. 
There will be no hypothesis testing 
for this study 
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11.2 Sample 
Size 
Determination 
Original text: 
A sample size of 613 randomized subjects (245 each in 
medium and high dose levels and 123 in placebo) are 
required to achieve 80% power, at the 7% significance 
level (one-sided) using a 2-group fisher exact test with 
equal allocation to each dose level. Calculation 
assumes a difference of 10.2% in MSD IgA fold rise 
between the two dose groups (72.7 % Vs. 62.5%). 
Placebo was added for safety comparison. The numbers 
of subjects per dose group are predicted to yield 
meaningful safety and immunogenicity results. 
Updated text: 
A sample size of 125 randomized subjects (50 each in 
medium and high dose levels and 25 in placebo) in 
addition to 10 sentinel subjects are 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. 
Modification based on clinical 
judgement  
11.5.2 Analysis 
of the Primary 
Safety End 
Points 
Original text: 
Primary-(measured from Day 1 through Day 365) 
requency, 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 last 
dose). 
Frequency, duration, and severity of SAEs, AESIs 
and NOCIs for 1 year following the study drug 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 
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Removed: Frequency, duration, and severity of 
SAEs, AESIs and NOCIs for 1 year following the 
study drug dose. 
Added a new endpoint:  
Exploratory (measured from Day 30 through Day 365) 
Frequency, duration, and severity of SAEs, AESIs and 
NOCIs for 1 year following the study drug dose. 
11.5.3 Analysis 
of Primary 
Immunogenicity 
End Points 
Original text: 
11.5.3 Analysis of Primary End Points 
Updated text: 
11.5.3 Analysis of Primary and Exploratory 
Immunogenicity End Points 
Original Text-Primary: 
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.  
Anti- IgA for both GI.1 and GII.4 by Meso Scale 
Discovery will be summarized descriptively.  
Updated text: 
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.  
For specific primary immunogenicity endpoints 
please refer to Section 8.2-Immunogenicity 
Assessments- Primary Immunogenicity 
Assessments: 
Original text Exploratory: 
none 
Clarified Primary 
Immunogenicity and added 
Exploratory Immunogenicity 
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Updated text: 
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. The 
analysis of these bio samples is optional. 
For specific exploratory immunogenicity endpoints 
please refer to Section 8.2-Immunogenicity 
Assessments- Exploratory Immunogenicity 
Assessments 
14.1 
Early 
Safety Data 
Review 
AND/OR 
Committee 
Original text: 
An initial safety review for this study is planned for the 
first 10 sentinel subjects who will receive the high dose 
and provide safety data after administration of 2×1011 
dose level. All safety data collected will be summarized 
and reviewed by the (Sponsor’s internal/external safety 
monitoring committee) for agreement of next steps. 
Updated text: 
An initial safety review for this study is planned for the 
first 10 sentinel subjects who will receive the high dose 
and provide safety data after administration of 2×1011 
dose level in a staggered manner, no more than two 
(2) subjects dosed in a 24-hour period. All subjects 
dosed will be observed for a minimum of 2 hours 
post dose. All safety data collected will be summarized 
and reviewed by the (Sponsor’s internal/external safety 
monitoring committee) for agreement of next steps. 
The original version of the protocol 
allowed for enrollment of the 10 
sentinel subjects without limitations. 
This amendment limits sentinel 
dosing to 2 subjects per 24-hour 
period and extends the sentinel 
observation period to 2 hours post 
dose. This modification was 
originally captured in a protocol 
clarification letter (PCL#3) and the 
ICF modified prior to this 
amendment. 
Appendix 6.0 Original text: 
Updated text: 
Capture protocol version history and 
provide a table of protocol changes 
and rationale 
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