A Phase 2b Double-Blinded, Randomized, Placebo-Controlled, Human Norovirus GI.1 (Norwalk Virus Inoculum) Challenge Study Following Administration of an Oral, Single-dose Norovirus Vaccine Expressing GI.1 VP1 and dsRNA Adjuvant to Protect Against Norovirus Gastroenteritis (NVG) in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Norovirus Infections
Sponsor: Vaxart

Protocol Number: VXA-NVV-201 
 
Official Title: A Phase 2b Double-blinded, Randomized, Placebo-Controlled, Human Norovirus GI.1 
(Norwalk Virus Inoculum) Challenge Study Following Administration of an Oral, Single-dose 
Norovirus Vaccine expressing GI.1 VP1 and dsRNA Adjuvant to Protect Against Norovirus 
Gastroenteritis (NVG) in Healthy Adult Volunteers 
 
NCT Number: NCT05212168 
 
Document Date: 25 May 2023  

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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TABLE OF CONTENTS: 
SIGNATURE PAGE/STATEMENT OF COMPLIANCE ...................................................2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................. 8 
CLINICAL PROTOCOL SYNOPSIS ................................................................................ 10 
Primary Endpoint .................................................................................................................19 
Secondary Endpoints ...........................................................................................................19 
1 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE ........................................................................................................................ 22 
1.1 
Background ............................................................................................................22 
1.2 
Norovirus vaccine: General Properties & Pharmacodynamics .............................24 
 
VXA-G1.1-NN Product Description .....................................................................24 
1.3 
Summary of Nonclinical Studies ...........................................................................24 
1.4 
Summary of Clinical Studies with Vaxart Oral Vaccine Platform ........................25 
 
Norovirus Phase 1 Study VXA-G11-101 ..............................................................25 
 
Norovirus Phase 1 Dose Optimization Study VXA-G11-102 ...............................28 
 
Clinical Study VXA-NVV-103 with VXA-G1.1-NN and VXA-G2.4-NS ...........30 
Summary of Safety ............................................................................................................. 31 
Summary of Immunogenicity Analysis .............................................................................. 32 
1.5 
Norovirus Human Challenge Model......................................................................33 
1.6 
NV Challenge Dose Titration Study and Dose Justification .................................36 
1.7 
Summary of Clinical Experience with Vaxart Oral Vaccine Platform .................38 
1.8 
Rationale for GI.1 Human Challenge Study (VXA-NVV-201) ............................39 
1.9 
Potential Risks and Benefits ..................................................................................39 
 
Vaccine Risks ........................................................................................................39 
 
Norovirus Challenge Risks ....................................................................................40 
 
Risk of Blood Draw ...............................................................................................40 
 
Known Potential Benefits ......................................................................................40 
2 
HYPOTHESIS, OBJECTIVES AND PURPOSE ...................................................... 40 
2.1 
Study Hypothesis ...................................................................................................40 
2.2 
Study Objectives ....................................................................................................40 
 
Primary Objective ..................................................................................................40 
 
Secondary Objectives ............................................................................................40 
 
Exploratory Objectives ..........................................................................................41 
3 
STUDY DESIGN AND ENDPOINTS ......................................................................... 41 
3.1 
Description of Study Design..................................................................................41 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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3.2 
Study Endpoints .....................................................................................................42 
 
Primary Endpoint ...................................................................................................42 
 
Secondary Endpoints .............................................................................................42 
 
Safety Endpoints ....................................................................................................42 
 
Immunogenicity Endpoints....................................................................................42 
4 
STUDY ELIGIBILITY, ENROLLMENT AND WITHDRAWAL ......................... 43 
4.1 
Subject Inclusion Criteria ......................................................................................43 
4.2 
Subject Exclusion Criteria .....................................................................................44 
4.3 
Withdrawal from the Study ...................................................................................46 
 
Reasons for Withdrawal or Termination ...............................................................46 
 
Handling of Subject Withdrawals or Termination ................................................47 
5 
STUDY DRUG .............................................................................................................. 48 
5.1 
Study Drug(s) and Control Description .................................................................48 
 
Drug Product Packaging and Labeling ..................................................................48 
 
Drug Product Storage and Stability .......................................................................48 
 
Drug Product Dosage Preparation and Administration .........................................49 
 
Study Drug Accountability ....................................................................................49 
6 
NV CHALLENGE INOCULUM................................................................................. 50 
6.1 
Formulation, Packaging, and Labeling of NV Challenge Virus ............................50 
6.2 
Storage and Stability of NV Challenge Virus .......................................................50 
6.3 
Preparation and Administration of NV Challenge Virus .......................................51 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................. 51 
7.1 
Pre-Screening Period (Day -90 to Screening) .......................................................51 
7.2 
Visit 00: Screening Visit (Study Day -45 to -1) ....................................................52 
7.3 
Visit 01: Study Day 1, Study Drug Administration...............................................52 
7.4 
Visit 02: Study Day 8 ............................................................................................53 
7.5 
Visit 03: Study Day 28, 1 day prior to challenge [+3 days for visit window and 
+30 days window for repeat Visit 03] .................................................................................53 
7.6 
Visit 04: Study Day 29 (Challenge Day) ...............................................................55 
 
Pre-challenge Assessments ....................................................................................55 
 
Viral Challenge Eligibility.....................................................................................55 
 
Viral Challenge Administration .............................................................................56 
 
Visits 04 – 08: Post-Challenge Observation Period  (Day 29 – Day 33 [+ 3 Days])
 
56 
7.7 
Visit 09: Study Day 36 (7 Days post challenge) ...................................................57 
7.8 
Visit 10: Study Day 57 (28 Days post challenge ± 3 days) ...................................58 

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7.9 
Visit 11 (Day 120) – Visit 14 (Day 300) Safety Follow-up Contacts ...................58 
7.10 
Visit 15: Study Day 365 (337 days post challenge + 1 week) End of Study 
Contact 58 
7.11 
Early Termination ..................................................................................................59 
 
Early Termination (Day 1 – Day 28; Vaccine Phase) ...........................................59 
 
Early Termination (–ay 29 - Day 57;  Challenge Phase) .......................................59 
 
Early Termination (Day 58 to Day 365 – Safety Follow-Up Period) ...................59 
7.12 
Unscheduled Visit(s) .............................................................................................60 
7.13 
Immunogenicity Assessments ...............................................................................60 
7.14 
Assessment of Clinical Illness ...............................................................................60 
7.15 
Norwalk Virus Infection ........................................................................................60 
7.16 
Microbiological Assessments ................................................................................61 
8 
MANAGEMENT OF EXPECTED NOROVIRUS ILLNESS .................................. 61 
8.1 
Clinical Evaluation ................................................................................................61 
8.2 
Study Definitions ...................................................................................................61 
8.3 
Measurement of Diarrhea and Vomitus .................................................................61 
8.4 
Management of Fluid Loss ....................................................................................62 
8.5 
Indications for Concomitant Medications .............................................................62 
8.6 
Prohibited and Controlled Medications/Treatments ..............................................63 
9 
ASSESSMENT OF SAFETY ....................................................................................... 63 
9.1 
Definition of Adverse Event ..................................................................................63 
9.1  
Solicited Symptom Reactogenicity Table .............................................................63 
9.1.2      Grading of Severity of an Adverse Event ..............................................................65 
 
Relationship to Challenge Virus ............................................................................65 
 
Relationship to Study Vaccination ........................................................................65 
9.2 
Definition of Serious Adverse Event .....................................................................66 
9.3 
Definition Adverse Events of Special Interest (AESI) ..........................................66 
9.4 
Definition of New Onset of Chronic Illness (NOCI) ............................................66 
9.5 
Study Halting Rules ...............................................................................................67 
9.6 
Safety Oversight ....................................................................................................67 
9.7 
Safety Monitoring Committee (SMC) ...................................................................67 
10 CLINICAL MONITORING ........................................................................................ 68 
11 STATISTICAL CONSIDERATIONS ........................................................................ 68 
11.1 
Study Hypothesis ...................................................................................................68 
11.2 
Sample Size Determination ...................................................................................69 
11.3 
Treatment Assignment Procedures ........................................................................69 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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Randomization Procedures ....................................................................................69 
 
Blinding Procedures ..............................................................................................70 
11.4 
Final Analysis Plan ................................................................................................70 
11.5 
Missing Values and Outliers ..................................................................................70 
11.6 
Interim Analysis ....................................................................................................71 
11.7 
Exploratory Analysis .............................................................................................71 
12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .. 72 
12.1 
Source Documentation ..........................................................................................72 
12.2 
Data Management ..................................................................................................72 
13 QUALITY ASSURANCE AND QUALITY CONTROL .......................................... 72 
14 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) ......................... 73 
14.1 
Ethical Standard .....................................................................................................73 
14.2 
Institutional Review Board ....................................................................................73 
14.3 
Informed Consent Process .....................................................................................73 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ................73 
14.5 
Subject Confidentiality ..........................................................................................74 
15 REFERENCES .............................................................................................................. 74 
APPENDIX A:        SCHEDULE OF EVENTS ................................................................ 77 
APPENDIX B:   CHALLENGE VIRUS PREPARATION ............................................... 78 
APPENDIX C:  GRADING OF SIGNS AND SYMPTOMS OF ACUTE      
GASTROENTERITIS ................................................................................ 82 
APPENDIX D:   MODIFIED VESIKARI SCALE (17 POINTS) ..................................... 83 
APPENDIX E:      LIST OF ADVERSE EVENTS OF SPECIAL INTEREST (AESIs) .. 84 
APPENDIX F: Preparation of NV Challenge Inoculum ..................................................... 87 
APPENDIX G:      SUMMARY OF CHANGES TO PROTOCOL ................................... 91 
 
TABLES AND FIGURES 
 
Table 1:  VXA-G1.1-NN Product Description .................................................................................... 24 
Table 2: Subject Enrollment in Study VXA-G11-101 ....................................................................... 26 
Table 3: Solicited Symptoms (Solicited TEAEs in Study VXA-G1.1-101) ...................................... 26 
Table 4: Geometric Mean Titer (GMT), GM Fold Rise (GMFR) and Statistical Significance 
for Leb and H1 BT50 assay in Study VXA-G11-101 ........................................................... 27 
Table 5: Treatment Groups and Dosing Regimens in Study VXA-G11-102 ..................................... 28 
Table 6: Solicited Adverse Events in Study VXA-G11-102 .............................................................. 29 
Table 7: Comparison of BT50 Antibody Results Among Groups in the 
VXA-G11-101 and VXA-G11-102 Trials ........................................................................... 29 
Table 8:   Design of Study VXA-NVV-103………………………………………………………….30 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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Table 9:   Summary of Solicited Symptoms of Reactogenicity (Study VXA-NVV-103)……………31 
Table 10: Norwalk Virus Infection and Illness Rates after Challenge with NV 8fIIa (Atmar Study) . 33 
Table 11: Dose response for Norwalk strain 8fIIa and 8fIIb (Teunis Study) ....................................... 34 
Table 12: Summary of Norovirus Challenge Studies – C. Moe’s Lab; Emory University .................. 34 
Table 13: Symptoms Reported After Challenge with Norwalk Strain 8fIIb ........................................ 35 
Table 14: Description of illness after challenge with two different doses of Norwalk virus  
(Study VXA-G11-201.1) .................................................................................................... 36 
Table 15: Summary of the correlation between acute gastroenteritis and NV positive by cohort…... 37 
Table 16: Characterization of diarrhea in subjects with acute gastroenteritis and NV positivity by 
cohort (by mean)…………………………………………………………………………...37 
Table 17: Clinical Studies Completed Using Vaxart Oral Ad5 Vaccine Platform, 2011-2017 ........... 38 
Table 18: Study Design and Vaccine Groups (Study VXA-NVV-201) ............................................... 42 
Table 19: Active Product Description (VXA-G1.1-NN) ..................................................................... 48 
Table 20: SOLICITED SYMPTOM REACTOGENICITY TABLE ………………………………   60 
Table 21: Power Calculations ………………………………………………………………..69 
 
Figure 1:  VP1-Specific Antibody Secreting Cells Measured 7 Days After Immunization  
(Study VXA-G1.1-101)........................................................................................................ 27 
Figure 2: Overall IgA ASC Response Rate After Either One or Two Doses  
(Study VXA-G1.1-102)........................................................................................................ 30 
 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
 
Adverse Event 
AESI  
Adverse Events of Special Interest 
ASC 
Antibody secreting cell 
BT50 
blocking titer fifty assay 
BUN 
blood urea nitrogen 
CBC 
Complete blood count 
CFR 
 
Code of Federal Regulations 
cGMP  
Current Good Manufacturing Practice 
CMP 
 
Clinical Monitoring Plan 
CoA 
 
Certificate of Analysis 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CyTOF  
Cytometry by Time of Flight 
DP 
 
Drug Product 
dsRNA  
Double-stranded ribonucleic acid 
ECG 
 
Electrocardiogram 
e-Diary  
Electronic diary 
ELISA  
Enzyme-linked Immunosorbent Assay 
FDA 
 
Food and Drug Administration 
GI 
 
Norovirus Genogroup I 
GII 
 
Norovirus Genogroup II 
GC 
 
Genome copies 
GCP 
 
Good Clinical Practice 
GERD  
Gastroesophageal reflux disease 
GLP 
 
Good Laboratory Practice 
GMFR  
Geometric mean fold rise 
GMP 
 
Good Manufacturing Practice 
GMT  
Geometric mean titer 
GRAS  
Generally recognized as safe 
HBGA 
Histo-blood group antigen 
HbsAg  
Hepatitis B surface antigen 
HCV 
 
Hepatitis C virus 
HDPE  
High-density polyethylene 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent or Institutional Ethics Committee 
IgA 
 
Immunoglobulin A 
IgG 
 
Immunoglobulin G 
IND 
 
Investigational New Drug Application 
IRB 
 
Institutional Review Board 
IU 
 
Infectious unit(s) 
IV 
 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLF 
 
Mucosal lining fluid 
MM 
 
Medical Monitor 
Nab 
 
Neutralizing antibody 
NOCI  
New Onset of Chronic Illness 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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NoV 
 
Norovirus 
NV 
 
Norwalk Virus 
NVG 
 
Norovirus gastroenteritis 
OHRP  
Office for Human Research Protections 
PBMC  
Peripheral Blood Mononuclear Cells 
PI 
 
Principal Investigator 
PF4  
 
Platelet Factor 4 antibody ELISA 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
rAd5 
 
recombinant Ad5 
qRT-PCR 
Quantitative Reverse Transcriptase Polymerase Chain Reaction 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
SAM 
 
Synthetic absorption matrix 
SigA 
 
Secretory IgA 
SMC 
 
Safety Monitoring Committee 
SOP 
 
Standard Operating Procedure 
TTS 
 
Thrombolytic and thrombocytopenic syndrome 
US 
 
United States 
USDA  
United States Department of Agriculture 
US EPA 
United States Environmental Protection Agency 
VLP 
 
Virus-like Particle 
VP1 
 
Viral protein 1, major capsid or surface protein of viruses 
WHO-DD 
World Health Organization Drug Dictionary 
 
 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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CLINICAL PROTOCOL SYNOPSIS 
Study Title 
A Phase 2b Double-Blinded, Randomized, Placebo-Controlled, Human 
Norovirus GI.1 (Norwalk Virus Inoculum) Challenge Study Following 
Administration of an Oral, Single-dose Norovirus Vaccine expressing GI.1 
VP1 and dsRNA adjuvant to Protect Against Norovirus Gastroenteritis 
(NVG) in Healthy Adult Volunteers  
Protocol Number 
VXA-NVV-201 
Sponsor 
Vaxart, Inc. 
IND Number 
16796 
Trial Phase 
Phase 2b 
Study Population 
Approximately  170 healthy male and female adult volunteers age 18 to 49 
years  inclusive with blood type O or A and who are confirmed H type-1 
antigen secretory positive (approximately 170 subjects will be randomized 
and vaccinated to ensure that at least 140 subjects are available to participate 
in the viral challenge 28 days post-vaccination)   
Investigational Site 
1 qualified US site (with isolation unit) 
• 
 
Investigational 
Product 
Active Vaccine: 
• 
Norovirus GI.1 Norwalk VP1 Vaccine (VXA-G1.1-NN), an Oral E1/E3-
Deleted Replication-Defective Recombinant Adenovirus serotype 5 with 
double-stranded ribonucleic acid (dsRNA) Adjuvant. The vaccine vector 
encodes for a full-length VP1 gene from Norwalk virus (NV). The 
adjuvant is a short hairpin RNA, expressed as a 21 nucleotide sequence 
(GAAACGA TATGGGCTGAATAC) as a tandem sequence in forward 
and reverse orientations separated by 6 nucleotides that comprise the 
loop of the RNA. The final drug product (DP) is formulated into enteric-
coated tablet. 
• 
Dose: 1x1011 IU±0.5 log 
 
Placebo Control: 
• 
Oral tablets similar in appearance and number to active vaccine tablets 
Multiple tablets of study drug will be dispensed to allow delivery of the 
intended vaccine dose (1x1011 IU).  A matching number of placebo tablets 
will be dispensed to maintain the study blinding.  
Viral Challenge 
Inoculum 
Norovirus GI.1 (Norwalk Virus Inoculum Lot 001-09NV and Sublot 2, IND 
14697) 
• 
Dose: 1x106 Genomic Copies (GC). A dose which allows 50% - 65% 
infectivity in the healthy adult population (per NV infection rate 
observed in the GI.1 viral titration study (Mateo, et al; 2019) 
Study Hypothesis 
Norovirus vaccine (VXA-G1.1-NN) will protect against Norovirus 
Gastroenteritis (NVG) related to norovirus (NoV) infection in the challenge 
model 
 
 
 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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Study Objectives 
 
 
Primary Objective 
• 
Determine the clinical efficacy of VXA-G1.1-NN compared to placebo, 
to protect against NVG caused by the Norwalk strain challenge 
inoculum. 
  
Secondary Objectives 
• 
Safety and tolerability of VXA-G1.1-NN oral vaccine 
• 
Determine the ability of VXA-G1.1-NN to modify disease severity 
(defined in Appendices C and D) compared to placebo 
• 
Determine the quantity and duration of norovirus shedding by qRT 
PCR 
• 
Evaluate the VP1 specific IgA ASC, HBGA blocking antibody, and 
VP1 specific serum IgG responses to VXA-G1.1-NN 
 
Exploratory Objectives 
• 
Determine correlation of immunogenicity parameters with clinical 
outcome 
• 
Further evaluate immunogenicity of VXA-G1.1-NN 
Study Definitions 
NVG is a composite endpoint defined as meeting one or more of the 
following definitions for both Acute Gastroenteritis and NV Infection. 
 
Acute Gastroenteritis (defined as meeting any one of the three   
 
 
categories listed below): 
 
• 
Diarrhea:  
o ≥ 3 loose or liquid stools produced in any 24-hour period, or  
o > 400g of loose or liquid stools produced in any  
24-hour period 
• 
Vomiting: ≥ 2 vomiting episodes in any 24-hour period, or 
• 
Diarrhea and vomiting:  
o One vomiting episode plus any loose or liquid stool in any 
24-hour period, or 
o One vomiting episode plus ≥ 2 of the following events in 
any 24-hour period:  
▪ 
nausea 
▪ 
fever (oral temperature ≥ 37.6C) 
▪ 
abdominal cramps or pains 
▪ 
abdominal gurgling or bloating  
▪ 
myalgia 
See Appendix C for grading scales for signs and symptoms of acute 
gastroenteritis.    
Norwalk Virus Infection: 
• 
NV infection as detected by qRT-PCR, > 1 positive post-challenge 
stool or emesis sample through day 8 post-challenge 
Study Design 
This is a Phase 2b randomized, double-blind, placebo-controlled vaccination 
and challenge study to assess the protective efficacy of the Norovirus 
vaccine (VXA-G1.1-NN). Approximately 170 healthy adults will be 
randomized in a 1:1 ratio to receive one oral dose of vaccine or placebo.  
• 
Arm 1: VXA-G1.1-NN oral vaccine tablets  
 
[1x1011 IU±0.5 log]; N=85 
• 
Arm 2: Placebo tablets similar in appearance and  
 
number to active vaccine tablets; N=85 

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To accommodate the limited size of the isolation unit that will be utilized for 
the challenge and post-challenge sequestration period, subjects will move 
through the study (enrollment, vaccination and challenge) sequentially in 14 
to 16 cohorts. Subjects will be randomized in cohorts of 10 to 12 each. 
Approximately 28 days post-vaccination, each cohort will be admitted to the 
isolation ward and challenged with the NV GI.1 Norwalk challenge strain.  
After challenge, subjects will be monitored for signs and symptoms of AGE 
at least twice daily from Day 29 to discharge.  Stool and emesis will be 
collected, and illness will be assessed using a modified Vesikari scale. 
Excretion of NV (shedding) will be monitored in stool and emesis. NV 
illness lasts 2-4 days and is self-limited.  
At 4 days post challenge (Day 33) asymptomatic subject will be discharged 
from the isolation ward and will be followed in a series of outpatient visits 
and telephone calls. Symptomatic subjects may be kept in the isolation ward 
for up to an additional 3 days. 
Approximately 170 subjects will be dosed in the vaccination phase to ensure 
at least 140 subjects (approximately 70 VXA-G1.1-NN vaccine and 70 
placebo) are available to participate in the challenge phase. 
Investigational Drug Product 
Approximate No. 
of Subjects 
Vaccination 
170 
VXA-G1.1-NN oral vaccine tablets  
[1x1011 IU±0.5 log] 
85 
Placebo tablets (identical to vaccine) 
85 
Challenge (Norwalk GI.1 Virus 
Inoculum) 
140 
VXA-G1.1-NN oral vaccine tablets  
[1x1011 IU±0.5 log] 
70 
Placebo tablets (identical to vaccine) 
70 
An independent Safety Monitoring Committee (SMC) will convene at pre-
defined intervals during the norovirus challenge period, and also ad hoc as 
needed during the vaccination and challenge periods, to oversee the safety of 
the study.  
Study Visits 
The following study visits and remote contacts will be conducted during the 
study (also see Appendix A: Schedule of Events): 
Vaccination Phase: 
• Pre-Screening Period (Days -90 to Screening) may be utilized for 
purposes of ascertaining subjects’ H type-1 antigen secretory status and 
blood type  
• Screening Period (Days -45 to -1) 
• Day 1 Visit (Baseline assessments; day of randomization and 
vaccination) 
• Day 8 Visit (safety and evaluation of immune response) 
• Day 28 (evaluation of immune response; 1 day prior to challenge, start 
inpatient stay)  
Challenge Phase: 

Norwalk GI.1 Challenge                                                                                               Protocol Number: VXA-NVV-201 
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• Day 29 (viral challenge, sequestration) 
• Days 30 to 33 (sequestration – discharge; +3 days and evaluation of 
immune response and safety assessment) 
• Day 36 Visit (evaluation of immune response and safety assessment) 
• Day 57 Visit (evaluation of immune response and safety assessment and 
end of active period) 
Safety Follow-Up: 
• Day 120, Day 180, Day 240 and Day 300 (follow-up contact) 
• Day 365 (follow-up phone call): Study completion 
Eligibility Criteria 
Inclusion Criteria: 
1. Male or female between the ages of 18 – 49 years, inclusive  
2. Able to give written informed consent 
3. Healthy1, as determined by the principal investigator (PI) or PI in 
consultation with the research monitor and Sponsor 
1No clinically significant health concerns or medical illness), as 
determined by medical history, physical examination, vital signs, 
electrocardiogram (ECG), and clinical laboratories (complete blood 
count [CBC], chemistry and urinalysis)  
4. Comprehension of the study requirements with ability and 
willingness to complete all assessments and comply with 
confinement period post viral challenge, and all scheduled visits and 
contacts 
5. Confirmed blood type (A or O) 
6. Demonstrated to be H type-1 antigen secretor positive (by saliva 
test) 
7. Body mass index between 17 and 35 kg/m2, inclusive, at Screening  
8. Female participants must have a negative pregnancy test at pre-
vaccination and pre-challenge and fulfill one of the following2 
2Criteria: 
a. At least one year post-menopausal; 
b. Surgically sterile; 
c. Use of oral, implantable, transdermal, intravaginal or 
injectable contraceptives for 30 days prior to immunization 
and until 60 days after challenge; 
i. A reliable form of contraception must be approved 
by the Investigator (eg, double barrier method, 
Depo-Provera, intrauterine device, Norplant, oral 
contraceptives, contraceptive patches, vaginal ring 
contraceptive) 
d. Not be sexually active (abstinent) or in a same sex 
relationship (must be discussed with site staff and 
documented) 
9. Male subjects must agree not to father a child or donate sperm, as 
well as to use contraception/barrier (a male condom) or be abstinent 
from heterosexual intercourse, from vaccination through the active 
period (Day 57) 
 

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Exclusion Criteria:  
1. Administration/use of any investigational drug or device 30 days 
prior to vaccination through the active period (Day 57) 
2. Administration of any licensed vaccine within 30 days prior to 
vaccination or planned use of the above stated during the active 
period (through Day 57) 
3. Presence of a significant medical condition3 which in the opinion of 
the investigator precludes participation in the study. 
3For example, psychiatric conditions, or gastrointestinal disease, 
such as peptic ulcer, symptoms or evidence of active gastritis or 
gastroesophageal reflux disease, inflammatory bowel disease, 
alcohol or illicit drug abuse/dependency, or other laboratory 
abnormalities 
4. Laboratory values outside the range of normal for platelet counts 
and the following coagulation tests: PT/INR, aPTT and fibrinogen 
5. 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: 
▪ 
Recent surgery other than removal/biopsy of cutaneous 
lesions  
▪ 
Immobility (confined to bed or wheelchair for 3 or more 
successive days)  
▪ 
Head trauma with loss of consciousness or documented 
brain injury  
▪ 
Receipt of anticoagulants for prophylaxis of thrombosis 
▪ 
Recent clinically significant infection 
6. Any one of the following ECG findings4 within 45 days prior to 
vaccination: 
4Exclusionary ECG findings: 
a. QTc F (interval duration > 450 msec (male) or > 470 msec 
 
(female) 
b. QRS interval greater than 120 msec 
c. PR interval greater than 220 msec 
d. Clinically significant ST-T wave changes or  
 
pathologic Q waves 
7. History of cancer or cancer treatment within past 3 years (excluding 
basal cell or squamous cell carcinomas) 

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8. Presence of immunosuppression or medical condition possibly 
associated with impaired immune responsiveness, including diabetes 
mellitus or angioedema 
9. Donation or use of blood or blood products within 30 days prior to 
vaccination through the active period (Day 57) 
10. Diagnosed bleeding disorder or significant bruising or bleeding 
difficulties that could make blood draws problematic 
11. Any condition that resulted in the absence or removal of the spleen 
12. Evidence of confirmed infection with human immunodeficiency 
virus (HIV), hepatitis B surface antigen (HbsAg) or hepatitis C virus 
(HCV) with confirmatory assays 
13. Abnormal stool pattern (fewer than 3 bowel movements per week or 
more than 3 per day) 
14. History of irritable bowel disease or inflammatory digestive or 
gastrointestinal condition5 that could affect the distribution / safety 
evaluation of an orally administered vaccine6 
5Such conditions may include but are not limited to: 
a. Esophageal Motility Disorder 
b. Malignancy 
c. Malabsorption (e.g. Celiac disease, gluten intolerance) 
d. Pancreaticobiliary disorders 
e. Irritable bowel syndrome 
f. 
Inflammatory Bowel Disease 
g. Surgical Resection with the exception of appendectomy or a 
minor resection that is deemed acceptable by investigator 
and sponsor 
h. Gastroesophageal reflux disease (GERD) 
i. 
Hiatal Hernia 
j. 
Peptic Ulcer  
(History of cholecystectomy is not exclusionary) 
6 targeting the mucosa of the small intestine 
 
15. Use of proton pump inhibitors, H2 blockers or antacids within 
7 days prior to vaccination through the active period (Day 57) 
16. Use of antibiotics within 30 days prior to vaccination through the 
active period (Day 57)7  
7Note: use of a brief (≤ 10 days) course of oral or topical antibiotic 
for minor URI, UTI, dental work, or skin infection allowed within 
the screening period, but must be completed 7 days prior to first 
vaccination 
17. Use of medication known to affect the immune function (e.g. 
systemic corticosteroids and others) within 14 days prior to 
vaccination through the active period (Day 57) 
18. Regular use of nonsteroidal anti-inflammatory drugs within 7 days 
prior to vaccination through the active period (Day 57) 

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19. Use of over-the-counter probiotics or antidiarrheals within 7 days 
prior to vaccination through the active period (Day 57) 
20. Evidence of recent (within 2 months of vaccination) or of current 
nonbacterial gastroenteritis suggestive of NV infection [vomiting or 
unformed or watery stools (> 2 during a 24-hour period)] 
21. Any gastroenteritis within the past 2 weeks prior to vaccination 
22. Acute disease within 72 hours prior to vaccination8 
8Defined as the presence of a moderate or severe illness with or 
without fever (as determined by the Investigator through medical 
history and physical examination). (Assessment may be repeated 
during screening period) 
23. Presence of a fever ≥ 38ºC measured orally at baseline 
24. History if hematochezia (blood in stool) or melena (black stool) 
25. Any significant hospitalization within the last year which in the 
opinion of the investigator or sponsor could interfere with study 
participation 
26. History of serious reactions to any vaccination such as anaphylaxis, 
respiratory problems, Guillain-Barre syndrome, hives or abdominal 
pain 
27. History of a hypersensitivity or allergic reaction to any component 
of the investigational vaccine or placebo9. Subjects with known fish 
allergies should be excluded 
9 including but not limited to fish gelatin 
28. History of drug, alcohol or chemical abuse within 1 year prior to 
vaccination 
29. Positive test for drugs of abuse or alcohol at screening, vaccination 
baseline and pre-challenge.10  
10except for previous marijuana use; concurrent or ongoing use of 
marijuana during the active study period  
30. Consistent/habitual smoking within 2 months prior to vaccination 
(defined as smoking ≥ 1 pack of cigarettes a day). Smoking is not 
permitted during the inpatient stay 
31. Other conditions11 that would jeopardize the safety or rights of a 
subject or interfere with the evaluation of the study 
11 in the clinical judgment of the investigator 
Social/Occupational: 
32. Living with or having daily contact with children < 5 years old or 
women known to be pregnant or nursing12  
12This includes significant contact at home, school, day-care, or 
equivalent facilities 
33. Living with or having daily contact with elderly persons  
> 70 years of age or infirmed, diapered individuals, persons with 
disabilities or incontinence13  
13This includes at work or visits to nursing homes and day-care or 
equivalent facilities 

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34. Employment in the food service industry such as restaurant or 
cafeteria facilities14  
14Specifically, this includes persons whose employment requires food 
handling and processing in the 4 weeks following viral challenge 
35. Health-care workers with patient contact expected in the 4 weeks 
following viral challenge 
36. Expected contact15 with immunocompromised persons16 in the 4 
weeks following viral challenge 
15 via employment or at home 
16 HIV-positive, receiving immunosuppressive medications such as 
oral steroids, anti-neoplastic agents 
37. Presence of household members who have received the Ad4 or Ad7 
vaccines within 2 months prior to vaccination 
38. Employment as an airline flight attendant or cruise ship crew, 
scheduled to work in the 4 weeks following challenge 
39. Persons planning to live in a confined environment (eg, a cruise, 
camp, etc.) in the 4 weeks following viral challenge 
Study Duration 
Each subject’s participation will last approximately 1 year post successful 
screening and enrollment 
• 
90 days study pre-screening 
• 
45 days study screening 
• 
28 days vaccination phase 
• 
28 days viral challenge and follow-up  
• 
365 days total safety follow-up post vaccination 
Randomization 
Subjects will be randomized in a 1:1 ratio to receive either oral VXA-G1.1-
NN vaccine or placebo. A randomization list will be prepared allocating 
subject identification numbers to the study treatment group. The 
randomization scheme will be provided to the unblinded research pharmacist 
at the clinical site. 
Blinding 
Investigators, clinical staff and study subjects will remain blinded until 
completion of the challenge phase (through Day 57) and validation of the 
clinical data. The Sponsor’s clinical team and laboratory personnel will also 
be blinded to subject treatment through Day 57 analyses.  
Each bottle of multi-dose DP/placebo tablets will be labeled with an open 
label. The unblinded research pharmacist will use the randomization list to 
prepare the dose of DP/placebo tablets. All DP/placebo preparation and 
administration will be performed per study specific procedures detailed in 
the Study Pharmacy Manual. 
Safety, 
Immunogenicity and 
Microbiological 
Assessments 
Safety Assessments:  
General: 
• 
SAEs, AESIs & NOCIs will be recorded from Baseline (Day 1) through 
Day 365 
 
Vaccination Period (Day 1 to Day 28): 
• 
Solicited symptoms of reactogenicity will be recorded daily from Day 1 
post vaccination through Day 8: 

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o Gastrointestinal reactions: nausea, vomiting, diarrhea and 
abdominal pain 
o Systemic reactogenicity: malaise/fatigue, anorexia, fever, headache 
and myalgia (muscle pain) 
• 
Unsolicited Aes will be recorded from Day 1 (post-vaccination) through  
Day 28 
• 
12-lead ECGs at Screening and pre-challenge (Day 28) 
• 
Vital signs and physical exams will be collected at Screening, Day 1  
(pre-dose), Day 8, and Day 28 (pre-challenge) 
• 
Safety laboratory will be performed at Screening, Day 1, Day 8 and Day 
28 (pre-challenge) as listed below: 
o CBC: Hemoglobin, Hematocrit, Platelet Count and Complete 
White Blood Cell Count 
o Serum chemistries: ALT, AST, Total Bilirubin, BUN, 
Creatinine, Random Glucose, Potassium and Sodium 
o Urinalysis: Glucose, Protein and Hemoglobin  
• 
Female participants will have serum/urine pregnancy tests at Screening, 
Day 1 (pre-dose, if more than 30 days from last test) and Day 28 pre-
challenge 
 
Challenge Period (Day 29 to Day 57):  
• 
Unsolicited Aes will continue to be recorded from challenge (Day 29) 
through end of active phase (Day 57) 
• 
Vital signs will be collected twice a day (am and pm) from challenge 
(Day 29) through discharge (Day 33 + 3 days) 
• 
Physical exams will be performed daily on Days 29 through discharge 
(Day 33 + 3 days) 
• 
Safety laboratory tests will be performed on Day 33. Additional time 
points may be collected if clinically indicated per the discretion of the 
Investigator 
 
Immunogenicity Assessments: 
Primary Immunoassays 
• VP1 specific IgA ASC (by ELISpot) 
• HBGA blocking antibodies (BT50) 
• VP1 specific serum IgG (by MSD) 
• VP1 specific serum IgA (by MSD) 
Exploratory Immunoassays 
• VP1 specific IgG ASC (by ELISpot) 
• VP1 specific IgG and IgA memory B cells (by ELISpot) 
• VP1 specific IgG and IgA from plasmablast cultures (by ELISA) 
• B cell immunophenotyping (by flow cytometry, CyTOF and/or single 
cell sequencing) 
• mucosal VP1 specific IgA (by ELISA or MDS), (fecal, saliva and nasal) 
 

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Blood Typing 
 Blood typing will be measured via blood group antigens (ABO) test    
 
Assessment of Clinical NV Illness (Acute Gastroenteritis): 
Following challenge (Day 29) subjects will be monitored for the following 
signs and symptoms of acute gastroenteritis twice a day unless greater 
frequency is clinically indicated: 
 
o diarrhea, vomiting, nausea, fever, myalgia 
o abdominal cramps or pain and abdominal gurgling or bloating 
 
Norwalk Virus Infection: 
• NV infection as detected by qRT-PCR, > 1 positive post-challenge stool 
or emesis sample through day 8 post-challenge. 
 
Microbiological Assessments:  
During the post-challenge phase (Day 29 – discharge [Day 33 + 3 days]) all 
stool and emesis specimens will be collected, weighed/measured for volume 
and tested for NV shedding through discharge. Stool samples will also be 
graded. A stool sample will also be collected at the Day 36 and Day 57 site 
visits. 
Study Endpoints 
Primary Endpoint 
• 
Occurrence of NVG caused by the challenge norovirus during 
inpatient challenge period. 
o NVG is a composite endpoint and is defined as meeting one or 
more of the definitions for both acute gastroenteritis and NV 
infection. 
Secondary Endpoints 
• 
Number of subjects with acute gastroenteritis during the inpatient 
challenge period. 
• 
Mean score using the Modified Vesikari Scale as a measure of 
severity of acute gastroenteritis post-challenge at discharge (up to 
Day 36)  
• 
Number of subjects with moderate or severe gastroenteritis 
(cumulative loose stools ≥ 1000 gms during the inpatient period) 
• 
Median duration (number of hours) of acute gastroenteritis among 
challenged subjects 
• 
Number of subjects with norovirus infection up to Day 36 post-
challenge (quantitative reverse transcriptase polymerase chain 
reaction [qRT-PCR] positive in stool, Norwalk virus antigen in stool 
• 
Geometric mean genome copies of norovirus shedding by qRT-PCR 
• 
Median duration (number of hours) of norovirus infection among 
challenge subjects 
• 
Number of incidences of diarrhea or emesis among challenge 
subjects 
 

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SAFETY 
• 
Vaccine (VXA-G11-N.N) 
o Solicited symptoms of reactogenicity x 7 days post-vaccination 
o Unsolicited Aes x 28 days post vaccination 
o SAEs, AESIs and NOCIs x 12 months post vaccination 
• 
Challenge Virus (Norwalk GI.1) 
o Unsolicited Aes x 28 days post challenge 
 
IMMUNOGENICITY 
Primary 
• 
VP1 specific IgA ASC response against Norwalk at Day 8 compared 
to placebo 
• 
GMT of HBGA blocking antibodies (by BT50) against Norwalk 
virus at Day 28 compared to placebo 
• 
VP1 specific serum IgG response at Day 28 compared to placebo  
• 
VP1 specific serum IgA at Day 28 compared to placebo 
Exploratory 
• 
Correlations between individual immunogenicity parameters and 
clinical efficacy 
• 
VP1 specific IgG ASC response against Norwalk at Day 8 compared 
to placebo 
• 
VP1 specific fecal IgA at Day 28 compared to placebo 
• 
VP1 specific saliva IgA at Day 8 and Day 28 compared to placebo 
• 
VP1 specific nasal IgA at Day 8 and Day 28 compared to placebo 
• 
Vaccine specific responses for memory IgA and/or IgG in B cells, 
IgA and IgG in plasmablasts, antibody repertoire sequencing 
analysis, flow cytometry (including homing and/or 
immunophenotyping analyses), cytof and/or other assays designed to 
evaluate cell mediated immunity 
Additional assessment of serum, fecal, saliva, and mucosal immunity at 
other time points (including post-challenge) may be performed 
Halting Rules 
The study will be halted (no new enrollment, vaccination or challenge will 
be allowed pending a SMC safety review) if any of the events described 
below are met during the conduct of the study.  
• 
Two or more subjects experience a treatment related serious adverse event 
(SAE) of any grade, or a treatment related grade 3 or 4 AE between study 
Day 1 and Day 28 (vaccination phase).  
• 
Two or more subjects experience a treatment related serious adverse event 
(SAE) of any grade, or a treatment related grade 3 or 4 unsolicited adverse 
event within 28 days after challenge. 
The SMC will provide study oversight throughout the duration of the trial 
interventional and safety follow-up period (Day 1 through Day 365 post-
vaccination). The IRB and CBER (Center for Biologics Evaluation and 
Research at the US FDA) will be notified if the study is halted for safety 
concerns. 
 
Statistical 
Considerations 
The study hypothesis is that norovirus vaccine, VXA-G1.1-NN, will protect 
against norovirus gastroenteritis related to norovirus infection in the challenge 
model. Protective efficacy (PE) will be estimated by the prevention of 

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norovirus gastroenteritis among vaccine recipients compared to placebo 
recipients in those who were challenged.  
 
The primary endpoint of this study is a composite of occurrence of NVG 
caused by the challenge norovirus during inpatient challenge period and is 
defined as meeting one or more of the definitions for both acute gastroenteritis 
and NV infection.  
 
An Interim analysis (IA) will take place after approximately 50% of the 
planned randomized subjects have completed challenge and been discharged 
from the research unit.  This IA will reassess the appropriateness of 
assumptions used for the primary efficacy endpoint when the trial was 
designed in a blinded manner to the study team.  The IA data will be 
analyzed in an unblinded manner for the SMC.  
 
An exploratory analyses will be performed after approximately 50  subjects 
of the planned randomized subjects have been vaccinated with the same IP 
lot and completed the challenge period. The results of 
the exploratory analyses will not impact the continuation of this study as 
planned, but rather, inform program development for other trials.  
 
Additionally, a blinded interim immunogenicity analysis will be performed 
on Cohorts 1-9 and shared with the sponsor. The results of the analyses will 
not impact the continuation of this study as planned, but rather, inform 
program development for other trials. 
 
Please refer to Section 11 for complete statistical considerations details in 
the protocol.  
 

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1 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
1.1 
Background 
Human noroviruses (NoV) are the leading cause of foodborne gastroenteritis and endemic diarrheal 
disease in the United States (US) and worldwide (1, 2).  Norovirus is highly infectious and is transmitted 
very efficiently from person to person in semi-enclosed environments, such as nursing homes, cruise 
ships, hospitals, military, schools and childcare centers (3). The major mode of transmission is by fecal-
oral spread, usually via contaminated food or water. Airborne transmission via aerosolization of the 
virus with vomiting has also been reported (4). The incubation period of norovirus is 10-51 hours. The 
clinical symptoms of norovirus include a sudden onset of nausea, vomiting, non-bloody diarrhea and 
abdominal cramps. Fever, headache and body aches have been reported as well. These symptoms 
usually last 2-4 days. Additionally, asymptomatic infections are estimated to occur in approximately 
one third of infected people (5). Infections occur year-round but peak in the colder months (November 
to April in the Northern Hemisphere). All ages are susceptible to infection; however, the elderly seem 
to be more susceptible. Viral shedding can last several weeks (6-55 days) with a peak of 1 -3 days after 
onset of illness (6, 7). Viral shedding precedes the onset of illness in up to 30% of infected people (5). 
Currently no specific therapy exists for norovirus gastroenteritis (NVG). The standard treatment is oral 
rehydration with fluids and electrolytes (8). 
 
Noroviruses (NoVs) belong to the family Caliciviridae.  Caliciviruses are divided into 4 genera: 
Norovirus, Sapovirus, Vesivirus and Lagovirus.  NoVs are genetically diverse viruses. The genus is 
divided into 6 genogroups. NoV Genogroups I, II and IV are human-transmitted. Genogroup I and II 
account for the majority of norovirus outbreaks (9). Each genogroup is further divided into genotypes 
based on the similarity of the amino acid sequence of the major viral capsid protein, VP1. Genogroup 
I contains 9 different genotypes and Genogroup II contains 22 different genotypes. Norwalk virus, the 
prototype human norovirus, is classified as a Genogroup I and Genotype 1 (GI.1) virus (2). Since the 
1990’s, GII.4 viruses have been responsible for more than 80% of all human norovirus infections, but 
non-GII.4 (Genogroup I and other Genogroup II genotypes) are also circulating in the population. Every 
2-4 years, a new GII.4 variant emerges and replaces the previously predominant variant (10, 11). In 
2012, a new GII.4 variant was identified in Australia.  This GII.4 variant, the Sydney strain is currently 
the most prevalent norovirus globally. It may have emerged by escape from herd immunity acquired 
against the previously predominant circulating strain (12, 13). In contrast, GII.17 norovirus has rarely 
been reported as a major genotype. However, in winter 2014-2015, a new GII.17 variant emerged and 
caused most of the outbreaks in China and Japan (14). Noroviruses are positive-sense, non-enveloped, 
single-stranded RNA viruses. The viral genome is 7.4-7.7 kb in length and comprises 3 open reading 
frames (ORFs) that encode both the structural and non-structural proteins. The ORF1 (~5kb) is in the 
first two-thirds of the genome and encodes ~200 kD large poly-protein that is cleaved into 6 different 
non-structural proteins essential for viral replication such as RNA dependent RNA polymerase. ORF2 
(~1.6kb) encodes a 57kDa single major capsid protein (VP1). VP1 is comprised of a conserved internal 
shell domain (S) and protruding domain (P). The P domain is further divided into a P1 stalk sub-domain 
and a surface-exposed highly variable P2 sub-domain. P2 sub-domain is the major immunogenic and 
antigenic determinant of the NoV.  VP1 forms a dimer and 90 dimers form a T=3, icosahedral viral 
particle. ORF3 (~0.6kb) encodes a 22kDa minor structural protein (VP2), whose function might 
package the viral genome into virions and assist capsid assembly. VP1 associates with VP2 at the 
interior surface (S domain) of the capsid (15, 16). 
 
The expression of VP1 results in spontaneous self-assembly of virus-like particles (VLP) without 
packaging the viral nucleic acid or proteins. VLP is a non-infectious particle and is morphologically 
and antigenically identical to the native NoV (17). 

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Histo-blood group antigens (HBGAs) are putative norovirus binding receptors or attachment factors. 
HBGAs are complex glycans that are expressed on the surfaces of red blood cells, gut, and respiratory 
epithelia. Different norovirus species display different HBGA binding profiles. The P2 sub-domain in 
VP1 appears to be the HBGA interaction site (18). 
 
Because norovirus cannot easily be cultured in tissue culture, classical virus neutralization cannot be 
directly measured. Instead, the VLP-HBGA blocking assay has been used as a surrogate to measure the 
ability of antibodies from antisera from infected people to block VLP binding to HBGA (19).  The 
duration of protective immunity upon natural infection is complex. Human challenge studies using 
Norwalk virus as the challenge virus suggested that short-term immunity to homologous virus develops 
and persists for up to 6 months. However, a subsequent study showed that longer-term immunity (27-
42 months) was not generated after homologous challenge (20, 21).  It is not completely clear what 
immune parameters are critical for protection from challenge, but one possibility is that mucosal 
Immunoglobulin A (IgA) may be able to hinder virus infection of epithelial cells.  Consistent with this, 
published challenge studies showed that an early induction of mucosal IgA or preexisting mucosal IgA 
response correlated with protection to Norwalk virus (7, 22).  In contrast to the results derived from the 
challenge studies that long-term immunity can be difficult to generate, the epochal pattern of evolution 
of pandemic GII.4 strongly suggests the development of herd immunity in the population (12). Some 
recent mathematical models based on modeling of epidemiological data estimated that protective 
immunity after natural infection may last 4 to 8 years (23).  In summary, these results suggest that 
natural immunity can develop, with some caveats as to whether long-term sterilizing immunity is 
possible. Several animal species including humanized mice, gnotobiotic pigs, gnotobiotic calves, and 
chimpanzees have been challenged with human NoV.  However, NoV infection of non-natural hosts 
generated variable clinical outcomes from asymptomatic to mild diarrhea, and limited success has been 
achieved to reveal all aspects of human infection (24). 
 
There are currently no licensed vaccines for norovirus. Experimental norovirus vaccines composed of 
VLPs expressing VP1 have been tested in mice and humans delivered orally and intranasally (25-29). 
Takeda Pharmaceutical Company (previously Ligocyte) conducted two short-term efficacy studies.  
Intranasal administration of Norwalk VLP vaccine was shown to reduce Norwalk virus-associated acute 
gastroenteritis (69% vs 37%) and Norwalk virus infection (82% vs 61%) following challenge with 
homologous Norwalk virus (30).  A subsequent study was conducted with intramuscular bivalent 
vaccine (Norwalk virus VLP and a consensus VLP derived from three GII.4 NoV strains). Healthy 
participants were challenged by GII.4 NoV (Cin strain 2003, Farmington Hill Strain variant). The 
vaccines were well tolerated and immunogenic. However, the incidence of GII.4 NoV-associated acute 
gastroenteritis (33% vs 26%) and GII.4 NoV infection (62.5% vs 54%) were not significantly reduced 
although severity of illness was reduced (31).  These GII.4 results seem rather unexpected since the 
intramuscular bivalent vaccine generated much higher total serum Immunoglobulin G (IgG) titers and 
blocking titers than the intranasal mucosal vaccine. One possible explanation is that the mucosal 
vaccine might provide better mucosal antibody responses, and thereby better local protection against 
norovirus infection (27). 
 
Norovirus is an enteric pathogen that infects the epithelial cells of the small intestine. Importantly, 
Vaxart’s platform is based on oral delivery to the intestinal mucosa, which is analogous to the natural 
route of norovirus infection and entry. In theory, mucosal immune responses local to the site of delivery 
should be more robust than mucosal responses generated by a more distally administered vaccine. 
Human and animal experience with Vaxart’s orally administered platform has demonstrated that 
substantial transgene specific intestinal IgA responses can be generated in addition to systemic IgG 
responses to the expressed antigen (influenza HA and norovirus VP1). These platform attributes may 
allow for better protection against norovirus infection than an injected protein-based vaccine. 
 

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1.2 
Norovirus vaccine: General Properties & Pharmacodynamics 
 
 
VXA-G1.1-NN Product Description 
VXA-G1.1-NN product description is summarized in Table 1. 
 
Table 1:  
VXA-G1.1-NN Product Description 
Generic name 
VXA-G1.1-NN 
Chemical name  
Ad-CMV-VP1(Norwalk virus)-BGH-CMV-luc dsRNA-SPA 
Genome size 
33,949 bp dsRNA genome  
Viral particle size 
80-100 nm 
 
VXA-G1.1-NN is E1/E3-deleted, replication-incompetent, adenovirus 5 vaccine vectors designed for 
use as a vaccine for prevention of NoV infection.  The vaccine vector encodes for a full-length VP1 
gene of Norwalk virus (VXA-G1.1-NN 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. 
 
1.3 
Summary of Nonclinical Studies 
Vaxart has conducted preclinical studies to determine the immunogenic potential of two NoV vaccine 
candidates, VXA-G1.1-NN (VP1 gene of Norwalk virus) in mice and VXA-G2.4-NS (VP1 gene of 
Sydney virus) in mice, ferrets and NHPs (Cynomolgus monkeys).  These studies showed that 
vaccination with VXA-G1.1-NN and VXA-G2.4-NS reliably elicited substantial and durable systemic 
serum IgG and intestinal (fecal) IgA responses in test animals and elicited serum-blocking antibody 
titers (blocking titer fifty assay [BT50]). A unique immune response elicited by oral vaccination is the 
induction of antibodies derived from intestinal B cells. After oral vaccination or enteric infection, B 
cells residing in the lamina propria (underneath the gut epithelial cells) predominantly produce 
dimeric/polymeric antibodies of the IgA isotype.  After binding to polymeric immunoglobulin receptor 
(also known as secretory component), the dimeric form of IgA antibodies travels across the gut 
epithelial cells into the lumen through facilitated transport (transcytosis), leaving a secretory component 
attached to dimeric IgA.  The resulting molecule is known as secretory IgA (SigA).  SigA serves as an 
additional external barrier to block enteric infection.  SigAs are eventually flushed out of the system 
and can be detected in fecal samples.  Given that the route of immunization is the same as the route of 
norovirus infection, it is reasonable to postulate that Vaxart’s VXA-G1.1-NN and VXA-G2.4-NS 
vaccines may enable higher degrees of localized protection against infection when compared to a 
parenteral immunization method.  This is supported by data on the immune responses generated in mice 
orally immunized with VXA-G1.1-NN when compared to mice intramuscularly injected with GI.1 
VLPs. Vaxart’s oral vaccine generated significantly higher fecal IgA when compared to the injectable 
formulation. 
 
As described above, Vaxart’s norovirus VP1 vaccines (VXA-G1.1-NN and VXA-G2.4-NS) use the 
same replication-defective viral vector backbone and adjuvant RNA sequence as the company’s early 
oral vaccine candidates for pandemic influenza (the A/Indonesia/05/2005 (H5N1) vaccine referred to 
as ND1.1 and for seasonal influenza (the A/California/ 04/2009 (H1N1) vaccine referred to as VXA-
A1.1.  Because the only difference between the vaccines is the antigen gene [NoV VP1 in VXA-G1.1-
NN and VXA-G2.4-NS versus A/California/04/2009 (H1N1) in VXA-A1.1 and A/Indonesia/05/2005 
(H5N1) in ND1.1], the preclinical studies from ND1.1 and VXA-A1.1 are relevant to and support the 

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clinical development of Vaxart’s NoV vaccines (VXA-G1.1-NN and VXA-G2.4-NS) for prevention of 
norovirus disease. 
 
Preclinical studies with ND1.1 showed that no vector distributed beyond the target tissues in the gut 
and that multiple oral immunizations over a 3-month period were well tolerated.  The ND1.1 test 
material used in the toxicology studies and for most of the other preclinical and clinical studies, was 
manufactured using the same process that is used to produce the Good Manufacturing Practice (GMP) 
material for the proposed clinical trial.  VXA-G1.1-NN and VXA-G2.4-NS vaccines is formulated as 
enteric-coated tablets for oral administration in clinical studies, similar to VXA-A1.1 clinical drug 
product (DP) lots.  It is important to note that in several nonclinical studies reported within this section 
a liquid formulation of the ND1.1 vaccine was delivered orally by gavage or via endoscopic instillation 
into the lumen of the duodenum because of technical limitations that prevented the use of enteric-coated 
tablets in the test animal species. 
 
The role of the adjuvant in the oral vaccine platform construct was studied with the seasonal vaccine 
candidate VXA-A1.1. The primary objective of the H1N1 immunogenicity study was to determine if a 
double-stranded ribonucleic acid (dsRNA) adjuvant could augment immune responses to the transgene 
expressed after transduction with the recombinant Ad5-based (rAd5) vector. Study results 
demonstrated that a co-expressed dsRNA adjuvant improved the immune responses to an orally 
administered antigen and that the immune responses generated could elicit protective immunity to H1 
influenza. 
 
In another immunogenicity study (Study No. WCB045), mice were immunized by oral gavage with 
varying doses of recombinant adenoviral vector expressing HA and dsRNA (VXA-A1.1) or one 
expressing HA but not the dsRNA adjuvant (rAd-HA). Three weeks post immunization the group 
treated with the adjuvanted vector demonstrated a significant anti-HA titer (1.0 x 104 geometric mean 
titers [GMT]) with all animals having a detectable titer, whereas the unadjuvanted group failed to 
generate a detectable response in any animals. The immune responses were significantly higher for the 
adjuvant compared to the non-adjuvant groups. These data indicate that the adjuvant enhances both the 
time of onset and the magnitude of the immune response. 
 
1.4 
Summary of Clinical Studies with Vaxart Oral Vaccine Platform 
Summary information on trials completed with Vaxart’s norovirus vaccine candidates is presented 
below.  For additional information refer to the Investigator’s Brochure. 
 
 
Norovirus Phase 1 Study VXA-G11-101 
This was a single-site, randomized, double-blind, placebo-controlled clinical trial of VXA-G11-NN 
oral norovirus vaccine to determine safety and immunogenicity. The tablet vaccine is comprised of a 
non-replicating adenovirus-based vector expressing the VP1 gene from the GI.1 norovirus strain and a 
dsRNA adjuvant.  
 
Between July and September of 2016, 152 subjects were screened, and 66 subjects were enrolled and 
dosed. Sixty five of 66 subjects completed safety and immunogenicity assessments through the active 
phase (Day 29); one subject in the placebo group withdrew before Day 7. The dose groups are described 
in Table 2. 
 
 
 
 

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Table 2: 
 Subject Enrollment in Study VXA-G11-101 
Vaccine group 
Dose 
Number of oral 
doses 
Number of 
subjects 
VXA-G1.1-NN 
low dose – 1x1010 IU 
1 
23 
VXA-G1.1-NN 
high dose – 1x1011 IU 
1 
23 
Placebo 
 
1 
20 
 
Safety Results 
The vaccine was well-tolerated, with no dose-limiting toxicities. Adverse events (AEs) were mild or 
moderate. All solicited AEs reported in this trial (n=46) were grade 1 or 2 in severity with the majority 
being mild events (44 grade 1, and 2 grades 2 events). The percentage of subjects with any solicited 
symptoms was similar between test and placebo treatments (Table 3). In the first 7 days following 
study drug administration, 35 study subjects had at least one solicited AEs reported with 25/46 (54%) 
subjects in the VXA-G1.1-NN vaccine groups and 10/20 (50%) subjects in the placebo groups. Diarrhea 
and headache were the most common solicited symptoms following VXA-G1.1-NN administration, 
both reported by 15 (33%) subjects in the treated groups. Headache and nausea were reported evenly 
across treatments, including placebo. The only solicited symptom demonstrating a statistically 
significant difference from placebo was diarrhea (P=0.0275), reported by 11 subjects in the high dose 
group. Nine of the 11 subjects reported mild severity diarrhea, while 2 subjects reported moderate 
severity episodes following the high dose vaccine. Onset of diarrhea (verbatim term “loose stools”) 
ranged from Day 1 to Day 6 following vaccine administration, and most episodes resolved within 1 
day. At no point did any of the loose stool symptoms impact normal activity such as work or school, 
and none required treatment with anti-diarrheal medications or rehydration therapy. There were no 
SAEs, AESIs or NOCIs reported in this study through Day 365. 
 
Table 3: 
 Solicited Symptoms (Solicited TEAEs in Study VXA-G11-101) 
Adverse Events 
Placebo 
Low dose 
High dose 
  
(n=20) 
(n=23) 
(n=23) 
Number of Subjects with Solicited Symptom 
TEAEs 
10 (50%) 
11 (48%) 
14 (61%) 
       Diarrhea 
3 (15%) 
4 (17%) 
11 (48%) 
       Abdominal Pain 
2 (10%) 
5 (22%) 
0 
       Nausea 
4 (20%) 
4 (17%) 
3 (13%) 
       Malaise 
2 (10%) 
1 (4%) 
3 (13%) 
       Headache 
8 (40%) 
8 (35%) 
7 (30%) 
 
Immunogenicity Results 
Antibody responses to Norovirus VP1 were assessed primarily by BT50 assay. Titers were measured by 
using either Leb or H1 synthetic glycan as the coating antigen. Using the Leb assay, 14/23 (61%) 
subjects had a 2-fold rise in the low dose group, and 18/23 (78%) had a 2-fold rise or greater in the high 
dose group. One subject in the placebo group had a greater than 2-fold rise. On day 28, the GMT by 
the Leb assay for low dose vaccine group was 59.0 (95% CI 33.0-105.4), a 2.3-fold geometric mean 
fold rise (GMFR) over the initial GMT of 26.2 (95% CI 16.6-41.2) at baseline. The GMT for the high 
dose vaccine group was 98.5 (95% CI 64.4-150.7), a 3.8-fold GMFR over the initial GMT of 25.8 (95% 
CI 18.3-36.2) at baseline (32). Similar observations were made for titers measured with H1. The high 
dose group had significantly increased titers compared to placebo on Day 28 by either Leb (P=0.0003) 
or H1 (P=0.001) BT50 assay Table 4. 

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peripheral blood post immunization.   In terms of fecal IgA, in the high dose group 9/19 (47%) subjects 
had a 4-fold or greater IgA responses at Day 28, and 9/21 (43%) subjects had 4-fold or greater response 
at Day 180; the average fold increases in the specific IgA/total IgA ratio were 17.2 and 9.7, respectively. 
Fecal IgA responses in the low dose group were similar to those of the high dose group, with 7/20 
(35%) and 5/16 (31%) showing 4-fold increases on Days 28, and 180, respectively. The average fold 
increase in specific IgA for the low dose group was 36.2 on Day 28 and 5.6 on Day 180.   
 
Flow cytometry was used to assess the intestinal cell homing potential post immunization. Substantial 
47hi (the intestinal mucosal) expression was observed on the activated B cells 7 days post 
immunization with up to 25% of all B cells having upregulated the intestinal homing receptor.  In terms 
of increases in memory IgA, the GMFR for IgA was 15.3 for the high dose group suggesting substantial 
expansion of the antigen specific memory cell pool.  Similarly, in the low dose group, a GMFR of 7.4 
for IgA was observed at Day 7. 
 
Summary 
The vaccine was well-tolerated, with no dose-limiting toxicities. AEs were mild or moderate. The 
primary immunological endpoint (increase in BT50 titers) was met in the high dose group (P=0.0003) 
with 78% showing ≥ 2-fold rise after a single immunization. Vaccine recipients also developed 
mucosally-primed VP1-specific circulating ASC, IgA+ memory B cells expressing gut homing receptor 
47) and fecal IgA, indicating robust and local responses clinically relevant to prevent norovirus 
infection. 
 
 
Norovirus Phase 1 Dose Optimization Study VXA-G11-102 
 
This was an open-label dose optimization trial of VXA-G1.1-NN oral norovirus vaccine to further 
determine safety and immunogenicity with differing dosing regimens. Fifteen subjects were enrolled 
in 1 of 4 cohorts for a total enrollment of 60 subjects.  The dose and dose regimen are described in 
Table 5. 
 
Table 5: 
 Treatment Groups and Dosing Regimens in Study VXA-G11-102 
Group 
Vaccine group 
Dose 
Number of 
oral doses 
Dosing 
days 
Number of 
subjects 
1 
VXA-G1.1-NN 
low dose – 1x1010 IU 
2 
0, 7 
15 
2 
VXA-G1.1-NN 
low dose – 1x1010 IU 
3 
0, 2, 4 
15 
3 
VXA-G1.1-NN 
low dose – 1x1010 IU 
2 
0, 28 
15 
4 
VXA-G1.1-NN 
high dose – 1x1011 IU 
2 
0, 28 
15 
 
 
Safety 
The oral vaccine was well tolerated. There were no SAEs, AESIs or NOCIs reported in this study 
through Day 365.  The most frequently reported symptoms are showed in Table 6. Diarrhea, which 
was a frequently reported symptom in the high dose group in the initial norovirus vaccine study (VXA-
G11-101), was not commonly reported in this study. 
 
 

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Table 6: 
 Solicited Adverse Events in Study VXA-G11-102 
 Solicited Treatment Emergent Adverse  
Events (TEAEs) 
Group 1 
Group 2 
Group 3 
Group 4 
(n=15) 
(n=15) 
(n=15) 
(n=15) 
Number of Subjects with Solicited TEAEs 
5 (33%) 
8 (53%) 
11 (73%) 
3 (20%) 
       Diarrhea 
0 
1 (7%) 
5 (33%) 
1 (7%) 
       Abdominal Pain 
1 (7%) 
1 (7%) 
3 (20%) 
1 (7%) 
       Nausea 
1 (7%) 
2 (13%) 
2 (13%) 
0 
       Malaise 
2 (13%) 
0 
2 (13%) 
1 (7%) 
       Feeling Hot 
0 
1 (7%) 
0 
0 
       Headache 
4 (27%) 
7 (47%) 
9 (60%) 
1 (7%) 
 
Immune Response 
The objective of the study was to compare schedules and dosing for the ability to elicit immune 
responses. BT50 titers were assessed at multiple times points, given that multiple doses were given. In 
the high dose group, 12 of 15 subjects had a 2-fold or greater increase in BT50 titers after the first dose 
and 14 of 15 subjects (92%) had a 2-fold or greater increase in BT50 titers after 2 doses. The GMT titer 
rose from 21.3 on day to 85.1 on day 28 for a 3.8 GMFR. The GMT at Day 56 were measured to be 
75.8, a GMFR of 3.6 over the baseline values. Table 7 compares the 101 and 102 high dose results. 
Other groups given lower doses of vaccine had lower response rates. Groups 1 and 3 had higher 
increases in the titers compared to Group 2, although this is not statistically significant. Using an 
ANCOVA model, the significance in the different groups to increase the GMFR, was found to be 
P=0.0008, 0.1224, 0.0004, and <0.0001 for groups 1 through 4 respectively at Day 56. This means all 
groups had statistically significant increases in the GMT except for group 2, which had a more modest 
increase in the titers. 
 
Table 7: 
Comparison of BT50 Antibody Results Among Groups in the  
 
 
VXA-G11-101 and VXA-G11-102 Trials 
Study 
Dose group 
Dosing 
(day) 
D0 
GMT 
D28 
GMT 
GMFR 
D56 
GMT 
GMFR 
D56 
101 
Placebo 
1 
24.6 
28.1 
1.1 
N/A 
N/A 
101 
High dose 
1 
25.8 
97.9 
3.8 
N/A 
N/A 
102 
High dose 
1 and 28 
21.3 
85.1 
4 
75.8 
3.6 
 
An additional immunological analysis was performed by comparing the IgA ASC responders between 
groups, Figure 2. The high dose group had 14 out of 15 subjects respond to the vaccine, with an average 
IgA ASC count of 698 per 1 x 106 PBMCs. Following a second dose, the subject that didn’t respond 
the first time had a significant increase in ASC counts so all 15 subjects (100%) were able to elicit an 
ASC response following two doses. The low dose groups were compared by examining the overall 
response rate, since the dosing and the analysis were performed at different intermediate timepoints. 
Group A had the highest overall response rate where 12/14 subjects (86%) were able to induce 
meaningful ASC responses after 1 or 2 doses. Slightly lower responders were observed in group B, 
where only a few subjects had a response after the first dose, but more subjects responded after 
additional vaccine doses.  Group C had the most variable responses of any group. The average number 
of spots was 839 per 1 x 106 cells after the first dose, but this was the result of several subjects having 
extremely high numbers of spots (3 subjects had greater than 1500 per 1 x 106), mixed with many 
subjects that didn’t respond at all.  A positive ASC was defined as higher than 8 spots per 106 PBMCs 
and at least 3 spots/well/3x105 PBMCs (IgA). 

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Figure 2: 
Overall IgA ASC Response Rate After Either One or Two Doses  
 
 
(Study VXA-G11-102) 
 
 
 
 Clinical Study VXA-NVV-103 with VXA-G1.1-NN and VXA-G2.4-NS 
 
Overall Study Design and Plan 
Protocol VXA-NVV-103 Entitled “A Phase 1b, Multi-Center, Randomized, Double-Blind, Placebo-
Controlled Safety and Immunogenicity Study of Adenoviral-vector Based Oral Norovirus Vaccines 
Expressing GI.1 or GII.4 VP1 with Monovalent or Bivalent Dosing in Healthy Adult Volunteers” is a 
multi-center, randomized, double-blind, placebo-controlled study to assess the safety and 
immunogenicity of monovalent GI.1, monovalent GII.4, bivalent GI.1/GII.4 norovirus vaccines, or 
placebo at differing dose levels with varying dosing schedules. 
After a sentinel lead-in group (n=5) dosed with GII.4 vaccine, subjects were randomized in a 1:1:2:1 
manner to one of four treatment arms (Table 8) and followed for primary safety and immunogenicity 
for 29 days and for long-term safety though Day 365. 
A total of 80 subjects entered the study and were randomized to study treatment. A total of 77 subjects 
completed the study. Three subjects in the Bivalent GII.4/GI.1 group discontinued the study (1 subject 
withdrew consent on Day 8, and 2 subjects were lost to follow up). 
 
Table 8:  
Design of Study VXA-NVV-103 
Group 
Vaccine 
Dose (IU) 
No. of Subjects 
1 
Monovalent GII.4 
5x1010 
5 sentinels  
 15 randomized 
2 
Monovalent GI.1 
5x1010 
15 randomized 
3 
Bivalent GII.4 and GI.1 
5x1010 x 2 
30 randomized 
4 
Placebo 
0 
15 randomized 
Total 
80 
IU = International Units 

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Summary of Safety 
There were no deaths, AESIs, NOCIs, or subject discontinuations due to TEAEs in this study through 
the duration of the Active Period (Day 29). Overall, 14 subjects reported a TEAE. The incidence of 
TEAEs was highest in the placebo group (33.3%) compared with the Monovalent GI.1 group (26.7%), 
Monovalent GII.4 group (15.0%), and the Bivalent GII.4/GI.I group (6.7%). Incidence of study vaccine 
related TEAEs was highest in the Monovalent GI.1 group (20%) compared with the placebo group 
(13.3%), Monovalent GII.4 group (5.0%), and the Bivalent GII.4/GI.I group (3.3%). One subject in the 
Monovalent GII.4 group reported an SAE of Hyperemesis Gravidarum. 
The highest number of possibly related TEAEs (20%) were reported in 3 subjects in the Monovalent 
GI.1 group. There was one probably related TEAE (6.7%) in the placebo group. Most subjects reported 
solicited symptoms that were mild in intensity. Five subjects reported solicited symptoms of Grade 3 
severity. Three subjects (1 each in the Monovalent GII.4 group, Monovalent GI.1 group, and Bivalent 
GII.4/GI.I group) had ≥ 1 severe solicited symptom. 
The incidence of diarrhea was higher across the vaccine treated subjects compared to placebo. The 
incidence of nausea and headache was highest in Bivalent GII.4/GI.I group compared to other groups. 
The incidence of malaise/fatigue was higher across the vaccine treated subjects compared to placebo. 
Myalgia and fever were reported only in the vaccine treated subjects (Table  9). 
No treatment-related trends were observed regarding clinical laboratory evaluations. Several laboratory 
TEAEs were reported; however, the investigator considered a mild TEAE of decreased blood 
phosphorus in 1 subject in the Bivalent GII.4/GI.1 group as possibly related to study vaccine. No trends 
were observed regarding vital signs or physical examinations with respect to subject safety. 
Table 9:  
Summary of Solicited Symptoms of Reactogenicity (Study VXA-NVV-103) 
Grades 1-3 
Monovalent 
GII.4  
(N=20) 
n (%) 
Monovalent 
GI.1  
(N=15) 
n (%) 
Bivalent 
GII.4/GI.I 
(N=30) 
n (%) 
Placebo 
(N=15) 
n (%) 
Number of Subjects with at least 1 
symptom of Grades 1-3 
9 
8 
16 
4 
Diarrhea 
4 (20.0) 
3 (20.0) 
6 (20.0) 
1 (6.7) 
Nausea 
3 (15.0) 
1 (6.7) 
6 (20.0) 
2 (13.3) 
Vomiting 
1 (5.0) 
0 (0.0) 
2 (6.7) 
0 (0.0) 
Abdominal Pain 
3 (15.0) 
1 (6.7) 
4 (13.3) 
2 (13.3) 
Malaise/Fatigue 
4 (20.0) 
4 (26.7) 
6 (20.0) 
1 (6.7) 
Myalgia (Muscle Pain) 
2 (10.0) 
2 (13.3) 
2 (6.7) 
0 (0.0) 
Anorexia 
0 (0.0) 
0 (0.0) 
1 (3.3) 
0 (0.0) 
Headache 
2 (10.0) 
2 (13.3) 
7 (23.3) 
2 (13.3) 
Fever 
1 (5.0) 
2 (13.3) 
1 (3.3) 
0 (0.0) 
Temperature 
 
 
 
 
< 99 F 
3 (15.0) 
3 (20.0) 
9 (30.0) 
2 (13.3) 
99 to 99.9 F 
5 (25.0) 
3 (20.0) 
6 (20.0) 
2 (13.3) 
>= 100 F 
1 (5.0) 
2 (13.3) 
1 (3.3) 
0 (0.0) 
  The temperature summarizes the highest temperature recorded for 7 days following each vaccine. 
  

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Summary of Immunogenicity Analysis 
A summary of immunogenicity results in the Active Period (Day 29) is provided below: 
• Statistically significant increases in Serum GI.1 BT50 GMT were seen in the Monovalent GI.1 group 
(p=0.0008) and Bivalent GII.4/GI.1 group (p=0.0084) compared with placebo. No significant 
differences in the GMT were seen between the Monovalent GI.1 and Bivalent GII.4/GI.1 groups 
(p=0.2772). 
• On Day 29, statistically significant increases in Serum GII.4 BT50 GMT were seen in the Monovalent 
GII.4 group (p= 0.0017) and Bivalent GII.4/GI.1 group (p<0.0001) compared with placebo. No 
significant differences in the GMT were seen between the Monovalent GII.4 and Bivalent 
GII.4/GI.1 groups (p=0.2320). 
• On Day 8, statistically significant increases in the average counts of GI.1 IgA were seen in the 
Monovalent GI.1 group (p<0.0001), Bivalent GII.4/GI.1 group (p<0.0001), and Monovalent GII.4 
group (p=0.0001) compared with placebo. No significant differences in the average counts of GI.1 
IgA were seen between the Monovalent GI.1 and Bivalent GII.4/GI.1 groups (p=0.6013). 
• On Day 8, statistically significant increases in the average counts of GII.4 IgA were seen in the 
Bivalent GII.4/GI.1 group (p<0.0001), Monovalent GII.4 group (p<0.0001) and Monovalent GI.1 
group (p=0.0080) compared with placebo. No significant differences in the average counts of GI.1 
IgA were seen between the Monovalent GII.4 and Bivalent GII.4/GI.1 groups (p=0.6079). 
• On Day 29, statistically significant increases in the GMT of VP1 specific serum GI.1 IgG were seen 
in the Monovalent GI.1 group (p=0.0010) and the Bivalent GII.4/GI.1 group (p=0.0092) compared 
with placebo. No significant differences in the GMT were seen between the Monovalent GI.1 and 
Bivalent GII.4/GI.1 groups (p=0.1293). 
• On Day 29, statistically significant increases in the GMT of VP1 specific serum GII.4 IgG were 
seen in the Bivalent GII.4/GI.1 group (p<0.0001) and the Monovalent GII.4 group (p=0.0001) 
compared with placebo. No significant differences in the GMT were seen between the Monovalent 
GII.4 and Bivalent GII.4/GI.1 groups (p=0.3932). 
• On Day 8, statistically significant increases in the average counts of ASC GI.1 IgG were seen in the 
Monovalent GII.4 group (p=0.0002), Monovalent GI.1 group (p=0.0019), and the Bivalent 
GII.4/GI.1 group (p<0.0001) compared with placebo. No significant differences in the average 
counts of ASC GI.1 IgG were seen between the Monovalent GI.1 and Bivalent GII.4/GI.1 groups 
(p=0.4172). 
• On Day 8, statistically significant increases in the average counts of ASC GII.4 IgG were seen in 
the Bivalent GII.4/GI.1 group (p<0.0001) and Monovalent GII.4 group (p<0.0001) compared with 
placebo. No significant differences in the average counts of ASC GII.4 IgG were seen between the 
Monovalent GII.4 and Bivalent GII.4/GI.1 groups (p=0.2694). 
• On Day 29, statistically significant increases in the GMT of VP1 specific serum GI.1 IgA were seen 
in the Monovalent GI.1 group (p=0.0391) compared with placebo. No significant differences in the 
GMT of VP1 specific serum GI.1 IgA were seen between the Monovalent GI.1 and Bivalent 
GII.4/GI.1 groups (p=0.6184). 
• On Day 29, statistically significant increases in the GMT of VP1 specific serum GII.4 IgA were 
seen in the Bivalent GII.4/GI.1 group (p=0.0002) and the Monovalent GII.4 group (p=0.0018) 
compared with placebo. No significant differences in the GMT of VP1 specific serum GII.4 IgA 
were seen between the Monovalent GII.4 and Bivalent GII.4/GI.1 groups (p=0.6295). 
 

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1.7 
Summary of Clinical Experience with Vaxart Oral Vaccine Platform 
 
Approximately 640 subjects have been enrolled in 13 clinical trials completed with Vaxart’s oral Ad5 
vaccine platform. Three phase 1 studies using the Norwalk GI.1 norovirus candidate (VXA-G1.1-NN) 
have been conducted in 206 subjects. A total of 640 subjects participated including 497 subjects who 
received Vaxart’s oral vaccines at varying dose levels and dosing schedules, across four clinical 
programs (seasonal and pandemic influenza, norovirus, RSV and coronavirus) and 143 subjects 
received placebo. To date, the vaccines were well tolerated, and in the placebo-controlled studies, the 
vaccine groups, at all dose levels, did not differ significantly in the frequency of adverse events (aEs) 
recorded from the placebo groups.  A summary of the clinical studies conducted using Vaxart’s vaccine 
platform is presented in Table 17. 
 
Table 17: 
 Clinical Studies Completed Using Vaxart Oral Ad5 Vaccine Platform  
Target 
Pathogen 
Vaccine 
Candidate(s) 
 
Protocol 
Number and 
(Oral Vaccine 
Formulation) 
Year 
Study 
Completed 
(Active 
Phase) 
Subjects 
with ≥ 1 
Vaccine 
Exposure 
Subjects 
Receiving 
Placebo 
Influenza H5 
ND1.1 
 
VXA01-001  
(H5 Capsule) 
2011 
42 
12 
VXA01-001A 
(H5 RCC) 
2012 
12 
- 
Influenza H1 
 
 
  
 
 
VXA-A1.1  
 
VXA02-001  
(H1 Tablet) 
2012 
25 
12 
VXA02-002  
(H1 RCC) 
2013 
37 
- 
VXA02-003  
(H1 Tablet) 
2014 
12 
12 
VXA-CHAL-201  
(H1 Tablet)  
[BARDA 
Funded] 
2017 
71 
36 
VXA-RLT-1  
(H1 Fast/Fed) 
2018 
8 
- 
Influenza B 
VXA-BYW.10 
 
VXA03-001  
(Flu B Tablet) 
2016 
38 
16 
Norovirus GI.1 
 
VXA-G1.1-NN 
 
VXA-G11-101 
(NV Tablet) 
2016 
46 
20 
VXA-G11-102 
(NV Tablet) 
2017 
60 
- 
Norovirus GI.1 
and GII.4 
VXA-G1.1-NN 
and  
VXA-G2.4-NS 
 
VXA-NVV-103 
(NV Tablet) 
2019 
65 
15 
RSV 
VXA-RSV-f 
 
VXA-RSV-101 
(RSV Tablet) 
2016 
46 
20 
Coronavirus 
VXA-CoV2-1 
VXA-COV2-101  
(SARS-CoV-2  
S & N Tablet) 
2021 
35 
0 
Total Subjects Dosed 
497 
143 
Ad5 = serotype 5 adenovirus; BARDA = Biomedical Advanced Research and Development Authority; BB-IND = biologic-
based investigational new drug; NV = norovirus; RCC = Radio-Controlled Capsule; RSV = respiratory syncytial virus 
 

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Safety in Vaxart’s oral vaccine programs has been assessed by examining the incidence of solicited 
symptoms of reactogenicity, aEs and serious aEs (SAEs) in the intent-to-treat (ITT) population of each 
study. Solicited local and systemic aEs were collected for 7 days following each vaccine administration 
using subject diary cards. Unsolicited aEs were collected for 28 days following last vaccination.  
Additionally, SAEs, aEs of special interest (AESIs) and new onset of chronic illness (NOCIs) were 
monitored throughout the one-year safety follow-up period.  No related SAEs, AESIs or NOCIs have 
been reported for any subject receiving single or multiple doses of Vaxart’s VAASTTM oral vaccines to 
date.   
 
1.8 
Rationale for GI.1 Human Challenge Study (VXA-NVV-201) 
The human challenge model has been used successfully to determine the efficacy of both GI.11 and 
GII.4 norovirus vaccines (30, 31). The challenge with GI.1 was more successful because the GI.1 
challenge induced illness in more control subjects. The challenge model has been called into question 
as an overly stringent model because the inoculum used in these studies induces illness in over half of 
the unvaccinated control subjects. In nature the dose may be much lower. For example, in the Atmar 
study using the GI.1 challenge the protective efficacy of a parenteral GI.1 NV vaccine was 47%. The 
hope is that the efficacy will be considerably higher in field studies.  The challenge study may also 
provide immunological data that may aid in determining an immunologic correlate of protection. A 
correlate of protection could greatly aid in predicting vaccine efficacy in different age groups.  An 
effective Norovirus vaccine must prevent the two most common norovirus genotypes, GI.1 and GII.4.  
Vaxart is developing a bivalent vaccine for use in the field. 
 
 
1.9 
Potential Risks and Benefits 
 
Vaccine Risks 
Vaxart’s Ad5 vector is a replication incompetent vaccine, lacking the E1 and E3 gene regions, which 
have been removed recombinantly.  Replication incompetent Ad5 has been used in over 200 gene 
therapy and vaccine studies in humans (36-39). VXA-G1.1-NN is an investigational new drug. Similar 
doses of the related investigational drugs (vaccines) ND1.1 and VXA-A1.1 have been tested in prior 
phase 1 and phase 2 studies; the numbers were relatively small (n = ~500 subjects). Based on the results 
from 3 studies completed with the VXA G1.1-NN norovirus vaccine, doses of 2 x 1011 ±0.5 logs, 
delivered by oral enteric tablet were safe and generally well tolerated in healthy male and female 
subjects. 
 
The safety monitoring practices employed by this protocol (ie, physical examination, vital 
signsgastrointestinal and systemic reactogenicity (solicited symptoms), 12-lead electrocardiogram 
(ECG), hematology, serum chemistry, urinalysis, immunogenicity assessments, and AE questioning) 
are adequate to protect the subjects’ safety and should detect all expected treatment-emergent AEs 
(TEAEs). 
 
Since the initiation of the current protocol, multiple injected adenovirus vectored vaccines approved 
for use via Emergency Use Authorization (EUA) for the prevention of COVID-19 have reported severe 
events of thrombosis in combination with thrombocytopenia (thrombosis with thrombocytopenia 
syndrome, TTS), in some cases accompanied by bleeding. Though the TTS events were reported with 
adenovirus vectored vaccines for COVID-19, the FDA has asked Sponsors of adenovirus vectored 
vaccines for other indications to broadly monitor for these risks. 
 
Investigators should be alert to the signs and symptoms of thromboembolism and/or thrombocytopenia. 
Study participants should be instructed to seek immediate medical attention if they develop symptoms 

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including, but not limited to, shortness of breath, chest pain, leg pain and/or swelling, persistent 
abdominal pain, severe or persistent headaches, blurred vision or other vision changes, mental status 
changes or seizures, petechia, purpura beyond the site of vaccination, and/or easy bruising/bleeding. 
The medical management of thrombosis with thrombocytopenia is different from the management of 
isolated thromboembolic diseases. Investigators should follow available guidelines for the assessment 
and treatment of thrombotic thrombocytopenia (e.g., American Society of Hematology 2021British 
Society for Haematology 2021; CDC 2021). The use of heparin may be harmful and alternative 
treatments may be needed. Consultation with hematologists is strongly recommended. 
 
Norovirus Challenge Risks 
The intended challenge NV dose of  1x106 GC is expected to elicit acute watery diarrhea within 12-72 
hours of ingestion in about half of the subjects. Persons that are blood group A or O and secretor-
positive are known to be more susceptible to NV. Nausea or vomiting, abdominal cramping or 
discomfort, and loss of appetite are also common symptoms. Fever is uncommon.  Dehydration can 
occur through loss of fluid from liquid stool and emesis. Since NoV infection is short-lived lasting 
usually 2 or 3 days severe dehydration is uncommon. Symptoms of severe dehydration can involve dry 
mouth, decreased urine, thirst, cold clammy skin, hypotension, lethargy, stupor, and muscle cramping. 
The complications of severe fluid loss include hypoglycemia (low blood sugar), acidosis, kidney 
failure, pulmonary edema (fluid in lungs), arrhythmia (heart rhythm abnormalities), coma, and death. 
Dehydration will be managed with aggressive fluid rehydration (oral and/or intravenous [IV]) with 
potassium repletion. It is expected that NoV shedding will occur in the stool; however, transmission 
from person to person is mitigated by housing the subjects on the research isolation ward until they 
meet the protocol discharge criteria. Subjects that maintain the standard hygiene (ie, hand washing with 
soap and water after defecation) are unlikely to transmit the strain person to person. 
 
Risk of Blood Draw 
The approximate volume of blood planned for collection from each subject over the course of the study 
presents no undue risk to the subjects nor does the possibility of collection (for wasting to ensure clean 
sample) of additional blood in the event an indwelling cannula is utilized and the possibility of 
additional blood for recheck of safety labs if deemed necessary by the Principal Investigator (PI). 
 
 
Known Potential Benefits 
Since these are experimental vaccines against norovirus, there are no benefits to the subjects for their 
participation in this research study. 
2 
HYPOTHESIS, OBJECTIVES AND PURPOSE 
2.1 
Study Hypothesis 
Norovirus vaccine (VXA-G1.1-NN) will protect against Norovirus Gastroenteritis (NVG) in the 
challenge model. 
2.2 
Study Objectives 
 
Primary Objective 
• 
Determine the clinical efficacy of VXA-G1.1-NN compared to placebo, to protect against NVG 
caused by the Norwalk strain challenge inoculum. 
 
Secondary Objectives 
• 
Safety and tolerability of VXA-G1.1-NN oral vaccine 

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• 
Determine the ability of VXA-G1.1-NN to modify disease severity (defined in Appendices C 
and D) compared to placebo 
• 
Determine the quantity and duration of norovirus shedding by qRT PCR 
• 
Evaluate the VP1 specific IgA ASC, HBGA blocking antibody, and VP1 specific serum IgG 
responses to VXA-G1.1-NN 
 
Exploratory Objectives 
• 
Determine correlation of immunogenicity parameters with clinical outcome 
• 
Further evaluate immunogenicity of VXA-G1.1-NN 
3 
STUDY DESIGN AND ENDPOINTS 
 
3.1 
Description of Study Design 
This is a Phase 2b randomized, double-blind, placebo-controlled vaccination and challenge study to 
assess the protective efficacy of the Norovirus vaccine (VXA-G1.1-NN). To ensure at least 140 subjects 
(approximately 85 NV vaccine and 85 placebo) are available to participate in the challenge phase, 
approximately 170 healthy young adults will be randomized in a 1:1 ratio to receive one oral dose of 
vaccine or placebo Table 18. Each subject will receive an oral dose of 1x1011 IU±0.5 log VXA-GI.1-
NN or placebo comprised of multiple tablets per dose. 
 
To accommodate the limited size of the isolation unit that will be utilized for the challenge and post-
challenge isolation period, subjects will move through the study (enrollment, vaccination and challenge) 
sequentially in a total of approximately 14 to 16 cohorts. Subjects will be randomized in cohorts of 
approximately 10 to 12 each. Approximately 28 days (+30 days) post-vaccination, each cohort will be 
admitted to the isolation ward and challenged with the NV GI.1 Norwalk challenge strain. After 
challenge, subjects will be monitored for signs and symptoms of AGE from Day 29 to discharge. Stool 
and emesis will be collected. Excretion of NV (shedding) will be monitored in stool and emesis. Illness 
will be assessed using a modified Vesikari scale. NV illness lasts 2-4 days and is self-limited. 
 
Four days post-challenge (Day 33) subjects will be evaluated for signs and symptoms of acute 
gastroenteritis.  If there is no clinical illness present, asymptomatic subjects will be discharged from the 
isolation ward and will be followed up in a series of outpatient visits and telephone calls. Symptomatic 
subjects will remain in the unit up to an additional 3 days (Day 36), per the judgement of the 
investigator. 
An independent Safety Monitoring Committee (SMC) will convene at pre-defined intervals during the 
norovirus challenge period, and also ad hoc as needed during the vaccination and challenge periods, 
to oversee the safety of the study. 
 
Each subject’s participation will last approximately 1 year post successful screening and enrollment 
• 
90 day pre-screening period 
• 
45 day screening period 
• 
28 day vaccination phase 
• 
28 day viral challenge and follow-up  
• 
365 day total safety follow-up post vaccination 
 
 
 
 

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Table 18: 
 Study Design and Vaccine Groups (Study VXA-NVV-201) 
Product/Test Agent 
No. of 
subjects 
VXA-G1.1-NN oral vaccine tablets [1x1011 IU±0.5 log] 
85 
Placebo identical to NVV 
85 
Challenge Norwalk Virus Strain [Lot 001-09NV and Sublot 2 
(1x106 GC)] 
140* 
*All subjects suitable to undergo challenge at Day 29 will participate in the challenge phase. 
 
3.2 
Study Endpoints 
 
Primary Endpoint 
• 
Occurrence of NVG caused by the challenge norovirus during inpatient challenge period. 
o NVG is a composite endpoint and is defined as meeting one or more of the definitions 
for both acute gastroenteritis and NV infection. 
 
Secondary Endpoints 
• 
Number of subjects with acute gastroenteritis during the inpatient challenge period 
• 
Mean score using the Modified Vesikari Scale as a measure of severity of acute gastroenteritis 
post-challenge at discharge (up to Day 36) 
• 
Number of subjects with moderate or severe gastroenteritis (cumulative loose stools ≥ 1000gms 
during the inpatient period)  
• 
Median duration (number of hours) of acute gastroenteritis among challenged subjects 
• 
Number of subjects with norovirus infection up to Day 36 post-challenge (quantitative reverse 
transcriptase polymerase chain reaction [qRT-PCR] positive in stool, Norwalk virus antigen in stool 
• 
Geometric mean genome copies of norovirus shedding by qRT-PCR 
• 
Median duration (number of hours) of norovirus infection among challenge subjects 
• 
Number of incidences of diarrhea or emesis among challenge subjects 
 
 
Safety Endpoints 
• 
Vaccine (VXA-G11-N.N) 
o Solicited symptoms of reactogenicity x 7 days post vaccination;  
o Unsolicited AEs x 28 days post vaccination;  
o SAEs, AESIs and NOCIs x 12 months post vaccination 
 
• 
Challenge Virus (Norwalk GI.1) 
o Unsolicited AEs x 28 days post challenge 
 
Immunogenicity Endpoints 
Primary 
• 
VP1 specific IgA ASC response against Norwalk at Day 8 compared to placebo 
• 
GMT of HBGA blocking antibodies (by BT50) against Norwalk virus at Day 28 compared to 
placebo 
• 
VP1 specific serum IgG response at Day 28 compared to placebo 
• 
VP1 specific serum IgA at Day 28 compared to placebo 
 
Exploratory 
• 
Correlations between individual immunogenicity parameters and clinical efficacy 

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• 
VP1 specific IgG ASC response against Norwalk at Day 8 compared to placebo 
• 
VP1 specific fecal IgA at Day 28 compared to placebo 
• 
VP1 specific saliva IgA at Day 8 and Day 28 compared to placebo 
• 
VP1 specific nasal IgA at Day 8  and Day 28 compared to placebo 
• 
Vaccine specific response for memory IgA and/or IgG in B cells, IgA and IgG in plasmablasts, 
antibody repertoire sequencing analysis, flow cytometry (including homing and/or 
immunophenotyping analyses), and other assays designed to evaluate cell mediated immunity 
Additional assessment of serum, fecal, saliva, and mucosal immunity at other time points (including 
post-challenge) may be performed 
4 
STUDY ELIGIBILITY, ENROLLMENT AND WITHDRAWAL 
4.1 
Subject Inclusion Criteria 
1. Male or female between the ages of 18 – 49 years, inclusive  
2. Able to give written informed consent 
3. Healthy1, as determined by the principal investigator (PI) or PI in consultation with the Medical 
Monitor and Sponsor 
1No clinically significant health concerns or medical illness), as determined by medical history, 
physical examination, vital signs, electrocardiogram (ECG), and clinical laboratories 
(complete blood count [CBC], chemistry and urinalysis)  
4. Comprehension of the study requirements with ability and willingness to complete all 
assessments and comply with confinement period post viral challenge, and all scheduled visits 
and contacts 
5. Confirmed blood type (A or O) 
6. Demonstrated to be H type-1 antigen secretor positive (by saliva test) 
7. Body mass index between 17 and 35 kg/m2, inclusive, at Screening  
8. Female participants must have a negative pregnancy test at pre-vaccination and pre-challenge 
and fulfill one of the following2 
 
2Criteria: 
a. At least one year post-menopausal; 
b. Surgically sterile; 
c. Use of oral, implantable, transdermal, intravaginal or injectable 
contraceptives for 30 days prior to immunization and until 60 days after 
challenge; 
i. A reliable form of contraception must be approved by the 
Investigator (eg, double barrier method, Depo-Provera, 
intrauterine device, Norplant, oral contraceptives, 
contraceptive patches, vaginal ring contraceptive) 
d. Not be sexually active (abstinent) or in a same sex relationship (must be 
discussed with site staff and documented) 
9. Male subjects must agree not to father a child or donate sperm, as well as to use 
contraception/barrier (a male condom) or be abstinent from heterosexual intercourse, from 
vaccination through the active/interventional period of the study (Day 57) 

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4.2 
Subject Exclusion Criteria 
1. Administration/use of any investigational drug or device 30 days prior to vaccination through 
the active period (Day 57) 
2. Administration of any licensed vaccine within 30 days prior to vaccination or planned use of 
the above stated during the active period (through Day 57) 
3. Presence of a significant medical condition3 which in the opinion of the investigator precludes 
study participation3 
3 For example, psychiatric conditions, or gastrointestinal disease, such as peptic ulcer, 
symptoms or evidence of active gastritis or gastroesophageal reflux disease, 
inflammatory bowel disease, alcohol or illicit drug abuse/dependency, or other 
laboratory abnormalities 
4. Laboratory values outside the range of normal for platelet counts and the following coagulation 
tests: PT/INR, aPTT and fibrinogen 
5. 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: 
▪ 
Recent surgery other than removal/biopsy of cutaneous lesions  
▪ 
Immobility (confined to bed or wheelchair for 3 or more successive days)  
▪ 
Head trauma with loss of consciousness or documented brain injury  
▪ 
Receipt of anticoagulants for prophylaxis of thrombosis 
▪ 
Recent clinically significant infection 
6. Any one of the following ECG findings4 within 45 days prior to vaccination: 
4Exclusionary ECG findings: 
a. 
QTc F (interval duration > 450 msec (male) or > 470 msec (female) 
b. 
QRS interval greater than 120 msec 
c. 
PR interval greater than 220 msec 
d. 
Clinically significant ST-T wave changes or pathologic Q waves 
7. History of cancer or cancer treatment within past 3 years (excluding basal cell or squamous 
cell carcinomas) 
8. Presence of immunosuppression or medical condition possibly associated with impaired 
immune responsiveness, including diabetes mellitus or angioedema 
9. Donation or use of blood or blood products within 30 days prior to vaccination through the 
active period (Day 57) 
10. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make 
blood draws problematic 
11. Any condition that resulted in the absence or removal of the spleen 

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12. Evidence of confirmed infection with human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) or hepatitis C virus (HCV) with confirmatory assays 
13. Abnormal stool pattern (fewer than 3 bowel movements per week or more than 3 per day) 
14. History of irritable bowel disease or inflammatory digestive or gastrointestinal condition5 that 
could affect the distribution / safety evaluation of an orally administered vaccine6 
5Such conditions may include but are not limited to: 
a. Esophageal Motility Disorder 
b. Malignancy 
c. Malabsorption(eg. Celiac disease, gluten intolerance)  
d. Pancreaticobiliary disorders 
e. Irritable bowel syndrome 
f. 
Inflammatory Bowel Disease 
g. Surgical Resection with the exception of appendectomy or a minor resection that is 
deemed acceptable by investigator and sponsor 
h. Gastroesophageal reflux disease (GERD) 
i. 
Hiatal Hernia 
j. 
Peptic Ulcer  
(History of cholecystectomy is not exclusionary) 
6 targeting the mucosa of the small intestine 
 
15. Use of proton pump inhibitors, H2 blockers or antacids within 7 days prior to vaccination 
through the active period (Day 57) 
16. Use of antibiotics within 30 days prior to vaccination through the active period (Day 57)7  
7Note: use of a brief (≤ 10 days) course of oral or topical antibiotic for minor URI, UTI, dental 
work, or skin infection allowed within the screening period, but must be completed 7 days prior 
to first vaccination 
17. Use of medication known to affect the immune function (e.g. systemic corticosteroids and 
others) within 14 days prior to vaccination through the active period (Day 57) 
18. Regular use of nonsteroidal anti-inflammatory drugs within 7 days prior to vaccination through 
the active period (Day 57) 
19. Use of over-the-counter probiotics or antidiarrheals within 7 days prior to vaccination through 
the active period (Day 57) 
20. Evidence of recent (within 2 months of vaccination) or of current nonbacterial gastroenteritis 
suggestive of NV infection [vomiting or unformed or watery stools (> 2 during a 24-hour 
period)] 
21. Any gastroenteritis within the past 2 weeks prior to vaccination 
22. Acute disease within 72 hours prior to vaccination8 
8Defined as the presence of a moderate or severe illness with or without fever (as determined 
by the Investigator through medical history and physical examination). (Assessment may be 
repeated during screening period) 
23. Presence of a fever ≥ 38ºC measured orally at baseline 
24. History if hematochezia (blood in stool) or melena (black stool) 
25. Any significant hospitalization within the last year which in the opinion of the investigator or 
sponsor could interfere with study participation 

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26. History of serious reactions to any vaccination such as anaphylaxis, respiratory problems, 
Guillain-Barre syndrome, hives or abdominal pain 
27. History of a hypersensitivity or allergic reaction to any component of the investigational 
vaccine or placebo9. Subjects with known fish allergies should be excluded 
9 including but not limited to fish gelatin 
28. History of drug, alcohol or chemical abuse within 1 year prior to vaccination 
29. Positive test for drugs of abuse or alcohol at Screening, vaccination baseline and pre-
challenge.10  
10except for previous marijuana use; concurrent or ongoing use of marijuana during the active 
study period 
30. Consistent/habitual smoking within 2 months prior to vaccination (defined as smoking ≥ 1 
pack of cigarettes a day). Smoking is not permitted during the inpatient stay 
31. Other conditions11 that would jeopardize the safety or rights of a subject or interfere with the 
evaluation of the study 
11 in the clinical judgment of the investigator 
Social/Occupational: 
32. Living with or having daily contact with children age < 5 years old or women known to be 
pregnant or nursing12  
12This includes significant contact at home, school, day-care, or equivalent facilities. 
33. Living with or having daily contact with elderly persons > 70 years of age or infirmed, diapered 
individuals, persons with disabilities or incontinence13  
13This includes at work or visits to nursing homes and day-care or equivalent facilities 
34. Employment in the food service industry such as restaurant or cafeteria facilities14  
14Specifically, this includes persons whose employment requires food handling and 
processing in the 4 weeks following viral challenge 
35. Health-care workers with patient contact expected in the 4 weeks following viral challenge 
36. Expected contact15 with immunocompromised persons16 in the 4 weeks following viral 
challenge 
15 via employment or at home 
16 HIV-positive, receiving immunosuppressive medications such as oral steroids, anti-
neoplastic agents 
37. Presence of household members who have received the Ad4 or Ad7 vaccines within 2 months 
prior to vaccination 
38. Employment as an airline flight attendant or cruise ship crew, scheduled to work in the 4 weeks 
following challenge. 
39. Persons planning to live in a confined environment (eg, a cruise, camp, etc.) in the 4 weeks 
following viral challenge 
4.3 
Withdrawal from the Study 
 
Reasons for Withdrawal or Termination 
Participation in the study is strictly voluntary.  Subjects have the right to withdraw from the study at 
any time and for any reason, without penalty.  The Principal Investigator and/or designee may, at her/his 
discretion, withdraw a subject from continuing in the study if it is in the subject’s best interest, or if the 

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subject is not willing or able to comply with the study requirements.  The reason for withdrawal will 
be documented. 
 
Handling of Subject Withdrawals or Termination 
If a subject withdraws or early terminates on study, every effort will be made to complete protocol-
specified safety follow-up procedures, with the consent of the subject, to capture protocol specified 
assessments and AEs, SAEs, AESIs and NOCIs (refer to Section 7.11 ).  
 
 

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5 
STUDY DRUG  
 
5.1 
 Study Drug(s) and Control Description  
 
VXA-G1.1-NN final DP is produced as small white enteric-coated tablets Table 19. The DP is 
formulated as compressed powdered solid material containing lyophilized drug substance (VXA-G1.1-
NN), tromethamine (TRIS), sucrose, arginine, hydrolyzed fish gelatin (type A), polyvinylpyrrolidone 
(PVP-grade K90), microcrystalline cellulose, pre-gelatinized starch, magnesium stearate, hydrophobic 
colloidal silica, and hydrochloric acid for pH adjustment.  With the exception of the active ingredient 
all excipients are used in US-licensed oral DPs currently listed in the FDA Inactive Ingredients 
Database and are GRAS categorized. 
 
Table 19: 
 Active Product Description (VXA-G1.1-NN) 
Generic name 
VXA-G1.1-NN 
Chemical name  
Ad-CMV-VP1(Norwalk virus)-BGH-CMV-luc dsRNA-SPA 
Genome size 
33,949 bp dsRNA genome  
Viral particle size 
80 -100 nm 
 
Placebo Description  
The placebo for this study is manufactured similarly to the active 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.  
 
 
Drug Product Packaging and Labeling 
 
DP tablets will be packaged into foil-sealed, HDPE screw-cap containers with 10 tablets per bottle.  
These will be provided to the clinical site pharmacy in an unblinded manner. 
 
All lots of DP bottles will be labeled with the 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 
and any additional information as required by regulatory agencies or clinical pharmacy Standard 
Operating Procedures (SOP). 
 
Secondary packaging of the DP upon dispensing from the pharmacy to the clinical staff for subject 
dosing will be determined with consideration of the sites’ pharmacy SOPs and outlined in the study 
pharmacy manual.  The final subject use material (cup or secondary bottle) will be appropriately labeled 
with the subject’s unique identifier, the time/date of dose preparation within the pharmacy, an 
expiration time and date, and additional information as deemed necessary.  
 
 
Drug Product Storage and Stability 
VXA-G1.1-NN vaccine and placebo tablets will be stored at 2 to 8°C at the clinical site until ready for 
use.  Test data on representative DP lots support the stability of the DP tablets stored at 2 to 8°C for at 
least 1 year from date of manufacture 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.  
DP tablets should not be frozen. Do not use and contact Sponsor if DP tablets have been frozen. 

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Drug Product Dosage Preparation and Administration 
 
Preparation of Drug Product Dose 
DP doses will be prepared at the site by the unblinded pharmacy staff for delivery to the clinical staff 
in a blinded manner.  The observed concentration of VXA-G1.1-NN active ingredient per tablet has 
been within the range of 2x109 IU – 5x1010 IU. The actual concentration of active vaccine per tablet is 
determined during release testing and provided to clinical sites within the Certificate of Analyses 
(CoAs).  Multiple tablets of the DP will be dispensed per dose to deliver the complete investigational 
dose of 1x1011 IU ± 0.5 logs within the vaccine treatment arm.  A matching number of placebo tablets 
will be administered to ensure blinding of the treatment groups. Refer to the Study Pharmacy Manual 
for detailed information on the drug product lots to be used for clinical dosing and the number of tablets 
to be administered. 
 
At least 15 minutes prior to administration, the dose container(s) will be removed from the refrigerator 
and allowed to equilibrate with room temperature.  Multiple subject doses may be withdrawn from the 
container with proper drug accountability.  If tablets remain in the primary bottle container upon 
preparation of subject doses, the desiccant pack should be replaced, and the container tightly capped 
before being returned to the refrigerator.  The DP containers may be held at ambient room temperature 
for no more than 4 hours prior to returning it to the refrigerator.  The containers should be placed in a 
dry location that is free from extreme sources of heat or light. 
 
Study Drug Administration 
Study subjects should be fasting and refrain from ingesting solid food for at least 4 hours prior to 
initiation of oral dosing.  Following randomization subjects will be dispensed their assigned DP dose 
(VXA-G1.1-NN or placebo tablets) on Day 1.  They will swallow the tablets with 360 to 480 mL of 
water followed by a light snack (e.g., crackers) to aid in tablet transit out of the stomach. Normal food 
consumption may resume 90 minutes after dosing.  
 
Dose Adjustments/Modifications/Delays 
Dose adjustments and or modifications are not planned or allowed under this clinical protocol.  All 
subjects should receive the full 1x1011 IU ± 0.5 logs dose or matching placebo at Day 1. Any 
modification from this planned dose should be recorded as a protocol deviation and reported to the 
Sponsor (or designee). 
 
 
Study Drug Accountability 
The Investigator and study site must ensure that an accurate record of DP disposition is maintained, 
and that study drug is dispensed only by authorized, unblinded personnel as documented on the 
delegation of authority log.  Records of product disposition and dispensing must consist at a minimum 
of the date received, date administered, quantity administered, and the subject to whom the drug was 
administered. 
The unblinded pharmacy staff will be responsible for maintaining accurate records of the shipment and 
dispensing of the study drug.  The investigational product records must be available for inspection by 
the Sponsor’s unblinded representative and is subject to inspection by a regulatory agency at any time.  
Copies of the records will be provided to the Sponsor at the end of the study.  An unblinded study 
monitor will review the investigational product records. 
Clinical Trials Materials Returns form and the drug accountability forms must be maintained in a 
blinded secure area throughout the duration of the study.  At the completion of the study, all unused 
product must be returned to the Sponsor or designee, per instruction by the Sponsor. 

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6 
NV CHALLENGE INOCULUM 
The Norovirus GI.1 (Norwalk Virus Inoculum Lot 001-09NV, IND 14697) inoculum was prepared 
from a 20% suspension of a liquid stool from a NV-infected subject in a previous human challenge 
study. This inoculum was prepared by extracting the virus from the stool suspension after several 
washes, sterilely filtering the virus extract into vials, and determining the titer of the extract. These 
procedures were performed under Good Manufacturing Practices conditions at 
 
 From there, the inoculum was sent to an outside contractor for safety 
testing. The preparation, qualification, and quantification of this inoculum were submitted to the FDA 
under IND 14697. 
 
To accommodate the increased sample size of the trial, additional GI.1 norovirus inoculum was diluted 
from the same original master stock Norwalk Virus Inoculum Lot 001-09NV purified bulk harvest 
(PBH), to challenge the additional Subjects.  The dilution process is attached as Appendix F and an 
updated IND 14697 subsequently submitted to the FDA with sterility, endotoxin, and titer testing 
results.   
 
6.1 
Formulation, Packaging, and Labeling of NV Challenge Virus 
Both the filled, purified product and the final patient use material are formulated in pure, distilled water 
with no other additives. The filled, purified material is provided to the clinical site in 1 mL sterile 
cryovials containing sufficient material for one final processing step just prior to use in a single subject.  
The filled, purified NV inoculum is labeled with the name of the manufacturer, the name of the product, 
the lot number of the product, the concentration of the virus, the date of manufacturing and a statement 
stating For Investigational Use Only. 
 
The Sublot 2 inoculum material diluted and prepared for single use to complete this challenge study 
was packaged in one 3mL cryovials.  The dilution and aliquoting of virus were performed at 
 with oversight by a representative from the original manufacturing 
team following the dilution procedure described in the Preparation of NV Challenge Inoculum Work 
Instruction, Appendix F. During the aliquoting of 001-09NV sublot 2, additional vials from the 
beginning, middle and end of the run were prepared for quality control testing and shipped on dry ice 
to either 
 or 
 for testing. 
 
6.2 
Storage and Stability of NV Challenge Virus 
The filled, purified material is stored long term in a controlled -80°C freezer. The final subject use 
material can be stored short term in either a 4°C refrigerator or can be held short term on wet ice. The 
final subject material is not held or stored for more than 8 hours. The long-term stability of frozen 
clinical-grade NoV prepared using the established procedures at the NoV Processing Facility in North 
Carolina has not been determined. Stability will be determined by periodically removing a vial of the 
filled, purified material from produced banks of vials and testing the material for sterility and viral titer 
via RNA qRT-PCR. The stability of the final subject use material has been pre-set at 8 hours. 
 
The final titer for 001-09NV PBH was 2.4 x10e6 genome copies (GC)/mL. The titer in 2009 was 5 x 
10e6 GC/mL. Titer of 001-09NV Final Fill sublot 1, a 1/10 dilution of 001-09NV PBH was 5 x 10e5 
GC/mL in 2009 and 2.9 x 10e5 in 2022. These results indicate the virus stock has been stable for more 
than 10 years. 
 
Additional vials of 001-09NV Final Fill sublot 2 were tested to better evaluate the equal distribution of 
the virus across the dilution aliquot run. The mean of all dilutions on the standard curve that passed 

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QC, for all nine vials across three independent assays was 5.36 10e5 GC/ml. The titer was consistent 
across the aliquoting run. Notably, the titer of 001-09NV sublot 1 ranged from 6 x 10e5 GC/mL to 3 x 
10e5 GC/mL between 2009 and 2022, indicating that 001-09NV Final Fill sublot 2 is performing 
consistently with 001-09NV Final Fill sublot 1. The reported titer is slightly higher than expected from 
the 1/8 dilution of master stock but falls within the established range of titer based on historic results 
of 001-09NV Final Fill sublot 1 (5 x 10e5 GC/mL +/- 2 x 10e5 GC/mL). 
 
 
6.3 
Preparation and Administration of NV Challenge Virus 
Subjects will receive a single oral dose of safety-tested inoculum approximately 28 days (+30 day 
window) post vaccination. The oral route was chosen because of ease of administration and successful 
precedent with this route from all other NoV challenge studies.  
 
Subjects will be challenged with a single oral dose of 1.1x106 GC of NV based on information from 
the NV GI.1 dose titration study VXA-G11-201.1, past challenge studies and the NV dose-response 
model (see Section 1.6).  The dose-response model and experience with this dose indicates that this 
dose is sufficient to result in an infection rate between 50% to 65% among susceptible, secretor-positive 
status individuals.  The dose is a single-subject dose (three 1-mL vials for a total of 3 mL of NV 
inoculum Lot 001-09NV, or one 3 mL vial for Sublot 2, IND 14697)  
Three (3) or one (1) vial(s) per subject will be thawed under sterile conditions and swabbed with 
disinfectant.  The inoculum vial(s) will be added to 100 mL of distilled water in a sterile, disposable, 
sealable cup under sterile conditions.  After mixing, the solution will look like a plastic glass of clear 
drinking water.  The sealed cup will be transported on ice to the subject for challenge.  
Since the inoculum contains live infectious human pathogen, biohazard precautions will be observed.  
This includes disposing of all waste in biohazard bags, cleaning equipment and materials that have 
come into potential contact with the inocula with 10% bleach solution.  Cups used for administration 
and any leftover inocula should also be cleaned with bleach and discarded.  If the subject, person 
administering dose, or person preparing inoculum spills the inoculum, the affected area must be 
immediately cleaned with a 10% bleach solution.  Hands should be washed thoroughly with soap and 
water. 
Partially used vials may not be used for human administration or for in vitro experimental studies. At 
the end of the study, the site will receive instruction from the Sponsor regarding the final disposition of 
any remaining NV inoculum.  
 
7 
STUDY PROCEDURES AND SCHEDULE 
Refer to the APPENDIX A:        SCHEDULE OF EVENTS 
7.1 
Pre-Screening Period (Day -90 to Screening) 
Subjects will be pre-screened for purposes of ascertaining H type-1 antigen secretory status and blood 
type. Subjects who are eligible for screening based on the results of the pre-screening assessments or 
known secretory status and blood type will be contacted by telephone and invited to return to the site 
to sign the ICF and enter the study specific screening period. 
 

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7.2 
Visit 00: Screening Visit (Study Day -45 to -1) 
If the subject is secretor positive (genetically susceptible) and blood type A or O, he or she will be 
invited to a full screening visit at the outpatient visit site. 
At this screening visit, the Study Investigator will perform a clinical assessment and blood will be 
collected for laboratory tests. At the time of screening, blood cell counts, blood chemistry, liver 
function, HIV, HBsAg, and HCV status will be tested: a pregnancy test will also be conducted for 
female participants. Vital signs will also be collected (temperature, blood pressure, heart rate, breathing 
rate) as well as height and weight for BMI calculation. A medical history and review of concomitant 
medications will also be performed.  
The Study Investigator will provide counseling as needed to subjects on the results of these tests, 
especially on HIV, HBV, and HCV status. Medical history, physical exam, vital signs and lab results 
must be within normal limits, or abnormalities deemed not clinically significant, at the time of screening 
for the subjects to participate in the study.  Subjects who are eligible to participate in the study will be 
contacted for enrollment.    
The following procedures will be performed to determine eligibility: 
• 
Informed consent 
• 
Demographics 
• 
Medical history 
• 
Eligibility criteria 
• 
Physical examination 
• 
Review of concomitant medications 
• 
Vital signs (including height and weight) 
• 
ECG 
• 
Blood screen (HIV, HBsAg, HCV) 
• 
Safety labs 
o CBC: Hemoglobin, Hematocrit, Platelet Count and Complete White Blood Cell Count 
o Serum Chemistry: ALT, AST, Total Bilirubin, BUN, Creatinine, Random Glucose, 
Potassium and Sodium  
o Urinalysis: Glucose, Protein and Hemoglobin 
• 
Blood Sample: coagulation tests, lab panel (PT/INR, aPTT and fibrinogen) 
• 
Female pregnancy test (serum) 
• 
Drug screen (urine and alcohol breath test) 
 
Subjects will be reminded to fast and refrain from ingesting solid food for at least 4 hours prior to the 
Day 1 study drug administration.  
 
7.3 
Visit 01: Study Day 1, Study Drug Administration 
Subjects will undergo the following assessments and procedures prior to randomization and study drug 
administration: 
• 
Assess inclusion/exclusion criteria 
• 
Physical examination (targeted) 
• 
Vital signs 
• 
Safety Labs  
o CBC 
o Serum Chemistry 

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o Urinalysis 
(Note: Safety labs do not need to be performed if screening safety lab tests were completed 
within 2 days prior to study drug administration on Day 1)  
• 
Female pregnancy test (urine) 
• 
Drug screen (urine and alcohol breath test) 
• 
Blood samples for immunogenicity (PBMCs, serum and fixed whole blood) 
• 
Fecal sample for immunogenicity  
• 
Saliva sample for immunogenicity 
• 
SAM (Synthetic Absorptive Matrix) for nasal mucosal lining fluid (MLF) evaluation 
• 
Review of concomitant medications 
• 
Medical history 
 
Refer to the Laboratory Manuals for details regarding sample collection and handling. 
 
Study eligibility will be reviewed and re-confirmed at this study visit. Those subjects who satisfy all 
inclusion criteria and none of the exclusion criteria will qualify and be eligible to be randomized into 
the study. 
The following procedures will be performed following randomization: 
• 
Study drug administration (vaccine or placebo) – administer study drug tablets, after subject 
has been fasting for at least 4 hours prior to start of dosing 
(please refer to Pharmacy Manual for detailed study drug administration instructions) 
• 
Solicited symptoms of reactogenicity e-Diary (electronic Diary) – dispense e-Diary to subject 
and provide instructions for use 
• 
Assess for solicited and unsolicited adverse events after initiation of study drug administration 
7.4 
Visit 02: Study Day 8 
Every effort should be undertaken to ensure the subject returns to the site on Day 8, exactly 7 days post 
vaccination, to allow optimal evaluation of immune response. Subjects will undergo the following 
assessments and procedures: 
• 
Physical examination (targeted) 
• 
Vital signs 
• 
Safety Labs 
o CBC 
o Serum Chemistry 
o Urinalysis 
• 
Review and collect solicited symptoms of reactogenicity e-Diary  
• 
Review of concomitant medications 
• 
Query for AEs 
• 
Blood samples for immunogenicity (PBMC and fixed whole blood) 
• 
Saliva sample for immunogenicity 
• 
SAM (nasal MLF evaluation) 
 
7.5 
Visit 03: Study Day 28, 1 day prior to challenge [+3 days for visit window and 
+30 days window for repeat Visit 03] 
All subjects will return to the site at Day 28 for safety assessments and collection of samples to complete 
the vaccination phase of the study.  

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Study subjects will begin their inpatient stay 1 day before challenge. Subjects will be assigned to a 
single room and instructed about the protocol-required procedures (e.g., stool handling), hygiene 
practices, and the “Rules and Procedures” to be followed while in the inpatient unit. Subjects will also 
be monitored for evidence of behaviors which might pose a safety risk to themselves, other subjects, or 
staff and could be cause for ineligibility for challenge and the remainder of the inpatient stay.  Refusal 
to comply with protocol-required procedures, adherence to hygiene practices could constitute 
ineligibility  
Any subject who is deemed ineligible will be discharged from unit prior to challenge. Subjects may 
return for re-evaluation of challenge eligibility within 30 days of their original Day 28 Visit.  If they 
are assessed to be eligible for challenge at that time, they may be included for challenge with a 
subsequent cohort.  
All subjects that continue to demonstrate eligibility will fast (defined by nothing by mouth except for 
water), starting from the midnight prior to the challenge day. 
Subjects will undergo the following assessments and procedures. Subjects will also be screened for 
eligibility for enrollment into the challenge phase: 
• 
Physical examination (targeted) 
• 
Vital signs 
• 
ECG 
• 
Safety Labs 
o CBC 
o Serum Chemistry 
o Urinalysis 
• 
Female pregnancy test (urine) 
• 
Stool sample for enteric pathogens (BioFire) 
• 
Influenza A & B antigen test 
• 
Drug screen (urine, alcohol breath test) 
• 
Blood samples for immunogenicity (PBMC, serum and fixed whole blood)  
• 
Fecal sample for shedding (pre-challenge baseline) 
• 
Fecal sample for immunogenicity  
• 
Saliva sample for immunogenicity 
• 
SAM (nasal MLF evaluation) 
• 
Review of concomitant medications 
• 
Query for AEs 
 
This visit is required for all subjects regardless of challenge status, since there are blood draws 
impacting immune endpoints from vaccination stage. It is a deviation if Visit 03 does not occur.  Visit 
3 has a +3 day window, followed by a +30 days window for repeat Visit 03, if needed, to rescreen 
subjects for challenge.  
 
Day 28 immunogenicity samples, including stool, should be collected at the subject’s original Day 28 
visit and do not need to be re-collected prior to challenge, if the subject’s challenge visit is delayed (+ 
30 days).  However, a stool sample is needed at the repeat Day 28 Visit, if challenge is postponed within 
window, for enteric pathogens (BioFire), if needed, and for shedding pre-challenge baseline. The stool 
sample for fecal immunogenicity may be collected 1 day or within 24 hours of Day 28 through pre-
challenge on Day 29. 
 

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BioFire GI Testing Guidance: 
• 
Subjects without symptoms of AGE in the 72 hours prior to Day 28 should not have BioFire 
GI pathogen assay 
• 
For subjects with symptoms of AGE in the 72 hours prior to challenge who test positive on 
BioFire for an enteric pathogen OTHER THAN NOROVIRUS, they may be re-evaluated for 
a future challenge as allowed by protocol.  
• 
If no AGE symptoms in the preceding 72 hours when evaluating for the next challenge AND 
the investigator considers the prior AGE fully resolved, that subject does not need a repeat 
BioFire GI pathogen test 
• 
Any subject in this situation should be discussed with Vaxart MM (including which pathogen 
was positive on BioFire at initial challenge screening) for approval to re-evaluate for 
challenge.  
• 
A subject that tests positive for Norovirus at Day 28 will be excluded from future norovirus 
challenge. 
 
 
 
7.6 
Visit 04: Study Day 29 (Challenge Day) 
 
 
Pre-challenge Assessments 
On the morning of challenge, fasting subjects will have baseline vitals (temperature, blood pressure, 
heart rate, breathing rate) recorded and a final eligibility confirmation (medical history and targeted 
physical examination) will be completed prior to oral ingestion of the challenge inoculum.   
 
 
Viral Challenge Eligibility 
Results of Day 28 assessments (except the immunological tests) as well as the pre-challenge 
assessments on Day 29, must be available and reviewed prior to virus administration.  Subjects 
who have any of the following conditions are not eligible for participation in the challenge phase: 
• clinically significant symptoms or signs of norovirus acute gastroenteritis (per the judgment 
of the investigator) as assessed by: 
o Investigator-assessed signs of norovirus illness  
o Targeted physical examination  
(exception: mild headache, with no signs or symptoms of infection and no fever, may 
be allowed); 
• positive for enteric pathogens (BioFire); 
• positive Influenza A or B antigen test result; 
• an oral temperature of >37.5°C; 
• 
any finding (clinical or laboratory value), that in the opinion of the investigator, should exclude 
the subject from viral challenge due to safety concern; 
• 
any conditions, that in the opinion of the investigator, might interfere with the subject’s ability 
to complete participation in the challenge (sequestration) phase, per protocol; 

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• 
any finding (clinical or laboratory value), that in the opinion of the investigator, might interfere 
with ability to assess the primary study objectives. 
 
Should a subject be deemed inappropriate for continued participation into the challenge phase, the 
reason for ineligibility will be documented and the subject will be rolled into the safety follow-up 
period. The subject will enter the safety follow-up period continue to be contacted through Day 365, 
as described in Section 7.9 .  
 
 
Viral Challenge Administration  
Subjects will have fasted overnight prior to viral challenge. Additionally, they should have nothing by 
mouth, except water, for 90 minutes before and after ingestion of the challenge inoculum.  Subjects 
will drink 100 mL of sodium bicarbonate solution (~1.3% NaHCO3) prior to viral challenge; 
approximately 1 minute later, subjects will ingest the NV inoculum (Lot 001-09NV and Sublot 2, IND 
14697) suspended in 100 mL of distilled water. 
 
 Visits 04 – 08: Post-Challenge Observation Period  
(Day 29 – Day 33 [+ 3 Days]) 
Following ingestion of the challenge inoculum, the following procedures will be performed: 
 
• 
Study subjects have daily targeted physical exams and will be monitored for symptoms of 
NV illness and vital signs twice daily while in the clinical research unit post-challenge.   
• 
All fecal samples will be graded for consistency (grade 1 to 5) and weighed.  
• 
All emesis will be collected and weighed when available.  
• 
Following challenge, anticipating signs and symptoms will be assessed. The maximum 
symptom severity for the day will be determined using a standard rating scale. 
• 
Anticipated signs and symptoms of norovirus acute gastroenteritis include:  diarrhea, vomiting, 
nausea, fever, abdominal cramps or pain, abdominal gurgling or bloating and myalgia.  These 
symptoms will be solicited and graded. 
• 
The maximum temperature, total diarrheal stool volume, number of diarrheal stools, total 
emesis volume, and number of emesis episodes will be calculated for each 24 h period during 
the inpatient stay. 
• 
On Day 33 (either prior to discharge or if subject remains sequestered) 
o Blood sample for Immunogenicity (PBMC and fixed whole blood) 
o Safety Labs 
▪ 
CBC  
▪ 
Serum Chemistry 
▪ 
Urinalysis 
o Discharge criteria must be assessed and met (per checklist) 
o NV signs and symptoms e-Diary will be dispensed prior to discharge with instruction 
for use, unless subject remains an inpatient through Day 36 (Day 33 + 3days)  
The nursing staff as well as the trained study staff will monitor the subject’s vital signs and assess for 
signs and symptoms of acute NoV illness twice daily from Day 29 post challenge to discharge.  if a 
subject experiences emesis or diarrhea after the last NV Signs and Symptoms assessment of the 
calendar day, the site will record the occurrence on the second Norovirus Signs and Symptoms form 
for the corresponding calendar day in which it occurred. If a subject experiences emesis or diarrhea 
after the first NV Signs and Symptoms assessment of the day but before 12:00pm, the site will record 

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the occurrence on the first Norovirus Signs and Symptoms for the corresponding calendar day on 
which it occurred. If a subject experience any of the other symptoms on the Norovirus Signs and 
Symptoms form after the last assessment of the calendar day, those symptoms will be recorded on the 
first assessment of the next day. Grading scales (Appendices C and D) will be used to classify 
diarrhea, nausea, and vomiting. Subjects will also be asked to rate symptoms of myalgia and fatigue 
as mild, moderate or severe.  AEs and concomitant medication usage will also be collected during the 
inpatient stay. During the first 4 days after challenge, subjects will receive daily weight, fluid intake, 
and fluid output measurements.  The Study Investigator, or his/her designated representative, will 
monitor subjects daily. The subjects will remain in the inpatient unit at least 4 days after challenge 
following enteric isolation procedures.  All staff in contact with subjects will be asked to wear 
Personal Protective Equipment of at least disposable gloves, gowns, and masks. 
A portion of stool and emesis samples passed by the subjects during their inpatient stay will be collected 
and stored at 4°C.  These specimens will be tested for the presence of the NoV challenge strain by qRT-
PCR. Fecal and saliva samples collected before challenge and 28 days after challenge will be tested for 
NoV viral protein 1 (VP1) antibody.  
On the day of discharge from the inpatient unit, approximately 60 mL of whole blood will be collected 
for PBMC isolation, and a sample for safety labs. 
7.6.4.1 
Discharge Criteria 
Study subjects will be evaluated for discharge 4 days after challenge (Day 33). If subject is still 
symptomatic with NV illness and it is clinically indicated, they will remain in the isolation unit for 
additional days up to Day 36. At the time of discharge, subjects will be instructed on the importance of 
hand washing and careful personal hygiene and given antimicrobial soap. Subjects will be asked to 
follow appropriate sanitation and hygiene for 1 month following virus ingestion.  At the time of 
discharge, subjects will be given stool collection kits to take home so that they can bring a stool sample 
within 24 hours of their return on Day 36 (first follow-up visit).  Subjects will also be dispensed an  
e-Diary that they will use to record signs and symptoms of NV illness daily through their Day 36 visit. 
7.6.4.2 
Early Termination/Early Discharge 
Subjects that desire to withdraw from the study or are withdrawn by the Investigator (eg, due to 
continuing non-compliance or safety concerns) during the inpatient period will be given instructions 
on appropriate follow up. If a subject desires to leave the inpatient containment unit early, the study 
staff will ensure the subject is no longer having symptoms, diarrhea, or emesis. A document of early 
termination/withdrawal will be completed by the study staff and co-signed by the subject.  The subject 
will not be compensated for any inpatient days that are not completed, including the day of early 
termination. 
7.7 
Visit 09: Study Day 36 (7 Days post challenge) 
A targeted physical exam and vital signs will be performed.  Subjects will bring in a stool collected 
within 24 hours of Day 36 visit. Subjects will be given stool collection kits to take home, so they can 
bring a stool specimen collected within 24 hours of their next follow-up visit (Day 57).  Subjects will 
be contacted to remind them of their follow-up appointment and to bring a stool specimen with them 
to their next appointment.  Subjects who do not bring in a stool specimen will be asked to drop off a 
specimen the next day.  At the clinical site, stool samples will be processed per Lab Manual 
Subjects who underwent challenge will undergo the following assessments and procedures: 
• 
Vital signs 
• 
Review of concomitant medications 
• 
Query for AEs 

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• 
Blood samples for immunogenicity (PBMC and fixed whole blood) 
• 
Saliva sample for immunogenicity 
• 
SAM (nasal mucosal lining fluid) 
• 
Symptom grading (signs of NoV infection) 
• 
Review and collect NV signs and symptoms e-Diary  
 
7.8 
Visit 10: Study Day 57 (28 Days post challenge ± 3 days) 
Subjects who underwent challenge will undergo the following assessments and procedures: 
• 
Physical examination (targeted) 
• 
Vital signs 
• 
Female pregnancy test (urine) 
• 
Blood samples for immunogenicity (serum, PBMC and fixed whole blood) 
• 
Fecal sample for shedding 
• 
Fecal sample for immunogenicity  
• 
Saliva sample for immunogenicity 
• 
SAM (nasal mucosal lining fluid) 
• 
Review of concomitant medications 
• 
Query for AEs 
 
Any subjects that did not undergo viral challenge should be contacted at Day 57 for safety follow-up 
and queried for SAEs, AESIs and NOCIs. 
 
For subjects who are ineligible for challenge phase, Section 7.8 of the protocol should be followed 
instead of Section 7.11; that is, subjects who are not challenged should begin the safety follow up at 
Visit 10 (Day 57). This visit may be a phone contact. No separate “early termination” visit needs to 
occur. Only subjects who truly terminate participation in the study should have an early termination 
visit.  
 
7.9 
Visit 11 (Day 120) – Visit 14 (Day 300) Safety Follow-up Contacts  
 
• 
Visit 11: Study Day 120 (92 days post challenge + 1 week) 
• 
Visit 12: Study Day 180 (152 days post challenge + 1 week) 
• 
Visit 13: Study Day 240 (212 days post challenge + 1 week) 
• 
Visit 14: Study Day 300 (272 days post challenge + 1 week) 
Subjects will be contacted (text/email/phone) every 2 months during the safety follow-up period and 
queried for the following:  
• 
Query for SAEs 
• 
Query for AESIs and NOCIs 
 
 
7.10 Visit 15: Study Day 365 (337 days post challenge + 1 week) End of Study 
Contact 
Subjects will be queried for the following during the Day 365 phone call:  End of study contact 
• 
Query for SAEs 
• 
Query for AESIs and NOCIs 

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7.11 Early Termination 
 
 Early Termination (Day 1 – Day 28; Vaccine Phase) 
Subjects will undergo the following assessments and procedures:  
• 
Physical examination 
• 
Safety labs  
o CBC  
o Serum Chemistry 
o Urinalysis 
• 
Vital signs 
• 
Urine pregnancy test (females) 
• 
Fecal sample for immunogenicity 
• 
Saliva sample for immunogenicity 
• 
Blood sample for Immunogenicity (see Appendix A for details of samples and testing to 
be performed)  
• 
Review and collect e-Diary if still in use prior to withdrawal 
• 
Review of concomitant medications 
• 
Query for AEs  
• 
Update contact information 
 Early Termination (–ay 29 - Day 57;  Challenge Phase) 
Subjects who underwent challenge and terminate during the challenge period will undergo the 
following assessments and procedures: 
• 
Physical examination 
• 
Vital signs 
• 
Urine pregnancy test (females) 
• 
Fecal sample for immunogenicity 
• 
Saliva sample for immunogenicity 
• 
Blood sample for Immunogenicity (see Appendix A for details of samples and testing to 
be performed)  
• 
SAM (nasal mucosal lining fluid) 
• 
Review and collect e-Diary if still in use prior to withdrawal 
• 
Review of concomitant medications 
• 
Query for AEs 
• 
Update contact information 
 
 
 Early Termination (Day 58 to Day 365 – Safety Follow-Up Period) 
Subjects who terminate early during the safety follow up period will undergo the following 
assessments:  
• 
Query for SAEs, AESIs and NOCIs 
 

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7.12 Unscheduled Visit(s) 
Subjects who experience any serious or severe adverse effects or experience an event of concern can 
be scheduled for an additional visit for further evaluation. If an unscheduled visit occurs, a member of 
the clinical study team (PI, sub-investigator, nurse coordinator, or clinical nurse) will evaluate the 
subject to determine the cause of the visit and provide care as needed. All procedures and/or sample 
collections should be documented within in unscheduled visit CRF. 
 
7.13 Immunogenicity Assessments 
Primary Immunoassays 
• 
VP1 specific IgA ASC (by MSD) 
• 
HBGA blocking antibodies (BT50) 
• 
VP1 specific serum IgG (by MSD) 
• 
VP1 specific serum IgA (by MSD) 
Exploratory Immunoassays 
• 
VP1 specific IgG ASC 
• 
VP1 specific IgG and IgA memory B cells (by ELISpot) 
• 
VP1 specific IgG and IgA from plasmablast cultures (by ELISA) 
• 
B cell immunophenotyping (by flow cytometry and/or single cell sequencing) 
• 
Fecal VP1 specific IgA (by ELISA or MSD) 
• 
Saliva VP1 specific IgA (by ELISA or MSD) 
• 
Mucosal VP1 specific IgA (by ELISA or MSD) 
• 
Fixed whole blood (by CyTOF or flow cytometry)  
 
Additional exploratory immunogenicity assays may also be performed to further evaluate the activity 
of the VXA-G1.1-NN vaccine candidate on samples stored for future use (with subjects’ consent).  Note 
that not all sample timepoints may be relevant for the some of the analysis, so not all assays will be 
performed at all timepoints. 
7.14 Assessment of Clinical Illness 
Following challenge, study subjects will be monitored twice a day unless greater frequency is 
clinically indicated through discharge (Day 33 + 3 days) for the following gastrointestinal signs and 
symptoms of norovirus illness: 
o diarrhea, vomiting, nausea, fever, myalgia 
o abdominal cramps, pain, gurgling or bloating 
7.15 Norwalk Virus Infection 
NV infection as detected by qRT-PCR, > 1 positive post-challenge stool or emesis sample through  
day 8 post-challenge. 

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7.16 Microbiological Assessments 
During the challenge phase sequestration period all fecal and emesis specimens will be 
weighed/measured for volume. All fecal and emesis will be collected daily and tested for NV. Stool 
will be graded. A stool sample will also be collected at Day 36 and Day 57. 
8 
MANAGEMENT OF EXPECTED NOROVIRUS ILLNESS 
8.1 
Clinical Evaluation 
After NV challenge, subjects will remain in the ward for at least 4 days. Vital signs (temperature, blood 
pressure, heart rate, respiratory rate) will be measured twice a day (am and pm) throughout the 
confinement period until discharge. Subjects will be interviewed daily by a study investigator to 
determine the occurrence of illness signs and symptoms. This data will be recorded on a standardized 
form and graded in severity according to a standardized scale.  A focused physical examination may be 
performed at the discretion of the Investigator according to the nature of a subject’s complaint. 
8.2 
Study Definitions 
Norovirus Gastroenteritis (NVG): 
NVG is a composite endpoint defined as meeting one or more of the following definitions for both 
Acute Gastroenteritis and NV Infection during the inpatient period. 
 
Acute Gastroenteritis (clinical NV illness): 
Acute Gastroenteritis (AGE) is defined as meeting any one of the three categories listed below: 
 
• 
Diarrhea:  
o ≥ 3 loose or liquid stools produced in any 24-hour period, or  
o > 400g of loose or liquid stools produced in any 24-hour period; 
• 
Vomiting: ≥ 2 vomiting episodes in any 24-hour period, or 
• 
Diarrhea and vomiting:  
o One vomiting episode plus any loose or liquid stool in any 24-hour period, or 
o One vomiting episode plus ≥ 2 of the following events in any 24-hour period:  
▪ 
nausea 
▪ 
fever (oral temperature ≥ 37.6C) 
▪ 
abdominal cramps or pains 
▪ 
abdominal gurgling or bloating  
▪ 
myalgia 
See Appendix C for grading scales for signs and symptoms of acute gastroenteritis.    
Norwalk Virus Infection: 
• 
NV infection as detected by qRT-PCR, > 1 positive post-challenge stool or emesis sample 
through day 8 post-challenge. 
 
8.3 
Measurement of Diarrhea and Vomitus 
Since diarrhea is anticipated to be a common occurrence, all subjects will be expected to collect every 
stool that is passed, from the time of challenge until discharge.  Subjects will be instructed to use a 
plastic stool collection basin (hat). Subjects will be instructed on how not to collect urine in the same 
container. All stools will be weighed and graded by the study staff.  The grading of stool is based on 
consistency and the definition of diarrhea is a grade 3 or higher in stool, as follows: 
• 
Grade 1 – well formed (does not take the shape of the container) 

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• 
Grade 2 – soft (does not take the shape of the container) 
• 
Grade 3 – thick liquid (diarrhea, takes the shape of the container readily) 
• 
Grade 4 – opaque watery diarrhea 
• 
Grade 5 – rice water diarrhea (clear watery) 
Any grade 3 or higher stool weight, will be used to estimate the volume of fluid loss (assume 
approximately 1-gram diarrheal stool = 1 mL of fluid lost).  
Similarly, any episodes of vomiting should be collected in either a stool “hat” or a plastic “kidney” 
basin, provided. If a vomiting or diarrhea episode is not able to be collected in a basin (e.g., the subject 
has an “accident” while sleeping or before they are able to reach a toilet), then the volume of the output 
will be estimated. 
8.4 
Management of Fluid Loss 
Subjects who develop diarrheal stools (grade 3 or higher) will begin oral fluid replacement at 1.5 times 
the stool volume. Vomitus will be replaced with oral fluids in equal amounts, 1:1 ratio.  If a subject 
develops severe watery diarrhea or persistent vomiting and cannot maintain full hydration by oral 
means, IV fluid replacement will be administered.   
Assessment of dehydration may include urine specific gravity and serum electrolytes (Sodium, 
Potassium, Chloride, Bicarbonate) and renal function (blood urea nitrogen [BUN] and creatinine) and 
physical assessment. 
An Investigator is available by telephone or beeper at all times. Nurses will notify the on-call 
Investigator if any of the following occurs in a subject who is experiencing diarrhea and/or vomiting: 
• 
Syncope 
• 
Complaint of dizziness or lightheadedness or established orthostatic hypotension 
• 
Urine specific gravity > 1.025 
• 
> 500 mL behind in ORS replacement 
• 
Vomiting of ≥ 500 mL once or total volume within the past 4 hours 
• 
High fever ≥ 39C (102.1F) 
• 
Severe headache, severe malaise, or severe abdominal pain 
• 
Subject has a complaint for which he/she requests treatment 
• 
Any other clinical situation that concerns the nurse 
 
8.5 
Indications for Concomitant Medications 
Any concomitant medication, prescription or over-the-counter, will be evaluated for continuation 
during the inpatient setting (eg, long-standing single-agent anti-hypertensive medication or cholesterol 
medication).  Any such medication will need to be discussed with and approved by the investigator 
prior to admission.  The supply of medication will be the responsibility of the subject and will be handed 
over to the research staff upon admission; daily administration will be recorded.  Any un-declared 
prescription or over-the-counter medications that are discovered during the inpatient stay will constitute 
a violation of the ward “Rules and Procedures.”  
Other medications may be administered during the study period as follows: 
• 
Smoking is not allowed on the ward, but subjects will be able to request a nicotine patch.  
• 
Anti-pyretics and analgesics (ie, ibuprofen, acetaminophen, aspirin, or similar non-steroidal 
agents) may be prescribed for severe headaches, other pains, or fevers (eg, sustained 
temperatures of ≥ 39C). 
• 
At the investigator’s discretion (eg, upon review of serum electrolyte results during severe 
diarrhea), oral potassium and/or IV fluids may be administered for repletion of electrolyte 
losses. 

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• 
Other medications, which are deemed necessary for the safety and welfare of the subject.  
The prescription of any medication must be ordered and signed by the investigator and each 
administration recorded. 
8.6 
Prohibited and Controlled Medications/Treatments 
All concomitant medications will be recorded from 30 days prior to start of screening through 
completion of the challenge active study period (Day 57). 
Subjects may not initiate new medications (or change the dose of an allowed concurrent medication) 
within 30 days prior to first vaccination, with exceptions, as outlined in the study exclusion criteria 
Section 4.2. Subjects will be questioned regarding any changes in concomitant medication usage 
through the end of the challenge active study period (Day 57).  Any changes from Baseline will be 
recorded within the corresponding Case Report Form (CRF). 
9 
ASSESSMENT OF SAFETY 
The safety assessment of the study vaccine and challenge virus will be through the detection and 
documentation of AEs, both solicited AEs and unsolicited AEs, and/or clinically significant laboratory 
abnormalities, from baseline (time of vaccination) through 28 days post-challenge. The occurrence of 
SAEs, AESIs and NOCIs will be reported through 12 months post vaccination –Day 1 - Day 365). 
9.1 
 Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject after administration of the investigational 
vaccine and that does not necessarily have a causal relationship with the investigational vaccine.  An 
AE can therefore be any unfavorable and unintended sign (including abnormal laboratory findings), 
symptoms, physical examinations, or disease temporally associated with the use of the investigational 
vaccine, whether related to the investigational vaccine.  This definition includes exacerbations of pre-
existing conditions.  Stable pre-existing conditions which do not change in nature or severity during 
the study are not considered AEs; however, these should be reported as part of the medical history. 
Solicited AEs are pre-specified reactogenicity symptoms including:  
• 
fever 
• 
nausea 
• 
vomiting 
• 
diarrhea 
• 
headache 
• 
malaise/fatigue 
• 
myalgia (muscle pain) 
• 
abdominal pain 
• 
anorexia 
 
9.1  Solicited Symptom Reactogenicity Table 
 
Subjects will utilize a solicited symptom e-Diary issued on the day of vaccination to daily record the 
events during the first 7 days following vaccination. These solicited symptoms will be graded as follows 
in Table 20: 
 

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Table 20 
SOLICITED SYMPTOM REACTOGENICITY TABLE 
 
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 
Event easily 
tolerated, causing 
minimal 
discomfort and no 
interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever for >24 
hours or some 
interference with 
activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
(muscle 
pain) 
None 
Event easily 
tolerated, causing 
minimal 
discomfort and no 
interference with 
activity 
Event sufficiently 
discomforting to 
interfere with 
daily activity 
Significant; 
Prevents daily 
activity 
ER visit or 
hospitalization 
Abdominal 
Pain 
None 
Event easily 
tolerated, causing 
minimal 
discomfort and no 
interference with 
activity 
Some interference 
with activity but 
no medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
Anorexia 
None 
Event easily 
tolerated, causing 
minimal 
discomfort and no 
interference with 
activity 
Some interference 
with activity but 
no medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
Nausea 
None 
No interference 
with activity 
Some interference 
with activity 
Prevents daily 
activity 
ER visit or 
hospitalization  
Vomiting 
None 
1 or 2 episodes in 
24 hours 
>2 episodes in 24 
hours 
Requires outpatient 
IV hydration 
ER visit or 
hospitalization  
Diarrhea 
None 
2 to 3 loose stools 
in 24 hours 
4–5 loose stools in 
24 hours 
6 or more loose 
stools in 24 hours  
ER visit or 
hospitalization 
Malaise/ 
Fatigue 
None 
Event easily 
tolerated, causing 
minimal 
discomfort and no 
interference with 
activity 
Some interference 
with activity 
Significant; 
Prevents daily 
activity 
ER visit or 
hospitalization 
a Everyday activity includes attendance at work, school, and usual habits of the subjects. 

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Unsolicited AEs are any AEs reported spontaneously by the subject, observed by the study personnel 
during study visits or those identified during review of medical records or source documents. 
Unsolicited AEs (all AEs not collected in the solicited symptom e-Diary during the first 7 days 
following vaccination) will be monitored and collected from the time of vaccination through Day 28 as 
AEs relevant to vaccination.  
 
Unsolicited AEs will be monitored and collected from post challenge (Day 29) through end of active 
phase (Day 57) as AEs relevant to challenge virus.  
9.1.2      Grading of Severity of an Adverse Event 
Severity of AEs will be graded as:  
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 and daily 
activities. 
Severe:  events interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the duration of the 
event at each level of intensity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Relationship to Challenge Virus  
Relationship (causality or attribution) of all AEs to NV infection, or to an alternate etiology (unrelated 
to the study) is part of the documentation process, but it is not a factor in determining what is (or is not) 
reported in the study.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported.  All AEs must have their relationship assessed using 1 of 2 terms:  related to NV 
infection, or not related (an alternate etiology can be identified and is likely or feasible).  To help assess, 
the following guidelines are used. 
 
Related to norovirus challenge:  There is a reasonable possibility that the NV infection caused the AE. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the NV 
illness and the AE, and there is no reasonable alternate etiology. 
 
Not Related:  There is not a reasonable possibility that the event is related to NV and there is a 
reasonable alternate etiology 
 
Relationship to Study Vaccination 
For all solicited and unsolicited AEs, including NOCIs, the Investigator will make a judgment regarding 
the relationship of the AE to the investigational product in a blinded manner. All AEs must be recorded 
in the source documents as well as the case report form (CRF). 
The degree of certainty with which an AE is attributable to study vaccine or an alternative cause will 
be determined by how well the event can be understood in terms of: 
• 
Temporal relation to administration of study vaccine administration 
• 
The existence of other plausible explanations for the AE 

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The relationship of the AE to study drug administration will be specified as follows: 
Not related: In the Investigator’s opinion, there is no causal relationship between study drug 
administration and the AE; 
Related: 
The AE follows a known temporal sequence from the time of study drug administration, 
cannot be explained by other disease or medications and the event is an objective and 
specific medical disorder or a recognized pharmacological phenomenon. 
 
9.2 
Definition of Serious Adverse Event  
A SAE is any AE that results in any of the following outcomes: 
1. Death 
2. A life-threatening event. Life-threatening events mean that the study subject was, in the 
opinion of the site PI or Sponsor, at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe.  
3. Requires inpatient hospitalization or prolongation of existing hospitalization  
4. Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5. Congenital abnormality or birth defect 
6. Important medical event that may not result in one of the above outcomes but may 
jeopardize the health of the study subject and/or requires medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of SAE. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
All SAEs will be: 
• recorded in the research record  
• reported to the local IRB, per local IRB guidelines 
• reviewed and evaluated by a study clinician and the PI 
• followed through resolution by a study clinician 
• All SAEs, life-threatening events and deaths, whether related or unrelated, will be reported 
to the study sponsor within 24 hours of site awareness.  
• Other SAEs regardless of relationship, will be reported to the study sponsor within 72 hours 
of site awareness  
 
9.3 
Definition Adverse Events of Special Interest (AESI) 
An AESI should not necessarily be classified to be a serious adverse event, even though the event may 
be clinically significant.  If an AESI is reported, Vaxart should be promptly informed and information 
relevant to the event should be promptly collected using the same process as that used for reporting 
serious adverse events (see Section 8.2) Please see list of AESIs on APPENDIX E: Lists of Adverse 
Events of Special Interest. 
 
9.4 
Definition of New Onset of Chronic Illness (NOCI) 
A NOCI is defined as diagnosis post study drug administration of a new medical condition, which is 
chronic in nature, including those potentially controllable by medication (eg, diabetes, asthma).  The 
occurrence of NOCIs will be queried for from Day 1 post-vaccination through the safety follow-up 
period (Day 365). 
 

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9.5 
Study Halting Rules 
 
The study will be halted (no new enrollment, vaccinations, or challenge will be allowed pending a SMC 
safety review) if any of the events described below are met during the overall conduct of the study 
(vaccine and challenge phase).  
• Two or more subjects experience a treatment related serious adverse event (SAE) of any 
grade, or a treatment related grade 3 or 4 AE between Day 1 and Day 28 (vaccination phase). 
• Two or more subjects experience a treatment related serious adverse event (SAE) of any 
grade, or a treatment related grade 3 or 4 unsolicited AE within 28 days after challenge. 
The SMC will provide study oversight throughout the duration of the trial interventional and safety 
follow-up period (Day 1 through Day 365 post-vaccination). The IRB and CBER will be notified if the 
study is halted for safety concerns. 
 
9.6 
Safety Oversight 
A Medical Monitor (MM) will perform the oversight of safety for this study. The MM is a physician 
experienced in the conduct of research clinical studies. The primary responsibility of the MM is to 
monitor subject safety. The MM will be responsible for reviewing the cumulative safety data, including 
a review of safety laboratory test results and AE reporting. The MM considers study-specific data as 
well as relevant background information about the disease, test agent, and target population under 
study. The MM is empowered to request a Safety Monitoring Committee (SMC) safety review which 
can suspend the study, recommend amendments to the protocol, and/or to request further information. 
9.7 
Safety Monitoring Committee (SMC) 
A SMC will be created for oversight and adjudication of AEs.  The committee will consist of 
independent physicians with vaccine clinical trials experience, and the MM, who does not enroll 
patients into the study.  The sponsor will have a member as a non-voting observer of the SMC. The 
Sponsor’s Chief Medical Officer (CMO) and the study’s PI will serve as a non-voting members of the 
SMC. The CMO’s main role will be to provide background information on the study protocol as well 
as past safety experience with the Vaxart oral vaccine platform. The PI will provide information on 
study conduct. The responsibilities of the SMC will be to: 
1) Review and be familiar with key clinical documentation concerning subject safety including but 
not limited to: study protocol, informed consent form, Investigator’s Brochure and the SMC 
Charter. 
2) Provide ongoing oversight of the study. Periodic safety reviews of the ongoing study will be 
conducted at pre-defined time points. Additionally, ad hoc meetings will be convened if any serious 
vaccine or study treatment related events or trends are observed. 
3) The SMC will also have formal meetings if any of the pre-specified Halting Rules are met to review 
safety data and make recommendations on how to proceed. The IRB will be notified if the study is 
halted for safety concerns. 
4) Review the symptomatic data collected for early cohorts in the challenge phase, blinded to 
treatment, to confirm the challenge virus is performing as anticipated may be undertaken.  If fewer 
subjects are showing symptoms, additional interim analyses may be recommended by the SMC.  
Any unblinded analyses will be restricted to the SMC. 
5) 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 

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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.  
10 CLINICAL MONITORING 
Site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial follows 
the currently approved protocol/amendment(s), with Good Clinical Practice (GCP), and with applicable 
regulatory requirement(s). Monitoring refers to the methods used by sponsors of investigational studies, 
or Contract Research Organizations (CROs) delegated site monitoring responsibilities, to oversee the 
conduct of, and reporting of data from, clinical investigations. Site monitoring includes ensuring 
appropriate clinical investigator supervision of study site staff and third-party contractors.   
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.  
11 STATISTICAL CONSIDERATIONS 
The primary endpoint of this study is a composite of occurrence of NVG caused by the challenge 
norovirus during inpatient challenge period and is defined as meeting one or more of the definitions for 
both acute gastroenteritis and NV infection.  
11.1 Study Hypothesis 
The study hypothesis is that norovirus vaccine, VXA-G1.1-NN, will protect against norovirus 
gastroenteritis related to norovirus infection in the challenge model. Protective efficacy (PE) will be 
estimated by the prevention of norovirus gastroenteritis among vaccine recipients compared to placebo 
recipients in those who were challenged.  
 
The null hypothesis is that the absolute protective efficacy is zero. The two-sided alternative hypothesis 
is that the absolute protective efficacy is not equal to zero. 
 
H0: PE = 0 
HA: PE ≠ 0 
The estimated protective efficacy is defined as: 
𝐴𝑅0−𝐴𝑅1
𝐴𝑅0
 
Where AR1 is the observed norovirus gastroenteritis rate among vaccinated subjects and AR0 is the 
norovirus gastroenteritis rate among subjects receiving placebo. 
 
A Fisher’s Exact Test with a 5% two-sided significance level will be used to evaluate the primary 
endpoint of clinical efficacy of VXA-G1.1-NN compared to placebo, to protect against NVG caused 
by the Norwalk strain challenge inoculum. The sample size will be determined in order to evaluate 
the primary endpoint using a Fisher’s Exact test with a 5% significance level (Section 11.2) 
 
The study hypothesis will also be evaluated using the Chi-Squared test as a sensitivity analysis for the 
primary endpoint as the Fisher’s Exact test can be overly conservative in some circumstances.  
 
An additional study hypothesis will also be evaluated as a sensitivity analysis. The null hypothesis 
will be that the absolute protective efficacy is zero, and the one-sided alternative hypothesis will be 
that the absolute protective efficacy is greater than zero.  

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 Blinding Procedures 
Investigators and subjects will remain blinded to treatment assignment until completion of the challenge 
phase (through Day 57) and validation of the clinical data. The Sponsor’s clinical team and laboratory 
personnel will also be blinded to subject treatment through Day 57 analyses. Investigators may be 
unblinded prior to the final Day 365 end-of-study follow-up phone call. 
 
Each bottle of multi-dose DP/placebo tablets will be labeled with an open label. The unblinded research 
pharmacist will use the randomization list to prepare the dose of DP/placebo tablets. All DP/placebo 
preparation and administration will be performed per study specific procedures detailed in the Study 
Pharmacy Manual. 
  
Only in a medical emergency, when knowledge of the study treatment is essential for further 
management of the subject, will the randomization code be broken. In the event that this is necessary, 
the PI or designee will provide the study identification number to the research pharmacist, who will 
provide the PI with the treatment assignment for that subject. The PI will notify the Sponsor 
immediately and document the event on the appropriate study documents. If time allows, the 
investigator will notify the Sponsor Medical Monitor (MM) prior to unblinding the treatment received 
by the individual subject. 
11.4 Final Analysis Plan 
Clinical, safety, reactogenicity, and challenge data through approximately Day 57 (28 days post 
challenge) will represent the primary clinical database for this trial. Once the last subject completes the 
Day 57 visit, the primary clinical database will be cleaned, monitored and locked. Unblinded analyses 
of primary and secondary endpoints, including available safety data, are planned. As it is anticipated 
that subjects will remain in long-term safety follow-up at the time of these analyses, blinded site 
clinicians and Medical Monitors not involved in the analysis, publication or clinical study report (CSR) 
preparation will be responsible for assessing SAEs and AESIs, and NOCIs, until all subjects have 
completed the final follow-up visit. All analyses of data included in the preliminary report for early 
release will be considered the final analysis of these data, and also included in the final CSR. 
Analysis of exploratory endpoints may be performed and released as the data are available from the 
research laboratories. Any such analyses would be considered the final analysis for the endpoint and 
included in the CSR. 
The final CSR will be completed after the last subject’s last visit is completed, and the final clinical 
database, including all long-term safety follow-up data, is cleaned, monitored and locked. Additional 
exploratory endpoint data not available at the time of CSR preparation may be included in an addendum 
to the CSR. 
A formal statistical analysis plan (SAP) will be developed and finalized prior to unblinding for any 
interim analysis and prior the primary clinical database lock, which defines the analyses to be included 
in the preliminary report and final CSR. 
11.5 Missing Values and Outliers 
All attempts will be made to collect all data per protocol. As missing data are expected to be minimal, 
no imputation will be performed for missing values. Any data point that appears to be erroneous or 
inexplicable based on clinical judgment will be investigated as a possible outlier. If data points are 
identified as outliers, sensitivity analyses will be performed to examine the impact of including or 
excluding the outliers. Any substantive differences in these analyses will be reported.  
 

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11.6 Interim Analysis 
 
Interim analysis (IA) will take place after about 50% of all randomized subjects have completed 
challenge and been discharged from the research unit.  This interim analysis will reassess the 
appropriateness of assumptions used for the primary efficacy endpoint when the trial was designed in 
a blinded manner to the study team.  The interim analysis data will be analyzed in an unblinded 
manner for the SMC to support the following recommendation rules shown in the section below. 
 
Conditional Power assessment and Sample size re-estimation rules at IA 
 
The sample size re-estimation rule will be set up using conditional power.  Conditional power will be 
used to assess the futility of continuing further investigation and / or for sample size re-estimation. If 
the conditional power is observed to be sufficiently small at the interim analysis, we would conclude 
that it is futile to continue the investigation.   
The sample size re-estimation rule (if necessary) will be defined using three thresholds for conditional 
power, denoted by 𝑐1, 𝑐2,  and 𝑐3.  The thresholds are given by: 
𝑐1=0.25, 𝑐2=0.5, 𝑐3=0.872 
 
These thresholds define the “underpowered interval” where it is most sensible to increase the 
trial’s sample size.  The total sample size in the trial may be modified at this interim analysis as 
follows: 
• 
If CP ≤𝑐1, retain the original sample size and stop the trial for futility.  
• 
If CP > 𝑐1 and CP ≤𝑐2 (unfavorable interval), premature to stop the study for futility. 
• 
If CP > 𝑐2 and CP ≤𝑐3 (underpowered interval), increase the sample size in all remaining 
trial arms to achieve the maximum conditional power of 87.2%.  
• 
If CP > 𝑐3, retain the original sample size and continue the trial.  
 
The sample size re-estimation rule is non-binding and could be overridden by the sponsor or SMC. 
Although the interim analysis results nor SMC recommendation to continue the study required a 
sample size re-estimation, the sponsor decided to add 20 additional subjects to first 19 challenged 
subjects in a different IP lot to offset variability in vaccine lot between the first two cohorts and all 
others.  
 
11.7 Exploratory Analysis  
 
An exploratory analysis will take place after approximately 50 subjects of the planned randomized 
subjects have been vaccinated with the same IP lot and completed the challenge period. The results of 
the exploratory analysis will not impact the continuation of this study as planned, but rather, inform 
program development for other trials.  
 
Additionally, a blinded interim immunogenicity analysis will be performed on Cohorts 1-9. The 
results of the analysis will not impact the continuation of this study as planned, but rather, inform 
program development for other trials. 
 

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12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
12.1 Source Documentation 
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’ e-Diaries, evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial.  All information on the CRF will be traceable to these source documents, which are 
generally maintained in the subject’s study file.  The source documents will also include a copy of the 
signed Informed Consent/ Health Insurance Portability and Accountability Act (HIPAA) authorization. 
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 study. 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 
patient, both the Sponsor and the Investigator are bound to keep this information confidential. 
All the information required by the protocol should be provided; any omissions require explanation.  
Each source document and corresponding CRF should be completed and available for monitoring 
and/or collection within a timely manner so that the monitor may check the entries for completeness, 
accuracy and legibility, ensure the CRF is signed by the Investigator, and transmit the data to the 
Sponsor. 
All source documents and CRF should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. When making 
a change or correction, cross out the original entry with a single line and initial and date the change. 
DO NOT ERASE, OVERWRITE OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL.  
The Investigator or designee must enter the information required by the protocol onto the CRF 
provided.  The Sponsor’s clinical site monitor will review the CRF for completeness and accuracy and 
instruct site personnel to make any required corrections or additions.  
12.2 Data Management 
Quality control audits of all key safety, laboratory, and clinical data in the database will be made after 
data entry has been completed.  Coexistent medical conditions, AEs and other medical events will be 
coded using MedDRA dictionary. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). When the database has been declared to be complete and 
accurate, the database will be locked.  Any changes to the database after that time can only be made by 
joint written agreement of the study team. 
13 QUALITY ASSURANCE AND QUALITY CONTROL 
This clinical trial is internally monitored for quality assurance.  A Protocol-Specific Quality Assurance 
Plan will be developed for this study. This plan, composed of Quality Control (QC) and Quality 
Assurance (QA), will be developed in collaboration with the PI, clinical study coordinator, Regulatory 
Affairs Specialist, and the QM Coordinator. The QC process will describe the day-to-day logic and 
edits checks of source documents, CRFs, and laboratory documents.  The QA process involves periodic 
retrospective audits of study records and prospective reviews of clinical operations and assurance that 
all research required training has been completed as applicable.  These audits also involve the review 
of the regulatory file, consent forms/process, eligibility, vaccine accountability and storage, specimen 
collection, processing, storage, and shipping.  All observations are reviewed with the PI, Study 

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Coordinator, and Clinical Research Manager; Corrective Action Plans are formulated in response to 
any issue. 
14 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) 
14.1 Ethical Standard 
The Investigator will ensure that this study is conducted in full conformity with the principles set forth  
in The Belmont Report:  Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research of the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal 
Regulations 25691 (1997).   
14.2 Institutional Review Board 
The local institution must provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate ethics review committee or IRB. Any amendments to 
the protocol or consent materials must also be approved before they are placed into use unless it is in 
the best interest of the subjects’ safety to implement changes prior to approval. In both the US and in 
other countries, only institutions holding a current U. S. Federal-Wide Assurance issued by the Office 
for Human Research Protections (OHRP) may participate.  
Prior to enrollment of subjects into this clinical study, the protocol and the informed consent form(s) 
(ICF) will be reviewed and approved by the appropriate IRB. Any amendments to the protocol or 
consent materials will also be reviewed and approved by the appropriate IRB. The responsible official 
for the IRB will sign the IRB letter of approval of the protocol prior to the start of this clinical study. If 
amendments to the protocol are required, the amendments will be submitted to the IRB; an IRB letter 
of approval of the amendment must be obtained prior to implementing the amendment. 
14.3 Informed Consent Process 
Prior to consenting for the full study, subjects will initially provide informed consent for pre-screening 
to test for secretor status and ABO blood type. Eligible subjects will be required to sign a study specific 
ICF before any assessments or evaluations required by the study are performed.  Informed consent will 
be initiated prior to the individual’s agreeing to participate in the study and continues throughout the 
individual’s study participation. The Informed Consent Form explains the storage and future use of 
specimens, and subjects will be asked to consent for future testing of samples.  Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subject.  Consent forms describing in 
detail the study, study procedures and risks are given to the potential subject and written documentation 
of informed consent is required prior to starting any study procedure.  Consent forms will be IRB-
approved, and the subject will be asked to read and review the document. Upon reviewing the 
document, the investigator will explain the research study to the subject and answer any questions that 
may arise.  The subjects will sign the informed consent document prior to any procedures being done 
specifically for the study.  The subject should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate.  The subject may withdraw consent at any 
time throughout the course of the trial.  A copy of the informed consent document will be given to the 
subject for their records.  The rights and welfare of the subject 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. 
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
This clinical study will include women and men who are 18 years of age and older, and all minorities 
who meet the inclusion/exclusion criteria, regardless of religion, sex, or ethnic background.   

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14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, their staff, and the Sponsor.  This 
confidentiality is extended to cover testing of biological samples and other testing in addition to the 
clinical information relating to subjects. 
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. 
The study monitors, or other authorized representatives of the sponsor 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. 
Subject identity data will be contained in paper study records which will be kept in a locked file cabinet 
and in a secure electronic database, accessible only to authorized users at the clinical site. The study 
database will be user-restricted and password-protected. The study database will identify subjects by a 
coded study Volunteer ID number assigned by clinical site personnel; thus subjects will not be 
identified by name. 
 
15 REFERENCES 
1. Bresee JS, Widdowson MA, Monroe SS, Glass RI. Foodborne viral gastroenteritis: challenges 
and opportunities. Clin Infect Dis. 2002;35(6):748-53. 
2. Debbink K, Lindesmith LC, Baric RS. The state of norovirus vaccines. Clin Infect Dis. 
2014;58(12):1746-52. 
3. Teunis PF, Moe CL, Liu P, Miller SE, Lindesmith L, Baric RS, et al. Norwalk virus: how 
infectious is it? J Med Virol. 2008;80(8):1468-76. 
4. Marks PJ, Vipond IB, Carlisle D, Deakin D, Fey RE, Caul EO. Evidence for airborne 
transmission of Norwalk-like virus (NLV) in a hotel restaurant. Epidemiol Infect. 
2000;124(3):481-7. 
5. Graham DY, Jiang X, Tanaka T, Opekun AR, Madore HP, Estes MK. Norwalk virus infection of 
volunteers: new insights based on improved assays. J Infect Dis. 1994;170(1):34-43. 
6. Atmar RL, Opekun AR, Gilger MA, Estes MK, Crawford SE, Neill FH, et al. Norwalk virus 
shedding after experimental human infection. Emerg Infect Dis. 2008;14(10):1553-7. 
7. Ramani S, Neill FH, Opekun AR, Gilger MA, Graham DY, Estes MK, et al. Mucosal and 
Cellular Immune Responses to Norwalk Virus. J Infect Dis. 2015;212(3):397-405. 
8. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 2009;361(18):1776-
85. 
9. Vega E, Barclay L, Gregoricus N, Shirley SH, Lee D, Vinje J. Genotypic and epidemiologic 
trends of norovirus outbreaks in the United States, 2009 to 2013. J Clin Microbiol. 
2014;52(1):147-55. 
10. Vega E, Barclay L, Gregoricus N, Williams K, Lee D, Vinje J. Novel surveillance network for 
norovirus gastroenteritis outbreaks, United States. Emerg Infect Dis. 2011;17(8):1389-95. 
11. Zheng DP, Widdowson MA, Glass RI, Vinje J. Molecular epidemiology of genogroup II-
genotype 4 noroviruses in the United States between 1994 and 2006. J Clin Microbiol. 
2010;48(1):168-77. 

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12. Debbink K, Lindesmith LC, Donaldson EF, Costantini V, Beltramello M, Corti D, et al. 
Emergence of new pandemic GII.4 Sydney norovirus strain correlates with escape from herd 
immunity. J Infect Dis. 2013;208(11):1877-87. 
13. Leshem E, Wikswo M, Barclay L, Brandt E, Storm W, Salehi E, et al. Effects and clinical 
significance of GII.4 Sydney norovirus, United States, 2012-2013. Emerg Infect Dis. 
2013;19(8):1231-8. 
14. de Graaf M, van Beek J, Vennema H, Podkolzin AT, Hewitt J, Bucardo F, et al. Emergence of a 
novel GII.17 norovirus - End of the GII.4 era? Euro Surveill. 2015;20(26). 
15. Karst SM, Wobus CE, Goodfellow IG, Green KY, Virgin HW. Advances in norovirus biology. 
Cell Host Microbe. 2014;15(6):668-80. 
16. Vongpunsawad S, Venkataram Prasad BV, Estes MK. Norwalk Virus Minor Capsid Protein VP2 
Associates within the VP1 Shell Domain. J Virol. 2013;87(9):4818-25. 
17. Jiang X, Wang M, Graham DY, Estes MK. Expression, self-assembly, and antigenicity of the 
Norwalk virus capsid protein. J Virol. 1992;66(11):6527-32. 
18. Donaldson EF, Lindesmith LC, Lobue AD, Baric RS. Viral shape-shifting: norovirus evasion of 
the human immune system. Nat Rev Microbiol. 2010;8(3):231-41. 
19. Harrington PR, Lindesmith L, Yount B, Moe CL, Baric RS. Binding of Norwalk virus-like 
particles to ABH histo-blood group antigens is blocked by antisera from infected human 
volunteers or experimentally vaccinated mice. J Virol. 2002;76(23):12335-43. 
20. Johnson PC, Mathewson JJ, DuPont HL, Greenberg HB. Multiple-challenge study of host 
susceptibility to Norwalk gastroenteritis in US adults. J Infect Dis. 1990;161(1):18-21. 
21. Parrino TA, Schreiber DS, Trier JS, Kapikian AZ, Blacklow NR. Clinical immunity in acute 
gastroenteritis caused by Norwalk agent. N Engl J Med. 1977;297(2):86-9. 
22. Lindesmith L, Moe C, Marionneau S, Ruvoen N, Jiang X, Lindblad L, et al. Human susceptibility 
and resistance to Norwalk virus infection. Nat Med. 2003;9(5):548-53. 
23. Simmons K, Gambhir M, Leon J, Lopman B. Duration of immunity to norovirus gastroenteritis. 
Emerg Infect Dis. 2013;19(8):1260-7. 
24. Tan M, Jiang X. Norovirus gastroenteritis, carbohydrate receptors, and animal models. PLoS 
Pathog. 2010;6(8):e1000983. 
25. Ball JM, Graham DY, Opekun AR, Gilger MA, Guerrero RA, Estes MK. Recombinant Norwalk 
virus-like particles given orally to volunteers: phase I study. Gastroenterology. 1999;117(1):40-8. 
26. Ball JM, Hardy ME, Atmar RL, Conner ME, Estes MK. Oral immunization with recombinant 
Norwalk virus-like particles induces a systemic and mucosal immune response in mice. J Virol. 
1998;72(2):1345-53. 
27. El-Kamary SS, Pasetti MF, Mendelman PM, Frey SE, Bernstein DI, Treanor JJ, et al. Adjuvanted 
intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that 
express homing receptors for mucosal and peripheral lymphoid tissues. J Infect Dis. 
2010;202(11):1649-58. 
28. Guerrero RA, Ball JM, Krater SS, Pacheco SE, Clements JD, Estes MK. Recombinant Norwalk 
virus-like particles administered intranasally to mice induce systemic and mucosal (fecal and 
vaginal) immune responses. J Virol. 2001;75(20):9713-22. 

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29. Tacket CO, Sztein MB, Losonsky GA, Wasserman SS, Estes MK. Humoral, mucosal, and 
cellular immune responses to oral Norwalk virus-like particles in volunteers. Clin Immunol. 
2003;108(3):241-7. 
30. Atmar RL, Bernstein DI, Harro CD, Al-Ibrahim MS, Chen WH, Ferreira J, et al. Norovirus 
vaccine against experimental human Norwalk Virus illness. N Engl J Med. 2011;365(23):2178-
87. 
31. Bernstein DI, Atmar RL, Lyon GM, Treanor JJ, Chen WH, Jiang X, et al. Norovirus Vaccine 
Against Experimental Human GII.4 Virus Illness: A Challenge Study in Healthy Adults. J Infect 
Dis. 2014;211(1):870. 
32. Kim L, Liebowitz D, Lin K, Kasparek K, Pasetti MF, Garg SJ, et al. Safety and immunogenicity 
of an oral tablet norovirus vaccine, a phase I randomized, placebo-controlled trial. JCI Insight. 
2018;3(13). 
33. Liu P, Hsiao HM, Jaykus LA, Moe C. Quantification of Norwalk virus inocula: Comparison of 
endpoint titration and real-time reverse transcription-PCR methods. J Med Virol. 
2010;82(9):1612-6. 
34. Leon JS, Kingsley DH, Montes JS, Richards GP, Lyon GM, Abdulhafid GM, et al. Randomized, 
double-blinded clinical trial for human norovirus inactivation in oysters by high hydrostatic 
pressure processing. Appl Environ Microbiol. 2011;77(15):5476-82. 
35. Seitz SR, Leon JS, Schwab KJ, Lyon GM, Dowd M, McDaniels M, et al. Norovirus infectivity in 
humans and persistence in water. Appl Environ Microbiol. 2011;77(19):6884-8. 
36. Dudding BA, Bartelloni PJ, Scott RM, Top FH, Jr., Russell PK, Buescher EL. Enteric 
immunization with live adenovirus type 21 vaccine. I. Tests for safety, infectivity, 
immunogenicity, and potency in volunteers. Infection and immunity. 1972;5(3):295-9. 
37. Emini EA, editor Ongoing Development and Evaluation of a Potential HIV-1 vaccine Using a 
Replication-Defective Adenoviral Vector. Keystone Conference on HIV Vaccines; 2003; Banff, 
Canada: Abstract 012. 
38. Schwartz AR, Togo Y, Hornick RB. Clinical evaluation of live, oral types 1, 2, and 5 adenovirus 
vaccines. Am Rev Respir Dis. 1974;109(2):233-9. 
39. Young LS, Searle PF, Onion D, Mautner V. Viral gene therapy strategies: from basic science to 
clinical application. J Pathol. 2006;208(2):299-318. 
 

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APPENDIX B:   
CHALLENGE VIRUS PREPARATION 
The Norovirus GI.1 (Norwalk Virus Inoculum Lot 001-09NV, IND 14697) inoculum was prepared by 
 and submitted to FDA for use in clinical trials 
under IND 14697.   The viral inoculum was prepared under Good Manufacturing Practices (GMP) 
conditions as described in this section.  Vaxart has received authorization to cross-reference 
’s 
IND, as well as obtained GI.1 inoculum supply from 
 to be utilized for viral challenge in the 
current GI.1 challenge protocol with the VXA-G1.1-NN vaccine. To ensure that the GI.1 inoculum 
remains within sterility and titer specifications, the virus lot is tested annually, and data submitted to 
the IND by 
 
 
 
Preparing Norovirus Inoculum According to cGMP 
The facility that was used to manufacture the inoculum is in the 
 at 
the 
. The facility consists of a processing room for 
producing inocula, a controlled access room for storage of released raw materials and controlled 
documents, a segregated lab bench to perform quality control tests, and a controlled access -80oC 
freezer used to store finished products. To avoid any cross contamination between products, only one 
product was produced at a time and the production room(s), and their associated equipment were 
broken down and sanitized between products. The Processing facility does not have HEPA filtered 
air. However, the facility generally has between Class 1000-Class 10,000 air during normal 
operations. All open steps were performed in a Class 100 Biosafety cabinet. 
Standard Operating Procedures Used in the Facility 
The facility has written Standard Operating Procedures (SOPs) that cover all operations.  A list of the 
SOPs that are used in the facility is shown in the tables below. Manufacturing data is recorded in 
production batch records that are prepared for each lot of material produced. Quality control data is 
recorded in logbooks assigned to each quality control program. Original versions of production and 
quality control records are maintained in the facility and copies are provided to investigators and 
regulatory groups as necessary. 
Table A:  SOPs for Facilities and Operations 
SOP No. 
SOP Description 
1000.01 
 
1002.01 
 
1003.02 
 
1004.01 
 
1005.01 
 
1006.01 
 
1007.01 
 
1008.01 
 
1011.01 
 
1012.01 
 
1013.01 
1014.01 
 
2001.02 
2020.01 
 
2032.01 
 
2033.01 
 
Standard Operating Procedures and Forms 
Employee Training 
Data Entry and Error Correction 
Signature Records and Signing Authorities 
Gowning and Flow for the Clinical Core of the JVL 
Formulation Lot Number Assignment 
External Regulatory Inspections 
Shipping 
Sampling Technique 
Technology Transfer 
Validation Protocol and Report 
Personnel Hygiene 
Processing Norovirus Infected Stool & Manufacturing 
Norovirus 
Control of Raw Materials 
Clinical Core Production Room Usage 

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2034.01 
 
2052.01 
 
2053.01 
 
2054.01 
 
2505.01 
2506.01 
3001.01 
 
3002.01 
 
3004.02 
 
3005.01 
 
3006.01 
 
3007.01 
 
3008.01 
 
3009.01 
 
3010.01 
 
4005.01 
 
4006.01 
4007.02 
4008.02 
 
5001.01 
 
5002.01 
 
5003.01 
 
5005.01 
 
5006.01 
 
5007.01 
5008.1 
Laminar Flow Biological Safety Cabinets 
Sample Storage and Tracking 
Raw Material Specifications 
Formulation Master Record  
Product Specification 
Batch Record for Processing Norovirus Samples 
Vialing Purified Norovirus 
Cleaning, Maintaining and Monitoring Equipment 
Preparation of Sanitation and Disinfectant Solutions 
Cleaning and Sanitizing the NPF 
Equipment Calibration 
Pipette Aids 
Operating, Maintaining and Calibrating the Met One  
RCS Air Sampler 
Equipment Identification 
Equipment Logbooks 
pH Measurement 
Environmental Monitoring for the NPF 
Determining Viral Titer of GI Norovirus by PCR 
Determining Viral Titer of GII Norovirus by PCR 
Responsibilities of Quality Assurance 
Quality Assurance Audits 
Documenting and Investigating Quality Variations 
Temporary Change Control 
Clinical Labels 
Production Lot Number Assignment 
Product Release 
 
Quality Control/Quality Assurance 
Compliance with current Good Manufacturing Practice (cGMP) is maintained through a quality 
systems approach. This approach involves developing specific quality control programs to address 
each of the regulatory requirements of GMP. The specific quality control and quality assurance 
programs that are used to maintain cGMP are listed below. Details on the facilities and operations 
control programs have been compiled in a Type V Facilities Drug Master File that will be maintained 
at the FDA. The investigator and other regulatory entities can access this file through letters of 
reference as necessary.  
Table B:   Facilities and Operations Controls 
Controls Description 
Controls over Facility and Equipment 
Controls over Organization and Personnel 
Sterilization and Cleaning Controls 
Raw Materials Controls 
Environmental Monitoring 
Packaging and labeling Controls 
Holding and Distribution Controls 
Laboratory Testing Controls 
Records, Documents and Change Controls 
Corrective and Preventative Action Programs 

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Sterility 
including 
Bacteriostasis 
+Fungistasis 
Immersion USP/21 CFR 610.12 
 Protocol #30744, 30751 
and 30736 
Negative 
Negative 
Mycoplasma 
Points to consider for Viral Stocks, GLP 
 Protocol # 30200 
Negative 
Negative 
Endotoxin 
BET/LAL Gel Clot I/A Assay, GMP 
 Protocol # 30743 
< 5000 
EU/mL 
235 EU/mL 
 
 

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APPENDIX E:      LIST OF ADVERSE EVENTS OF SPECIAL INTEREST (AESIs) 
Gastrointestinal Disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
 
Liver Disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune Hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
 
Metabolic Diseases 
• 
Addison’s disease 
• 
Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• 
Diabetes mellitus type 1 
• 
Grave’s or Basedow’s disease 
 
Coagulopathy 
• 
Acquired amegakaryocytic thrombocytopenia  
• 
Axillary vein thrombosis  
• 
Cerebral venous thrombosis 
• 
Disseminated intravascular coagulation 
• 
Hepatic vein thrombosis 
• 
Intracranial venous sinus thrombosis 
• 
Portal vein thrombosis 
• 
Pulmonary thrombosis 
• 
Severe fever with thrombocytopenia syndrome 
• 
Thrombocytopenia 
• 
Thrombotic thrombocytopenia purpura 
• 
Transverse sinus thrombosis 
• 
Vena cava thrombosis 
• 
Amegakaryocytic thrombocytopenia 
• 
Cavernous sinus thrombosis 
• 
Deep vein thrombosis 
• 
Embolism venous 
• 
Immune thrombocytopenia 
• 
Mesenteric vein thrombosis 
• 
Pulmonary embolism 
• 
Pulmonary venous thrombosis 
• 
Subclavian vein thrombosis 
• 
Thrombocytopenia purpura 
• 
Thrombosis 
• 
Vena cava embolism 
• 
Venous thrombosis 
 

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Musculoskeletal Disorders 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis (including Still’s disease) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatic 
• 
Polymyositis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Rheumatoid Arthritis 
• 
Scleroderma, including diffuse systemic form and CREST Syndrome 
• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) 
and undifferentiated spondyloarthritis. 
• 
Systemic lupus erythematous 
• 
Systemic sclerosis 
 
Neuroinflammatory Disorders 
• 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non-infections 
encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis)  
• 
Cranial nerve disorders, including paralysis/paresis (e.g., Bell’s palsy) 
• 
Guillain-Barre syndrome, including Miller Fisher syndrome and other variants 
• 
Immune related peripheral neuropathies and plexopathies, including chronic inflammatory 
demyelinating polyneuropathy, multifocal motor neuropathy and polyneuropathies associated 
with monoclonal gammopathy 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse Myelitis 
 
Skin Disorders 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases (including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Morphea 
• 
Lichen planus 
• 
Psoriasis 
• 
Sweet’s syndrome 
• 
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 angiitis), Buerger’s disease thromboangiitis obliterans), necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type 
unspecified), Henoch-Schönlein purpura, Behcet’s syndrome, leukocytoclastic vasculitis. 

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Others 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, 
and mesangioproliferative glomerulonephritis) 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Autoimmune thrombocytopenia 
• 
Goodpasture syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Pernicious anemia 
• 
Raynaud’s phenomenon 
• 
Sarcoidosis 
• 
Sjogren’s syndrome 
• 
Stevens-Johnson Syndrome 
• 
Uveitis 
 

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APPENDIX F: Preparation of NV Challenge Inoculum 
IND 14697, Amendment 31, 001-09NV Sublot 2, Manufacture and Stability and Sterility 
Testing Results: Preparation of NV Challenge lnoculum Work Instruction 
 
1. 
PURPOSE 
 
The purpose of this Work Instruction (WI) is to document the activities related to the dilution 
and preparation of an administration dose of Norwalk Virus lnoculum Lot 001-09NV sublet 
2, IND 14697. This procedure may be repeated for multiple Cohorts and Subjects using 
completely new disposable equipment and reagents for each cohort and administration at 
 
 
2. 
SCOPE 
 
The principles outlined in this WI apply to Pharmacy staff who must conduct the procedures 
in a Class II microbiological safety cabinet. Staff must wear appropriate personal protective 
equipment (PPE), including at minimum face masks, sterile gloves, gowns, and eye 
protection. Additionally, hair and shoe covers, will be also required. This WI will apply to 
the Dilution of the Stock material provided by 
 preparation of Retained Samples for 
subsequent lot release and stability/sterility testing and preparation of individual dosing vials 
for the current study (VXA-NVV-201). 
 
3. 
ABBREVIATIONS 
 
BSC - Biological Safety Cabinet NTF - Note to File 
NV - Norwalk virus 
 
 SWFI - Sterile Water For Injection 
TMF - Trial Master File 
 
4. 
MATERIALS 
 
o 
PPE (
 SOP# COES-105-.01) 
o 
Sterile Glass Beaker (SO ml MFR: Pyrex) 
o 
Sterile Glass Beaker (1000 ml MFR: Pyrex) 
o 
Cryovials/Cryotubes (3 ml Cryovial MFR: Simport; 5 ml Cryovial MFG: 
VWR) 
o 
Sciences Pipettes (1 ml Pipette MFR: Eppendorf, 5 ml Pipette MFR: 
PhysioCare) 
o 
Sterile Water for Injection (SO ml vials MFR: Fresenius Kabi) 
o 
20 ml Syringe for Diluent (MFR: McKesson) 
o 
3ml Syringe Luer-Lok™Tip MFR : B-D 
o 
Mini-Spike Vented Dispensing Pin with Luer Slip SAFSITE Valve (MFR : B 
Braun) 
 

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5. 
EQUIPMENT 
 
o 
Vortex (Vortex - VWR Analog Vortex Mixer MFR: VWR) 
o 
Freezer (Ultra-Low Temperature Freezer MFR: New Brunswick Model: Ul0l-
86) 
o 
BSC (Labgard, Class II, Type A2 BSC MFR: Nuaire Model: NU-425-200) 
 
6. 
WORK INSTRUCTIONS 
 
6.1 
The Pharmacist or designee will swab the outside of the tube with disinfectant 
and allow the frozen stock material provided by 
 (25-35 ml Norwalk Virus 
lnoculum-5.0 X 10e6 genome copies (GC)/ml, Lot 001-09NV, IND 14697) to thaw 
on ice in the Class II microbiological safety cabinet. 
 
6.2 
Upon observation of thawing, the Pharmacist or designee will gently Vortex the 
liquid material for several minutes (minimum, 5 mins.}, then: 
 
6.2.1 Remove 6 x 1ml aliquots for virus titering. Aliquots will be shipped on dry ice 
for priority overnight delivery to 
 The remainder of the stock NV will be stored 
at 4 degrees Celsius (Refrigerated) until 
 reports titer results and commencing 
6.3. 
 
Stock titer will be quantified by qRT-PCR of three aliquots according to SOP 4007.02 
(
 Three additional aliquots will be reserved as back up samples. 
 
The determined titer of 0019-09NV PBH master stock was 2.4 GC/ml, outside the 
established range of 5 x 10e6 gc/ml +/- 2 X 10e6 gc/ml. Therefore, the stock dilution 
was calculated for a final titer of 3 x 10e5 GC/ml, the current reported titer of the 
doses in use. Calculation of the dilution is reported in the Work Sheet for 
Determining the Dilution of 001-09NV PBH. A dilution of 1:8 was determined to be 
needed to yield 3 x 10e5 GC/ml. 
 
 
Lot release testing plan (
 will ship test samples directly to each Test 
Operator) 
 

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6.3 
The Pharmacist or designee will transfer 25 ml of the stock NV to a sterile 50 ml 
beaker and begin the 1:8 dilution of the stock material. 
 
6.4 
Transfer 12.5 ml of the stock material into a sterile 1000-ml glass beaker containing 
62.5 ml SWFI and gently swirl/mix for several minutes (minimum, 5 mins), then 
 
6.5 
Transfer the remainder of the stock material to the 75 ml from 6.3 and add an 
additional 62.5 ml SWFI and gently swirl/mix for several minutes (minimum, 5 mins.}, then 
 
6.6 
Rinse the stock material container thoroughly into the bottle with an additional 50 ml 
SWFI and gently swirl/mix for several minutes (minimum, 5 mins.), finally 
 
6.7 
The total volume {200 ml, 3x10e5 GC / ml} is ready for individual pipetting of the 
dosing administration vials (3 ml) and of various retained samples (1 ml} to be harvested at 
commencement, middle and completion of aliquoting vials for the challenge dosing. All 
dosing and retained samples will be stored at -60C. 
• 
Commencement - 21, 1 ml vials for sterility, endotoxin and V. titer 
• 
Middle - 6, 1 ml vials for V. titer 
• 
End - 21, 1 ml vials for sterility, endotoxin and V. titer 
 
6.8 
The Pharmacist/designee will then begin aliquoting the 1:8 dilution NV into the 
designated retained (1 ml) and "dosing" sample vials (3 ml) as described in 6.7 into the 
appropriate size sterile vials. 
 
6.9 
The Pharmacist/designee will prepare the vials in the following order: 
 
 
6.9.1 Twenty-one (21) 1 ml samples (in 3 ml sterile cryotubes) 
 
6.9.2 Twenty-five (25) 3 ml dosing vials (in 5 ml sterile cryotubes) 
 
6.9.3 Six (6) 1 ml samples (in 3 ml sterile cryotubes) 

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6.9.4 Twenty-four (24) 3 ml dosing vials (in 5 ml sterile cryotubes} 
 
6.9.5 Twenty-one (21) 1 ml samples (in 3 ml sterile cryotubes) 
 
All of the 3 mL dosing vials will be held (5-60 degrees C.) until finalization of lot 
release testing and FDA approval of IND update. 
 
Preparation and Administration of the Individual NV Challenge 
 
6.10 
One, 3 ml vial per subject from 6.9.2 or 6.9.4 above will be thawed (following frozen 
storage). The vial should be swabbed with disinfectant. Each 3 ml vial of inoculum will be 
added to 100 ml of distilled water in a sterile, disposable, sealable cup under sterile 
conditions. After mixing, the solution will look like a plastic glass of clear drinking water 
 
6.11 
The sealed cup will be transported on ice to each subject for challenge. 
 
Since the inoculum contains live infectious human pathogen, biohazard precautions 
will be observed. This Includes disposing of all waste in biohazard bags, cleaning 
equipment and materials that have come into potential contact with the inocula with 
10 % bleach solution. Cups used for administration and any leftover inocula should 
also be cleaned with bleach and discarded. 
 
If the subject, person administering the dose, or the person preparing inoculum spills 
the inoculum, the affected area must be immediately cleaned with 10% bleach 
solution. Hands must be washed thoroughly with disinfectant soap and water. 
 
Partially used vials will be disinfected and discarded and may not be used for human 
administration or for any in vitro experimental studies. 
 
 
 
 
 

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APPENDIX G:      SUMMARY OF CHANGES TO PROTOCOL 
PROTOCOL VXA-NVV-201 HISTORY : 
Document  
Date  
Protocol Amendment 5.0, Version 6.0  
25 May 2023 
Protocol Amendment 4, Version 5.0 
07 February 2023 
Protocol Amendment 3, Version 4.0 
23 June 2022 
Protocol Amendment 2; Version 3.0 
07 January 2022 
Protocol Amendment 1; Version 2.0  
01 December 2021 
Original Protocol; Version 1.0  
28 October 2018 
 
VXA-NVV-201 Protocol Amendment 5, Version 6.0, 25 May 2023 
 
Protocol Amendment 5 (Version 6.0) of this phase 2 Norovirus GI.1 challenge protocol (VXA-NVV-201) 
was finalized in June 2022 and approved by the IRB.  It is being amended to incorporate sample size increase, 
clarify Day 28 visit procedures, provide details on new NoV virus inoculum, update the statistical methods 
section to incorporate sensitivity analyses for the primary endpoint, and correct other minor typographical 
errors. A description of the changes along with a brief rationale for each change is presented in the table 
below. 
 
Section No.  
& Title 
Description of Change  
Brief Rationale 
Cover page-Product 
Original text: 
 
Challenge strain: Norovirus GI.1 (Norwalk 
Virus Inoculum Lot 001-09NV) 
 
Updated text: 
 
(Norwalk Virus Inoculum Lot 001-09NV 
and Sublot 2) 
Update Inoculum Lot 
Administrative 
changes to Protocol 
Cover Page and 
footers 
Updated Protocol Version 
Updated sponsor new protocol version 
number and date. 
List of Abbreviations 
and Acronyms 
Original text: international units 
Updated text: infectious units 
Provided intended meaning of IU 
 
 
Clinical Synopsis 
Study Population 
Original Text: 
140 healthy male and female adult 
volunteers age 18 to 49 years inclusive with 
blood type O or A and who are confirmed H 
Updated for actual intended sample size 

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type-1 antigen secretory positive 
(approximately 140 subjects will be 
randomized and vaccinated to ensure that at 
least 120 subjects are available to participate 
in the viral challenge 28 days post-
vaccination) 
Updated text: 
Approximately 170 healthy male and female 
adult volunteers age 18 to 49 years  
inclusive with blood type O or A and who 
are confirmed H type-1 antigen secretory 
positive (approximately 170 subjects will be 
randomized and vaccinated to ensure that 
approximately 140 subjects are available to 
participate in the viral challenge 28 days 
post-vaccination)   
Clinical Protocol 
Synopsis 
Viral Challenge Inoculum 
Original text: 
Norovirus GI.1 (Norwalk Virus Inoculum 
Lot 001-09NV, IND 14697) 
Updated text: 
Norovirus GI.1 (Norwalk Virus Inoculum 
Lot 001-09NV and Sublot 2, IND 14697) 
Update Challenge Inoculum 
Clinical Protocol 
Synopsis 
Study design 
Original text: 
This is a Phase 2b randomized, double-
blind, placebo-controlled vaccination and 
challenge study to assess the protective 
efficacy of the Norovirus vaccine (VXA-
G1.1-NN). Approximately 140 healthy 
adults will be randomized in a 1:1 ratio to 
receive one oral dose of vaccine or placebo. 
• Arm 1: VXA-G1.1-NN oral vaccine tablets 
[1x1011 IU±0.5 log]; N=70 
• Arm 2: Placebo tablets similar in 
appearance and number to active vaccine 
tablets; N=70 
Update Arm size, sample size and 
cohort increase 

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To accommodate the limited size of the 
isolation unit that will be utilized for the 
challenge and post-challenge sequestration 
period, subjects will move through the study 
(enrollment, vaccination and challenge) 
sequentially in 10 to 12 cohorts. 
Updated text: 
This is a Phase 2b randomized, double-
blind, placebo-controlled vaccination and 
challenge study to assess the protective 
efficacy of the Norovirus vaccine (VXA-
G1.1-NN). Approximately 170 healthy 
adults will be randomized in a 1:1 ratio to 
receive one oral dose of vaccine or placebo.  
• 
Arm 1: VXA-G1.1-NN oral vaccine 
tablets  
[1x1011 IU±0.5 log]; N=85 
• 
Arm 2: Placebo tablets similar in 
appearance and  
number to active vaccine tablets; 
N=85 
To accommodate the limited size of the 
isolation unit that will be utilized for the 
challenge and post-challenge sequestration 
period, subjects will move through the study 
(enrollment, vaccination and challenge) 
sequentially in 14 to 16 
Original text: 
Approximately 140 subjects will be dosed in 
the vaccination phase to ensure at least 120 
subjects (~ 60 VXA-G1.1-NN vaccine and 
60 placebo) are available to participate in 
the challenge phase. 

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Updated text: 
Approximately 170 subjects will be dosed in 
the vaccination phase to ensure at least 140 
subjects (approximately 70 VXA-G1.1-NN 
vaccine and 70 placebo) are available to 
participate in the challenge phase. 
Updated table:
 
3.1 Study Design and 
Endpoints 
Original text: 
This is a Phase 2b randomized, double-
blind, placebo-controlled vaccination and 
challenge study to assess the protective 
efficacy of the Norovirus vaccine (VXA-
G1.1-NN). To ensure at least 120 subjects 
(approximately 70 NV vaccine and 70 
placebo) are available to participate in the 
challenge phase, approximately 140 healthy 
young adults will be randomized in a 1:1 
ratio to receive one oral dose of vaccine or 
placebo Table 18. Each subject will receive 
an oral dose of 1x1011 IU±0.5 log VXA-
GI.1-NN or placebo comprised of multiple 
tablets per dose. 
Updated text: 
This is a Phase 2b randomized, double-
blind, placebo-controlled vaccination and 
Update sample size 

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challenge study to assess the protective 
efficacy of the Norovirus vaccine (VXA-
G1.1-NN). To ensure at least 140 subjects 
(approximately 85 NV vaccine and 85 
placebo) are available to participate in the 
challenge phase, approximately 170 healthy 
young adults will be randomized in a 1:1 
ratio to receive one oral dose of vaccine or 
placebo Table 18. Each subject will receive 
an oral dose of 1x1011 IU±0.5 log VXA-
GI.1-NN or placebo comprised of multiple 
tablets per dose. 
Table 10: Study 
Design and Vaccine 
Groups 
Original text: 
VXA-G1.1-NN oral vaccine tablets [1x1011 
IU±0.5 log]=70 
Placebo identical to NVV=70 
Challenge Norwalk Virus Strain [Lot 001-
09NV (1x106 GC)]=120* 
Updated text: 
VXA-G1.1-NN oral vaccine tablets [1x1011 
IU±0.5 log]=85 
Placebo identical to NVV=85 
Challenge Norwalk Virus Strain [Lot 001-
09NV and Sublot 2 (1x106 GC)]=140 
Update sample size 
6.0  
NV 
CHALLENGE 
INOCULUM 
Added following text 
Updated text: 
To accommodate the increased sample size 
of the trial, additional GI.1 norovirus 
inoculum was diluted from the same original 
master stock Norwalk Virus Inoculum Lot 
001-09NV purified bulk harvest (PBH), to 
challenge the additional Subjects.  The 
dilution process is attached as Appendix F 
and an updated IND 14697 subsequently 
Clarification on dilution of original 
master inoculum stock 

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submitted to the FDA with sterility, 
endotoxin, and titer testing results.   
6.1 Formulation, 
Packaging, and 
Labeling of NV 
Challenge Virus 
Added following text 
Updated text: 
The Sublot 2 inoculum material diluted and 
prepared for single use to complete this 
challenge study was packaged in one 3mL 
cryovials.  The dilution and aliquoting of 
virus were performed at 
 in 
 with oversight by a 
representative from the original 
manufacturing team following the dilution 
procedure described in the Preparation of 
NV Challenge Inoculum Work Instruction, 
Appendix F. During the aliquoting of 001-
09NV sublot 2, additional vials from the 
beginning, middle and end of the run were 
prepared for quality control testing, and 
shipped on dry ice to either 
 or 
 for testing. 
Clarification on workflow of diluting of 
the original master inoculum stock 
6.2 
Storage and 
Stability of NV 
Challenge Virus 
Added following text 
Updated text: 
The final titer for 001-09NV PBH was 2.4 
x10e6 genome copies (GC)/mL. The titer in 
2009 was 5 x 10e6 GC/mL. Titer of 001-
09NV Final Fill sublot 1, a 1/10 dilution of 
001-09NV PBH was 5 x 10e5 GC/mL in 
2009 and 2.9 x 10e5 in 2022. These results 
indicate the virus stock has been stable for 
more than 10 years. 
Additional vials of 001-09NV Final Fill 
sublot 2 were tested to better evaluate the 
equal distribution of the virus across the 
dilution aliquot run. The mean of all 
dilutions on the standard curve that passed 
QC, for all nine vials across three 
independent assays was 5.36 10e5 GC/ml. 
The titer was consistent across the 
aliquoting run. Notably, the titer of 001-
09NV sublot 1 ranged from 6 x 10e5 
Updated Stability and titer information 
for new inoculum stock (sublot 2) 

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GC/mL to 3 x 10e5 GC/mL between 2009 
and 2022, indicating that 001-09NV Final 
Fill sublot 2 is performing consistently with 
001-09NV Final Fill sublot 1. The reported 
titer is slightly higher than expected from 
the 1/8 dilution of master stock but falls 
within the established range of titer based on 
historic results of 001-09NV Final Fill 
sublot 1 (5 x 10e5 GC/mL +/- 2 x 10e5 
GC/mL). 
7.5 
Visit 03: 
Study Day 28, 1 day 
prior to challenge [+3 
days for visit window 
and +30 days window 
for repeat Visit 03] 
Added following text: 
The stool sample for fecal immunogenicity 
may be collected 1 day or within 24 hours of 
Day 28 through pre-challenge on Day 29. 
Clarification of Visit 3 procedures 
7.6.3 Viral 
Challenge 
Administration 
Original text: 
Subjects will have fasted overnight prior to 
viral challenge. Additionally, they should 
have nothing by mouth, except water, for 90 
minutes before and after ingestion of the 
challenge inoculum.  Subjects will drink 100 
mL of sodium bicarbonate solution (~1.3% 
NaHCO3) prior to viral challenge; 
approximately 1 minute later, subjects will 
ingest the NV inoculum (Lot 001-09NV, 
IND 14697) suspended in 100 mL of 
distilled water. 
Updated text: 
Subjects will have fasted overnight prior to 
viral challenge. Additionally, they should 
have nothing by mouth, except water, for 90 
minutes before and after ingestion of the 
challenge inoculum.  Subjects will drink 100 
mL of sodium bicarbonate solution (~1.3% 
NaHCO3) prior to viral challenge; 
approximately 1 minute later, subjects will 
ingest the NV inoculum (Lot 001-09NV and 
Sublot 2, IND 14697) suspended in 100 mL 
of distilled water. 
Updated inoculum lots 
Definition of Adverse 
Event 
Original text: 
Subjects will utilize a solicited symptom e-
Diary issued on the day of vaccination to 
Added language mapping solicited 
symptoms to the US FDA 
Reactogenicity grading scale 

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daily record the events during the first 7 
days following vaccination.  
Updated text: 
Subjects will utilize a solicited symptom e-
Diary issued on the day of vaccination to 
daily record the events during the first 7 
days following vaccination. These solicited 
symptoms will be graded as follows: 
Added Grading table 
11.1 Study 
Hypothesis 
Original text: 
The study hypothesis is that norovirus 
vaccine, VXA-G1.1-NN, will protect against 
norovirus gastroenteritis related to norovirus 
infection in the challenge model. Protective 
efficacy (PE) will be estimated by the 
prevention 
of 
norovirus 
gastroenteritis 
among vaccine recipients compared to 
placebo recipients in those who were 
challenged.  
The null hypothesis is that the absolute 
protective efficacy is zero. The two-sided 
alternative hypothesis is that the absolute 
protective efficacy is not equal to zero. 
H0: PE = 0 
HA: PE ≠ 0 
The estimated protective efficacy is defined 
as: 
𝐴𝑅0−𝐴𝑅1
𝐴𝑅0
 
Where AR1 is the observed norovirus 
gastroenteritis 
rate 
among 
vaccinated 
subjects 
and 
AR0 
is 
the 
norovirus 
gastroenteritis rate among subjects receiving 
placebo. 
Updated text: 
The study hypothesis is that norovirus 
vaccine, VXA-G1.1-NN, will protect against 
Updated to clarify that the two-sided 
Fisher’s Exact Test will be used to 
evaluate the primary endpoint for the 
trial and to add sensitivity analyses for 
the primary endpoint to aid in 
interpretation of the primary analysis 
results. 

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norovirus gastroenteritis related to norovirus 
infection in the challenge model. Protective 
efficacy (PE) will be estimated by the 
prevention 
of 
norovirus 
gastroenteritis 
among vaccine recipients compared to 
placebo recipients in those who were 
challenged.  
The null hypothesis is that the absolute 
protective efficacy is zero. The two-sided 
alternative hypothesis is that the absolute 
protective efficacy is not equal to zero. 
H0: PE = 0 
HA: PE ≠ 0 
The estimated protective efficacy is defined 
as: 
𝐴𝑅0−𝐴𝑅1
𝐴𝑅0
 
Where AR1 is the observed norovirus 
gastroenteritis 
rate 
among 
vaccinated 
subjects 
and 
AR0 
is 
the 
norovirus 
gastroenteritis rate among subjects receiving 
placebo. 
A Fisher’s Exact Test with a 5% two-sided 
significance level will be used to evaluate 
the primary endpoint of clinical efficacy of 
VXA-G1.1-NN compared to placebo, to 
protect against NVG caused by the Norwalk 
strain challenge inoculum. The sample size 
will be determined in order to evaluate the 
primary endpoint using a Fisher’s Exact test 
with a 5% significance level (Section 11.2) 
The study hypothesis will also be evaluated 
using the Chi-Squared test as a sensitivity 
analysis for the primary endpoint as the 
Fisher’s Exact test can be overly 
conservative in some circumstances.  
An additional study hypothesis will also be 
evaluated as a sensitivity analysis. The null 
hypothesis will be that the absolute 
protective efficacy is zero, and the one-sided 
alternative hypothesis will be that the 
absolute protective efficacy is greater than 
zero.  
H0: PE = 0 

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HA: PE > 0 
This hypothesis will be evaluated using a 
one-sided Fisher’s Exact test. The two 
sensitivity analyses described above will not 
be used for decision making for this trial; 
rather, these are sponsor-requested 
corroborative analyses to aid in the 
interpretation of the primary analysis results 
and facilitate planning for potential future 
studies. The formal statistical analysis plan 
(SAP) will provide additional guidance for 
interpreting results among the sensitivity 
analyses. 
11.2 
Sample Size 
Determination 
Original text: 
Considering the first 19 subjects enrolled in 
the trial were vaccinated with a different 
vaccine lot than all subsequent subjects, an 
additional 20 subjects will be enrolled to 
minimize variability. Thus, 
approximately140 subjects will be 
randomized and vaccinated to ensure that at 
least 120 subjects are available to participate 
in the viral challenge 28 days post-
vaccination. 
Updated text: 
Considering the first 19 subjects enrolled in 
the trial were vaccinated with a different 
vaccine lot than all subsequent subjects, an 
additional 30 subjects will be enrolled to 
minimize variability. Furthermore, a new 
sublot of the virus inoculum is needed to 
complete challenge of the added subjects so 
an additional 20 Subjects will be enrolled to 
reduce potential variability and mitigate 
unexpected results.  Thus, approximately170 
subjects will be randomized and vaccinated 
to ensure that approximately 140 subjects 
are available to participate in the viral 
challenge 28 days post-vaccination.  The 
increased sample size may also facilitate 
determining an immunologic correlate of 
protection. 
Updated statistical methodology, power 
calculations and sample size 

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Appendix F: 
Preparation of NV 
Challenge Inoculum 
See updated text in Appendix F 
Added Work instruction for preparation 
of NV Challenge Inoculum 
SUMMARY OF 
CHANGES TO 
PROTOCOL 
Renamed the Table of Amendments to 
Appendix G 
Clarification 
 
VXA-NVV-201 Protocol Amendment 4, Version 5.0, 07 February 2023 
 
Protocol Amendment 4 (Version 5.0) of this phase 2 Norovirus GI.1 challenge protocol (VXA-NVV-201) 
was finalized in June 2022 and approved by the IRB.  It is being amended to incorporate sample size increase, 
addition of an exploratory analysis after approximately 50 Subjects complete the challenge period and being 
vaccinated under the same lot, adding a blinded interim immunogenicity analysis for the same subjects 
included in the planned interim analysis, as well as other administrative changes for clarity. A description of 
the changes along with a brief rationale for each change is presented in the table below. 
 
Section No.  
& Title 
Description of 
Change  
Brief Rationale 
Administrative 
changes to Protocol 
Cover Page  
Updated Protocol 
Version 
Updated sponsor new protocol version number and date. 
Clinical Protocol 
Synopsis; Study 
Design 
Updated Study 
Population by 
increasing the 
number of healthy 
volunteers 
Increased the number of healthy Volunteers from 100 to 140. 
Count of Randomized and Vaccinated subjects increased from 
120 to 140 to ensure that at least 120 subjects are available to 
participate in the viral challenge 28 days post-vaccination 
Clinical Protocol 
Synopsis; Study 
Design. 
Updated the study 
Design and number 
of subjects in the 
table. 
Approximately 140 subjects will be dosed in the vaccination 
phase to ensure at least 120 subjects (~ 60 VXA-G1.1-NN 
vaccine and 60 placebo) are available to participate in the 
challenge phase. 
Investigational Drug Product 
No. of Subjects 
Vaccination 
140 
VXA-G1.1-NN oral vaccine 
tablets  
[1x1011 IU±0.5 log] 
70 
Placebo tablets (identical to 
vaccine) 
70 
Challenge (Norwalk GI.1 
Virus Inoculum) 
120 
VXA-G1.1-NN oral vaccine 
tablets  
[1x1011 IU±0.5 log] 
60 
Placebo tablets (identical to 
vaccine) 
60 

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Clinical Protocol 
Synopsis; Statistical 
Considerations 
Updated the 
statistical 
considerations for 
Exploratory Analysis 
and added an 
additional blinded 
interim 
immunogenicity 
Analysis. 
An exploratory analyses to be performed after approximately 
50  subjects of the planned randomized subjects that have been 
vaccinated with the same IP lot and completed the challenge 
period. The results of the exploratory analyses will not impact 
the continuation of this study as planned, but rather, inform 
program development for other trials. 
Additionally, a blinded interim immunogenicity analysis will 
be performed on Cohorts 1-5 and shared with the sponsor. The 
results of the analyses will not impact the continuation of this 
study as planned, but rather, inform program development for 
other trials. 
 
Section 7 STUDY 
PROCEDURE AND 
SCHEDULE. 7.5 
Updated the section 
Name 7.5 ‘Visit 03: 
Study Day 28, 1 
day prior to 
challenge [+3 days 
for visit window 
and +30 days 
window for repeat 
Visit 03. Also 
Removed Note. 
Updated the Section Name from “Visit 03: Study Day 28 
[+30 days], 1 day prior to challenge” to  
“Visit 03: Study Day 28, 1 day prior to challenge [+3 days 
for visit window and +30 days window for repeat Visit 03]  
* Removed - Note: Day 28 immunogenicity samples should be 
collected at the subject’s original Day 28 visit and do not need 
to be re-collected prior to challenge, if the subject’s challenge 
visit is delayed (+ 30 days). 
Section 7 STUDY 
PROCEDURE AND 
SCHEDULE. 7.5 
Added Additional 
Notes and specific 
guidance on BioFire 
GI Guidance 
The visit is required for all subjects regardless of challenge 
status, since there are blood draws impacting immune 
endpoints from vaccination stage. It is a deviation if Visit 03 
does not occur. 
Day 28 immunogenicity samples should be collected at the 
subject’s original Day 28 visit and do not need to be re-collected 
prior to challenge, if the subject’s challenge visit is delayed (+ 
30 days).  
Visit 3 has a +3 day window, followed by a +30 days 
window for repeat Visit 03, if needed, to rescreen subjects 
for challenge.  
BioFire GI Testing Guidance: 
• 
Subjects without symptoms of AGE in the 72 hours 
prior to Day 28 should not have BioFire GI pathogen 
assay 
• 
For subjects with symptoms of AGE in the 72 hours 
prior to challenge who test positive on BioFire for an 
enteric pathogen OTHER THAN NOROVIRUS, they 

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may be re-evaluated for a future challenge as allowed 
by protocol.  
• 
If no AGE symptoms in the preceding 72 hours when 
evaluating for the next challenge AND the investigator 
considers the prior AGE fully resolved, that subject 
does not need a repeat BioFire GI pathogen test 
• 
Any subject in this situation should be discussed with 
Vaxart MM (including which pathogen was positive 
on BioFire at initial challenge screening) for approval 
to re-evaluate for challenge.  
• 
A subject that tests positive for Norovirus at Day 28 
will be excluded from future norovirus challenge. 
 
Section 7.6.4: Visits 
04 – 08: Post-
Challenge 
Observation Period  
(Day 29 – Day 33 [+ 
3 Days]) 
Added additional 
instructions related 
to Emesis or 
Diarrhea occurred 
after the Last NV 
signs and symptoms 
and first NV 
symptoms of the day 
but before 12:00Pm. 
. If a subject experiences emesis or diarrhea after the first NV 
Signs and Symptoms assessment of the day but before 
12:00pm, the site will record the occurrence on the first 
Norovirus Signs and Symptoms for the corresponding 
calendar day on which it occurred. If a subject experience any 
of the other symptoms on the Norovirus Signs and Symptoms 
form after the last assessment of the calendar day, those 
symptoms will be recorded on the first assessment of the next 
day 
Section 7.8: Visit 10: 
Study Day 57 (28 
Days post challenge 
± 3 days) 
Added additional 
guidance for the 
subjects who are 
ineligible for 
challenge phase. 
For subjects who are ineligible for challenge phase, Section 7.8 
of the protocol should be followed instead of Section 7.11; that 
is, subjects who are not challenged should begin the safety 
follow up at Visit 10 (Day 57). This visit may be a phone 
contact. No separate “early termination” visit needs to occur. 
Only subjects who truly terminate participation in the study 
should have an early termination visit.  
 
Section 7.9: Visit 11 
(Day 120) – Visit 14 
(Day 300) Safety 
Follow-up Contacts  
Added the number of 
days expected  for 
each visit  
• 
Visit 11: Study Day 120 (92 days post challenge + 1 
week) 
• 
Visit 12: Study Day 180 (152 days post challenge + 1 
week) 
• 
Visit 13: Study Day 240 (212 days post challenge + 1 
week) 
• 
Visit 14: Study Day 300 (272 days post challenge + 1 
week) 
 
Section 7.10: Visit 15: 
Study Day 365 (337 
days post challenge + 
1 week) End of Study 
Contact 
 
Added Number of 
days to the name of 
the visit 
Updated the section Name from “Visit 15: Study Day 365 End 
of Study Contact” to “Visit 15: Study Day 365 (337 days post 
challenge + 1 week) End of Study Contact 
 

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Section 7.11: Early 
Termination 
Removed wordings 
in section 7.11.2 
Early Termination 
(Day 29 - Day 57;  
Challenge Phase) 
***REMOVED ***  Subjects who did not undergo 
challenge and discontinue between Days 29 and Day 
57 do not need the above listed ET assessments, but 
rather should be managed as early terminations during 
the Safety Follow-up Period (see Section 7.11.3 ). 
 
Section 11: 
STATISTICAL 
CONSIDERATIONS; 
Updated the 
considerations for 
table 20 in section 
11.2. Sample size 
determination 
Considering the first 2 cohorts of the trial were vaccinated with 
a different IP lot than in all subsequent cohorts, it was decided 
to add 20 additional subjects to first 19 subjects challenged in a 
different IP lot into the trial. Thus, approximately 170 subjects 
will be randomized and vaccinated to ensure that at least 140 
subjects are available to participate in the viral challenge 28 
days post-vaccination. 
 
Section 11.6: Interim 
Analysis. 
Updated the section 
related to interim 
analysis. 
Although the interim analysis results nor SMC recommendation 
to continue the study required a sample size re-estimation, 
Vaxart decided to add 20 additional subjects to first 19 
challenged subjects in a different IP lot to offset variability in 
vaccine lot between the first two 
cohorts and all others. 
Section 11.7: 
Exploratory Analysis 
Updated the details 
related to 
exploratory Analysis 
and an additional 
blinded interim 
immunogenicity 
Analysis. 
An exploratory analysis will take place after approximately 50  
subjects of the planned randomized subjects have been 
vaccinated with the same IP lot and completed the challenge 
period. The results of the exploratory analysis will not impact 
the continuation of this study as planned, but rather, inform 
program development for other trials.  
Additionally, a blinded interim immunogenicity analysis will 
be performed on Cohorts 1-5. The results of the  analysis will 
not impact the continuation of this study as planned, but rather, 
inform program development for other trials. 
 
 
VXA-NVV-201 Protocol Amendment 3, Version 4.0, 23 June 2022 
 
Protocol Amendment 2 (Version 3.0) of this phase 2 Norovirus GI.1 challenge protocol (VXA-NVV-201) 
was finalized in January 2022, and was approved by the IRB.  Study enrollment and challenge for the first 2 
cohorts was conducted under Amendment 2.  The protocol is being amended to incorporate changes to the 
study drug section as subsequent cohorts will be dosed with drug product lots that allow administration via a 
single dose of tablets (rather than three sub-doses).  Additionally, information to support an interim analysis 
following completion of challenge in ~50 subjects (50%) has been incorporated into the protocol. Minor 
changes to the sample collection schedule, as well as the Sponsor and Clinical Site study teams have been 
incorporated within Protocol Amendment 3 (Version 4.0). A description of the changes along with a brief 
rationale for each change is presented in the table below. 
 
 

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Section No.  
& Title 
Description of Change  
Brief Rationale 
 Administrative 
changes to Protocol 
Cover Page  
Updated Contact Information and 
Protocol Version 
 Updated sponsor and site contact and new protocol 
version number and date. 
Synopsis: Study 
Design  
Section 7.14 
Assessment of 
Clinical Illness 
Post Vaccination, change in the 
frequency of collection of NVV 
Signs and symptoms during the 
inpatient period 
 
The frequency of collection of NVV signs and 
symptoms post challenge has been modified for 
optimal data collection from every 2 hours during the 
first 48 hours to twice a day (am and pm) for the 
duration of the post challenge sequestration period.  
Synopsis: Study 
Visits: Challenge 
Phase  
Section 8 Clinical 
Evaluation:  
Updated immunogenicity and 
safety assessments  
Evaluation of immune response and safety 
assessment were added on Day 33 and 57 of 
challenge phase to allow for a more complete 
immune response dataset.  
Synopsis: Safety, 
Immunogenicity and 
Microbiological 
Assessments 
Updated frequency of collection 
of vital signs collection  
The frequency of collection of vital signs has been 
modified from every 2 hours for the first 48 hours to 
twice a day (am and pm) during the post-vaccination 
phase until discharge. This approach allows for 
adequate data collection while balancing the burden 
on study subjects and site staff. 
Synopsis: Study 
Endpoint; Section 
3.2.4. Immunogenicity 
Endpoints : 
Updated exploratory endpoints  
Saliva and nasal samples collection was added on 
Day 8 to allow for a more complete immune response 
dataset.  
Synopsis: Statistical 
Considerations 
Section 11: Statistical 
Considerations 
Study hypothesis updated and 
details added regarding planned 
interim analysis 
Information added in support of the Interim Analysis. 
Section 5.1.3 Drug 
Product Dose 
Preparation and 
Administration 
Updated Study drug 
administration information and 
added reference to pharmacy 
manual 
Section was updated to remove language on sub-
doses as new lot of DP to be utilized to dose 
remaining cohorts will utilize a single dose approach; 
reference to pharmacy manual was added.  
Section 7.4 Visit 02: 
Study Day 8 
Added saliva and nasal 
samples collection  
To evaluate presence of NoV viral protein (VP1) 
antibody on Day 8,  saliva and nasal samples 
collections were added.  
Section 7.6.  
Visits 04 – 08: Post 
Challenge  
Observation Period  
(Day 29 – Day 33 [+ 
3 Days]) 
Updated frequency of 
collection of vital signs and 
NVV signs and symptoms  
collection of immunogenicity 
blood samples  
To allow for more accurate and timely collection 
of NVV signs and symptoms for analysis, 
frequency of collection of signs and symptoms 
was changed from every 2 hours to twice a day 
(am and pm). 
Fixed whole blood sample collection was added 
to be collected on Day 33 to evaluate further 
immunogenicity during the challenge phase.   

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Section 7.13 
Immunogenicity 
Assessment  
Updated Immunogenicity 
Assessment  
Removed Ad5 neutralizing antibody and  
Nab responses by norovirus enterocyte culture 
assay (optional) 
 
 
 
VXA-NVV-201 Protocol Amendment 2 (Version. 3.0), 07 January 2022 
 
Overall Rationale for the Amendment:  
 
Protocol Amendment 1 (Version 2.0) of this phase 2 Norovirus GI.1 challenge protocol (VXA-NVV-201) was 
finalized in December 2021, was approved by the IRB and submitted for review.  However, during study set-
up areas for modification were identified. These included the need to add testing for influenza A & B prior to 
viral challenge and to clarify that subjects must be negative for enteric pathogens (via BioFire) as well as 
influenza prior to challenge.  Additionally, to ensure more accurate and timely collection of solicited symptoms 
of reactogenicity post vaccination and signs and symptoms of norovirus illness post viral challenge the use of 
an e-Diary (rather than paper diary card) is being implemented in Amendment 2. Lastly, the initial drug product 
lot of VXA-G1.1-NN vaccine tablets to be utilized for dosing in this study has a concentration of 2.2x109 IU 
per tablet.  Therefore, to deliver the full clinical dose of 1x1011 IU±0.5 log ~45 tablets will need to be 
administered.  To accommodate delivery of the high number of tablets, dosing at Day 1 has been divided into 
3 sub-doses of 15 tablets per sub-dose, administered 2 hours apart over a 4-hour period.  In addition to the 
changes described above, a few minor modifications for added consistency and clarify have also been 
incorporated into Amendment 2 (Version 3.0). 
 
The table below summarizes the changes incorporated into Amendment 2 and provides a brief rationale for 
each modification. 
 
Section No.  
& Title 
Description of Change 
Brief Rationale 
List of 
Abbreviations 
and Acronyms 
Additions of e-Diary 
Updated with new terms utilized in 
Amendment 2 for sake of completeness. 
Globally 
throughout 
Protocol 
Reference to diary cards has been modified to e-
Dairy (electronic diary) 
To allow for more accurate and timely 
collection of solicited symptoms of 
reactogenicity post vaccination and signs 
& symptoms of norovirus illness post viral 
challenge, e-Diary will be used instead of 
paper diary cards. 
Synopsis 
4.1 Subject 
Inclusion 
Criteria  
Inclusion Criteria # 9: Italicized text added 
 
Male subjects must agree not to father a child or 
donate sperm, as well as to use 
contraception/barrier (a male condom) or be 
abstinent from heterosexual intercourse, from 
vaccination through the active period (Day 57) 
The inclusion criteria regarding male birth 
control and contraception was expanded 
for added clarification.  

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Section 1.6: 
Table 14 
Table 14:   Description of illness after challenge 
with two different doses of Norwalk virus (Study 
VXA-G11-201.1) 
The formatting for table 14 for corrected.  
No changes were incorporated to the data 
presented. 
Section 5.1.3: 
Drug Product 
Dosage 
Preparation and 
Administration 
Section 7.3: 
Visit 01: Study 
Day 1, Study 
Drug 
Administration  
Preparation of Drug Product: the following 
paragraph was added: 
The initial lot of VXA-G1.1-NN DP [Lot: DP-
05.21001] that will be utilized for clinical dosing 
in this protocol has a concentration of 2.2x109 
IU per tablet. Therefore, multiple tablets (n=45) 
of the DP will be dispensed per dose to deliver 
the complete investigational dose of 1x1011 IU ± 
0.5 logs in the active treatment group. To 
maintain the study blind, the same number of 
placebo tablets (n=45) will be dispensed to 
subjects in the control group. 
Study Drug Administration – additional 
information was added as shown below: 
Study subjects should be fasting and refrain from 
ingesting solid food for at least  4 hours prior to 
initiation of oral dosing.  Following 
randomization subjects will be dispensed their 
assigned DP dose (VXA-G1.1-NN or placebo 
tablets) on Day 1.  Dosing will be divided into 
three sub-dosing periods: Time = 0 (dose 1/3), 
Time = 2 hours (dose 2/3) and Time = 4 hours 
(dose 3/3). At each of the 3 sub-dosing periods 
15 tablets will be dispensed, which subjects will 
swallow with 360 to 480 mL of water. After each 
sub-dose subjects will be dispensed a light snack 
(e.g., crackers) to aid in tablet transit out of the 
stomach. A total of 45 tablets will be dispensed 
to deliver a full vaccine dose of 1x1011 IU ± 0.5 
logs or a matching placebo dose.  Normal food 
consumption may resume 90 minutes after 
dosing. 
The VXA-G1.1-NN vaccine DP [Lot# 
DP-05-25001] that will supply dosing in 
this study has a per tablet concentration of 
2.2x109 IU.  Therefore, to deliver the full 
clinical dose of 1x1011 IU±0.5 log ~45 
tablets will need to be administered.  To 
accommodate delivery of the high number 
of tablets and to ensure adequate 
absorption in the small intestines, dosing 
at Day 1 has been divided into 3 sub-
doses of 15 tablets per sub-dose, 
administered 2 hours apart over a 4-hour 
period 
 
Information on study drug administration 
procedures with sub-dosing over 4 hours 
was added. 
Section 7.2 Visit 
00: Screening 
Visit (Study Day 
-45 to -1  
Appendix A : 
Schedule of 
Events 
The Blood sample for BT50 titer was removed 
from the screening assessments 
This test was within this section in error.  
No immunogenicity samples are being 
collected prior to Day 1. 
Section 7.3  
Visit 01: Study 
Day 1, Study 
A note was added indicating the following: 
(Note: Safety labs do not need to be performed if 
screening safety lab tests were completed within 
Modification was incorporated stating that 
if the safety labs for the screening visit 
were collected within 2 days of the 

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Drug 
Administration 
Appendix A: 
Schedule of 
Events 
2 days prior to study drug administration on 
Day 1)  
baseline visit at Day 1, then the screening 
values can be utilized for Day 1 safety 
assessments and do not need to be 
repeated. 
Section 7.5: 
Visit 03: Study 
Day 28 [+30 
days], 1 day 
prior to 
challenge 
The following note has been added: 
Note: Day 28 immunogenicity samples should be 
collected at the subject’s original Day 28 visit 
and do not need to be re-collected prior to 
challenge, if the subject’s challenge visit is 
delayed (+ 30 days).  
Note added to clarify that Day 28 
immunogenicity samples should be 
collected at the scheduled visit (4 weeks 
posts vaccination), even if the subject’s 
challenge visit is delayed (+ 30 days), to 
allow consistency across all subject data 
for this timepoint.   
Section 7.5: 
Visit 03: Study 
Day 28 [+30 
days], 1 day 
prior to 
challenge 
Appendix A: 
Schedule of 
Events 
Influenza A & B antigen test has been added to 
the pre-challenge assessments at Day 28 (+ 30 
days) 
Screening for influenza A & B has been 
added pre-challenge to ensure that 
subjects infected with flu are not 
participating in the viral challenge. 
Screening out these subjects will ensure 
that infectious subjects are not being 
admitted to the clinical isolation unit, 
and to help ensure that signs & 
symptoms associated with flu are not 
being interpreted as associated with NV 
illness.  
Section 7.6.2 : 
Viral Challenge 
Eligibility 
The following to criteria added to the list for viral 
challenge eligibility: 
• positive for enteric pathogens (BioFire) 
• positive Influenza A or B antigen test result 
Screening out subjects positive for 
enteric pathogens and influenza will 
ensure that infectious subjects are not 
being admitted to the clinical isolation 
unit, and to help ensure that assessments 
of signs & symptoms of  NV illness are 
not confounded due to preexisting 
infection. 
Section 15: 
References 
Section was moved to be presented directly 
following Section 14. 
Moved to remain with the body of the 
protocol rather than following the 
Appendices. No change to content was 
incorporated. 
Additional minor wording, spelling and/or formatting modifications have been incorporated 
for added clarity and consistency. 
 
 

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VXA-NVV-201 Protocol Amendment 1 (Version. 2.0), 01 December 2021 
 
Overall Rationale for the Amendment:  
 
The original version of this phase 2 Norovirus GI.1 challenge protocol (VXA-NVV-201) was 
finalized in October 2018 and submitted for CBER and IRB review.  Although approvals were 
obtained, subject enrollment was not initiated due to insufficient supply of investigational drug 
product (VXA-G1.1-NN vaccine) at the time.  The study is being reinitiated at this time utilizing the 
same sample size and study design as the original protocol.  Updates to the background and clinical 
experience sections, as well as the Sponsor and Clinical Site location and study teams have been 
incorporated within Protocol Amendment 1. Additionally, safety and risk information has been 
updated to incorporate clinical experience with the Vaxart oral vaccine platform as well as 
regulatory input obtained over the past few years. 
 
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 
Title Page 
Vaxart’s address and study team contact information 
has been updated.  
The Clinical site’s address and contact information has 
been updated to reflect new contact.  
The title page has been updated to 
reflect current information on the 
Sponsor and clinical site. 
List of 
Abbreviations 
and Acronyms 
Additions of CyTOF, Nab, PF4 and TTS 
Updated with new terms utilized in 
Amendment 1 for sake of 
completeness. 
Synopsis  
6.3 Preparation 
and 
Administration 
of NV Challenge 
Virus 
Information on the Viral inoculum illness/infection rate 
has been updated based on the G1.1 titration study 
completed in 2019 (Mateo, et al). 
Original 60%- 70%- changed to 50%-65% 
Updated to reflect most current 
information. 
Synopsis 
Cohort sizes have been updated based on 
 
new isolation ward capacity 
The size of the subject cohorts has 
been reduced to accommodate the 
size of the clinical isolation unit 
which has 10 subject rooms. 
Synopsis 
4.2 Subject 
Exclusion 
Criteria  
Exclusion Criteria:  
An exclusion criterion has been added to exclude 
subjects at risk for clotting events and 
thrombocytopenia #4 and #5 
4. Laboratory values outside the range of normal for 
platelet counts and the following coagulation 
tests: PT/INR, aPTT and fibrinogen 
5. Any of the following history or conditions that 
may lead to higher risk of clotting events and/or 
thrombocytopenia: 
Per guidance received from FDA, 
subjects will be screened for risk 
factors of clotting disorders prior to 
dosing and excluded if they have 
laboratory values or family history 
that places them at higher risk of 
thrombocytopenia and thrombosis 
syndrome (TTS), that has been 
reported  with some injected Ad5 
vectored vaccines for COVID-19. 

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i. Family or personal history of bleeding or 
thrombosis 
j. History of heparin-related thrombotic events, 
and/or receiving heparin treatments 
k. History of autoimmune or inflammatory 
disease 
l. Presence of any of the following conditions 
known to increase risk of thrombosis within 6 
months prior to screening: 
▪ 
Recent surgery other than removal/biopsy 
of cutaneous lesions  
▪ 
Immobility (confined to bed or wheelchair 
for 3 or more successive days)  
▪ 
Head trauma with loss of consciousness or 
documented brain injury  
▪ 
Receipt of anticoagulants for prophylaxis 
of thrombosis 
▪ 
Recent clinically significant infection 
(See Section 2.1: Potential Risks and 
Benefits). 
4.2 Subject 
Exclusion 
Criteria 
Exclusion Criterion #6: ECG findings within 30 days 
was changed to 45 days 
The evaluation period for ECG was 
modified to match the protocol 
screening period. 
4.2 Subject 
Exclusion 
Criteria 
Exclusion Criterion #14: Added in clarification for 
Malabsorption to include e.g. Celiac disease, gluten 
intolerance 
Additional information added for 
sake of clarification. 
4.2 Subject 
Exclusion 
Criteria 
Exclusion Criterion #24: Removed stool sample with 
occult blood during screening and added in its place, 
History if hematochezia (blood in stool) or melena 
(black stool). 
Vaxart has dosed ~600 adult subjects 
up to age 80 years with its oral Ad5 
vaccines.  A safety signal (solicited 
and/or unsolicited AEs) related to GI 
bleeding has not been observed.  
Hence to facilitate the screening 
process, the test for occult blood at 
screening has been removed.  
However, a new exclusion criterion 
which specifically excludes 
individuals with any history of GI 
bleed has been added. 
4.2 Subject 
Exclusion 
Criteria 
Exclusion Criterion #29: Added clarification for the 
drug test positive for marijuana; concurrent or ongoing 
use of marijuana during the active study period. 
Additional information added for 
sake of clarification. 
Synopsis  
Within Safety, Immunogenicity and Microbiological 
Safety Assessments: Solicited symptoms of 
reactogenicity. Myalgia (Muscle pain) was added 
Inadvertently left out of the original 
protocol 

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Synopsis 
3.2.4 
Immunogenicity 
Endpoints 
7.13 
Immunogenicity 
Assessments 
Within Safety, Immunogenicity and Microbiological 
Assessments and Study Endpoints:  
VP1 specific serum IgA (by MSD) was added into the 
Primary Immunoassays and removed from Exploratory 
Immunoassays.  
Both the VP1 Specific serum IgA and IgG will be run 
by MSD instead of ELISA 
Updates incorporated based on 
advancements in assay development 
achieved by Vaxart over past few 
years. The VP1 specific serum IgA 
(by MSD) will be qualified, hence 
elevated to a primary assay in the 
protocol. 
Synopsis 
3.2.4 
Immunogenicity 
Endpoint 
7.2 Visit 00: 
Screening Visit  
Additional information added for safety laboratory 
panels 
Additional information added for 
sake of clarification. 
1.4 Summary of 
Clinical Studies 
with Vaxart Oral 
Vaccine 
Platform 
Section updated to incorporate safety and 
immunogenicity information on clinical trials 
completed in last several years. 
Modified to include updated 
information. 
1.4.3 Clinical 
Study VXA-
NVV-103 with 
VXA-G1.1-NN 
and VXA-G2.4-
NS 
Additional information on the VXA-NVV-103 was 
added. Including: 
• 
Overall Study Design and Plan 
• 
Table 8: Design of Study VXA-NVV-103 
• 
Summary of safety  
• 
Table 9: Summary of Solicited symptoms of 
reactogenicity 
• 
Summary of Immunogenicity Analysis  
Modified to include updated 
information. 
1.6  NV 
Challenge Dose 
Titration Study 
and Dose 
Justification 
Additional information from the VXA-G11-201.1 
Study: 
• 
Table 14: Description of illness after challenge 
with two different doses of Norwalk virus 
(Study VXA-G11-201.1). Was updated with all 
compiled data 
• 
Clinical outcome was added 
• 
Table 15: Summary of the correlation between 
acute gastroenteritis and NV positivity by 
cohort. Added 
• 
Table 16: Characterization of diarrhea in 
subjects with acute gastroenteritis and NV 
positivity by cohort (by mean). Added 
Modified to include updated 
information. 
1.7  Summary of 
Clinical 
Experience with 
Vaxart Oral 
Vaccine Platform 
Summary of Clinical Experience with Vaxart Oral 
Vaccine Platform section and Table 7 where updated to 
include recent completed studies.  
Modified to include updated 
information. 

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1.9 Potential 
Risks and 
Benefits  
Additional of:  
“Since the initiation of the current protocol, multiple 
injected adenovirus vectored vaccines approved for use 
via Emergency Use Authorization (EUA) for the 
prevention of COVID-19 have reported severe events of 
thrombosis in combination with thrombocytopenia 
(thrombosis with thrombocytopenia syndrome, TTS), in 
some cases accompanied by bleeding. Though the TTS 
events were reported with adenovirus vectored 
vaccines for COVID-19, the FDA has asked Sponsors 
of adenovirus vectored vaccines for other indications to 
broadly monitor for these risks. 
Investigators should be alert to the signs and symptoms 
of thromboembolism and/or thrombocytopenia. Study 
participants should be instructed to seek immediate 
medical attention if they develop symptoms including, 
but not limited to, shortness of breath, chest pain, leg 
pain and/or swelling, persistent abdominal pain, severe 
or persistent headaches, blurred vision or other vision 
changes, mental status changes or seizures, petechia, 
purpura beyond the site of vaccination, and/or easy 
bruising/bleeding. The medical management of 
thrombosis with thrombocytopenia is different from the 
management of isolated thromboembolic diseases. 
Investigators should follow available guidelines for the 
assessment and treatment of thrombotic 
thrombocytopenia (e.g., American Society of 
Hematology 2021British Society for Haematology 
2021; CDC 2021). The use of heparin may be harmful 
and alternative treatments may be needed. Consultation 
with hematologists is strongly recommended”. 
Because Vaxart’s VXA-G1.1-NN 
investigational vaccine utilizes an 
adenovirus vectored design, and per 
the direction of the FDA, information 
on the risks of thromboembolism and 
/or thrombocytopenia have been 
added to Section 1.9 of the protocol.  
1.9.2 Norovirus 
Challenge Risks 
The amount of time expected to elicit acute watery 
diarrhea was changed to 12-72 hrs from 18 to 48 hrs 
Information was updated based on 
the findings in the GI.1 norovirus 
titration study (VXA-NVV-201.1). 
7.2 Visit 00: 
Screening Visit 
Addition of  
•Blood Sample: coagulation tests, lab panel (PT/INR, 
aPTT and fibrinogen 
Subjects will be reminded to fast and refrain from 
ingesting solid food for at least 4 hours prior to the Day 
1 study drug administration 
A blood sample for coagulation 
testing was added at screening to 
evaluate for risk factors related to 
clotting. 
Based on findings from other Vaxart 
vaccine trials, it was determined that 
a 4 hour fast (rather than 8 hours) 
prior to study drug administration 
should be sufficient. 
7.3 Visit 01 : 
Study Day 1, 
Study Drug 
Administration 
Addition of: 
Drug screen (urine and alcohol breath test) 
A drug screen was added to study 
day 1 (prior to vaccination) as part of 
the screening process. 

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7.5 Visit 03 : 
Study Day 28 
[+30 days], 1 day 
prior to challenge 
Addition of:  
Any subject who is deemed ineligible will be 
discharged from unit prior to challenge. Subjects may 
return for re-evaluation of challenge eligibility within 
30 days of their original Day 28 Visit.  If they are 
assessed to be eligible for challenge at that time, they 
may be included for challenge with a subsequent 
cohort. 
A 30-day window was added to the 
pre-challenge visit (Day 28) to add 
flexibility for subjects that may not 
be eligible or available at the original 
visit timepoint. This change is not 
expected to impact the study 
immunogenicity and efficacy 
evaluations, however, will aid in 
reducing the screen failure rate for 
the challenge period. 
7.11.2 Early 
Termination (Day 
29 - Day 57;  
Challenge Phase 
Addition of: 
Subjects who did not undergo challenge and 
discontinue between Days 29 and Day 57 do not need 
the above listed ET assessments, but rather should be 
managed as early terminations during the Safety 
Follow-up Period (see Section 7.11.3) 
Information added for sake of 
clarification. 
7.13 
Immunogenicity 
Assessments 
Addition of:  
Additional exploratory immunogenicity assays may 
also be performed to further evaluate the activity of the 
VXA-G1.1-NN vaccine candidate on samples stored for 
future use (with subjects’ consent).  Note that not all 
sample timepoints may be relevant for the some of the 
analysis, so not all assays will be performed at all 
timepoints 
Information added for sake of 
clarification. 
11.4 Final 
Analysis Plan 
Deletion of: 
A preliminary report will be prepared by the SDCC 
after the primary clinical database is locked and all 
serological data through approximately 28 days post 
challenge are received. These analyses may be made 
available to the sponsor for planning subsequent trials 
and for publication. These analyses will not be used to 
make any decisions concerning the conduct of this trial. 
Information was deleted as not 
relevant for the clinical protocol. 
14.3 Informed 
Consent Process 
Addition of: 
The Informed Consent Form explains the storage and 
future use of specimens, and subjects will be asked to 
consent for future testing of samples 
Information added for sake of 
clarification. 
Appendix E : List 
of Adverse 
Events of Special 
Interest 
Addition of: 
Coagulopathy 
• 
Acquired amegakaryocytic thrombocytopenia  
• 
Axillary vein thrombosis  
• 
Cerebral venous thrombosis 
• 
Disseminated intravascular coagulation 
• 
Hepatic vein thrombosis 
• 
Intracranial venous sinus thrombosis 
• 
Portal vein thrombosis 
The list of AESI to be monitored 
under this protocol was updated 
based on the most recent list of 
events received by FDA for Vaxart’s 
oral Ad5 vaccine candidates. 

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• 
Pulmonary thrombosis 
• 
Severe fever with thrombocytopenia syndrome 
• 
Thrombocytopenia 
• 
Thrombotic thrombocytopenia purpura 
• 
Transverse sinus thrombosis 
• 
Vena cava thrombosis 
• 
Amegakaryocytic thrombocytopenia 
• 
Cavernous sinus thrombosis 
• 
Deep vein thrombosis 
• 
Embolism venous 
• 
Immune thrombocytopenia 
• 
Mesenteric vein thrombosis 
• 
Pulmonary embolism 
• 
Pulmonary venous thrombosis 
• 
Subclavian vein thrombosis 
• 
Thrombocytopenia purpura 
• 
Thrombosis 
• 
Vena cava embolism 
• 
Venous thrombosis 
Additional minor wording, spelling and/or formatting modifications have been incorporated 
for added clarity and consistency.