Conditions: COVID-19
Keywords: oral vaccine SARS-CoV-2 tablet vaccine
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 66
Healthy volunteers: yes

Brief summary:
Part 1: An open label, dose and age escalation phase to evaluate the safety and immunogenicity of VXA-CoV2-1.1-S with a repeat-dose vaccination schedule in healthy adults aged 18 - 75 years old that are either vaccine naive or have received prior vaccination with an mRNA (messenger ribonucleic acid) vaccine for the prevention of COVID-19.

Part 2: This phase will assess the efficacy of prophylactic VXA-CoV2-1.1-S against confirmed COVID-19 occurring from 7 days after second dose with a repeat-dose vaccination schedule in healthy adults compared to placebo. Safety and immunogenicity of VXA-CoV2-1.1-S will also be evaluated in this phase.

Detailed description:
Part 1: This is an open-label, dose-ranging phase of the study to determine the safety and immunogenicity of an orally administered adenoviral-vector based vaccine (VXA-COV2-1.1-S) expressing a SARS-CoV-2 antigen and dsRNA adjuvant. Post screening activities, healthy adult volunteers, either naïve or prior vaccinated with an mRNA COVID-19 vaccine, aged 18 - 55 yrs old, and then 56 - 75 yrs old, will be enrolled into the study in 8 subgroups. Participants will receive either a low or a high dose of an oral tableted vaccine at Days 1 and Day 29. The total study period will last \~ 2 months during the active phase, with a total 12 month safety follow-up period post last vaccination. Safety, reactogenicity and immunogenicity assessments will be performed at set times during the study active and follow-up periods. Subjects will be monitored for symptoms of COVID-19 throughout the duration of the study follow-up period. An independent data monitoring committee (IDMC) will provide safety oversight through the duration of the trial. Safety and immunogenicity data will inform on the dose selection for Part 2.

Part 2: This will be a placebo-controlled phase with the vaccine dose level selected from Part 1. Subjects will receive two doses of vaccine or placebo at Days 1 and 29. Subjects will be followed as in Part 1 for safety and immunogenicity. They will also be followed for 6 months for efficacy.

Arms:
arm 1: 1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who are vaccine naïve arm 2: 1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who are vaccine naïve arm 3: 1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who are vaccine naïve arm 4: 1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who are vaccine naïve arm 5: 1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who have received prior vaccinations with an mRNA vaccine arm 6: 1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who have received prior vaccinations with an mRNA vaccine arm 7: 1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who have received prior vaccinations with an mRNA vaccine arm 8: 1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who have received prior vaccinations with an mRNA vaccine arm 9: Repeat dose vaccinations with VXA-CoV2-1.1-S at dose selected from Part 1 in healthy male and female adult volunteers 18 to 75 years old arm 10: Repeat dose administration with matching placebo tablets in healthy male and female adult volunteers 18 to 75 years old

Interventions: intervention 1: VXA-CoV2-1.1-S intervention 2: Placebo Tablets
Intervention descriptions: intervention 1: COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine intervention 2: Placebo tablets matching the active vaccine tablets

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number: VXA-COV2-201 
Official Title: A Phase 2, Double-Blind, Multi-Center, Randomized, Placebo-Controlled, Dose-
Ranging Trial to Determine the Safety, Immunogenicity and Efficacy of an Adenoviral-Vector Based 
Vaccine (VXA-CoV2-1.1-S) Expressing a SARS-CoV-2 S Protein and dsRNA Adjuvant Administered 
Orally to Healthy Adult Volunteers 
NCT Number: NCT05067933 
Document Date: 04 August 2022 


CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 2, Double-Blind, Multi-Center, Randomized, Placebo-Controlled, 
Dose-Ranging Trial to Determine the Safety, Immunogenicity and Efficacy of 
an Adenoviral-Vector Based Vaccine (VXA-CoV2-1.1-S) Expressing a SARS-
CoV-2 S Protein and dsRNA Adjuvant Administered Orally to Healthy Adult 
Volunteers  
Protocol Number: 
VXA-COV2-201 
Product Name: 
SARS-CoV-2 E1-/E3-Deleted Replication Defective Recombinant Adenovirus 
5 with dsRNA Adjuvant Oral Tablet Vaccine (VXA-CoV2-1.1-S) 
Indication: 
Prevention of Coronavirus Disease 2019 (COVID-19) caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) 
Study Phase: 
Phase 2 
Sponsor:  
Vaxart Inc. 
170 Harbor Way; Suite 300 
South San Francisco, CA 94080 
IND Number: 
027602 
Sponsor Contact: 
 
Phone: 
 email: 
 
Medical Monitors: 
 
 Sponsor Medical Monitor 
Phone: 
; email: 
 
 
Clinical Operations, ICON 
Phone: 
; email: 
 
Version and Date: 
Prior Version: 
Version 5.0 (Amendment 4), 04 August 2022 
Version 4.0 (Amendment 3), 09 November 2021 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential investigators, 
consultants, study staff, and applicable independent Ethics Committees and/or Institutional Review Boards.  
The contents of this document shall not be disclosed to others without written authorization from Vaxart (or authorized 
designees) unless it is necessary to obtain informed consent from potential study participants. 
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Vaxart, Inc. 
 
Protocol: VXA-COV2-201 
Version 5.0 
Page 3 of 104  
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TABLE OF CONTENTS 
SIGNATURE PAGE/STATEMENT OF COMPLIANCE .................................................................................................. 2 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF TABLES .............................................................................................................................................................. 5 
1. 
PROTOCOL SUMMARY .................................................................................................................................. 6 
1.1. 
SYNOPSIS ....................................................................................................................................................... 6 
1.2. 
SCHEDULE OF ACTIVITIES ................................................................................................................................. 17 
2. 
INTRODUCTION .......................................................................................................................................... 21 
2.1. 
STUDY RATIONALE ......................................................................................................................................... 21 
2.1.1. 
Justification for Dose ............................................................................................................................ 22 
2.2. 
BACKGROUND ............................................................................................................................................... 22 
2.3. 
BENEFIT/RISK ASSESSMENT ............................................................................................................................. 23 
2.3.1. 
Risk Assessment ................................................................................................................................... 23 
2.3.2. 
Benefit Assessment .............................................................................................................................. 25 
2.3.3. 
Overall Benefit/Risk Conclusion ........................................................................................................... 25 
3. 
PART 1 - OPEN-LABEL LEAD-IN .................................................................................................................... 26 
3.1. 
PART 1 OBJECTIVES AND ENDPOINTS ................................................................................................................. 26 
3.2. 
PART 1 STUDY DESIGN ................................................................................................................................... 27 
3.2.1. 
Part 1: Enrollment and Initial Vaccination ........................................................................................... 28 
3.2.2. 
Part 1: Eligibility for Second Vaccination ............................................................................................. 28 
3.2.3. 
Part 1 Scientific Rationale for Study Design ......................................................................................... 30 
3.2.4. 
Study Duration ..................................................................................................................................... 30 
3.3. 
PART 1 ELIGIBILITY CRITERIA ............................................................................................................................ 30 
3.3.1. 
Part 1 Inclusion Criteria ........................................................................................................................ 30 
3.3.2. 
Part 1 Exclusion Criteria ....................................................................................................................... 32 
4. 
PART 2 – DOUBLE-BLIND PLACEBO-CONTROLLED ....................................................................................... 35 
4.1. 
PART 2 OBJECTIVES AND ENDPOINTS ................................................................................................................. 35 
4.2. 
PART 2 STUDY DESIGN ................................................................................................................................... 36 
4.2.1. 
Part 2: Enrollment and Initial Vaccination ........................................................................................... 36 
4.2.2. 
Part 2: Eligibility for Second Dose of Study Drug ................................................................................. 36 
4.2.3. 
Part 2 Scientific Rational for Study Design ........................................................................................... 37 
4.2.4. 
Part 2 Study Duration .......................................................................................................................... 37 
4.3. 
PART 2 ELIGIBILITY CRITERIA ............................................................................................................................ 38 
4.3.1. 
Part 2 Inclusion Criteria ........................................................................................................................ 38 
4.3.2. 
Part 2 Exclusion Criteria ....................................................................................................................... 39 
5. 
STUDY DRUG, CONCOMITANT THERAPY AND LIFE-STYLE CONSIDERATIONS .............................................. 42 
5.1. 
STUDY DRUG ADMINISTRATION ........................................................................................................................ 42 
5.2. 
COMPLIANCE OF STUDY DRUG .......................................................................................................................... 43 
5.2.1. 
Dose Adjustments/Modifications/Delays ............................................................................................ 43 
5.3. 
HANDLING AND ACCOUNTABILITY ..................................................................................................................... 43 
5.4. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ............................................................................ 44 
5.4.1. 
Assignment of a Participant Number ................................................................................................... 44 
5.4.2. 
Randomization (Part 2 only) ................................................................................................................ 44 
5.4.3. 
Blinding and Unblinding (Part 2 only) .................................................................................................. 44 
5.5. 
TREATMENT OF OVERDOSE .............................................................................................................................. 45 
5.6. 
CONCOMITANT THERAPY ................................................................................................................................ 45 
5.6.1. 
Prohibited Concomitant Medication .................................................................................................... 45 
5.7. 
SCREEN FAILURES .......................................................................................................................................... 45 
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5.8. 
END OF STUDY DEFINITION .............................................................................................................................. 46 
5.9. 
INTERVENTION AFTER THE END OF THE STUDY ..................................................................................................... 46 
6. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT WITHDRAWAL FROM STUDY ...................................... 47 
6.1. 
STUDY HALTING RULES ................................................................................................................................... 47 
6.1.1. 
Part 1 Halting Rules ............................................................................................................................. 47 
6.1.2. 
Part 2 Halting Rules ............................................................................................................................. 47 
6.2. 
DISCONTINUATION OF STUDY DRUG .................................................................................................................. 48 
6.3. 
PARTICIPANT WITHDRAWAL FROM THE STUDY .................................................................................................... 48 
6.4. 
LOST TO FOLLOW-UP ...................................................................................................................................... 49 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................................................... 50 
7.1. 
EFFICACY AND IMMUNOGENICITY ASSESSMENTS .................................................................................................. 50 
7.1.1. 
SARS-CoV-2 Infection and COVID-19 Diagnosis ................................................................................... 50 
7.1.2. 
Immunogenicity ................................................................................................................................... 52 
7.2. 
SAFETY ASSESSMENTS .................................................................................................................................... 53 
7.2.1. 
Physical Examination ........................................................................................................................... 53 
7.2.2. 
Vital Signs ............................................................................................................................................ 53 
7.2.3. 
Clinical Safety Laboratory Assessments ............................................................................................... 53 
7.3. 
TREATMENT-EMERGENT ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............................................................. 54 
7.3.1. 
Time Period and Frequency for Collecting TEAE, MAAE SAE and Other Reportable Safety Event 
Information ........................................................................................................................................................ 54 
7.3.2. 
Method of Detecting TEAEs, MAAEs and SAEs .................................................................................... 57 
7.3.3. 
Follow-up of AEs, MAAEs and SAEs ...................................................................................................... 57 
7.3.4. 
Regulatory Reporting Requirements for SAEs ...................................................................................... 57 
7.3.5. 
Death Events ........................................................................................................................................ 57 
7.3.6. 
Pregnancy ............................................................................................................................................ 57 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................................... 59 
8.1. 
SAMPLE SIZE DETERMINATION ......................................................................................................................... 59 
8.1.1. 
Part 1 ................................................................................................................................................... 59 
8.1.2. 
Part 2 ................................................................................................................................................... 59 
8.2. 
POPULATIONS FOR ANALYSES ........................................................................................................................... 60 
8.3. 
STATISTICAL ANALYSES ................................................................................................................................... 60 
8.3.1. 
Part 1 - Open Label Lead-in Phase ....................................................................................................... 60 
8.3.2. Part 2- Double Blind, Placebo Controlled ................................................................................................. 62 
8.4. 
INTERIM ANALYSIS ......................................................................................................................................... 65 
8.5. 
SAFETY OVERSIGHT ........................................................................................................................................ 66 
8.5.1. 
Internal Sponsor Review ...................................................................................................................... 66 
8.5.2. 
Independent Data Monitoring Committee (IDMC) .............................................................................. 66 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................................... 67 
9.1. 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....................................................... 67 
9.1.1. 
Regulatory and Ethical Considerations ................................................................................................ 67 
9.1.2. 
Financial Disclosure.............................................................................................................................. 67 
9.1.3. 
Informed Consent Process .................................................................................................................... 68 
9.1.4. 
Exclusion of Women, Minorities, and Children (Special Populations) .................................................. 68 
9.1.5. 
Data Protection .................................................................................................................................... 68 
9.1.6. 
Dissemination of Clinical Study Data ................................................................................................... 68 
9.1.7. 
Data Quality Assurance ....................................................................................................................... 69 
9.1.8. 
Source Documents ............................................................................................................................... 69 
9.1.9. 
Publication Policy ................................................................................................................................. 70 
9.2. 
APPENDIX 2: SAFETY CLINICAL LABORATORY TESTS .............................................................................................. 71 
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9.3. 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING ................................................................................................................................................................. 72 
9.3.1. 
Definition of TEAE (Unsolicited and Solicited) ...................................................................................... 72 
9.3.2. 
Definition of MAAE .............................................................................................................................. 72 
9.3.3. 
Definition of SAE .................................................................................................................................. 73 
9.3.4. 
Recording of TEAE, MAAE and/or SAE ................................................................................................. 74 
9.3.5. 
Reporting of SAEs and MAAEs ............................................................................................................. 80 
9.4. 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY INFORMATION ......................................... 82 
9.4.1. 
Definitions ............................................................................................................................................ 82 
9.4.2. 
Contraception Guidance ...................................................................................................................... 83 
9.4.3. 
Collection of Pregnancy Information ................................................................................................... 84 
9.5. 
APPENDIX 5: MEDICALLY ATTENDED ADVERSE EVENTS (MAAES) ........................................................................... 86 
9.6. 
APPENDIX 6: ABBREVIATIONS .......................................................................................................................... 88 
9.7. 
APPENDIX 7: SUMMARY OF CHANGES TO PROTOCOL ............................................................................................ 91 
10. 
REFERENCES ......................................................................................................................................... 103 
 
List of Tables 
 
Table 1 
Part 1 Groups, Doses and Sample Size .................................................................. 14 
Table 2 
Part 2 – Treatment Arms, Dose and Sample Size .................................................. 15 
Table 3 
Schedule of Activities – Part 1 .............................................................................. 17 
Table 4 
Schedule of Activities – Part 2 .............................................................................. 19 
Table 5 
Study Drug ............................................................................................................. 42 
Table 6 
Definitions of COVID-19 Severity ........................................................................ 51 
Table 7 
Qualifying Symptoms of Suspected COVID-19 ................................................... 52 
Table 8 
Adverse Event Reporting Timelines to the Sponsor .............................................. 56 
Table 9 
Protocol-Required Safety Laboratory Assessments .............................................. 71 
Table 10 
Grading of Solicited Symptoms of Reactogenicity ............................................... 76 
Table 11 
Grading of Laboratory Abnormalities (Serum Chemistry) ................................... 78 
Table 12 
Grading of Laboratory Abnormalities (Hematology) ............................................ 79 
Table 13 
Grading of Laboratory Abnormalities (Urinalysis) ............................................... 79 
 
 
 
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1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title 
A Phase 2, Double-Blind, Multi-Center, Randomized, Placebo-Controlled, Dose-Ranging Trial 
to Determine the Safety, Immunogenicity and Efficacy of an Adenoviral-Vector Based Vaccine 
(VXA-CoV2-1.1-S) Expressing a SARS-CoV-2 S Protein and dsRNA Adjuvant Administered 
Orally to Healthy Adult Volunteers  
Study Rationale and Hypothesis 
VXA-Cov2-1.1-S is an E1/E3-deleted, replication-incompetent, adenovirus 5 vaccine vector 
designed for use as an oral vaccine for the prevention of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection. The vaccine vector encodes the full-length Spike protein 
(S) of SARS-CoV-2. The adjuvant consists of a double-stranded ribonucleic acid (RNA) Toll-
like receptor 3 (TLR3) agonist which enhances immune induction to expressed antigen in the gut
mucosa.
SARS-CoV-2, a positive-sense single-stranded RNA virus presumed to be of zoonotic origin, is 
highly contagious in humans and is the cause of the ongoing worldwide pandemic of coronavirus 
disease 2019 (COVID-19). There is an urgent public health need for rapid development of novel 
interventions to prevent the spread of this disease, including prophylactic measures, such as 
vaccines. 
A unique and advantageous immune response elicited by oral vaccination is the induction of 
antibodies derived from mucosal cells. Given that the mucosal route of immunization produces 
superior mucosal immunity compared to injected vaccines, it is hypothesized that VXA-CoV2-
1.1-S oral vaccine may enable higher degrees of mucosal protection against infection when 
compared to a parenteral immunization method. 
VXA-CoV2-1.1-S is designed to elicit both antibody and T cell responses, mucosally and 
systemically, to SARS-CoV-2. Prior completed Phase 1 and 2 clinical studies with the Vaxart 
Vector Adjuvant Antigen Standard Technology (VAAST™) platform have demonstrated 
protective immunity to other viruses (influenza, norovirus, and respiratory syncytial virus) with 
both systemic and mucosal immune responses against the antigen of choice (Kim, 2016; Kim, 
2018; Liebowitz, 2020). 
A Phase 1 open-label, dose-ranging study to evaluate the safety and immunogenicity of an earlier 
vaccine candidate, VXA-CoV2-1, in healthy young adults is ongoing under Protocol VXA-
COV2-101. VXA-CoV2-1.1-S is similar to VXA-CoV2-1 and was manufactured using the same 
VAAST platform, with the exception that the new construct does not express the N protein and 
has a slightly modified version of the S protein to provide better stability when expressed on the 
surface of a cell. The ongoing VXA-COV2-101 study completed enrollment with 35 subjects 
receiving one or two administrations of low dose vaccine (1x1010 IU) or a single higher dose 
(5x1010 IU).  Solicited symptoms of reactogenicity were collected for 7 days following each 
vaccination and were mild to moderate in severity and transient in nature resolving without 
intervention/medication.  Unsolicited adverse events (AEs) were collected through Day 57 
(Study Active Period); five subjects reported a total of 6 unsolicited AEs that were all mild in 
severity.  No subjects have reported any serious adverse events (SAEs) or medically attended 
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adverse events (MAAEs) on this study to date. Subjects are currently in the Safety Follow-up 
Period (through Day 390) and being monitored for SAEs and MAAEs. Refer to the 
Investigator’s Brochure for additional information. 
The current Phase 2 study, comprised of 2 parts, is designed to assess the safety, tolerability, 
immunogenicity, and efficacy of the VXA-CoV2-1.1-S oral vaccine with a repeat-dose 
vaccination schedule in healthy adult volunteers. Part 1 will utilize an open-label dose and age 
escalation design to evaluate the early safety, tolerability and immunogenicity of the VXA-
CoV2-1.1-S vaccine at two dose levels in a stepwise manner. Subjects will be enrolled into two 
cohorts; Cohort 1 will enroll subjects naïve to any prior vaccination against COVID-19 or history 
of COVID-19 and Cohort 2 will enroll subjects who have received 2 doses of an mRNA vaccine 
for the prevention of COVID-19 under Emergency Use Authorization (EUA) or FDA approved 
at least 6 months prior to study vaccination at Day 1.  Part 1 will inform on the safe and 
immunogenic dose with which to advance into Part 2, the randomized, double-blind, placebo-
controlled phase of the study which will also evaluate the efficacy of VXA-CoV2-1.1-S 
compared to placebo.   
Though there is prior Phase 1 experience with the similar VXA-CoV2-1 vaccine in 35 
participants with doses up to 5x1010 IU under Protocol VXA-COV2-101, Vaxart intends to 
utilize a conservative stepwise dose escalation schedule starting at a low dose of 1x1010 IU with 
VXA-CoV2-1.1-S in the current protocol to allow safely advancing from the young adult 
population (18 – 55 years of age) into the older population (56 – 75 years of age). Two dose 
levels, a low dose of 1x1010 IU, and then a high dose of 1x1011 IU will be investigated with 
cohorts of 12 subjects each in the younger age range, and then in the older age range.  These 4 
cohorts will be mirrored for subjects that are COVID-19 and vaccine naïve and those with prior 
vaccination who have received two doses of an mRNA vaccine for the prevention of SARS-
CoV-2 infection, for a total enrollment of 96 subjects in Part 1.  The safety data from the prior 
Phase 1 study will be leveraged to move from one dose and age cohort to the next in an informed 
manner after evaluation of reactogenicity and unsolicited AE data through Day 8. It will be 
important to enroll the cohorts in Part 1 as expeditiously as possible and advance into Part 2 of 
the study at the selected dose of VXA-CoV2-1.1-S, especially in the naïve participant cohorts 
(those without prior exposure or vaccination against SARs-CoV-2 to be enrolled under this 
protocol) as this population is becoming increasingly difficult to recruit. Data from Part 1 will be 
reviewed by the IDMC and submitted to the IND for FDA review prior to initiating enrollment in 
Part 2. 
 
 
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Objectives and Endpoints  
Part 1- Open Label Lead-in Phase 
Objectives 
Endpoints 
Primary 
To evaluate the safety and 
tolerability of VXA-CoV2-
1.1-S with a repeat-dose 
vaccination schedule in 
healthy adults at two dose 
levels 
• Frequency, duration, and severity of solicited symptoms of 
reactogenicity (local, systemic) for 1 week following each 
vaccination 
• Frequency, duration, and severity of unsolicited treatment-
emergent adverse events (TEAEs), serious AEs (SAEs), and 
medically attended AEs (MAAEs) during the study Active 
period (Day 57). MAAEs will be determined by (1) active 
monitoring for COVID-19 and vaccine-associated enhanced 
disease (VAED), and (2) monitoring for potential immune-
mediated medical conditions including AEs of special interest 
(AESIs) and new onset of chronic illness (NOCIs).  
Secondary 
To assess long-term safety 
of VXA-CoV2-1.1-S  
• Frequency, duration, and severity of all SAEs, and MAAEs 
including monitoring for COVID-19, VAED, AESIs and 
NOCIs through one year post last dose  
To assess the 
immunogenicity of VXA-
CoV2-1.1-S with a repeat-
dose vaccination schedule 
in healthy adults at two 
dose levels 
Key immunogenicity endpoints: 
• SARS-CoV2-specific Immunoglobulin G (IgG) and 
Immunoglobulin A (IgA) antibody levels by Mesoscale 
Discovery (MSD) assay 
• Neutralizing serum antibody titers to SARS-CoV-2  
Additional immunogenicity endpoints: 
• T cell responses by Intracellular Cytokine Cytometry (ICC) 
• Antigen S-specific IgA in nasal swabs 
• Antigen S-specific IgA in saliva 
• Anti-Adenovirus type 5 (Ad5) serum antibodies (optional) 
 
 
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Exploratory 
To assess the efficacy of 
prophylactic VXA-CoV2-1.1-S 
against confirmed COVID-19 
occurring from 7 days after 
second dose with a repeat-dose 
vaccination schedule in healthy 
adults at two dose levels 
• Frequency, duration and severity of virologically 
confirmed COVID-19 illness and serologically 
confirmed SARS-CoV-2 infection occurring from 7 
days following second study drug dose administration 
Part 2 – Double Blind, Placebo-Controlled Phase 
Objectives 
Endpoints 
Primary  
To assess the efficacy of 
prophylactic VXA-CoV2-1.1-S 
against confirmed COVID-19 
occurring from 7 days after 
second dose with a repeat-dose 
vaccination schedule in healthy 
adults compared to placebo 
• Frequency duration and severity of virologically 
confirmed COVID-19 illness and serologically 
confirmed SARS-CoV-2 infection occurring from 7 days 
following second study drug dose administration 
To evaluate the safety and 
tolerability of VXA-CoV2-1.1-
S with a repeat-dose 
vaccination schedule in healthy 
adults compared to placebo 
• Frequency, duration, and severity of solicited symptoms 
of reactogenicity (local, systemic) for 1 week following 
each vaccination 
• Frequency, duration, and severity of unsolicited TEAEs, 
SAEs, and MAAEs through the active period (4 weeks 
post last dose), efficacy period and safety follow-up 
period. MAAEs will be determined by (1) active 
monitoring for COVID-19 and VAED through the active 
period (4 weeks post last dose), and (2) monitoring for 
potential immune-mediated medical conditions including 
AESIs and NOCIs for one year post last dose. 
Secondary  
To assess long-term safety of  
VXA-CoV2-1.1-S  
• Frequency, duration, and severity of all SAEs, and 
MAAEs including monitoring for COVID-19, VAED, 
AESIs and NOCIs through one year post last dose  
To assess the immunogenicity 
of VXA-CoV2-1.1-S with a 
repeat-dose vaccination 
schedule in healthy adults 
compared to placebo 
 
 
Key immunogenicity endpoints: 
• SARS-CoV2-specific IgG and IgA antibody levels using 
MSD assays 
• Neutralizing serum antibody titers to SARS-CoV-2 
Additional immunogenicity endpoints: 
• Antigen S-specific IgA in nasal swabs 
• Antigen S-specific IgA in saliva 
•  
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Overall Study Design 
This is a 2-part study. 
Each study part will include a Screening Period, Active Period and a Safety Follow-up Period. 
Study assessments and visits will be conducted as shown in the Schedule of Activities (SoA) in 
Section 1.2 within Table 3 and Table 4 for study Part 1 and Part 2, respectively. 
Part 1 Design 
Part 1 utilizes an open-label, repeat-dose, dose and age escalation design to evaluate the VXA-
COV2-1.1-S oral vaccine in two cohorts. Cohort 1 will evaluate approximately 36 total healthy 
adult participants that are naïve (no prior vaccination against SARS-CoV-2 infection and no 
history of prior COVID-19 or SARS-CoV-2 infection) across 3 groups of 12 subjects each, 
encompassing 2 age groups and 2 dose levels. Cohort 2 will evaluate approximately 36 healthy 
adult participants who have no history of prior COVID-19 or SARS-CoV-2 infection and have 
received 2 doses of an EUA or FDA approved COVID-19 mRNA vaccine across 3 groups of 12 
subjects each, encompassing 2 age groups and 2 dose levels. Enrollment will be performed in a 
sequential manner with at least 12 subjects in the younger age group (18-55 years) completing 
within the dose level, prior to enrollment of the older age group (56-75 years) at that dosage. 
 
Population 
Cohort 
VXA-CoV2-1.1-S  
Dose Levels* 
Age 
(years) 
Vaccination 
Timepoints 
No. of 
Participants 
 Naive 
1a 
1x1010 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
 
12 
 Prior vaccinated 
2a 
1x1010 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
12 
IDMC Data Review1 
Naive 
1b 
1x1011 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
12 
Naive 
1c 
1x1010 I.U. ±0.5 log 
56 – 75  
Day 1 & Week 4  
12 
Prior vaccinated 
2b 
1x1011I.U. ±0.5 log 
18 – 55 
 Day 1 & Week 4 
12 
Prior vaccinated 
2c 
1x1010 I.U. ±0.5 log 
56 – 75 
Day 1 & Week 4 
12 
IDMC Data Review2 
 
IDMC = Independent Data Monitoring Committee. 
1 IDMC to review safety data through Week 1 for 12 subjects in group a before enrollment will begin in b and c. 
 
2 IDMC to review safety data for all subjects within each age group and initial immunogenicity data from Part 1, to make 
recommendations on dose selection for randomized, placebo-controlled phase, before enrollment begins in Part 2. 
Cohorts 1 and 2 (naïve and prior vaccinated subjects, respectively) will enroll in parallel, and the IDMC may review safety data 
for the two Cohorts separately if the enrollment rates between the two groups vary.  
 
After signing an informed consent, participants will undergo screening assessments to determine 
study eligibility over a 30-day Screening Period.  
On Day 1, eligible participants will be enrolled sequentially to receive their 1st oral vaccination 
according to their assigned treatment group as specified in Table 1. 
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During the Active Period, participants will record daily symptoms of reactogenicity for 1 week 
post each vaccination, administered on Day 1 and Week 4, using a Solicited Symptom Diary. 
They will return to the site at 1 and 4 weeks following each vaccination, as specified in the SoA, 
to have safety assessments and samples collected for evaluation of immunogenicity. Post 
completion of the Week 1 visit by all subjects in a specified cohort, as detailed in  
Table 1, the Independent Data Monitoring Committee (IDMC) will review Day 1 to Week 1 
safety data and make recommendations as to whether to proceed to the next cohort(s). Upon 
completion of active portion of Part 1, the IDMC will review safety and preliminary 
immunogenicity data from all cohorts and make recommendations to the Sponsor on the VXA-
CoV2-1.1-S dose level to evaluate in Part 2. A summary of safety and immunogenicity data with 
the intended dose for Part 2 will be submitted to FDA for review and concurrence prior to 
initiation of enrollment in Part 2. 
At the Week 4 visit participants will have safety assessments to evaluate suitability to receive the 
second vaccination as outlined in Section 3.2.2.  Participants with any of the following 
conditions will not be eligible to receive a second vaccine dose: 
• Positive pregnancy test at Day 29 (female participants), 
• Occurrence of any possibly, probably or definitely treatment-related Grade 3 or 4 AE or 
SAE following the initial vaccination  
• Occurrence of any Grade 3 or 4 AE or SAE following the initial vaccination without 
plausible alternative explanation 
• Presence of acute illness or significant new medical condition including positive SARS-
COV-2 rapid molecular test prior to dosing 
 
Participants deemed ineligible due to presence of acute illness or new medical condition may be 
re-assessed during the visit window (+7 days), and if the condition resolves, may receive their 
second vaccination within 1 week of their scheduled Week 4 Visit. In such situations the 
Principal Investigator must contact the study Medical Monitor and gain consensus on the 
decision to continue participant with study vaccinations prior to administration of the second 
dose.  
Upon completion of the study Active Period (Week 8 Visit) participants will enter the Safety 
Follow-up Period and be monitored for SAEs, MAAEs and for exposure to and/or symptomatic 
COVID-19 including VAED through to Month 13/End of Study (EOS). In addition, these 
participants will be evaluated for immunogenicity as specified in the SoA (Table 3). During the 
Safety Follow-up Period participants will return to the site at Months 7 and 13 for safety 
monitoring and collection of samples for evaluation of immunogenicity; they will also be 
contacted by phone monthly between site visits to query for safety and exposure to and/or 
symptomatic COVID-19. 
Any participant who discontinues study drug early (does not receive the second dose) will enter 
the Safety Follow-up Period a month earlier at Week 4 and will be monitored for safety and 
exposure to and/or symptomatic COVID-19 as described above, and complete immunogenicity 
assessments through EOS per the SoA (Table 3).  
Any participant reporting COVID-19 like illness or exposure to COVID-19 during the study will 
be asked to return to the site for an unscheduled visit to test for SARS-CoV-2 infection. 
Participants with confirmed SARS-CoV-2 infection, at any time during the study period, will be 
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asked to provide a nasal swab sample every two days after their confirmatory COVID-19 test, 
until they test negative, to monitor for duration of infection. The duration of q2day testing post 
confirmed SARS-CoV-2 infection should end after 10 days if still testing positive at that time. 
Any FDA Authorized rapid molecular test (e.g. LUCIRA COVID-19 Test) can be used for home 
or on-site testing for monitoring COVID-19 infection. They will also be monitored for clinical 
disease severity (see Section 7.1.1, Table 6) and outcome. The participant will be counseled to 
notify their Primary Care Physician of their positive SARS-CoV-2 status and seek medical care 
should they become symptomatic. 
An IDMC will provide safety oversight throughout the duration of the study. If the protocol 
halting rules are met at any time during the study (refer to Section 6.1.1 for Part 1 and 
Section 6.1.2 for Part 2), enrollment and dosing will be suspended pending a full IDMC review 
(Section 8.5.2). The Sponsor’s Medical Monitor(s) (or designees) will perform safety oversight 
(Section 8.5.1). 
Part 2 Design and Overview 
Part 2 will utilize a double-blind, randomized, placebo-controlled, repeat-dose design that will 
enroll 800 eligible participants between the ages of 18 and 75 years of age, including a minimum 
of 200 participants > 55 years of age. Randomization will be stratified by age (18 – 55 years and 
56 – 75 years) and region (if sites in multiple countries are utilized). 
After signing an informed consent, participants will complete assessments to determine their 
eligibility within a 30-day Screening period.  
 
On Day 1, eligible participants will be randomized in a 1:1 ratio to either active (VXA-CoV2-
1.1-S) or control (matching placebo tablets) group (Table 2): 
• Active: VXA-CoV2-1.1-S (dose to be selected from Part 1) 
• Control: matching placebo  
During the Active Period, participants will record daily symptoms of reactogenicity for 1 week 
post each study drug administration (Day 1 and Week 4), using a Solicited Symptom Diary. 
Participants will return to the site at 1 and 4 weeks following each vaccination, as specified in the 
SoA to have safety assessments and samples collected for evaluation of immunogenicity (Table 4).   
As in Part 1, at the Week 4 visit participants will have safety assessments to evaluate suitability 
to receive the second vaccination as outlined in Section 4.2.2.  Participants with any of the 
following conditions will not be eligible to receive a second vaccine dose: 
 
• Positive pregnancy test at Day 29 (female participants), 
• Occurrence of any possibly, probably or definitely treatment-related Grade 3 or 4 AE or 
SAE following the initial vaccination  
• Occurrence of any Grade 3 or 4 AE or SAE following the initial vaccination without 
plausible alternative explanation 
• Presence of acute illness or significant new medical condition including positive SARS-
COV-2 rapid molecular test prior to dosing 
 
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Participants deemed ineligible due to presence of acute illness or new medical may be re-
assessed during the visit window (+7 days), and if the condition resolves, may have a second 
vaccination within 1 week of their scheduled Week 4 Visit.  In such situations the Principal 
Investigator must contact the study Medical Monitor and gain consensus on the decision to 
continue participant with study vaccinations prior to administration of the second dose.   
Following completion of the Active Period (Week 8 visit) participants will continue to be 
monitored for SAEs, MAAEs and for exposure to and/or symptomatic COVID-19 through 
Month 13/EOS during the study Safety Follow-up Period. In addition, these participants will be 
evaluated for immunogenicity as specified in the SoA (Table 4).  
Any participant who discontinues study drug early (does not receive the second dose) will enter 
the Safety Follow-up Period a month earlier at Week 4 and will be monitored for safety and 
exposure to and/or symptomatic COVID-19 as described above, and complete immunogenicity 
assessments through EOS per the SoA (Table 4).  
Any participant reporting COVID-19 like illness or exposure to COVID-19 will be asked to 
return to the site for an unscheduled visit to test for SARS-CoV-2 infection. Participants with 
confirmed SARS-CoV-2 infection, at any time during the study period, will be asked to provide 
a nasal swab every two days after their confirmatory COVID-19 test, until they are negative, to 
monitor for duration of infection. They will also be monitored for clinical disease severity 
(Section 7.1.1, Table 6), and outcome, including potential VAED. The participant will be 
counseled to notify their Primary Care Physician of their positive SARS-CoV-2 status and seek 
medical care should they become symptomatic. 
Participants will be followed via site visits and monthly phone calls in order to monitor for 
COVID-19 (symptoms or exposure) starting from 7 days following their second vaccination in 
the Active Period.  The study Efficacy Period, as described in Duration of Study Participation in 
Table 2, will last until the last participant randomized has completed their Month 7 visit (6 
months post last study drug administration), after which the study database will be cleaned and 
locked, and the primary efficacy analyses performed.  At this time the treatment assignments will 
be unblinded and Part 2 participants in the placebo group will have the opportunity to receive 
vaccination(s) against COVID-19 as detailed in Section 5.9.  
An interim analysis for efficacy may also be performed if 18 cases of confirmed COVID-19 are 
reported prior to the planned efficacy analysis at completion of Month 7 visits by all participants.  
The IDMC will provide safety oversight throughout the duration of the study. If the protocol 
halting rules are met at any time during the study (refer to Section 6.1.1 for Part 1 and 
Section 6.1.2 for Part 2), enrollment and dosing will be suspended pending a full IDMC review 
(Section 8.5.2). The Sponsor’s Medical Monitor(s) (or designees) will perform safety oversight 
(Section 8.5.1). 
Treatment Group and Number of Participants 
Part 1 – Open-Label Lead-in (N = ~ 72 Participants) 
This phase will include healthy male and female adult volunteers 18 to 75 years old, inclusive, in 
the following cohorts: 
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• Cohort 1- Healthy adults who are naïve (no prior vaccinations against COVID-19 and no 
history of COVID-19) and are at low risk of developing severe COVID-19 upon potential 
infection with SARS-CoV-2 
• Cohort 2- Healthy adults who are prior vaccinated (have received two doses of an EUA 
or FDA approved mRNA COVID-19 vaccine at least 6 months prior to enrollment [Day 
1] and are at low risk of developing severe COVID-19 upon potential infection with 
SARS-CoV-2 
Approximately Seventy-two  (72) subjects will be enrolled in a stepwise manner as outlined in 
Table 1. 
 
Table 1 
Part 1 Groups, Doses and Sample Size  
 
Population 
Cohort 
VXA-CoV2-1.1-S  
Dose Levels* 
Age 
(years) 
Vaccination 
Timepoints 
No. of 
Participants 
 Naive 
1a 
1x1010 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
 
12 
 Prior vaccinated 
2a 
1x1010 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
12 
IDMC Data Review1 
Naive 
1b 
1x1011 I.U. ±0.5 log 
18 – 55 
Day 1 & Week 4  
12 
Naive 
1c 
1x1010 I.U. ±0.5 log 
56 – 75  
Day 1 & Week 4  
12 
Prior vaccinated 
2b 
1x1011I.U. ±0.5 log 
18 – 55 
 Day 1 & Week 4 
12 
Prior vaccinated 
2c 
1x1010 I.U. ±0.5 log 
56 – 75 
Day 1 & Week 4 
12 
 
IDMC Data Review2 
*Multiple tablets may be administered to deliver the full intended dose. 
IDMC = Independent Data Monitoring Committee. 
1 IDMC to review safety data through Week 1 for 12 subjects in group a before enrollment will begin in b and c. 
 
2 IDMC to review safety data  for all subjects within each age group and initial immunogenicity data from Part 1 to make 
recommendations to Sponsor on dose selection for randomized, placebo-controlled phase, before enrollment begins in Part 2. 
Cohorts 1 and 2 (naïve and prior vaccinated subjects, respectively) will enroll in parallel. The IDMC may review safety data for 
the subgroups within each of these two cohorts separately if the enrollment rates between the two cohorts vary.  
 
Duration of Study Participation 
For each participant in Part 1 the duration of study activities is expected to last as follows: 
Study Period (Part 1) 
Duration  
Screening Period:  
30 days  
Active Period:  
8 weeks* 
Safety Follow-up Period:  
11 months 
Total duration of participation: 
~14 months 
*Participants who discontinue study drug early will enter the Safety Follow-up Period at Week 4. 
 
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Part 2 – Randomized, Double-blind, Placebo-controlled (N = 800 Participants) 
Healthy male and female adult volunteers 18 to 75 years old (inclusive) will be randomized in 
Part 2 as outlined in Table 2.  A minimum of 200 of the total 800 participants in Part 2 will be 
>55 years of age.  
Table 2 
Part 2 – Treatment Arms, Dose and Sample Size 
 
Treatment Arms 
Treatment* 
Treatment 
Timepoints 
No. of 
Participants** 
Active 
Oral tableted VXA-CoV2-1.1-S vaccine 
(Dose to be selected after Part 1 data review) 
Day 1 & Week 4 
400 
Control 
Matching oral placebo tablet(s) 
Day 1 & Week 4 
400 
*   Multiple tablets may be administered to deliver the full intended dose. 
** A minimum of 200 participants (25%) in Part 2 will be >55 years old. 
 
Duration of Study Participation 
For each participant in Part 2 the duration of study activities is expected to last as follows: 
Study Period (Part 2) 
Duration  
Screening Period:  
30 days  
Active Period:  
8 weeks* 
Efficacy Evaluation: 
~6 months (starting 7 days after second dose) 
Safety Follow-up Period:  
11 months 
Total duration of participation: 
~14 months 
*   Participants who discontinue study drug early will enter the Safety Follow-up Period at Week 4. 
**The study database will be cleaned and locked following completion of the efficacy period. Treatment 
assignments for Part 2 will be unblinded following completion of the primary efficacy analyses.  
 
Scheduled Study Visits  
Study Period 
Part 1 and Part 2 Site Visits 
Screening 
Day -30 to Day -1 
Active  
Week 0 (Day 1) – First dose administration 
Week 1 (Day 8)  
Week 4 (Day 29) – Second dose administration 
Week 5 (Day 36) 
Week 8 (Day 57) – End of Study Active Period Visit 
Safety Follow-up 
Months 3, 4, 5, 6, 8, 9, 10, 11 and 12 (phone calls) 
Month 7  
Month 13 – End of Study Visit 
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Study Sites 
Part 1:  4 to 8 qualified clinical sites in the United States (U.S.). 
Part 2:  30 to 60 qualified clinical sites in the U.S., Latin America, South Africa and/or India, as 
required to complete study enrollment.  
 
Independent Data Monitoring Committee (IDMC): 
Refer to Section 8.5.2 for information on IDMC scheduled meetings for Part 1 and study 
oversight for Parts 1 and 2.
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1.2. 
Schedule of Activities 
 
Table 3 
Schedule of Activities – Part 1  
 
Screening 
Active Study Period 
Safety Follow-up Period 
Notes 
Study Day/Week/Month 
  Day  
-30 to -1  
Wk 0  
(D1) 
Wk 1 
   (D8) 
Wk 4  
 (D29) 
Wk 5 
 (D36) 
Wk 8/ET 
(D57) 
Months 7 and 
13/EOS 
 Months 3 – 6 and 
8 – 12 
Day (D), Week (Wk) 
Months 3 – 6 and 8 – 12 are remote visits (phone calls) 
 
Visit Window (days) 
 
N/A 
0 
+7  
0 
±2 
±7 
±7 
  
Informed consent 
X 
  
  
  
  
  
 
 
  
Inclusion/Exclusion 
X 
X 
  
X 
  
  
 
 
  
Demographics 
X 
  
  
  
  
  
 
 
  
Medical history 
X 
  
  
  
  
  
 
 
  
Serology  
X 
  
  
  
  
  
 
 
HIV, HCV, HBV 
Urine drug screen 
X 
  
  
  
  
  
 
 
  
Physical examination 
X 
X* 
X* 
X* 
X* 
X* 
 
 
* Targeted  
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
  
Safety laboratory tests 
X# 
X† 
X 
X 
X 
X 
 
 
#  Coagulation tests only at screening as part of safety lab 
panel (PT, PTT and fibrinogen) 
† If screening laboratory tests are done within 2 days of 
baseline, no need to repeat at baseline. 
 
Urinalysis  
X 
X† 
X 
X 
X 
X 
 
 
Pregnancy test 
X 
X 
  
X 
  
 
 
 
Pregnancy testing should include serum hCG at screening. 
Sites should confirm negative urine pregnancy test for all 
women on Days 1 and 29 prior to dosing 
SARS-CoV-2 rapid Ab test 
Xa 
Xa 
 
 
 
 
 
 
a. This test is only for Cohort 1 (naïve subjects). It will need 
to be repeated at Day 1 only if Screening test completed >7 
days prior to the Day 1 Visit. 
Nasal Swab for SARS-
CoV-2 (RT- PCR) 
  
Xb 
  
 
  
 
 
 
b. Collect swab predose at Day 1.  
SARS-CoV-2 Rapid 
Molecular Test* 
 
X 
 
X 
 
 
 
 
Confirm negative on-site rapid molecular test prior to each 
dose.  Rapid molecular test to be done at any time during the 
study if participant reports symptoms and/or exposure to 
COVID-19. If positive, repeat rapid molecular test at home 
or on-site for monitoring COVID-19 infection q2days until 
negative or up to 10 days if still testing positive, refer to 
section 7.1.1 
 
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Screening 
Active Study Period 
Safety Follow-up Period 
Notes 
Study Day/Week/Month 
  Day  
-30 to -1  
Wk 0  
(D1) 
Wk 1 
   (D8) 
Wk 4  
 (D29) 
Wk 5 
 (D36) 
Wk 8/ET 
(D57) 
Months 7 and 
13/EOS 
 Months 3 – 6 and 
8 – 12 
Day (D), Week (Wk) 
Months 3 – 6 and 8 – 12 are remote visits (phone calls) 
 
Visit Window (days) 
 
N/A 
0 
+7  
0 
±2 
±7 
±7 
  
Vaccination 
  
X 
  
X 
  
  
 
 
Participants must be assessed for suitability for 2nd dose, per 
Section 3.2. If they are not eligible for their 2nd dose, 
participants will enter the Safety Follow Up period at Week 4. 
Dispense Solicited 
Symptom Diary 
  
X 
  
X 
  
  
 
 
 
 
Review & Collect Solicited 
Symptom Diary 
  
  
X 
  
X 
  
 
 
  
Review Prior & Concurrent 
Medication 
X 
X 
X 
X 
X 
X 
 
 
  
Query for TEAEs, SAEs 
and MAAEs  
  
X 
X  
X 
X 
X 
Xc 
Xc 
c. Only SAEs ,and MAAEs including AESIs and NOCIs will 
be collected during the Safety Follow-up Period. 
Query for exposure to 
and/or Symptoms of 
COVID-19d 
 
X 
X 
X 
X 
X 
X 
X 
d. Unscheduled visit must be completed if participant reports 
symptoms or exposure to COVID-19, refer to section 7.1.1 
Immunogenicity Assessments 
 
 
 
 
 
 
SARS-CoV2-specific 
IgG/IgA (serum) 
 
Xe  
 
X 
 
X 
X 
 
 e. An aliquot of serum collected at baseline will be stored for 
testing (e.g. PF4 antibody ELISA) should an AE related to 
blood clots be reported anytime during the study period. 
Neutralizing Ab to SARS-
CoV-2 (serum) 
 
X  
 
X 
 
X 
X 
 
 
 Fixed whole blood 
 
X  
X 
X 
X 
 
 
 
Additional exploratory immunoassays  
T cell responses by ICC 
 
X 
X 
X 
X 
 
 
 
 
Anti Ad5 antibodies 
(serum) Optional 
 
X 
 
X 
 
X 
 
 
 
Nasal swab for antigen S-
specific IgA 
 
X 
 
X 
 
X 
X 
 
 
Saliva sample for antigen 
S-specific IgA 
 
X  
 
X 
 
X 
X 
 
  
Abbreviations: Ab, Antibody; ; COVID-19, coronavirus disease 2019; Cytof, Mass cytometry; EOS, End of Study; ET, Early Termination; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; 
HIV, Human Immunodeficiency Virus; ICC, intracellular cytokine cytometry; IgA, immunoglobulin A; IgG, immunoglobulin G; MAAE, medically attended adverse events; NP, 
Nasopharyngeal; PBMC, peripheral blood mononuclear cells; RT-PCR, reverse transcription polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory 
syndrome coronavirus 2; TEAE, treatment-emergent adverse events; WOCBP, women of childbearing potential; PF4, platelet factor 4. 
 
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Table 4 
Schedule of Activities – Part 2  
 
Screening 
Active Study Period 
Safety Follow-up 
Period 
Notes 
Study Day/Week/Month 
  Day  
 -30 to -1  
Wk 0  
(D1) 
Wk 1 
   (D8) 
Wk 4  
 (D29) 
Wk 5 
 (D36) 
Wk 8/ET 
(D57) 
Months 7* 
and 13/EOS 
 Months 3 – 6 
and 8 – 12 
Day (D), Week (Wk) 
Months 3 – 6 and 8 – 12 are remote visits (phone calls) 
 
Visit Window (days) 
 
N/A 
0 
+7  
0 
±2 
±7 
±7 
 *Treatment group will be unblinded when the last 
participant completes Month 7 Visit (see Section 5.9) 
Informed consent 
X 
  
  
  
  
  
 
 
  
Inclusion/Exclusion 
X 
X 
  
X 
  
  
 
 
  
Demographics 
X 
  
  
  
  
  
 
 
  
Medical history 
X 
  
  
  
  
  
 
 
  
Physical examination 
X 
X† 
X† 
X† 
X† 
X†  
 
 
† Targeted  
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
  
Safety laboratory tests 
X 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP) 
X 
X 
  
X 
  
 
 
 
Can be serum or urine. 
SARS-CoV-2 rapid Ab testa  
X 
X 
 
 
 
 
 
 
a. Test to be repeated at Day 1 only if Screening test 
completed >7 days prior to the Day 1 Visit. 
Nasal Swab for SARS-CoV-2 (RT- PCR) 
  
X 
  
 
  
 
 
 
Collect swab predose at Day 1.  
Collect swab at any time during the study if 
participant reports symptoms and/or exposure to 
COVID-19. If test positive, collect samples at 2-day 
intervals until a negative test result is observed. 
Vaccination 
  
X 
  
Xb 
  
  
 
 
b. Participants must be assessed for suitability for 2nd 
dose, per Section 4.2. If they are not eligible for their 
2nd dose, participants will enter the Safety Follow Up 
period at Week 4. 
Dispense Solicited Symptom Diary 
  
X 
  
X 
  
  
 
 
 
 
Review & Collect Solicited Symptom 
Diary 
  
  
X 
  
X 
  
 
 
  
Review Prior & Concurrent Medication 
X 
X 
X 
X 
X 
X 
 
 
  
Query for TEAEs, SAEs and MAAEs  
  
X 
X  
X 
X 
X 
Xc 
Xc 
c. Only SAEs and MAAEs will be collected during 
the Safety Follow-up Period. 
Query for exposure to and/or Symptoms of 
COVID-19d 
 
X 
X 
X 
X 
X 
X 
X 
d. Unscheduled visit must be completed if 
participant reports symptoms or exposure to 
COVID-19. 
 
 
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Immunogenicity Assessments 
 
 
 
 
 
 
SARS-CoV2-specific IgG/IgA (serum) 
 
Xe  
 
X 
 
X 
X 
 
 e. An aliquot of serum collected at baseline will be 
stored for testing (e.g. PF4 antibody ELISA) should 
an AES related to blood clots be reported anytime 
during the study period. 
Neutralizing Ab to SARS-CoV-2 (serum) 
 
X  
 
X 
 
X 
X 
 
 
Fixed whole blood 
 
X  
X 
X 
X 
 
 
 
Additional exploratory immunoassays  
Nasal swab for antigen S-specific IgA 
 
X 
 
X 
 
X 
X 
 
 
Saliva sample for antigen S-specific IgA 
 
X  
 
X 
 
X 
X 
 
  
Abbreviations: Ab, Antibody; ; COVID-19, coronavirus disease 2019; Cytof, Mass cytometry; EOS, End of Study; ET, Early Termination; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; 
HIV, Human Immunodeficiency Virus; ICC, intracellular cytokine cytometry; IgA, immunoglobulin A; IgG, immunoglobulin G; MAAE, medically attended adverse events; NP, 
Nasopharyngeal; PBMC, peripheral blood mononuclear cells; RT-PCR, reverse transcription polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory 
syndrome coronavirus 2; TEAE, treatment-emergent adverse events; WOCBP, women of childbearing potential; PF4,  platelet factor 4. 
 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
VXA-CoV2-1.1-S is an E1/E3-deleted, replication-incompetent, adenovirus 5 (Ad5) vaccine 
vector designed for use as an oral vaccine for the prevention of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection. The vaccine vector encodes the full-length 
Spike protein (S) of SARS-COV-2. The adjuvant consists of a double-stranded RNA Toll-like 
receptor 3 (TLR3) agonist which enhances immune induction to expressed antigen in the gut 
mucosa. 
SARS-CoV-2, a positive-sense single-stranded ribonucleic acid (RNA) virus presumed to be of 
zoonotic origin, is highly contagious in humans and is the cause of the ongoing worldwide 
pandemic of coronavirus disease 2019 (COVID-19). There is an urgent public health need for 
rapid development of novel interventions to prevent the spread of this disease, including 
prophylactic measures, such as vaccines. 
A unique and advantageous immune response elicited by oral vaccination is the induction of 
antibodies derived from mucosal cells. Given that the mucosal route of immunization produces 
superior mucosal immunity compared to injected vaccines, it is hypothesized that VXA-CoV2-
1.1-S oral vaccine may enable higher degrees of mucosal protection against infection when 
compared to a parenteral immunization method. 
VXA-CoV2-1.1-S is designed to elicit both antibody and T cell responses (systemic and 
mucosal) to SARS-CoV-2. Prior completed Phase 1 and 2 clinical studies with the Vaxart Vector 
Adjuvant Antigen Standard Technology (VAAST™) platform have demonstrated protective 
immunity to other viruses (influenza, norovirus, and respiratory syncytial virus) with both 
systemic and mucosal immune responses against the antigen of choice (Kim, 2016; Kim, 2018; 
Liebowitz, 2020). 
A Phase 1 open-label, dose-ranging study to evaluate the safety and immunogenicity of an earlier 
vaccine candidate, VXA-CoV2-1, in healthy young adults is ongoing under Protocol VXA-
COV2-101. VXA-CoV2-1.1-S is similar to VXA-CoV2-1 and was manufactured using the same 
VAAST platform, with the exception that the new construct does not express the N protein and 
has a slightly modified version of the S protein to provide better stability when expressed on the 
surface of a cell. The ongoing VXA-COV2-101 study completed enrollment with 35 subjects 
receiving one or two administrations of low dose vaccine (1x1010 IU) or a single higher dose 
(5x1010 IU).  Solicited symptoms of reactogenicity were collected for 7 days following each 
vaccination and were mild to moderate in severity and transient in nature resolving without 
intervention/medication.  Unsolicited adverse events (AEs) were collected through Day 57 
(Study Active Period); five subjects reported a total of 6 unsolicited AEs that were all mild in 
severity.  No subjects have reported any serious adverse events (SAEs) or medically attended 
adverse events (MAAEs) on this study to date. Subjects are currently in the Safety Follow-up 
Period (through Day 390) and being monitored for SAEs and MAAEs. Refer to the 
Investigator’s Brochure for additional information. 
The current Phase 2 study, comprised of 2 parts, is designed to assess the safety, tolerability, 
immunogenicity, and efficacy of the VXA-Cov2-1.1-S oral vaccine with a repeat-dose 
vaccination schedule in healthy adult volunteers. Part 1 will utilize an open-label dose and age 
escalation design to evaluate the early safety, tolerability and immunogenicity of the VXA-
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CoV2.1.1-S vaccine at two dose levels in a stepwise manner.  Part 1 will inform on the safe and 
immunogenic dose with which to advance into Part 2, the randomized, double-blind, placebo-
controlled phase of the study which will also evaluate the efficacy of VXA-CoV2.1.1-S 
compared to placebo.   
Though there is prior Phase 1 experience with the similar VXA-CoV2-1 vaccine in 35 
participants with doses up to 5x1010 IU under Protocol VXA-COV2-101, Vaxart intends to 
utilize a conservative stepwise dose escalation schedule starting at a low dose of 1x1010 IU with 
VXA-CoV2-1.1-S in the current protocol to allow safely moving from the young adult 
population (18 – 55 years of age) into the older population (56 – 75 years of age). Two dose 
levels, a low dose of 1x1010 IU and then a high dose of 1x1011 IU will be investigated with 
cohorts of 12 subjects in the younger age range, and then 12 subjects in the older age range.  
These 4 cohorts will be identical for subjects that are COVID-19 and vaccine naïve (Cohort 1) 
and those that have been prior vaccinated with two doses of an EUA or FDA approved mRNA 
vaccine for the prevention of SARS-CoV-2 infection (Cohort 2), for a total enrollment of 96 
subjects in Part 1.  The safety data from the prior Phase 1 study will be leveraged to move from 
one dose and age cohort to the next in an informed and expeditious manner after evaluation of 
reactogenicity and unsolicited AE data through Day 8.  
Data from Part 1 will be reviewed by the IDMC and submitted to the IND for FDA review prior 
to initiating enrollment in Part 2. 
  
2.1.1. 
Justification for Dose 
Based on the safety results observed in completed and ongoing studies with prior vaccines 
utilizing the VAASTTM platform and based on the safety and immunogenicity observed in the 
VXA-COV2-101 trial with similar VXA-CoV2-1 oral vaccine, the levels of VXA-CoV2-1.1-S to 
be investigated in Part 1 of this Phase 2 study are 1x1010 IU ± 0.5 log (low dose) and 1x1011 IU ± 
0.5 log (high dose), with two doses administered 4 weeks apart. 
Approximately 500 subjects have been immunized with multiple Vaxart recombinant adenovirus 
serotype 5 (rAd5) vaccine candidates at doses up to 1x1011 IU with repeat administration. The 
dose levels tested demonstrated a favorable safety profile and generated generally strong immune 
responses. Therefore, doses in a similar range will be used in the evaluation of the VXA-CoV2-
1.1-S vaccine in Part 1 of this study.  Early immunogenicity and safety data from Part 1 will be 
utilized to select the VXA-CoV2-1.1-S dose to be evaluated in Part 2.  
2.2. 
Background 
The rapid global spread of SARS-CoV-2 has resulted in substantial global morbidity and 
mortality from COVID-19 along with extensive social and economic burden. As of August 2021, 
SARS-CoV-2 has been responsible for more than 200 million infections and 4.3 million deaths 
worldwide (data from https://coronavirus.jhu.edu/). 
SARS-CoV-2 is transmitted via respiratory droplets (fomites infectious particles) within a range 
of about 2 meters and direct contact with contaminated surfaces. The median incubation period is 
estimated to be 4-5 days, and the majority (97.5%) develop symptoms within 11.5 days 
(confidence interval (CI), 8.2 to 15.6 days) of infection (Guan, 2020; Lauer, 2020). Infection 
with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, 
mild, moderate, severe to critical. Clinical symptoms usually include fever, cough, and dyspnea 
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(Guan, 2020; Jiang, 2020; Rodriguez-Morales, 2020; Rothan, 2020); a small population of 
patients also may suffer from gastrointestinal symptoms (Guan, 2020; Guo, 2020). The majority 
of patients will have uncomplicated or mild disease whereas others will develop severe disease 
requiring oxygen therapy, and some will progress to require mechanical ventilation and intensive 
care unit support. Approximately 14% (95%, CI 6.2-21.5%) of hospitalized patients have fatal 
outcomes (case fatality rate, CFR) (Rodriguez-Morales, 2020). The elderly and people with 
preexisting conditions, especially heart disease, respiratory conditions, and diabetes, appear to be 
more susceptible to severe infection and death.  
The SARS-CoV-2 virus contains four structural proteins (spike (S), nucleocapsid (N), envelope 
(E), and membrane (M) proteins). The S glycoprotein, being a large multi-functional trans-
membrane protein, plays the vital role of viral attachment, fusion, and entry into the host cell by 
binding to the human angiotensin-converting enzyme 2 (ACE2) receptor (Kuba, 2010; Guo, 
2020; Kaur, 2020; Wan, 2020; Wrapp, 2020). High expression levels of ACE2 are present in 
alveolar cells of the lungs, absorptive enterocytes of the ileum and colon, and possibly even in 
oral tissues such as the tongue (Xu, 2020). 
Many efforts are currently directed towards the development of vaccines against COVID-19 to 
avert the pandemic; most of the developing vaccine candidates are using the S-protein of SARS-
CoV-2 with injected technologies for administration of proteins, RNA or DNA (Kaur, 2020). 
The mucosal route is critical for transmission of coronaviruses, yet most vaccine candidates do 
not engage it, instead relying solely on high serum antibody concentrations to reach the lungs. 
Vaxart has a different approach that uses a tablet to administer a well-characterized gene-based 
vaccine backbone, and a more sophisticated antigen. 
Vaxart’s Ad5 vector is replication incompetent, as a consequence of lacking the E1 and E3 gene 
regions, which have been removed recombinantly. Replication incompetent Ad5 (and oral 
adenoviral vaccines) have been used in over 200 gene therapy and vaccine studies in humans. 
Human and animal experience with Vaxart’s orally administered vaccine platform has 
demonstrated that substantial transgene specific nasal and intestinal IgA responses can be 
generated in addition to systemic IgG responses to the expressed antigen (influenza) (Kim, 2016; 
Kim, 2018; Liebowitz, 2020). These platform attributes may allow for better protection against 
coronavirus infection than an injected protein-based vaccine, or any approach focused on 
inducing serum antibody responses.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of VXA-CoV2-1.1-S 
is provided in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of VXA-CoV2-1.1-S may be found in the Investigator’s Brochure. 
2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Drug VXA-CoV2-1.1-S 
Vaccine-associated 
enhanced disease 
(VAED) 
This is a theoretical risk. Animal studies on 
other coronaviruses have revealed low risk 
possibility that appearance of low-level IgG 
Monitor COVID-19 
symptoms throughout the 
study. Severity will be 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
antibodies to non-neutralizing S protein epitopes 
can enhance coronavirus infection (antibody-
dependent enhancement, ADE). In macaques, 
an inactivated injected vaccine has produced 
some evidence of ADE, and in hamsters, an S 
protein-based vaccine also produced ADE 
(Kam, 2007; Wang, 2016).  
assessed using case 
definition (Section 7.1.1). 
Potential for vaccine 
related hypersensitivity, 
including anaphylaxis 
 
Similar to other drugs, vaccines have the 
potential to cause allergic reactions. Vaccine 
components including immunizing antigens, 
adjuvants, culture derived proteins (e.g. gelatin) 
and other agents may have the potential to cause 
complications. 
Monitor participants for 
any allergic reactions and 
onset of new illness during 
the trial duration. 
Potential for systemic 
and gastrointestinal 
events (fever, 
headache, myalgia, 
abdominal pain, 
anorexia, nausea, 
vomiting, vomiting, 
diarrhea, and 
malaise/fatigue) 
following vaccination. 
 
These systemic events are common adverse 
reactions seen with other vaccines, as noted in 
the Food and Drug Administration (FDA) 
Center for Biologics Evaluation and Research 
(CBER) guidelines on toxicity grading scales 
for healthy adult volunteers enrolled in 
preventive vaccine clinical studies. Given the 
route of delivery and mechanism of action for 
an ingestible vaccine some additional 
gastrointestinal (GI) events may also be 
observed. 
Actively monitor systemic 
and GI-associated reactions 
(solicited symptoms) for 7 
days following each study 
drug administration. 
Potential for severe 
events of thrombosis in 
combination with 
thrombocytopenia 
(Thrombosis with 
thrombocytopenia 
syndrome, TTS), in 
some cases 
accompanied by 
bleeding, as reported in 
rare cases following 
vaccination with two 
injected adenovirus-
vectored COVID-19 
vaccines. 
Severe cases of TTS have been reported 
following vaccination with two adenovirus-
vectored COVID-19 vaccines: the AstraZeneca 
COVID-19 vaccine (ChAdOx1; replication-
deficient chimpanzee adenoviral vector 
ChAdOx1) and the Johnson and Johnson 
COVID-19 vaccine (Ad26.COV2.S; replication-
incompetent adenovirus serotype 26 vector). 
Reports include cases of thrombocytopenia in 
combination with arterial and venous 
thrombosis at unusual sites, such as cerebral 
venous sinus thrombosis (CVST) and 
splanchnic vein thrombosis, as well as more 
common sites such as veins of the lower 
extremity. Onset of symptoms associated with 
these AEs has typically occurred within 4 weeks 
after vaccination, and most commonly within 1-
2 weeks after vaccination, although some cases 
have been reported with later onset of 
symptoms. Cases have been reported mostly in 
women under 60 years of age, although cases 
have also been reported in men and in women 
older than 60 years. Some of these cases have 
been fatal. A causal relationship between these 
events and the two vaccines is considered 
Exclude enrollment of 
participants at higher risk of 
clotting events per review 
of medical history, physical 
exam and safety laboratory 
tests at screening. Actively 
monitor for 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, 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
plausible. The exact pathophysiology of TTS is 
still under investigation. At this time, a 
mechanism related to the adenovirus vectors 
cannot be excluded.  
and/or easy bruising/ 
bleeding. 
2.3.2. 
Benefit Assessment 
Benefits to individual participants may include receipt of a potentially efficacious COVID-19 
vaccine during a global pandemic, access to COVID-19 diagnostic testing, and contribution to 
research to help others in a time of global pandemic. 
2.3.3. 
Overall Benefit/Risk Conclusion 
Taking into account the measures to be utilized to minimize risk to participants taking part in this 
study, the potential risks identified in association with the VXA-CoV2-1.1-S vaccine for the 
prevention of COVID-19 are justified by the anticipated benefits that may be afforded to healthy 
naïve and prior vaccinated participants. 
 
 
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3. 
PART 1 - OPEN-LABEL LEAD-IN 
3.1. 
Part 1 Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the safety and 
tolerability of VXA-CoV2-1.1-S 
with a repeat-dose vaccination 
schedule in healthy adults at two 
dose levels 
• Frequency, duration, and severity of solicited 
symptoms of reactogenicity (local, systemic) for 1 
week following each vaccination 
• Frequency, duration, and severity of unsolicited 
treatment-emergent adverse events (TEAEs), 
serious AEs (SAEs), and medically attended AEs 
(MAAEs) during the study Active period (Day 57). 
MAAEs will be determined by (1) active 
monitoring for COVID-19 and vaccine-associated 
enhanced disease (VAED), and (2) monitoring for 
potential immune-mediated medical conditions 
including AEs of special interest (AESIs) and new 
onset of chronic illness (NOCIs).  
Secondary 
To assess long-term safety of  
VXA-CoV2-1.1-S  
• Frequency, duration, and severity of all SAEs, and 
MAAEs including monitoring for COVID-19, 
VAED, AESIs and NOCIs through one year post 
last dose  
To assess the immunogenicity of 
VXA-CoV2-1.1-S with a repeat-
dose vaccination schedule in healthy 
adults at two dose levels 
Key immunogenicity endpoints: 
• SARS-CoV2-specific Immunoglobulin G (IgG) and 
Immunoglobulin A (IgA) antibody levels by 
Mesoscale Discovery (MSD) assay 
• Neutralizing serum antibody titers to SARS-CoV-2  
•  
Additional immunogenicity endpoints: 
• T cell responses by Intracellular Cytokine 
Cytometry (ICC) 
• Antigen S-specific IgA in nasal swabs 
• Antigen S-specific IgA in saliva 
• Anti-Adenovirus type 5 (Ad5) serum antibodies 
(optional) 
 
 
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Exploratory 
To assess the efficacy of 
prophylactic VXA-CoV2-1.1-S 
against confirmed COVID-19 
occurring from 7 days after second 
dose with a repeat-dose vaccination 
schedule in healthy adults at two 
dose levels 
• Frequency, duration and severity of virologically 
confirmed COVID-19 illness and serologically 
confirmed SARS-CoV-2 infection occurring from 7 
days following second study drug dose 
administration 
 
3.2. 
Part 1 Study Design 
Part 1 is an open-label, lead-in, dose and age escalation phase evaluating VXA-COV2-1.1-S oral 
vaccine in healthy adult participants with repeat dose administration; this part of the study will 
enroll a total of approximately 72 subjects across 2 cohorts. Cohort 1 will evaluate 36 total 
healthy adult participants that are naïve (no prior vaccination against SARS-CoV-2 infection and 
no history of prior COVID-19 or SARS-CoV-2 infection) across 3 groups of 12 subjects each, 
encompassing 2 age groups and 2 dose levels. Cohort 2 will evaluate 36 healthy adult 
participants who have no history of prior COVID-19 or SARS-CoV-2 infection and have 
received 2 doses of an EUA or FDA approved COVID-19 mRNA vaccine across 3 groups of 12 
subjects each, encompassing 2 age groups and 2 dose levels. Enrollment will be performed in a 
sequential manner with at least 12 subjects in the younger age group (18-55 years) completing 
within their dose level, prior to enrollment of the older age group (56-75 years) at that dosage. 
• Cohort 1- Healthy adults who are naïve (no prior vaccinations against COVID-19 and no 
history of COVID-19) and are at low risk of developing severe COVID-19 upon potential 
infection with SARS-CoV-2 
• Cohort 2- Healthy adults who are prior vaccinated (have received two doses of an EUA 
or FDA approved mRNA COVID-19 vaccine at least 6 months prior to enrollment [Day 
1], no history of COVID-19 and are at low risk of developing severe COVID-19 upon 
potential infection with SARS-CoV-2 
The study includes a Screening Period, Active Period and a Safety Follow-up Period. Study 
assessments will be conducted as shown in the Schedule of Activities (SoA) in Section 1.2 
(Table 3). 
After signing an informed consent, participants will undergo screening assessments to determine 
study eligibility over a 30-day Screening Period.  
 
 
 
 
 
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3.2.1. 
Part 1: Enrollment and Initial Vaccination 
On Day 1, eligible participants will be enrolled sequentially to receive their 1st oral vaccination 
according to their assigned treatment group as specified in Table 1.   
Population 
Cohort 
VXA-CoV2-1.1-S  
Dose Levels* 
Age 
(years) 
No of Doses 
No. of 
Participants 
 Naive 
1a 
Low Dose: 1x1010 I.U. ±0.5 log 
18 – 55 
2 
 
12 
 Prior vaccinated 
2a 
Low Dose: 1x1010 I.U. ±0.5 log 
18 – 55 
2  
12 
IDMC Data Review1 
Naive 
1b 
High Dose: 1x1011 I.U. ±0.5 log 
18 – 55 
2 
12 
Naive 
1c 
Low Dose: 1x1010 I.U. ±0.5 log 
56 – 75  
2  
12 
Prior vaccinated 
2b 
High Dose: 1x1011I.U. ±0.5 log 
18 – 55 
2 
12 
Prior vaccinated 
2c 
Low Dose: 1x1010 I.U. ±0.5 log 
56 – 75 
2 
12 
IDMC Data Review2 
* Multiple tablets may be administered to deliver the full intended dose. 
† Doses will be administered on Day 1 and Week 4.   
1 IDMC to review safety data through Week 1 for 12 subjects in a before enrollment will begin in b or c. 
 
2 IDMC to review safety data for all subjects within each age group and initial immunogenicity data from Part 1 to make 
recommendations to Sponsor on dose selection for randomized, placebo-controlled phase, before enrollment begins in Part 2 
Cohorts 1 and 2 (naïve and prior vaccinated subjects, respectively) will enroll in parallel. The IDMC may review safety data for 
the subgroups within each of these two cohorts separately if the enrollment rates between the two cohorts vary.  
 
During the Active Period, participants will record daily symptoms of reactogenicity for 1 week 
post each vaccination, administered on Day 1 and Week 4, using a Solicited Symptom Diary. 
They will return to the site at 1 and 4 weeks following each vaccination, as specified in the SoA, 
to have safety assessments and samples collected for evaluation of immunogenicity. Post 
completion of the Week 1 visit by all subjects in a specified cohort, as detailed in  
Table 1, the IDMC will review Day 1 to Week 1 safety data and make recommendations as to 
whether to proceed to the next cohort(s). Upon completion of enrollment in Part 1, the IDMC 
will review safety and preliminary immunogenicity data from all cohorts  and make 
recommendations to the Sponsor on the VXA-CoV2-1.1-S dose level to evaluate in Part 2. A 
summary of Part 1 safety and immunogenicity data with the intended dose for Part 2 will be 
submitted to FDA for review and concurrence prior to initiation of enrollment in Part 2. 
 
3.2.2. 
Part 1: Eligibility for Second Vaccination 
At the Week 4 visit participants will have safety assessments to evaluate suitability to receive the 
second vaccination including physical exam, vital signs, pregnancy test (female participants), 
SARS-CoV-2 rapid molecular test, and assessment of adverse events and new concomitant 
medication usage.  Participants meeting any of the following exclusion criteria will not be 
eligible to receive their second vaccine administration: 
 
Exclusion Criteria for Second Vaccine Dose: 
• Positive pregnancy test at Day 29 (female participants), 
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• Occurrence of any possibly, probably or definitely treatment-related Grade 3 or 4 AE or 
SAE following the initial vaccination  
• Occurrence of any Grade 3 or 4 AE or SAE following the initial vaccination without 
plausible alternative explanation 
• Presence of acute illness or significant new medical condition including positive SARS-
COV-2 rapid molecular test prior to dosing 
 
 
Participants deemed ineligible due to presence of acute illness or new medical condition may be 
re-assessed during the visit window (+7 days), and if the condition resolves, may receive their 
second vaccination within 1 week of their scheduled Week 4 Visit.  In such situations the 
Principal Investigator must contact the study Medical Monitor and gain consensus on the 
decision to continue participant with study vaccinations prior to administration of the second 
dose.   
Upon completion of the study Active Period (Week 8 Visit) participants will enter the Safety 
Follow-up Period and be monitored for SAEs, MAAEs and for exposure to and/or symptomatic 
COVID-19, including the potential for VAED, through the Month 13/End of Study (EOS). In 
addition, these participants will be evaluated for immunogenicity as specified in the SoA 
(Table 3). During the Safety Follow-up Period participants will return to the site at Months 7 and 
13 for safety monitoring and collection of samples for evaluation of immunogenicity; they will 
also be contacted by phone monthly between site visits to query for safety and exposure to and/or 
symptomatic COVID-19. 
Any participant who discontinues study drug early (does not receive the second dose) will enter 
the Safety Follow-up Period a month earlier at Week 4 and will be monitored for safety and 
exposure to and/or symptomatic COVID-19 as described above, and complete immunogenicity 
assessments through EOS per the SoA (Table 3).  
Any participant reporting COVID-19 like illness or exposure to COVID-19 during the study will 
be asked to return to the site for an unscheduled visit to test for SARS-CoV-2 infection. 
Participants with confirmed SARS-CoV-2 infection, at any time during the study period will be 
asked to provide a nasal swab sample every two days after their confirmatory COVID-19 test, 
until they test negative, to monitor for duration of infection. The duration of q2day testing post 
confirmed SARS-CoV-2 infection should end after 10 days if still testing positive at that time. 
Any FDA Authorized rapid molecular test (e.g. LUCIRA COVID-19 Test) can be used for home 
or on-site testing for monitoring COVID-19 infection. They will also be monitored for clinical 
disease severity (see Section 7.1.1, Table 6) and outcome. The participant will be counseled to 
notify their Primary Care Physician of their positive SARS-CoV-2 status and seek medical care 
should they become symptomatic. 
An Independent Data Monitoring Committee (IDMC) will provide safety oversight throughout 
the duration of the study. If the protocol halting rules are met at any time during the study (refer 
to Section 6.1.1 for Part 1 and Section 6.1.2 for Part 2), enrollment and dosing will be suspended 
pending a full IDMC review (Section 8.5.2). The Sponsor’s Medical Monitor(s) (or designees) 
will perform safety oversight (Section 8.5.1). 
 
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3.2.3. 
Part 1 Scientific Rationale for Study Design 
Part 1 is an open-label, lead-in, dose and age escalation lead-in phase to allow assessing the 
following parameters in subjects that are naïve to prior vaccination and COVID-19 and those 
who have received two prior vaccinations against SARS-CoV-2 with an EUA or FDA approved 
mRNA vaccine: 
• 
Collection of additional safety data in young adults. Though doses as high as two times 
1x1011 IU ± 0.5 log have been tested with other oral vaccines using the VAAST™ platform, 
in the Phase 1 study with VXA-CoV2-1 (S and N protein construct), the highest dose tested 
was 5x1010 IU ± 0.5 log due to limited drug product availability. Safety of VXA-CoV2-1.1-
S will be evaluated at two dose levels in Part 1 to allow optimal dose selection for the 
larger, placebo-controlled phase in Part 2; doses to be tested will include 1x1010 IU ± 0.5 
log (low dose) and 1x1011 IU ± 0.5 log (high dose). 
• 
Collection of safety data in older healthy adults with repeat dose administration at the 
lower dose level .  Safety data collected in Part 1 will inform inclusion of this population in 
Part 2. 
• 
Collection of preliminary data on the immunogenicity of VXA-CoV2-1.1-S vaccine at 2 
potentially clinically active doses, 1x1010 IU ± 0.5 log (low dose) and 1x1011 IU ± 0.5 log 
(high dose). Based on early (Day 8) immunogenicity data from Part 1, the dose level for 
Part 2 will be selected. 
3.2.4. 
Study Duration 
Each subject is expected to participate in the study as follows: 
Study Period (Part 1) 
Duration  
Screening Period:  
30 days  
Active Period:  
8 weeks* 
Safety Follow-up Period:  
11 months 
Total duration of participation: 
~14 months 
*Participants who discontinue study drug early (do not receive the second dose) for any reason will enter the Safety 
Follow-up Period at Week 4. 
3.3. 
Part 1 Eligibility Criteria 
3.3.1. 
Part 1 Inclusion Criteria 
To be eligible for this study, participants must meet all the following criteria: 
Age 
1. 18 – 75 years of age (inclusive) at the time of signing the Informed Consent Form (ICF). 
Type of Participants 
2. Cohort 1 ONLY – Naive of any prior vaccination for the prevention of COVID-19 
(tested using a rapid antibody test) at screening and within 7 days prior to the enrollment 
(Day 1). 
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3. Cohort 2 ONLY – Have received prior immunizations (both doses) with an EUA or 
FDA approved mRNA vaccine for the prevention of COVID-19, at least 6 months prior 
to enrollment (Day 1).  
4. In stable and good health, without significant medical illness, based on medical history, 
physical examination, vital signs, and clinical laboratory tests1 as determined by the 
Investigator. 
5. Safety laboratory values1 within the following range criteria at screening:  
a. Laboratory values within normal range or grade 1 outside the range of normal with 
no clinical significance (NCS) for the following analytes: alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and bilirubin,  
blood urea nitrogen (BUN), creatinine, glucose, potassium, and sodium 
b. Laboratory values within normal range for platelet counts2 and the following 
coagulation tests: PT/INR, aPTT and fibrinogen 
6. Body mass index (BMI) between 17 and 32 kg/m2 at screening. Investigators must ensure 
subjects with BMI between 30-32 do not have any additional risk factors for severe 
COVID-19, per the CDCs guidelines as listed under exclusion criteria #3. 
7. Capable of providing signed informed consent.  
8. Available for all planned visits and phone calls, and willing to complete all protocol-
defined procedures and assessments (including ability and willingness to swallow 
multiple small enteric-coated tablets per vaccine dose). 
Gender and Reproductive Considerations 
9. Male or female participants. 
Contraception use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. Refer to Appendix 4 
(Section 9.4). 
10. Female participants must not be breastfeeding and must have a negative pregnancy test at 
screening and before each vaccination and fulfill one of the following criteria: 
a. At least 1 year post-menopausal (defined as amenorrhea for ≥12 consecutive 
months prior to Screening without an alternative medical cause). 
Women under 60 years will need to verify post-menopausal status via a follicle-
stimulating hormone (FSH) test if another option to prevent potential pregnancy 
will not be utilized for 30 days prior to baseline vaccination and until 60 days 
after the last vaccination. 
b. Surgically sterile 
c. Use of oral, implantable, transdermal or injectable contraceptives for 30 days 
prior to initial vaccination and until 60 days after the last vaccination. 
                                                 
1 Clinical laboratory tests (hematology, serum chemistry, and urinalysis). Abnormal lab values should be graded 
using the site’s testing lab reference range for guidance, whether local or central. 
2 If platelets are abnormal, a normal NaCitrate platelet test is needed 
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d. A reliable form of contraception must be approved by the Investigator (e.g., 
double barrier method, Depo-Provera, intrauterine device, Norplant, oral 
contraceptives, contraceptive patches). 
e. Not be sexually active (abstinent) or be in a relationship with partner who is 
sterile (must be discussed with site staff and documented). 
3.3.2. 
Part 1 Exclusion Criteria 
Participants must be excluded from this study if they meet any of the following criteria: 
Medical Conditions 
1. Clinically significant acute illness within 72 hours prior to vaccination defined as the 
presence of a moderate or severe illness (as determined by the Investigator through medical 
history and physical exam) (assessment may be repeated during screening period). 
2. Current or known previous infection with SARS-CoV-2 or receipt of any therapeutic for the 
prevention or treatment of COVID-19, Middle East Respiratory Syndrome (MERS), or 
severe acute respiratory syndrome (SARS). [EUA or FDA approved mRNA vaccines for 
the prevention of SARS-CoV-2 infection taken at least 6 months prior to enrollment are 
permitted in Cohort 2] 
3. Individuals with the following underlying medical conditions who are at higher risk (or 
might be at higher risk) of severe illness from COVID-19 per the guidance from the Centers 
for Disease Control and Prevention (CDC): 
a. Cancer, including history of cancer or treatment within past 3 years (excluding 
basal cell carcinoma or squamous cell carcinoma) 
b. Chronic kidney disease 
c. Chronic obstructive pulmonary disease (COPD) 
d. Immunocompromised state from solid organ transplant, or other medical 
condition 
e. Serious heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies 
f. Sickle cell disease 
g. Uncontrolled type 2 diabetes mellitus 
h. Asthma (moderate to severe) 
i. Cerebrovascular disease 
j. Cystic fibrosis 
k. Uncontrolled hypertension or high blood pressure 
l. Immunocompromised state from blood or bone marrow transplant, immune 
deficiencies, HIV, use of corticosteroids, or use of other immune weakening 
medicines 
m. Neurologic conditions, such as dementia 
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n. Liver disease 
o. Pregnancy or breast feeding 
p. Pulmonary fibrosis 
q. Chronic smoking (≥ 1 cigarette per day) 
r. Thalassemia 
s. Type 1 diabetes mellitus 
4. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make 
blood draws problematic. 
5. Any condition that resulted in the absence or removal of the spleen. 
6. Any other condition that in the clinical judgment of the Investigator would jeopardize the 
safety or rights of a participant participating in the study, would render the participant unable 
to comply with the protocol or would interfere with the evaluation of the study endpoints. 
Diagnostic Assessments 
7. Temperature ≥38.0ºC (100.4°F) within 24 hours prior to the planned study vaccination 
(assessment may be repeated during screening period). 
8. Positive HIV, Hepatitis B surface antigen (HBsAg) or HCV tests at the screening visit. 
9. History of gastrointestinal bleeding (e.g. melena or hematochezia) 
Prior/Concurrent Therapy 
Note: The Active Period is defined as the time period from Day 1 through Week 8, or 4 weeks 
post last vaccination. 
10. Receipt of a licensed influenza vaccine within 14 days prior to baseline vaccination or 
another licensed vaccine within 28 days prior to baseline vaccination, or planned 
administration during the study active period. 
11. Use of antiviral medications, including anti-retrovirals within 1 week before vaccination or 
planned use during the active study period. 
12. Use of antibiotics, proton pump inhibitors, H2 blockers or antacids within 1 week before 
vaccination or planned use during the active study period. 
13. Use of medications known to affect the immune function (e.g., systemic corticosteroids and 
others) within 14 days before vaccination or planned use during the active study period. 
14. Daily use of nonsteroidal anti-inflammatory drugs, sulfonylureas, and angiotensin II blockers 
within 1 week before vaccination or planned use during the active study period. 
15. Positive urine drug screen for drugs of abuse at screening (except for previous marijuana 
use); concurrent or planned use of marijuana during the active study period. 
16. Administration of any investigational vaccine, drug or device within 8 weeks preceding 
vaccination, or planned use within the duration of the study. 
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Other Exclusions 
17. Donation or use of blood or blood products within 4 weeks prior to vaccination or planned 
donation during the study period. 
18. Any significant hospitalization within the last year which in the opinion of the Investigator or 
Sponsor could interfere with study participation. 
19. History of drug, alcohol or chemical abuse within 1 year of screening. 
20. History of hypersensitivity or allergic reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin. 
21. 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  
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4. 
PART 2 – DOUBLE-BLIND PLACEBO-CONTROLLED 
4.1. 
Part 2 Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary  
To assess the efficacy of 
prophylactic VXA-CoV2-1.1-S 
against confirmed COVID-19 
occurring from 7 days after second 
dose with a repeat-dose vaccination 
schedule in healthy adults 
compared to placebo 
• Frequency duration and severity of virologically 
confirmed COVID-19 illness and serologically 
confirmed SARS-CoV-2 infection occurring from 7 
days following second study drug dose 
administration 
To evaluate the safety and 
tolerability of VXA-CoV2-1.1-S 
with a repeat-dose vaccination 
schedule in healthy adults 
compared to placebo 
• Frequency, duration, and severity of solicited 
symptoms of reactogenicity (local, systemic) for 1 
week following each vaccination 
• Frequency, duration, and severity of unsolicited 
TEAEs, SAEs, and MAAEs through the active 
period (4 weeks post last dose), efficacy period and 
safety follow-up period. MAAEs will be determined 
by (1) active monitoring for COVID-19 and VAED 
through the active period (4 weeks post last dose), 
and (2) monitoring for potential immune-mediated 
medical conditions including AESIs and NOCIs for 
one year post last dose. 
Secondary  
To assess long-term safety of  
VXA-CoV2-1.1-S  
• Frequency, duration, and severity of all SAEs, and 
MAAEs including monitoring for COVID-19 and 
potential VAED, AESIs and NOCIs through one 
year post last dose.  
To assess the immunogenicity of 
VXA-CoV2-1.1-S with a repeat-
dose vaccination schedule in 
healthy adults compared to placebo 
 
 
Key immunogenicity endpoints: 
• SARS-CoV2-specific IgG and IgA antibody levels 
using MSD assays 
• Neutralizing serum antibody titers to SARS-CoV-2 
Additional immunogenicity endpoints: 
• Antigen S-specific IgA in nasal swabs 
• Antigen S-specific IgA in saliva 
 
 
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4.2. 
Part 2 Study Design 
Part 2 will utilize a double-blind, randomized, placebo-controlled, repeat-dose design that will 
enroll 800 eligible participants between the ages of 18 and 75 years of age, including a minimum 
of 200 participants > 55 years of age. Randomization will be stratified by age (18 – 55 years and 
56 – 75 years) and region (if sites in multiple countries are utilized). 
After signing an informed consent, participants will complete assessments to determine their 
eligibility within a 30-day Screening period.  
 
4.2.1. 
Part 2: Enrollment and Initial Vaccination 
On Day 1, eligible participants will be randomized in a 1:1 ratio to either active (VXA-CoV2-
1.1-S) or control (matching placebo tablets) group. (Table 2): 
• Active: VXA-CoV2-1.1-S (dose to be selected from Part 1) 
• Control: matching placebo  
During the Active Period, participants will record daily symptoms of reactogenicity for 1 week 
post each study drug administration (Day 1 and Week 4), using a Solicited Symptom Diary. 
Participants will return to the site at 1 and 4 weeks following each vaccination, as specified in the 
SoA to have safety assessments and samples collected for evaluation of immunogenicity (Table 4).   
4.2.2. 
Part 2: Eligibility for Second Dose of Study Drug 
Similar to Part 1, at the Week 4 visit participants will have safety assessments to evaluate 
suitability to receive the second vaccination including physical exam, vital signs, pregnancy test 
(female participants) and assessment of adverse events and new concomitant medication usage.  
Participants meeting any of the following exclusion criteria will not be eligible to receive their 
second vaccine administration: 
 
Exclusion Criteria for Second Vaccine Dose: 
• Positive pregnancy test at Day 29 (female participants), 
• Occurrence of any possibly, probably or definitely treatment-related Grade 3 or 4 AE or 
SAE following the initial vaccination  
• Occurrence of any Grade 3 or 4 AE or SAE following the initial vaccination without 
plausible alternative explanation 
• Presence of acute illness or significant new medical condition  
Participants deemed ineligible due to presence of acute illness or new medical condition may be 
re-assessed during the visit window (+7 days), and if the condition resolves, may have a second 
vaccination within 1 week of their scheduled Week 4 Visit.  In such situations the Principal 
Investigator must contact the study Medical Monitor and gain consensus on the decision to 
continue participant with study vaccinations prior to administration of the second dose.     
Following completion of the Active Period (Week 8 visit) participants will continue to be 
monitored for SAEs, MAAEs and for exposure to and/or symptomatic COVID-19 including 
potential VAED through Month 13/End of Study (EOS) during the study Safety Follow-up 
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Period. In addition, these participants will be evaluated for immunogenicity as specified in the 
SoA (Table 4).  
Any participant who discontinues study drug early (does not receive the second dose) will enter 
the Safety Follow-up Period a month earlier at Week 4 and will be monitored for safety and 
exposure to and/or symptomatic COVID-19 as described above, and complete immunogenicity 
assessments through EOS per the SoA (Table 4).  
Any participant reporting COVID-19 like illness or exposure to COVID-19 will be asked to 
return to the site for an unscheduled visit to test for SARS-CoV-2 infection. Participants with 
confirmed SARS-CoV-2 infection, at any time during the study period, will be asked to provide 
a nasal swab every two days after their confirmatory COVID-19 test, until they are negative, to 
monitor for duration of infection. They will also be monitored for clinical disease severity 
(Section 7.1.1, Table 6), and outcome, including the potential for VAED. The participant will be 
counseled to notify their Primary Care Physician of their positive SARS-CoV-2 status and seek 
medical care should they become symptomatic. 
Participants will be followed via site visits and monthly phone calls in order to monitor for 
COVID-19 (symptoms or exposure) starting from 7 days following their second vaccination in 
the Active Period.  The study Efficacy Period will last until the last participant randomized has 
completed their Month 7 visit (6 months post last study drug administration), after which the 
study database will be cleaned and locked, and the primary efficacy analyses performed.  At this 
time the treatment assignments will be unblinded and Part 2 participants in the placebo group 
will have the opportunity to receive vaccination(s) against COVID-19 as detailed in Section 5.9.  
An interim analysis for efficacy may also be performed if 18 cases of confirmed COVID-19 are 
reported prior to the planned efficacy analysis at completion of Month 7 visits by all participants.  
The IDMC will provide safety oversight throughout the duration of the study. If the protocol 
halting rules are met at any time during the study (refer to Section 6.1.1 for Part 1 and 
Section 6.1.2 for Part 2), enrollment and dosing will be suspended pending a full IDMC review 
(Section 8.5.2). The Sponsor’s Medical Monitor(s) (or designees) will perform safety oversight 
(Section 8.5.1). 
4.2.3. 
Part 2 Scientific Rational for Study Design 
Part 2 is a double-blind placebo-controlled, repeat-dose phase to evaluate the safety, 
immunogenicity and efficacy of VXA-CoV2-1.1-S compared to placebo in the target population. 
4.2.4. 
Part 2 Study Duration 
Each subject is expected to participate in the study as follows: 
Study Period (Part 2) 
Duration  
Screening Period:  
30 days  
Active Period:  
8 weeks* 
Efficacy Evaluation:** 
~6 months (starting 7 days after second dose) 
Safety Follow-up Period:  
11 months 
Total duration of participation: 
~14 months 
*   Participants who discontinue study drug early will enter the Safety Follow-up Period at Week 4. 
**The study database will be cleaned and locked following completion of the efficacy period. Treatment 
assignments for Part 2 will be unblinded following completion of the primary efficacy analyses.  
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4.3. 
Part 2 Eligibility Criteria 
4.3.1. 
Part 2 Inclusion Criteria 
To be eligible for this study, participants must meet all of the following criteria: 
Age 
1.  18 – 75 years of age (inclusive) at the time of signing the ICF. 
Type of Participants 
2. 
Negative for current or prior SARS-CoV-2 infection (tested using a rapid antibody test) 
at screening and within 7 days prior to the Baseline visit. 
3. 
In stable and good health, without significant medical illness, based on medical history, 
physical examination, vital signs, and clinical laboratory tests as determined by the 
Investigator. 
4. 
Safety laboratory values within the range of normal for platelet counts2 and the following 
coagulation tests: PT/INR, aPTT and fibrinogen 
5. 
BMI between 17 and 32 kg/m2 at screening. 
6. 
Capable of providing signed informed consent. 
7. 
Available for all planned visits and phone calls, and willing to complete all protocol-
defined procedures and assessments (including ability and willingness to swallow 
multiple small enteric-coated tablets per vaccine dose). 
Gender and Reproductive Considerations 
8. 
Male or female participants. 
Contraception use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. Refer to Appendix 4 
(Section 9.4). 
9. Female participants must not be breastfeeding and must have a negative pregnancy test at 
screening and before each vaccination and fulfill one of the following criteria: 
a. At least 1 year post-menopausal (defined as amenorrhea for ≥12 consecutive months 
prior to Screening without an alternative medical cause). 
Women under 60 years will need to verify post-menopausal status via a follicle-
stimulating hormone (FSH) test if another option to prevent potential pregnancy will 
not be utilized for 30 days prior to baseline vaccination and until 60 days after the last 
vaccination. 
b. Surgically sterile 
c. Use of oral, implantable, transdermal or injectable contraceptives for 30 days prior to 
initial vaccination and until 60 days after the last vaccination. 
                                                 
2 If platelets are abnormal, a normal NaCitrate platelet test is needed. 
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d. A reliable form of contraception must be approved by the Investigator (e.g., double 
barrier method, Depo-Provera, intrauterine device, Norplant, oral contraceptives, 
contraceptive patches). 
e. Not be sexually active (abstinent) or be in a relationship with partner who is sterile 
(must be discussed with site staff and documented). 
 
4.3.2. 
Part 2 Exclusion Criteria 
Participants must be excluded from this study if they meet any of the following criteria: 
Medical Conditions 
1. Clinically significant acute illness within 72 hours prior to vaccination defined as the 
presence of a moderate or severe illness (as determined by the Investigator through 
medical history and physical exam) (assessment may be repeated during screening 
period). 
2. Known previous infection with SARS-CoV-2 or receipt of any therapeutic for the 
prevention or treatment of COVID-19, Middle East Respiratory Syndrome (MERS), or 
severe acute respiratory syndrome (SARS). 
3. Individuals with the following underlying medical conditions: 
a. Cancer, including history of cancer or treatment within past 3 years (excluding 
basal cell carcinoma or squamous cell carcinoma) 
b. Chronic kidney disease 
c. Chronic obstructive pulmonary disease (COPD) 
d. Immunocompromised state from solid organ transplant, or other medical 
condition 
e. Serious heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies 
f. Sickle cell disease 
g. Uncontrolled type 2 diabetes mellitus 
h. Asthma (moderate to severe) 
i. Cerebrovascular disease 
j. Cystic fibrosis 
k. Uncontrolled hypertension or high blood pressure 
l. Immunocompromised state from blood or bone marrow transplant, immune 
deficiencies, HIV, use of corticosteroids, or use of other immune weakening 
medicines 
m. Neurologic conditions, such as dementia 
n. Liver disease 
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o. Pregnancy or breast feeding 
p. Pulmonary fibrosis 
q. Chronic smoking (≥ 1 cigarette per day) 
r. Thalassemia 
s. Type 1 diabetes mellitus 
4. Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make 
blood draws problematic. 
5. Any condition that resulted in the absence or removal of the spleen. 
6. Any other condition that in the clinical judgment of the Investigator would jeopardize the 
safety or rights of a participant participating in the study, would render the participant unable 
to comply with the protocol or would interfere with the evaluation of the study endpoints. 
Diagnostic Assessments 
7. Temperature ≥38.0ºC (100.4°F) within 24 hours prior to the planned study vaccination 
(assessment may be repeated during screening period). 
Prior/Concurrent Therapy 
Note: The Active Period is defined as the time period from Day 1 through Week 8, or 4 weeks 
post last vaccination. 
8. Receipt of a licensed influenza vaccine within 14 days prior to baseline vaccination or 
another licensed vaccine within 28 days prior to baseline vaccination, or planned 
administration during the study active period. 
9. Use of antiviral medication , including anti-retrovirals, within 1 week before vaccination or 
planned use during the active study period. 
10. Use of antibiotics, proton pump inhibitors, H2 blockers or antacids within 1 week before 
vaccination or planned use during the active study period. 
11. Use of medications known to affect the immune function (e.g., systemic corticosteroids and 
others) within 14 days before vaccination or planned use during the active study period. 
12. Daily use of nonsteroidal anti-inflammatory drugs, sulfonylureas, and angiotensin II blockers 
within 1 week before vaccination or planned use during the active study period. 
13. Positive urine drug screen for drugs of abuse at screening (except for previous marijuana 
use); concurrent or planned use of marijuana during the active study period. 
14. Administration of any investigational vaccine, drug or device within 8 weeks preceding 
vaccination, or planned use within the duration of the study. 
Other Exclusions 
15. Donation or use of blood or blood products within 4 weeks prior to vaccination or planned 
donation during the study period. 
16. 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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17. History of drug, alcohol or chemical abuse within 1 year of screening. 
18. History of hypersensitivity or allergic reaction to any component of the investigational 
vaccine, including but not limited to fish gelatin. 
19. 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  
 
 
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5. 
STUDY DRUG, CONCOMITANT THERAPY AND LIFE-STYLE 
CONSIDERATIONS 
Study drug is defined as investigational drug (VXA-CoV2-1.1-S), or placebo, intended to be 
administered to a study participant according to the study protocol. 
5.1. 
Study Drug Administration 
VXA-CoV2-1.1-S is an E1/E3-deleted, replication-incompetent, adenovirus 5 vaccine vector 
designed for use as an oral vaccine. The vaccine vector encodes the full-length Spike protein (S) 
of SARS-COV-2 specific antigen. The adjuvant consists of a double-stranded RNA Toll-like 
receptor 3 (TLR3) agonist which enhances immune induction to expressed antigen in the gut 
mucosa. 
Table 4 
Study Drug 
Intervention Name 
VXA-CoV2-1.1-S (Part 1 and Part 2) 
Placebo (Part 2 only) 
Type  
biologic 
Matching placebo 
Dose Formulation 
enteric-coated tablets 
enteric-coated tablets 
Unit Dose Strength(s) 
The target concentration of drug 
product (DP) per tablet will vary per 
manufacturing lot (e.g. 5x109 to 
1.7x1010 International Units [IU] each). 
Multiple tablets may be dispensed to 
deliver the target dose. 
 
Dosage Level(s) 
Low dose:        1x1010 IU ± 0.5 log  
High dose:       1x1011 IU ± 0.5 log  
 
The number of tablets per dose will be 
determined based on potency assay 
during release testing of each DP tablet 
lot. Multiple tablets may be 
administered to constitute the full dose. 
Dosing instructions will be described 
in detail within the Pharmacy Manual. 
Matching placebo tablets in 
appearance and number of 
tablets administered.  
Route of Administration 
Oral 
Administration 
instructions 
Participants should fast and refrain from ingesting solid food for at 
least 4 hours prior to oral dosing. A trained member of the site study 
staff will dispense the tablet(s) constituting the assigned dose to the 
participant. The participants will swallow the tablets with 360 to 
480 mL of water followed by a light snack (e.g., crackers) at time of 
dosage administration to aid in tablet transit out of the stomach. 
Normal food consumption may resume 90 minutes after dosing. For 
more information refer to the Study Pharmacy Manual. 
Sourcing 
Study drug will be provided to the site centrally by the Sponsor or 
designated representative. 
Packaging and Labeling  
The tablets are packaged in foil-sealed, high-density polyethylene 
(HDPE) screw-cap containers with 10 tablets per bottle. 
All packaging and labeling operations for study drug will be performed 
according to Good Manufacturing Practices (GMP) for Medicinal 
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Intervention Name 
VXA-CoV2-1.1-S (Part 1 and Part 2) 
Placebo (Part 2 only) 
Products and the relevant regulatory requirements. Label text for the 
study drug bottle will at a minimum include name of the manufacturer, 
the protocol number, the name of the product, the lot number of the 
product, the concentration of the vaccine, and the date of 
manufacturing or expiration. 
Secondary packaging of the study drug upon dispensing from the 
pharmacy to the clinical staff for participant dosing will be determined 
with consideration of the sites’ pharmacy standard operating 
procedures and outlined in the study pharmacy manual. 
The final dispensing container (cup or secondary bottle) will be 
appropriately labeled with the participant’s unique identifier, the 
time/date of dose preparation within the pharmacy and additional 
information as deemed necessary per the site’s Standard Operating 
Procedures (SOPs). 
Storage Condition 
VXA-CoV2-1.1-S vaccine tablets will be stored at 2 to 8°C at the 
clinical site until ready for use. Tablets should not be frozen. Do not 
use and contact Sponsor if DP tablets have been frozen. 
 
5.2. 
Compliance of Study drug 
Participants will receive study drug directly from the Investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and recorded in the electronic Case Report Form (eCRF). The dose of study 
drug and study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study drug. 
5.2.1. 
Dose Adjustments/Modifications/Delays 
Dose adjustments and or modifications are not planned or allowed under this clinical protocol. 
All participants should receive the full dose they are assigned to, either the low dose (1x1010 IU ± 
0.5 log) or the high dose (1x1011 IU ± 0.5 log) at the protocol-defined study visits (Day 1 and 
Week 4) after meeting eligibility. Any modification from this schedule or planned dose should 
be recorded as a protocol violation and reported to the Sponsor (or designee). 
5.3. 
Handling and Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for study drug received and any discrepancies are reported and 
resolved before use of study drug. 
2. Only participants enrolled in the study may receive study drug and only authorized site 
staff may supply or administer study drug. All study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized 
site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
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4. At the end of the study, the monitor will conduct a final drug reconciliation for all 
participants and the study site overall. All records of study drug administration, 
accountability records and study drug disposition records will be examined and 
reconciled by the study monitor. Further details will be provided in the Study Pharmacy 
Manual. 
Further guidance and information for the final disposition of unused study drug are provided in 
the Pharmacy Manual. 
5.4. 
Measures to Minimize Bias: Randomization and Blinding 
5.4.1. 
Assignment of a Participant Number 
Each participant who signs informed consent will be assigned a participant number. This number 
will be used as the primary identification for the complete duration of the study. After the 
participant has signed the informed consent form (ICF), the Investigator will enter the participant 
into the Screening section of the electronic case report form (eCRF). 
5.4.2. 
Randomization (Part 2 only) 
Participants in Part 2 will be randomized in a 1:1 ratio to receive VXA-CoV2-1.1-S (at dose 
selected from Part 1 of the study) or matching placebo. 
Randomization will be centralized across all study sites by region using the Randomization and 
Trial Supply Management (RTSM) system. 
Randomization will be stratified by age (18 – 55 years and 56 – 75 years) and region (if sites in 
multiple countries are utilized). 
5.4.3. 
Blinding and Unblinding (Part 2 only) 
Participants, Investigators, site personnel and the Sponsor (except as described below) will be 
blinded to individual participant treatment assignment in Part 2. 
Study drug doses will be prepared at the study sites by an unblinded research pharmacist(s) who 
will be provided treatment assignment through a RTSM System. 
Sponsor representative(s) will also have access to unblinded individual participant treatment 
assignments for the purposes of study-required activities, including management of study drug 
inventory, production of summaries of data for IDMC review, and performance of bioanalytical 
analysis. These personnel will not be directly involved in the conduct of the study. 
An IDMC will periodically convene to review unblinded overall safety and emerging efficacy 
results (Section 8.5). 
The RTSM system will be programmed with blind-breaking instructions. In case of a medical 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
participant’s treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. The Investigator should notify the Sponsor’s 
Medical Monitor (or designee) prior to unblinding using the RTSM system. The Investigator(s) 
must document and report to the Medical Monitor any breaking of the treatment code. The date 
and reason that the blind was broken must be recorded in the source documentation. 
Appropriate personnel at the Sponsor (or designee) will unblind suspected unexpected serious 
adverse reactions (SUSARs) for the purpose of reporting to authorities as required per each local 
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regulation. The Sponsor will submit SUSARs to Regulatory Agencies in blinded or unblinded 
fashion according to local law. The Sponsor will submit SUSARs to Investigators in a blinded 
fashion. 
5.5. 
Treatment of Overdose 
Any overdose of study drug should be recorded in the eCRF (including quantity of the excess 
dose and the duration of the overdose). AEs associated with an overdose or incorrect 
administration of study drug should be recorded in the AE eCRF. An overdose will not be 
considered an SAE unless the outcome of the overdose meets seriousness criteria. 
There is no specific management of an overdose of VXA-CoV2-1.1-S. Participants should be 
closely monitored for toxicities and managed appropriately. 
5.6. 
Concomitant Therapy 
Concomitant medication is defined as any prescription or over-the-counter preparation. 
Use of concomitant medication from 4 weeks before Day 1 (Part 1 or Part 2) through 4 weeks 
after the last dose of study (completion of Active Period) must be recorded in the eCRF from the 
participant’s medical file along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Medications for pre-existing medical conditions or required for a medical condition during the 
study are allowed if not considered exclusionary. 
The Sponsor's Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
5.6.1. 
Prohibited Concomitant Medication 
Medications specifically prohibited in the exclusion criteria are not allowed during the Active 
Period (Section 3.3.2 prior/concurrent therapy), unless deemed medically necessary by the 
Investigator. 
5.7. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure candidates to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Re-screening/re-assessment outside the Screening period will be possible on a case-by-case basis 
following Sponsor approval. Participants allowed to be re-screened will be assigned a new 
screening number (with referral in eCRF to the previous screening number); such participants 
will be determined a permanent screen failure after the second screening determines the 
participant is ineligible. 
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5.8. 
End of Study Definition 
In both Part 1 and Part 2, a participant is considered to have completed the study if they complete 
the EOT visit at Week 8 (end of Active period). Participants are considered to complete Safety 
Follow-up if they complete the EOS visit at Month 13. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5.9. 
Intervention after the End of the Study 
Following completion of the study Efficacy period in Part 2, the study database will be cleaned 
and locked and the treatment assignments unblinded.  At this time subjects who were 
randomized to the placebo group under the current protocol will have the opportunity to receive 
vaccination(s) against COVID-19 via one of the following options: 
• Receipt of an approved COVID-19 vaccine (standard-of care) in the region within which 
they are located (paid for by the Sponsor), or 
• Receipt of a Vaxart oral tableted vaccine for the prevention of COVID-19 under an open-
label extension protocol 
The specific approach to be utilized will be further defined and added to the protocol based on 
the availability of approved COVID-19 vaccines closer to the completion of Part 2. 
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6. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
WITHDRAWAL FROM STUDY 
6.1. 
Study Halting Rules  
The study will be halted (no new enrollments and no further study vaccinations) pending an 
IDMC safety review if any of the below rules are met prior to the start of randomization in Part 
2, or the end of the Active Period (4 weeks after the last study drug) in Part 1, whichever is later. 
6.1.1. Part 1 Halting Rules 
1. Any participant experiences a vaccine-related SAE. 
2. Two or more participants experience the same or similar Grade ≥3 solicited AE (first and 
second vaccinations to be assessed separately). 
3. Two or more participants experience the same or similar Grade ≥3 unsolicited single AE 
preferred term or clinical laboratory AE which the investigator assesses as possibly, 
probably or definitely related to study vaccine. 
4. Occurrence of severe COVID-19 in any participant as defined below. If this halting rule 
is met, all available clinical, nonclinical safety and immunogenicity data will be reviewed 
by the IDMC to evaluate for potential vaccine enhanced COVID-19. 
Per FDA’s June 2020 Guidance Development and Licensure of Vaccines to Prevent COVID-
19, severe COVID-19 disease is defined as virologically confirmed SARS-CoV-2 infection 
with any of the following: 
a. Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 
beats per minute, heart rate > 125 per minute, peripheral hemoglobin oxygen 
saturation [SpO2] <93% on room air at sea level or partial pressure of oxygen 
[PaO2]/fraction of inspired oxygen [FiO2] < 300 mm Hg) 
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or extracorporeal membrane oxygenation 
[ECMO]) 
c. Evidence of shock (Systolic blood pressure < 90 mm Hg, diastolic blood pressure 
<60 mm Hg, or requiring vasopressors) 
d. Significant acute renal, hepatic, or neurologic dysfunction 
e. Admission to an intensive care unit (ICU) 
f. Death 
6.1.2. 
Part 2 Halting Rules 
1. Any participant experiences a vaccine-related SAE. 
2. Five or more participants experience the same or similar Grade ≥3 solicited AE (first and 
second vaccinations to be assessed separately). 
3. Five or more participants experience the same or similar grade ≥3 unsolicited single AE 
preferred term or clinical laboratory AE which the investigator assesses as possibly, 
probably or definitely related to study drug administration. 
4. Occurrence of severe COVID-19 in any participant, per the definition above, and IDMC 
determines there is evidence of vaccine enhanced COVID-19. If this halting rule is met, 
all available clinical and preclinical safety and immunogenicity data will be reviewed by 
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the IDMC to evaluate for potential vaccine enhanced COVID-19. 
6.2. 
Discontinuation of Study Drug 
In some instances, it may be necessary for a participant to permanently discontinue study drug 
(that is, not receive the second vaccination). Please also refer to halting rules described in 
Section 6.1.  
Permanent discontinuation of study drug does not mean withdrawal from the study, and the 
participant will be encouraged to remain in the study and continue to complete all study visits. At 
the time of treatment completion or study drug discontinuation, the Early Termination (ET) visit 
should be completed as shown in the SoA (Section 1.2). Participants should continue to be 
followed for safety, immunogenicity and efficacy even if they discontinue study drug 
prematurely unless they withdraw consent. 
Participants may discontinue or be discontinued from study drug at any time. A participant may 
discontinue study drug for reasons including but not limited to: 
• Adverse event 
• Death 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by participant* (*only for discontinuing study drug, but will remain in 
study) 
The reason for participant discontinuation from study drug will be recorded in the eCRF. 
6.3. 
Participant Withdrawal from the Study 
Participants have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A participant may 
withdraw from the study for reasons including but not limited to: 
• Death 
• Withdrawal by participant 
• Lost to follow-up 
• Study terminated by Sponsor 
The reason for participant withdrawal from the study will be recorded in the eCRF. 
At the time of withdrawal from the study, the ET visit should be completed, as shown in the SoA 
(Section 1.2). 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
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If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
6.4. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
(Section 1.2) is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• Participants who experience any serious or severe TEAEs, MAAEs or experience any 
event of concern including symptoms of, or a potential exposure to, SARS-CoV-2 
should be instructed to contact the study site and be scheduled for a visit for further 
evaluation. If an unscheduled visit occurs, the reason for the visit and data collected 
during the visit should be recorded and entered into the unscheduled eCRF. 
7.1. 
Efficacy and Immunogenicity Assessments 
Planned time points for efficacy assessments are provided in the SoA in Section 1.2. 
7.1.1. 
SARS-CoV-2 Infection and COVID-19 Diagnosis 
Participants will be monitored for SARS-CoV-2 infection and/or symptomatic COVID-19 in the 
following manner: 
• Testing for prior exposure by rapid antibody (Ab) test at Screening and Baseline (pre-
vaccination) if Screening test >7 days prior to Baseline Visit (Part 1 Cohort 1 only). 
• Testing by an FDA authorized rapid molecular test at any time a participant reports 
illness compatible with COVID-19 or reports known/ possible exposure to COVID-19. A 
sample will also be collected at Baseline to test for potential of pre-dose exposure should 
confirmation of negative infection be needed in participants who contract COVID-19 
during the study. 
• A negative onsite rapid molecular test is required  prior to dosing at Days 1 and 29. This 
testing is needed given the high rates of COVID-19 being observed at clinical sites with 
the spread of Omicron variant. 
Any participant reporting COVID-19 like illness or exposure to COVID-19 during the study will 
be asked to return to the site for an unscheduled visit to test for SARS-CoV-2 infection. Any 
FDA authorized rapid molecular test (e.g. LUCIRA COVID-19 Test) may be used for home or 
on-site testing for monitoring COVID-19 infection.. Participants with confirmed SARS-CoV-2 
infection at any time during the study period will be asked to provide a nasal sample for rapid 
molecular test every two days after their confirmatory test until they test negative. The duration 
of q2day testing should end after 10 days if still testing positive at that time. They will also be 
monitored for clinical disease duration, severity, and outcome. The participant will be counseled 
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to notify their Primary Care Physician of their positive SARS-CoV-2 status and seek medical 
care should they become symptomatic. 
The occurrence of virologically confirmed (by polymerase chain reaction [PCR] or rapid 
molecular test to SARS-CoV-2) symptomatic mild, moderate, or severe COVID-19 is 
defined in Table 5. 
Subjects with confirmed COVID-19 will be evaluated for severity of disease as well as for 
the potential for vaccine-associated enhanced disease (VAED). 
 
Table 5 
Definitions of COVID-19 Severity  
Mild  
At least one or more of the following: 
• Fever (defined by subjective or objective measure, regardless of use of anti-pyretic 
medications) 
• New onset cough 
• ≥ 2 COVID-19 respiratory/non-respiratory symptoms in Table 6 AND 
• Does not meet criteria for moderate or severe disease 
Moderate 
At least one or more of the following: 
• Fever (defined by subjective or objective measure, regardless of use of anti-pyretic 
medications) + any 2 COVID-19 symptoms in Table 6 for ≥ 3 days (need not be 
contiguous days) 
• High fever (≥ 38.4°C) for ≥ 3 days (need not be contiguous days) Any evidence of 
significant LRTI: 
- 
Shortness of breath (or breathlessness or difficulty breathing) with or without exertion 
(greater than baseline) 
- 
Tachypnea: 20 to 29 breaths per minute at rest 
- 
SpO2: 94% to 95% on room air 
- 
Abnormal chest x-ray or chest CT consistent with pneumonia or LRTI 
- 
Adventitious sounds on lung auscultation (e.g., crackles/rales, wheeze, rhonchi, 
pleural rub, stridor) 
AND 
• Does not meet criteria for severe disease 
Severe 
At least one or more of the following: 
• Tachypnea: ≥ 30 breaths per minute at rest 
• Resting heart rate ≥ 125 beats per minute 
• SpO2: ≤ 93% on room air or PAO2/FiO2 < 300 
• High flow oxygen therapy or NIV/NIPPV (e.g., CPAP or BiPAP) 
• Mechanical ventilation or ECMO 
• One or more major organ system dysfunction or failure (e.g., cardiac/circulatory, 
pulmonary, renal, hepatic, and/or neurological, to be defined by diagnostic 
testing/clinical syndrome/interventions), including any of the following: 
o ARDS 
o Acute renal failure 
o Acute hepatic failure 
o Acute right or left heart failure 
o Septic or cardiogenic shock (with shock defined as SBP < 90 mm Hg OR 
o DBP < 60 mm Hg 
o Acute stroke (ischemic or hemorrhagic) 
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o Acute thrombotic event: AMI, DVT, PE 
o Requirement for: vasopressors, systemic corticosteroids, or hemodialysis 
• Admission to an ICU 
• Death 
Abbreviations: AMI = acute myocardial infarction; ARDS = acute respiratory distress syndrome; BiPAP = bi-level positive 
airway pressure; CPAP = continuous positive air pressure; CT = computed tomography; DBP = diastolic blood pressure; DVT = 
deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; FiO2 = fraction of inspired oxygen; ICU = intensive 
care unit; LRTI = lower respiratory tract infection; NIV = non-invasive ventilation; NIPPV = non-invasive positive pressure 
ventilation; PAO2 = partial pressure of oxygen in the alveolus; PE = pulmonary embolism; SBP = systolic blood pressure; SpO2 
= oxygen saturation.  
Table 6 
Qualifying Symptoms of Suspected COVID-19  
• 
Fever 
• 
New onset cough  
• 
New onset or worsening of shortness of breath or difficulty breathing 
compared to baseline  
• 
New onset fatigue  
• 
New onset generalised muscle or body aches  
• 
New onset headache lasting ≥ 48 hours  
• 
New loss of taste or smell  
• 
Acute onset of sore throat, congestion, and runny nose  
• 
New onset nausea, vomiting, or diarrhea lasting ≥ 48 hours 
7.1.2. 
Immunogenicity 
Samples will be collected from all participants for immunogenicity assessment according to the 
time points specified in the SoA (Section 1.2; Table 3 and Table 4). The following 
immunoassays will be performed: 
Key immunogenicity assessments: 
Part 1: 
− SARS-CoV2-specific IgG/IgA by MSD (Serum) 
− Neutralizing antibody titers to SARS-CoV-2 (Serum) 
−  
Part 2: 
− SARS-CoV2-specific IgG/IgA by MSD (Serum) 
− Neutralizing antibody titers to SARS-CoV-2 (Serum) 
Additional Immunogenicity Assessments: 
Part 1: 
− T cell responses by intracellular cytokine cytometry (ICC) 
− Antigen S-specific IgA (Nasal Swabs) 
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− Antigen S-specific IgA (Saliva) 
− Anti Ad5 antibodies (optional), (Serum) 
 Part 2: 
− Antigen S-specific IgA (Nasal Swabs) 
− Antigen S-specific IgA (Saliva) 
Additional exploratory immunoassays may also be run to further characterize the immune 
response of the VXA-CoV2-1.1-S vaccine.  Sample collection, processing and shipping details 
are provided within the General and Immunogenicity Laboratory Manuals. 
7.2. 
Safety Assessments 
The safety of VXA-CoV2-1.1-S will be evaluated through the reporting of solicited symptoms of 
reactogenicity for 1 week following each study drug administration, unsolicited TEAEs for 4 
weeks following each study drug administration, and SAEs and MAAEs including AESIs, 
NOCIs for up to 56 weeks following the first vaccine dose. Because the VXA-CoV2-1.1-S 
vaccine contains a double-stranded RNA (dsRNA), adjuvant MAAEs will be collected through 
one year post last dose to address the theoretical potential for induction of autoimmune or auto-
inflammatory diseases, as is standard for this class of vaccines.  The conditions listed in 
Appendix 5 (Section 9.5), as well as any other unexpected medical conditions requiring medical 
attention will be monitored during the Safety Follow-up period. Subjects will also be monitored 
for exposure to SARS-CoV2 and symptomatic SARS-CoV2 infection (COVID-19) as noted in 
section 7.1.1. Subjects with symptomatic COVID-19 will be further evaluated for severity of 
disease and the potential for VAED.  
Planned time points for all safety assessments are provided in the SoA. 
7.2.1. 
Physical Examination 
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular system, respiratory system, abdomen (gastrointestinal, liver and spleen) and 
neurological system. Height and weight will also be measured and recorded at Screening. 
A targeted, symptom-directed physical examination will include, at a minimum, assessments of 
the skin, respiratory system, cardiovascular system, and abdomen (liver and spleen). 
7.2.2. 
Vital Signs 
Blood pressure, heart rate, and respiratory rate will be measured after the participant has been 
resting for 5 minutes. Vital signs will be measured prior to any blood draw that occurs at the 
same timepoint. 
7.2.3. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 (Section 9.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. 
• All laboratory tests with values considered clinically significant during participation 
in the study or within 14 days after the last dose of study drug should be repeated 
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until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Sponsor’s Medical Monitor (or designee). If such 
values do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, and the Sponsor notified. 
• Laboratory values which are abnormal AND lead to either the requirement for an 
intervention, the requirement for additional medications, or are felt to otherwise be 
medically important should be recorded as adverse events in the eCRF. Only 
abnormal labs that are clinically significant, per the judgement of the investigator, 
should be reported as treatment-emergent adverse events, which should be graded 
based on the clinical scenario. Further, the grading of these adverse events should be 
based on guidance provided in protocol Section 9.3.4.1 – Grading the Severity of 
TEAEs. 
• Hematology or serum chemistry parameters will be graded according to the FDA 
toxicity grading scale (Section 9.3.4.1.2) and will be adjusted  to align with local 
laboratory reference ranges (Part 1 only) for clinically significant abnormal laboratory 
tests. Subjects have the ability to rescreen once should screening values fall outside of 
the allowed eligibility criteria, per the discretion of the Investigator.  Post-screening 
abnormal lab results with toxicity grade 3 or above that are deemed not clinically significant 
by the investigator and not captured as adverse events will be included separately in the 
clinical study report. 
• Pregnancy testing should include serum hCG  at screening. Negative urine pregnancy 
test should be confirmed on Days 1 and 29 prior to dosing.. 
7.3. 
Treatment-Emergent Adverse Events and Serious Adverse Events 
The definitions of a TEAE (solicited and unsolicited), MAAE and SAE can be found in 
Appendix 3 (Section 9.3). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of a TEAE (solicited and unsolicited), MAAE, or SAE. 
Investigators remain responsible for following up TEAEs, MAAEs, SAEs and other reportable 
safety events for outcome. 
7.3.1. 
Time Period and Frequency for Collecting TEAE, MAAE SAE and Other 
Reportable Safety Event Information 
All TEAEs (solicited and unsolicited), MAAEs, SAEs and other reportable safety events that 
occur after the consent form is signed but before study administration must be reported by the 
Investigator if the event cause the participant to be excluded from the study or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure. 
Table 7 below summarizes the different reporting timelines for TEAEs (unsolicited and 
solicited), MAAE, SAEs, SUSAR, and pregnancy. 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
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All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from awareness, as indicated in Appendix 3 
(Section 9.3). The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
 
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Table 7 
Adverse Event Reporting Timelines to the Sponsor 
Type of Event 
TEAE (unsolicited) 
TEAE (solicited) 
MAAE 
SAE / SUSAR 
Pregnancy 
Reporting period 
From first dose until 4 
weeks after last dose of 
study drug 
1 week after each 
study drug 
administration 
 
From first dose until 
EOS 
From first dose until 
EOS. 
From first dose until 
EOS 
Reporting 
Timelines to the 
Sponsor  
Entered into the clinical 
database on an ongoing 
basis  
Entered into the 
clinical database on an 
ongoing basis 
Within 24 hours 
Within 24 hours  
Within 24 hours 
Reporting 
Method 
AE eCRF 
Solicited Symptom 
Diary 
AE eCRF 
AE eCRF 
Pregnancy form 
Abbreviations: AE = adverse event; eCRF = electronic Case Report Form; EOS = end of study; MAAE = medically attended adverse event; SAE = serious adverse 
event; SUSAR = suspected unexpected serious adverse reaction; TEAE = treatment-emergent adverse event 
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7.3.2. 
Method of Detecting TEAEs, MAAEs and SAEs 
Appendix 3 provides the method of recording (Section 9.3.4), evaluating severity 
(Section 9.3.4.1), and assessing causality (Section 9.3.4.2) of AEs, MAAEs and SAEs and the 
procedures for completing and transmitting SAE reports (Section 9.3.5). 
Care will be taken not to introduce bias when detecting AEs, MAAEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
7.3.3. 
Follow-up of AEs, MAAEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and evaluations as medically indicated to elucidate the nature and causality of the 
AE, MAAE, or SAE as fully as possible. This may include laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
New or updated information will be recorded in the originally submitted documents. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
AEs, including pregnancy, will be followed by the Investigator as specified in Appendix 4. 
7.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of the study drug under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of the study drug under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• For all studies, Investigator safety reports must be prepared for SUSAR according to 
local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure (IB) and will notify the 
IRB/IEC, if appropriate according to local requirements. 
7.3.5. 
Death Events 
Events resulting in death will be an SAE regardless of association to study drug. Death is an 
outcome and should not be reported as an event term. The event that leads to the death should be 
reported as the SAE term. 
7.3.6. 
Pregnancy 
• In the case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration of study drug but may remain in the study. 
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• Details of all pregnancies in female participants and female partners of male 
participants will be collected as outlined in Appendix 4 (Section 9.4). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 9.4). 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
 
 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Sample Size Determination 
8.1.1. 
Part 1 
Part 1 is an open-label, lead in, repeat-dose, dose and age escalation design to evaluate the VXA-
COV2-1.1-S oral vaccine in two cohorts with repeat dose administration. Cohort 1 will enroll 
approximately a total of 36 healthy adult participants that are naive (no prior vaccination against 
SARS-CoV-2 infection and no history of prior COVID-19 or SARS-CoV-2 infection) across 3 
groups of 12 subjects each, encompassing 2 age groups and two dose levels. Cohort 2 will enroll 
approximately a total of  36 healthy adult participants who have received two doses of an EUA 
or FDA approved mRNA vaccine for the prevention of SARS-CoV-2 infection across 3 groups 
of 12 subjects each, encompassing 2 age groups and two dose levels.  
 
There are no sample size calculations utilized for Part 1; the cohort size is estimated to provide 
informative safety and immunogenicity data to allow dose selection for safely proceeding to Part 2. 
8.1.2. 
Part 2 
The number of participants to be randomized in Part 2 (VXA-CoV2-1.1-S and placebo) is 
predicted to yield meaningful immunogenicity and efficacy results to inform how best to proceed 
into later stage studies. In previous human studies with Ad5 vectored oral tableted vaccines using 
the same vaccine platform (Ad5 vectored vaccine coding for target virus-specific antigens and a 
dsDNA adjuvant), the vaccine was well tolerated at total doses up to 2x1011 IU. 
All testing will be performed at alpha = 0.05. All tests will be two-sided. Assuming attack rate in 
unvaccinated group (ARU) = 5% and vaccine efficacy (VE) = 90%, 341 participants would be 
required per treatment arm, yielding 95% power.  
The total sample size for Part 2 of this study (2 arms) would be 682. To allow for a ~15% 
dropout rate, 800 participants will be randomized. 
Unvaccinated Attack Rate (ARU): 5% 
2-sided Alpha 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
ARU 
5% 
5% 
5% 
5% 
5% 
5% 
5% 
5% 
VE 
90% 
90% 
90% 
90% 
95% 
95% 
95% 
95% 
Power 
80% 
85% 
90% 
95% 
80% 
85% 
90% 
95% 
SS/Arm 
207 
236 
276 
341 
177 
202 
236 
292 
Sample Size (part 2 of 
study, two arms) 
414 
 
472 
682 
354 
404 
472 
584 
Interim looks at the efficacy using O’Brien Fleming Boundaries. One interim analysis may 
be conducted during the study by the IDMC if 18 confirmed cases of COVID-19 are observed 
prior to the completion of Month 7 visits, 6 months following the second vaccination, by all 
subjects. Given a power estimate of 95%, the study may be stopped by the Sponsor for 
overwhelming efficacy at the interim look if alpha < 0.003. The study will continue if this 
criterion is not met (and may be continued even if it is met per Sponsor’s review and FDA 
agreement).  If the decision is made to continue the study until completion at 6 months post last 
vaccination, alpha < 0.05. 
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8.2. 
Populations for Analyses 
Analysis Population 
Description 
Screened 
All subjects who enter screening (assigned a screening number) 
Randomized  
All participants who are assigned a randomization number  
Dose 1 evaluable 
immunogenicity 
All eligible randomized participants who receive the study intervention to 
which they are randomly assigned at the first dose, have at least 1 valid and 
determinate immunogenicity result after Dose 1, have blood collection within 
an appropriate window after Dose 1, and have no other important protocol 
deviations. 
Dose 2 evaluable 
immunogenicity 
All eligible randomized participants who receive 2 doses of the study 
intervention to which they are randomly assigned, within the predefined 
window, have at least 1 valid and determinate immunogenicity result after 
Dose 2, have blood collection within an appropriate window after Dose 2, and 
have no other important protocol deviations. 
Dose 1 all-available 
immunogenicity 
All randomized participants who receive at least 1 dose of the study 
intervention with at least 1 valid and determinate immunogenicity result after 
Dose 2. 
Evaluable efficacy 
All eligible randomized participants who receive all study intervention 
dose(s) as randomized within the predefined window and have no other 
important protocol deviations. 
All-available efficacy 
All randomized participants who receive at least 1 dose of the study 
intervention.  
Safety 
All randomized participants who receive at least 1 dose of the study drug. 
8.3. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock for any 
of the planned analyses. It will describe the participant populations to be included in the analyses 
and the procedures for accounting for missing, unused, and spurious data. This section provides a 
summary of the planned statistical analyses of the primary, secondary, and tertiary/exploratory 
endpoints. 
8.3.1. Part 1 - Open Label Lead-in Phase 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Descriptive statistics (counts and percentages) will be used to present the following: 
• 
Frequency, duration, and severity of solicited symptoms of reactogenicity (local, 
systemic) for 1 week following each vaccination 
• 
Frequency, duration, and severity of unsolicited treatment-emergent adverse events 
(TEAEs), serious AEs (SAEs), and medically attended AEs (MAAEs). MAAEs 
include (1) active monitoring for COVID-19 and vaccine-associated enhanced 
disease (VAED), and (2) monitoring for potential immune-mediated medical 
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conditions including AEs of special interest (AESIs) and new onset of chronic illness 
(NOCIs) 
Descriptive statistics will be provided for each reactogenicity endpoint for each dose and 
vaccine group. Local reactions and systemic events from Day 1 through Day 8 after each 
vaccination will be presented by severity and cumulatively across severity levels. 
Descriptive summary statistics will include counts and percentages of participants with 
the indicated endpoint and the associated Clopper-Pearson 95% CIs. 
Secondary 
 
 
Frequency, duration, and severity of all SAEs, and MAAEs including monitoring for 
COVID-19, VAED, AESIs and NOCIs through one year post last dose 
Key immunogenicity endpoints: 
• 
SARS-CoV2-specific Immunoglobulin G (IgG) and Immunoglobulin A (IgA) 
antibody levels by Mesoscale Discovery (MSD) assay 
• 
Neutralizing serum antibody titers to SARS-CoV-2  
Additional immunogenicity endpoints: 
• 
T cell responses by intracellular cytokine cytometry (ICC) 
• 
Antigen S-specific IgA in nasal swabs 
• 
Antigen S-specific IgA in saliva 
• 
Anti-Ad5 serum antibodies (optional) 
Geometric mean titers/concentrations (GMTs/GMCs) of SARS-CoV-2 neutralizing titers, 
S-binding IgG level,  , and S-binding IgA levels serum, nasal and saliva), GMTs/GMCs 
and 2-sided 95% CIs and other reported antigens will be provided for by treatment group 
at the following time points: 
• 
Day 1, Week 4, Week 8, Optional (Month 7, and Month 13) 
• 
Geometric means will be calculated as the mean of the assay results after making 
the logarithm transformation and then exponentiating the mean to express results 
on the original scale. Two-sided 95% CIs will be obtained by taking natural log 
transforms of concentrations/titers, calculating the 95% CI with reference to the 
t-distribution, and then exponentiating the confidence limits.  
The geometric mean fold rise (GMFR) of SARS-CoV-2 neutralizing titers, S-binding IgG 
level, and S-binding IgA level. For SARS-CoV-2 neutralizing titers, S-binding IgG levels, 
and S-binding IgA levels, the GMFRs and 2-sided 95% CIs will be provided by treatment 
group at the following time points: 
• 
 Week 4, Week 8, Optional (Month 7, and Month 13) 
GMFRs will be limited to participants with non-missing values prior to the first dose and 
at the postvaccination time point. The GMFR will be calculated as the mean of the 
difference of logarithmically transformed assay results (later time point – earlier time 
point) and exponentiating the mean. The associated 2-sided CIs will be obtained by 
calculating CIs using Student’s t-distribution for the mean difference of the 
logarithmically transformed assay results and exponentiating the confidence limits.  
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Percentage of participants with ≥4-fold rise (or other assessments as per the SAP) in 
SARS-CoV-2 neutralizing titers, S1-binding IgG level, and RBD-binding IgG level will 
be summarized by treatment group at the following timepoints. 
• 
 Week 4, Week 8, Optional (Month 7, and Month 13) 
For all the immunogenicity endpoints, the analysis will be based on the Dose 1 and Dose 
2 evaluable immunogenicity populations. An additional analysis will be performed based 
on the all-available immunogenicity populations if there is a large enough difference in 
sample size between the all-available immunogenicity populations and the evaluable 
immunogenicity populations. Participants will be summarized according to the vaccine 
group to which they were randomized. 
 
Additional immunogenicity data will be assessed as per the SAP.  Missing serology data 
will not be imputed. 
Exploratory 
Descriptive statistics (counts and percentages) will be used to present the following: 
• 
Frequency, duration and severity of virologically confirmed COVID-19 illness 
and serologically confirmed SARS-CoV-2 infection occurring from 7 days 
following second study drug dose administration 
  
8.3.2. Part 2- Double Blind, Placebo Controlled 
Endpoint 
Statistical Analysis Methods 
Primary: 
1. Primary 
Efficacy 
2. Secondary 
Efficacy 
3. Safety 
 
All analyses will be performed at 6 months post last vaccination. The 
database will be locked and unblinded at this time the efficacy and safety 
analysis will be conducted. 
The evaluable efficacy population will be the primary analysis population for all 
efficacy analyses. Additional analyses based on the all-available efficacy 
population will be performed. 
1. Primary Efficacy 
Frequency of virologically confirmed COVID-19 illness and serologically 
confirmed SARS-CoV-2 infection occurring from 7 days following second study 
drug dose administration.   
Ratio of confirmed COVID-19 illness from 1 week after the Dose 2 per 1000 
person-years of follow-up in participants without evidence of infection for the 
active vaccine group to the placebo group VE will be estimated by 100 × (1 – 
IRR), where IRR is the calculated ratio of confirmed COVID-19 illness per 1000 
person-years follow-up in the active vaccine group to the corresponding illness 
rate in the placebo group from 1 week after the Dose 2.  
VE will be analyzed using a beta-binomial model. After the above objective is 
met, the second primary endpoint will be evaluated as below. Ratio of confirmed 
COVID-19 illness from 1 week after the Dose 2 per 1000 person-years of follow-
up in participants with and without evidence of infection (prior to 1 week after 
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receipt of Dose 2) for the active vaccine group to the placebo group VE will be 
estimated by 100 × (1 – IRR), where IRR is the calculated ratio of confirmed 
COVID-19 illness per 1000 person-years follow-up in the active vaccine group to 
the corresponding illness rate in the placebo group from 1 week  after the second 
dose. VE will be analyzed using a beta-binomial model.  
The efficacy analysis for the first primary objective evaluation will be based on 
the participants without evidence of infection before vaccination and included in 
the evaluable efficacy population and in the all-available efficacy population. 
The efficacy analysis for the second primary objective evaluation will be based on 
all participants included in the evaluable efficacy population and in the all-
available efficacy population. 
For the primary endpoint analysis, missing efficacy data will not be imputed. A 
sensitivity analysis will be performed by imputing missing values with the 
assumption of missing at random (MAR). A missing efficacy endpoint may be 
imputed based on predicted probability using the fully conditional specification 
method. Other imputation methods without the MAR assumption may be 
explored. The details will be provided in the SAP. 
2. Secondary Efficacy 
First: Ratio of confirmed COVID-19 illness from 1 week after the second dose per 
1000 person-years of follow-up in participants without evidence of infection for 
the active vaccine group to the placebo group. 
Second: Ratio of confirmed COVID-19 illness from 1 week after the second dose 
per 1000 person-years of follow-up in participants with and without evidence of 
infection for the active vaccine group to the placebo group. 
These secondary efficacy objectives will be evaluated sequentially in the order 
specified above after the primary objectives are met.  
The analysis will be based on the evaluable efficacy population. The analysis 
methodology used for the primary efficacy endpoints will be applied for the 
analysis of the above secondary efficacy endpoints. The following secondary 
efficacy endpoints will be evaluated descriptively with 95% CIs. Ratios of 
confirmed COVID-19 illness (according to the CDC-defined symptoms) from 1 
week after the second dose per 1000 person-years of follow-up in participants 
without evidence of infection for the active vaccine group to the placebo group 
Ratios of confirmed COVID-19 illness (according to the CDC-defined symptoms) 
from 1 week after the second dose per 1000 person-years of follow-up in 
participants with and without evidence of infection for the active vaccine group to 
the placebo group VE = 100 × (1 – IRR) will be estimated with confirmed 
COVID-19 illness according to the CDC-defined symptoms from 1 week after the 
second dose. The 2-sided 95% CI for VE will be derived using the Clopper-
Pearson method as described by Agresti (Agresti, 2002). Missing efficacy data 
will not be imputed. 
3. Safety and tolerability 
The safety population will be used for all safety analyses. 
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Descriptive statistics will be used to present the following, for each treatment 
group: 
• Frequency, duration, and severity of solicited symptoms of reactogenicity 
(local, systemic) for 1 week following each vaccination 
• Frequency, duration, and severity of unsolicited TEAEs, SAEs, and MAAEs 
through the active period (4 weeks post last dose) efficacy period and safety 
follow-up period. MAAEs include (1) active monitoring for COVID-19 and 
VAED through the active period (4 weeks post last dose); and (2) monitoring 
for potential immune-mediated medical conditions including AESIs and 
NOCIs for one year post last dose. 
Secondary:   
Long-term Safety 
 
 
Immunogenicity 
Frequency, duration, and severity of all SAEs, and MAAEs including monitoring 
for COVID-19, AESIs and NOCIs through one year post last dose 
 
See section 8.2 (Populations for Analyses) for a descriptive of the populations 
used for these analyses. 
 
Key immunogenicity endpoints: 
• SARS-CoV2-specific IgG and IgA antibody levels using MSD assays 
• Neutralizing serum antibody titers to SARS-CoV-2 
Additional immunogenicity endpoints: 
• Antigen S-specific IgA in nasal swabs 
• Antigen S-specific IgA in saliva 
Geometric mean titers/concentrations (GMTs/GMCs) of SARS-CoV-2 
neutralizing titers, S-binding IgG level, and  S- binding IgA level for SARS-CoV-
2 neutralizing titers, S-binding IgG levels, and S-binding IgA levels, 
GMTs/GMCs and 2-sided 95% CIs will be provided for by treatment group at the 
following time points: 
• 
Day 1, Week 4, Week 8, Month 7, and Month 13 after Dose 1 
Geometric means will be calculated as the mean of the assay results after making 
the logarithm transformation and then exponentiating the mean to express results 
on the original scale. Two-sided 95% CIs will be obtained by taking natural log 
transforms of concentrations/titers, calculating the 95% CI with reference to the 
t-distribution, and then exponentiating the confidence limits.  
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level, and 
RBD-binding IgG level. For SARS-CoV-2 neutralizing titers, S1-binding IgG 
levels, and RBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be 
provided by treatment group at the following time points: 
• 
 Day 1, Week 4, Week 8, Month 7, and Month 13 after Dose 1 
GMFRs will be limited to participants with non-missing values prior to the first 
dose and at the postvaccination time point. The GMFR will be calculated as the 
mean of the difference of logarithmically transformed assay results (later time 
point – earlier time point) and exponentiating the mean. The associated 2-sided 
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CIs will be obtained by calculating CIs using Student’s t-distribution for the mean 
difference of the logarithmically transformed assay results and exponentiating the 
confidence limits.  
Percentage of participants with ≥4-fold rise in SARS-CoV-2 neutralizing titers, 
S1-binding IgG level, and RBD-binding IgG level will be summarized by 
treatment group. 
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and RBD-binding 
IgG levels, percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise 
will be provided for by treatment group at the following time points: 
• 
Day 1, Week 4, Week 8, Month 7, and Month 13 after Dose 1 
The Clopper-Pearson method will be used to calculate the CIs. GMR of SARS-
CoV-2 neutralizing titer to S1-binding IgG level and to RBD-binding IgG level. 
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and RBD-binding 
IgG levels, the GMRs and 2-sided 95% CIs will be provided by treatment group at 
the following time points: 
• 
Day 1, Week 4, Week 8, Month 7, and Month 13 after Dose 1 
GMRs will be limited to participants with non-missing values for both SARS-
CoV-2 neutralizing titers and S1-binding IgG level/RBD binding IgG level at each 
time point. The GMR will be calculated as the mean of the difference of 
logarithmically transformed assay results (e.g., SARS-CoV-2 neutralizing titers 
minus S1-binding IgG level for each participant) and exponentiating the mean. 
Two-sided CIs will be obtained by calculating CIs using Student’s t-distribution 
for the mean difference of the logarithmically transformed assay results and 
exponentiating the confidence limits.  
For all the immunogenicity endpoints, the analysis will be based on the Dose 1 
and Dose 2 evaluable immunogenicity populations. An additional analysis will be 
performed based on the all-available immunogenicity populations if there is a 
large enough difference in sample size between the all-available immunogenicity 
populations and the evaluable immunogenicity populations. Participants will be 
summarized according to the vaccine group to which they were randomized. 
Missing serology data will not be imputed. 
 
8.4. 
Interim Analysis 
During Part 1, following completion of the Active Period by all Cohorts, the database will be 
cleaned and locked. 
During Part 2, an interim analysis will occur at 18* confirmed cases of SARS-CoV2 infection.  
In addition to efficacy, this interim analysis would also include evaluation of safety and 
immunogenicity through Week 8.  If 18 confirmed cases are not identified, the study will be 
considered complete at 6 months post last vaccination and the database will be locked and 
unblinded.  At this time the efficacy analysis will be conducted, O’Brien-Fleming methods will 
be used for halting rules (O'Brien, 1979): 
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• If P = 0.003 at the interim analysis, the study may be stopped for overwhelming 
efficacy.  
• If the study completes as planned (i.e., 6 months post last vaccination), it will be 
determined to be successful if P ≤ 0.05. 
*VE null = 30% (since that is lower bound from the FDA) and VE_Alt = 80% and ARU = 0.05 we get p0 = 0.41 
and p1 = 0.17 which gives a total target number of events of around 31 (with ~5 from vaccine group and 26 in 
placebo so if we add in the other dose then looking at around 36 total events) using POT0 if we simplify down to 
one primary dose vs placebo calculation. So interim analysis at 1/2 * 36 = 18 events (or 6 months post last 
vaccination, whichever is first) (Follmann, 2020).  
The SAP will describe the planned interim analysis in greater detail. 
8.5. 
Safety Oversight 
8.5.1. 
Internal Sponsor Review 
Safety data will be monitored on an ongoing basis by the Investigator (or medically qualified 
designee) and the Sponsor’s Medical Monitor (or designee) in order to promptly identify and flag 
any event that potentially contributes to a halting rule (Section 6.1). 
A Sponsor’s Medical Monitor (or designee) will perform the oversight of safety for this study. 
Additional local medical monitors may also be employed to aid with safety oversight locally. 
The lead Medical Monitor will be a physician experienced in the conduct of research clinical 
studies whose primary responsibility will be to monitor participant safety. The Medical Monitor 
will be responsible for reviewing the cumulative safety data, including a review of safety 
laboratory test results and adverse event reporting. The Medical Monitor will be familiar with 
study-specific data as well as relevant background information about the disease, investigational 
drug, and target population under study. The Medical Monitor(s) will be empowered to request 
an IDMC safety review which can suspend the study, recommend amendments to the protocol, 
and/or to request further information. 
8.5.2. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be assigned by the Sponsor prior to the beginning of the study and will provide 
ongoing oversight of the study. 
The IDMC will provide study oversight throughout the duration of the study period (Day 1 
through EOS). The IDMC will perform a review of safety data  of all participants in Part 1. 
Enrollment and dosing in Part 2 will only commence following the IDMC’s recommendation to 
proceed. A summary of safety and immunogenicity data with the intended dose for Part 2 will 
also be submitted to FDA for review and concurrence prior to initiation of enrollment in Part 2. 
In Part 2, unblinded data will be provided to the IDMC to ensure halting rules are applied based 
on observations of events in the vaccine treatment groups, regardless of dose level. 
Additionally, ad hoc meetings will be convened if any predefined halting rules (see Section 6.1) 
are met, any serious vaccine related events or trends are observed, or the IDMC has concerns of 
potential vaccine enhanced disease (following the occurrence of a COVID-19, as defined in 
Section 7.1.1). 
Further details regarding data safety monitoring guidelines will be included in the IDMC 
Charter, which is the governing document that supersedes this section of the protocol. 
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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
9.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
−      Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations 
9.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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9.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
 
9.1.4. 
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 
volunteers of all races and ethnicities who meet the inclusion/exclusion criteria, regardless of 
religion, sex, or ethnic background. 
9.1.5. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
9.1.6. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be an integrated clinical and statistical report prepared according to the ICH E3 
guidelines. 
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Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
9.1.7. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain attributable, legible, contemporaneous, original, accurate, and 
complete documentation (source data) that supports the information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Details describing monitoring strategy (e.g., risk-based initiatives in operations and quality such 
as risk management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
review of the data. 
The Sponsor maintains ultimate responsibility for the quality and integrity of study data, even if 
study-related duties and functions are transferred to other individuals or organizations (e.g., 
contractors or contract research organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the Case Report Form (CRF) by authorized site personnel are attributable, legible, 
contemporaneous, original, accurate, and complete from source documents; that the safety and 
rights of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and applicable 
regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator per ICH-GCP and local regulations or institutional policies. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
9.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents should be generated utilizing good 
documentation practices and are filed at the Investigator’s site. 
Source documents are original documents, data, and records from which the participant’s CRF 
data are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
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previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
9.1.9. 
Publication Policy 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. Requests for publication of 
site specific data should be presented to the Sponsor for review and approval at least 90 days 
prior to submission for publication. 
 
 
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9.2. 
Appendix 2: Safety Clinical Laboratory Tests 
• The tests detailed in Table 8 will be performed by either the central testing laboratory 
or the local laboratory, unless otherwise specified. 
• All safety laboratories, hematology and serum chemistry are to be drawn by standard 
phlebotomy techniques, into the central lab provided tubes or the site prescribed 
appropriate tubes for the specific tests and amounts prescribed by local laboratory. 
Refer to the laboratory manual for further details on specimen collection and handling 
procedures. 
• Protocol-specific requirements for inclusion or exclusion of participant are detailed in 
Section 3.3 for Part 1 and Section 4.3 for Part 2 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 8 
Protocol-Required Safety Laboratory Assessments  
Test* 
Testing Panel/Analytes 
Hematology  
Hemoglobin, hematocrit, platelet count1, and complete white blood cell count 
Serum Chemistry  
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, BUN, creatinine, random glucose, potassium and sodium  
Coagulation Tests 
Tests for clotting parameters: PT/INR, aPTT and fibrinogen (performed as 
part of the safety laboratory testing at Screening) 
Urinalysis 
Protein, glucose ketones and hemoglobin 
Other laboratory 
assessments 
Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus antibody types 1 and 2 (Screening only) 
Urine drug screen 
Amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, 
opiates, methylenedioxymethamphetamine, phencyclidine, 
tetrahydrocannabinol 
Other laboratory 
assessments 
Female participants: Serum (screening) or urine pregnancy test, (human 
chorionic gonadotropin) 
*Refer to the Schedule of Activities for Part 1 (Table 3) and Part 2 (Table 4) to determine which 
safety laboratory assessments are required for each study phase and specific site visits. 
2  If platelets are abnormal, a normal NaCitrate platelet test is needed 
 
 
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9.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
9.3.1. 
Definition of TEAE (Unsolicited and Solicited) 
TEAE Definition 
• 
A TEAE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention, 
occurring after first dose of study drug. 
• 
NOTE: A TEAE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
 
Definition of Unsolicited and Solicited TEAE 
• 
Unsolicited TEAEs are any TEAEs reported spontaneously by the participant, observed by the 
study personnel during study visits or those identified during review of medical records or source 
documents. Unsolicited TEAEs (all TEAEs not collected in the Solicited Symptom Diary during 
the first week following each vaccination) will be monitored and collected from the time of each 
vaccination through 4 weeks post each vaccination (1st vaccination through Week 4 and 2nd 
vaccination through Week 8). 
• 
Solicited TEAEs are predefined systemic signs and symptoms of reactogenicity for which the 
participant is specifically questioned, and which are noted by the participant in their Solicited 
Symptom Diary, including: 
 fever (any temperature 100°F or higher) 
 headache 
 myalgia (muscle pain) 
 abdominal pain 
 anorexia (defined and not eating) 
 nausea 
 vomiting 
 diarrhea 
 malaise/fatigue 
Participants will utilize a Solicited Symptom Diary issued on the day of each vaccination to record 
solicited TEAE daily for the 1 week following each vaccination on Day 1 and Week 4. 
9.3.2. 
Definition of MAAE 
Medically Attended Adverse Events Definition 
MAAEs are defined as TEAEs with medically-attended visits including hospital, emergency room, 
urgent care clinic, or other visits to or from medical personnel for any reason. Routine study visits will 
not be considered medically-attended visits. New onset of chronic illness/diseases (NOCI) and AEs of 
Special Interest (AESIs) will be collected as part of the MAAEs. MAAEs are to be reported for all 
participants from the moment of vaccination until 12 months after the vaccination. Refer to Appendix 5 
(Section 9.5) for list of AESIs that should be monitored in this study. 
 
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Events Meeting the TEAE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study drug administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
TEAE or SAE if they fulfill the definition of TEAE or SAE. “Lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an TEAE or SAE. 
 
Events NOT Meeting the TEAE Definition 
• 
Events that occurred from consent to pretreatment 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
9.3.3. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was 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 
• 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
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An SAE is defined as any serious adverse event that, at any dose: 
4. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Is a suspected transmission of any infectious agent via a medicinal product 
7. Other situations: 
• 
Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations such as significant medical events that may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
o 
Examples of such events include invasive or malignant cancers, intensive treatment for allergic 
bronchospasm, blood dyscrasias, convulsions or development of intervention dependency or 
intervention abuse. 
9.3.4. 
Recording of TEAE, MAAE and/or SAE 
AE and SAE Recording 
• 
When a TEAE/MAAE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the 
event. 
• 
The investigator will then record all relevant TEAE/MAAE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
to the Sponsor in lieu of completion of the Sponsor required form. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to the Sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
9.3.4.1. 
Grading the Severity of TEAEs 
Assessment of Severity 
All TEAEs will be assessed by the investigator using a protocol-defined grading system. For events not 
included in the protocol-defined grading system, the following guidelines will be used to quantify 
severity: 
Mild:  events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
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Moderate:  events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
Severe:  events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating. 
Life threatening:  any adverse drug experience that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a 
reaction that had it occurred in a more severe form, might have caused death. 
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. Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
9.3.4.1.1. Grading of Solicited Treatment-Emergent Adverse Events 
Subjects should be instructed to rate solicited symptoms of reactogenicity that are collected 
within their Solicited Symptom Diary based on the severity scale presented in Table 9.  Grading 
should be reviewed with the participant at each site occurring through 1 week post each 
vaccination (Day 1 - Week 1 and Week 4 - Week 5).  
 
 
 
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Table 9 
Grading of Solicited Symptoms of Reactogenicity 
 
Symptom 
Grading 
Normal 
Mild 
Moderate 
Severe 
Life Threatening 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever 
(oral temp) 
< 100.4°F 
(< 38.0°C) 
100.4 – 101.1°F 
(38.0 – 38.4°C) 
101.2 – 102.0°F 
(38.5 – 38.9°C) 
102.1 – 104°F 
(39.0 – 40°C) 
> 104.0°F 
(>40°C) 
Headache 
None 
No interference with 
activity 
Repeated use of 
nonnarcotic pain 
reliever > 24 hours or 
some interference 
with activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
None 
Easily tolerated, 
causing minimal 
discomfort and does 
not interfere with 
everyday activitiesa 
Sufficiently 
discomforting to 
interfere with 
everyday activities 
Prevents normal 
everyday activities or 
requires medical 
advice 
ER visit or 
hospitalization 
Abdominal 
Pain 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Anorexia 
None 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Nausea/ 
Vomiting 
None 
No interference with 
activity or 1 to 2 
episodes/24 hours 
Some interference 
with activity or >2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
None 
2 to 3 loose stools or 
< 400 gms/24 hours 
4–5 stools or 400 
to 800 gms/24 hours 
6 or more watery stools 
or > 800gms/24 hours 
or requires outpatient 
IV hydration 
ER visit or 
hospitalization 
Malaise/ 
Fatigue 
None 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
a Everyday activities include attendance at work, school and usual habits of the participants. 
9.3.4.1.2. Grading of Laboratory Abnormalities 
 
Only abnormal labs that are clinically significant, per the judgement of the investigator, should 
be reported as treatment-emergent adverse events, which should be graded based on the clinical 
scenario. Further, the grading of these adverse events should be based on guidance provided in 
protocol Section 9.3.4.1 for events not included in the protocol-defined grading system. 
Tables 10 (serum chemistry), 11 (hematology) and 12 (urinalysis) present FDA toxicity grading 
information for vaccine studies, which include guidance to consider institutional normal ranges 
in determining lab toxicity grade. These ranges may be utilized by the Sponsor when evaluating 
any overall trends in lab abnormalities observed across study (sites and central labs) but should 
not be utilized when reporting clinically significant unsolicited AEs.  Only post-screening safety 
laboratory tests will have toxicity grades assessed in Part 1 analysis. Post-screening abnormal lab 
results with toxicity grade 3 or above that are not deemed clinically significant by the 
investigator and not captured as adverse events will be displayed separately in the clinical study 
report. 
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Table 10 
Grading of Laboratory Abnormalities (Serum Chemistry) 
Seruma 
Mild 
Moderate 
Severe 
Potentially Life 
Threatening 
(Grade 1) 
(Grade 2) 
(Grade 3) 
(Grade 4) 
Sodium – Hyponatremia mEq/L 
132 to 134 
130 to 131 
125 to 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 to 145 
146 to 147 
148 to 150 
> 150 
Potassium – Hyperkalemia mEq/L 
5.1 to 5.2 
5.3 to 5.4 
5.5 to 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 
3.5 to 3.6 
3.3 to 3.4 
3.1 to 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 
65 to 69 
55 to 64 
45 to 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
 
100 to 110 
110 to 125 
 
111 to 125 
126 to 200 
 
>125 
>200 
Insulin 
requirements or 
hyperosmolar coma 
BUN mg/dL 
23 to 26 
27 to 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 to 1.7 
1.8 to 2.0 
2.1 to 2.5 
> 2.5 or requires 
dialysis 
Calcium – hypocalcemia mg/dL 
8.0 to 8.4 
7.5 to 7.9 
7.0 to 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 to 11.0 
11.1 to 11.5 
11.6 to 12.0 
> 12.0 
Magnesium – hypomagnesemia 
mg/dL 
1.3 to 1.5 
1.1 to 1.2 
0.9 to 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 to 2.5 
2.0 to 2.2 
1.6 to 1.9 
< 1.6 
CPK – mg/dL 
1.25 to 1.5 x ULN 
1.6 to 3.0 x ULN 
3.1 to 10 x ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia g/dL 
2.8 to 3.1 
2.5 to 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 to 6.0 
5.0 to 5.4 
< 5.0 
-- 
Alkaline phosphate – increase by 
factor 
1.1 to 2.0 x ULN 
2.1 to 3.0 x ULN 
3.1 to 10 x ULN 
> 10 x ULN 
Liver Function Tests – ALT, AST 
increase by factor 
1.1 to 2.5 x ULN 
2.6 to 5.0 x ULN 
5.1 to 10 x ULN 
> 10 x ULN 
Bilirubin – when accompanied by 
any increase in Liver Function Test 
increase by factor 
1.1 to 1.25 x ULN 
1.26 to1.5 x ULN 1.51 to 1.75 x ULN
> 1.75 x ULN 
Bilirubin – when Liver Function 
Test is normal; increase by factor 
1.1 to 1.5 x ULN 
1.6 to 2.0 x 
ULN 
2.0 to 3.0 x 
ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 to 1.5 x ULN 
1.6 to 2.0 x 
ULN 
2.1 to 5.0 x 
ULN 
> 5.0 x ULN 
ULN = upper limit of normal 
a  The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. Refer to section 9.3.4.1.2. 
 
 
 
 
 
 
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Table 11 
Grading of Laboratory Abnormalities (Hematology) 
Hematologya 
Mild 
Moderate 
Severe 
Potentially Life 
Threatening 
(Grade 1) 
(Grade 2) 
(Grade 3) 
(Grade 4) 
Hemoglobin (Female), gm/dL 
11.0 to 12.0 
9.5 to 10.9 
8.0 to 9.4 
< 8.0 
Hemoglobin (Female) change 
from baseline value, gm/dL 
Any decrease to 
1.5 
1.6 to 2.0 
2.1 to 5.0 
> 5.0 
Hemoglobin (Male), gm/dL 
12.5 to 13.5 
10.5 to 12.4 
8.5 to 10.4 
< 8.5 
Hemoglobin (Male) change from 
baseline value, gm/dL 
Any decrease to 
1.5 
1.6 to 2.0 
2.1 to 5.0 
> 5.0 
WBC increase, cell/mm
3 
10,800 to 15,000 
15,001 to 20,000 
20,001 to 
25,000 
> 25,000 
WBC decrease, cell/mm
3 
2,500 to 3,500 
1,500 to 2,499 
1,000 to 1,499 
< 1,000 
Lymphocytes decrease, cell/mm
3 
750 to 1,000 
500 to 749 
250 to 499 
< 250 
Neutrophils decrease, cell/mm
3 
1,500 to 2,000 
1,000 to 1,499 
500 to 999 
< 500 
Eosinophils, cell/mm
3 
650 to 1500 
1501 to 5000 
> 5000 
Hypereosinophilic 
Platelets Decreased, cell/mm
3 
125,000 to 140,000 
100,000 to 
124,000 
25,000 to 
99,000 
< 25,000 
PT, increase by factor 
1.0 to 1.10 x ULN 
1.11 to 1.20 x 
ULN 
1.21 to 1.25 x 
ULN 
> 1.25 ULN 
PTT, increase by factor 
1.0 to 1.2 x ULN 
1.21 to 1.4 x ULN 
1.41 to 1.5 x 
ULN 
> 1.5 x ULN 
Fibrinogen increase, mg/dL 
400 to 500 
501 to 600 
> 600 
-- 
Fibrinogen decrease, mg/dL 
150 to 200 
125 to 149 
100 to 124 
< 100 or 
associated with 
gross bleeding 
or DIC 
DIC =  disseminated intravascular coagulation; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit 
of normal; WBC = white blood cell 
a  The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. Refer to section 9.3.4.1.2 
 
Table 12 
Grading of Laboratory Abnormalities (Urinalysis) 
Urine* 
Mild 
Moderate 
Severe 
Potentially Life Threatening 
(Grade 1) 
(Grade 2) 
(Grade 3) 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for hyperglycemia 
Blood (microscopic),  
red blood cells per 
high power field 
1 to 10 
11 to 50 
> 50 and/or 
gross blood 
Hospitalization or packed red blood 
cells transfusion 
a  The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. Refer to section 9.3.4.1.2 
 
 
 
 
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9.3.4.2. 
Assessment of Causality 
Assessment of Causality 
• 
For all solicited symptoms and unsolicited TEAEs, including SAEs and MAAEs, the Investigator 
will make a judgment regarding the relationship of the AE to the study vaccine. All TEAEs must 
be recorded in the source documents as well as eCRF. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each TEAE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the TEAE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial transmission 
of the SAE data to the Sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
The relationship of the AE to study vaccine administration will be specified as follows: 
Not related: 
In the Investigator’s opinion, there is no causal relationship between study 
vaccine administration and the TEAE; 
Possibly Related: 
The TEAE follows a reasonable temporal sequence from the time of study 
vaccine administration but there may be another equally likely explanation for 
the event (e.g., the participant’s clinical state or other medications); 
Probably Related: 
The TEAE follows a reasonable temporal sequence from the time of study 
vaccine administration and cannot be reasonably explained by the known 
characteristics of the participant’s clinical state; 
Definitely Related: 
The TEAE follows a known temporal sequence from the time of study vaccine 
administration, cannot be explained by other disease or medications and the 
event is an objective and specific medical disorder or a recognized 
pharmacological phenomenon. 
9.3.5. 
Reporting of SAEs and MAAEs 
SAE Reporting to Sponsor (or designee) via an Electronic Data Collection Tool. MAAEs should 
be reported to the Sponsor in a similar manner to SAEs. 
• 
The primary mechanism for reporting an SAE to the Sponsor (or designee) will be the electronic 
data collection tool. 
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SAE Reporting to Sponsor (or designee) via an Electronic Data Collection Tool. MAAEs should 
be reported to the Sponsor in a similar manner to SAEs. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) or to the Medical Monitor 
by telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
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9.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
9.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterilized (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. 
Premenarchal 
2. 
Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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9.4.2. 
Contraception Guidance 
Male Subjects: 
Male participants are eligible to participate if they agree to the following from informed consent 
through 60 days after the last dose of study drug 
• Refrain from donating sperm, except for the purpose of fertility analysis as part of 
this protocol 
PLUS: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier (a male condom)
Female Subjects: 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
− Is not a woman of childbearing potential (WOCBP) 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency (see table 
below), from consent through 60 days after the last dose of study drug, and agrees 
not to donate eggs (ova, oocytes) for the purpose of reproduction during this 
period. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study drug. 
− A WOCBP must have negative urine or serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) 
at extension enrollment visit before first administration of study drug in this study 
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. A reliable form of 
contraception must be approved by the Investigator (e.g., double barrier method, Depo-Provera, 
intrauterine device, Norplant, oral contraceptives, contraceptive patches). 
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Highly Effective Methodsa That Have Low User Dependency  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsa That Are User-Dependent  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.) 
a Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 
 
 
 
9.4.3. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant: 
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• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. 
• After obtaining the necessary signed ICF from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
Sponsor will attempt to follow the female partner to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. The Sponsor will follow the female partner until birth or termination of 
pregnancy when possible. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Subjects who become pregnant 
Any female participant who becomes pregnant while participating in the study will discontinue 
study drug or be withdrawn from the study. Additionally: 
• The investigator will collect pregnancy information, which will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the Sponsor. The participant will be followed 
until birth or termination of pregnancy. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study drug by the investigator will be reported to the Sponsor. While the investigator 
is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
 
 
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9.5. 
Appendix 5: Medically Attended Adverse Events (MAAEs) 
 
MAAEs are defined as TEAEs with medically-attended visits including hospital, emergency room, urgent 
care clinic, or other visits to or from medical personnel for any reason. New onset of chronic 
illness/diseases (NOCI) and AEs of Special Interest (AESIs) will be collected as part of the MAAEs. The 
following adverse events (AEs) for potential immune-mediated medical conditions as well as 
events associated with thrombosis and thrombocytopenia are AEs of special interest (AESIs) and 
include new onset of chronic illness (NOCIs). These events should be monitored for actively and 
reported to the Sponsor in an expedited manner as outlined in Section 9.3.5. 
Gastrointestinal disorders: 
Liver disorders: 
• 
Celiac disease 
• 
Autoimmune cholangitis 
• 
Crohn’s disease 
• 
Autoimmune Hepatitis 
• 
Ulcerative colitis 
• 
Primary biliary cirrhosis 
• 
Ulcerative proctitis 
• 
Primary sclerosing cholangitis 
Metabolic diseases: 
• 
Addison’s disease 
• 
Diabetes mellitus type 1 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave’s or Basedow’s disease 
Coagulopathy: 
• 
Acquired amegakaryocytic 
thrombocytopenia 
• 
Amegakaryocytic thrombocytopenia 
• 
Axillary vein thrombosis 
• 
Cavernous sinus thrombosis 
• 
Cerebral venous thrombosis 
• 
Deep vein thrombosis 
• 
Disseminated intravascular coagulation 
• 
Embolism venous 
• 
Hepatic vein thrombosis 
• 
Immune thrombocytopenia 
• 
Intracranial venous sinus thrombosis 
• 
Mesenteric vein thrombosis 
• 
Portal vein thrombosis 
• 
Pulmonary embolism 
• 
Pulmonary thrombosis 
• 
Pulmonary venous thrombosis 
• 
Severe fever with thrombocytopenia 
syndrome 
• 
Subclavian vein thrombosis 
• 
Thrombocytopenia 
• 
Thrombocytopenia purpura 
• 
Thrombotic thrombocytopenia purpura 
• 
Thrombosis 
• 
Transverse sinus thrombosis 
• 
Vena cava embolism 
• 
Vena cava thrombosis 
• 
Venous thrombosis 
Musculoskeletal disorders: 
• 
Antisynthetase syndrome 
• 
Polymyalgia rheumatic 
• 
Dermatomyosotis 
• 
Polymyositis 
• 
Juvenile chronic arthritis (including Still’s 
disease) 
• 
Psoriatic arthropathy 
• 
Mixed connective tissue disorder 
• 
Relapsing polychondritis 
• 
Scleroderma, including diffuse systemic 
form and CREST Syndrome 
• 
Rheumatoid arthritis 
• 
Systemic lupus erythematous  
• 
Systemic sclerosis  
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• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s Syndrome) and 
undifferentiated spondyloarthritis. 
Neuroinflammatory disorders: 
• 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non-infections encephalitis, 
encephalomyelitis, myelitis, myeloradiculomyelitis)  
• 
Immune related peripheral neuropathies and plexopathies, including chronic inflammatory demyelinating 
polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal 
gammopathy 
• 
Cranial nerve disorders, including 
paralysis/paresis (e.g., Bell’s palsy) 
• 
Guillain-Barre syndrome, including Miller Fisher 
syndrome and other variants 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse Myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders: 
• 
Autoimmune bullous skin diseases 
(including pemphigus, pemphigoid and 
dermatitis herpetiformis 
• 
Rosacea 
• 
Alopecia aerate 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Psoriasis 
• 
Morphoea 
• 
Sweet’s syndrome 
• 
Lichen planus 
• 
Vitiligo 
Vasculitis: 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu’s arteritis and temporal arteritis 
• 
Medium sized/and or small vessels vasculitis including: polyarthritis nodosa, Kawasaki’s disease, 
microscopic polyangiitis, Wegener’s granulomatosis, Churg-Strauss syndrome (allergic granulomatous 
angititis), Buerger’s disease thromboangitis obliterans), nerotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet’s 
syndrome, leulocytoclassic vasculitis 
Others: 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, membranaoprolifative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune hemolytic anemia 
• 
Raynaud’ phenomenon 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Autoimmune thrombocytopenia 
• 
Sjogren’s syndrome 
• 
Goodpasture syndrome 
• 
Stevens-Johnson Syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Uveitis 
 
 
 
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9.6. 
Appendix 6: Abbreviations 
Term 
Description 
Ab 
Antibody 
ACE2 
Angiotensin-converting enzyme 2 
Ad5 
Adenovirus type 5 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMI 
Acute myocardial infarction 
ARDS 
Acute respiratory distress syndrome 
ARU 
Attack rate in unvaccinated 
ASC 
Antibody secreting cells 
AST 
Aspartate aminotransferase 
BiPAP 
Bi-level positive airway pressure 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention 
CFR 
Case fatality rate 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences  
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease 2019 
CPAP 
Continuous positive air pressure 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group  
Cytof 
Mass Cytometry 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
DP 
Drug product 
dsRNA 
Double-stranded RNA 
DVT 
Deep vein thrombosis 
E 
Envelope 
ECMO 
Extracorporeal membrane oxygenation  
eCRF 
Electronic case report form 
EOS 
End of Study 
ET 
Early Termination 
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FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practices 
GI 
Gastrointestinal 
GMC 
Geometric mean concentration 
GMFR 
Geometric mean fold rise 
GMP 
Good manufacturing practice 
GMT 
Geometric mean titer 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICC 
Intracellular cytokine cytometry 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IU 
International units 
LRTI 
Lower respiratory tract infection 
M 
Membrane 
MAAE 
Medically attended adverse event 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MSD 
Mesoscale Discovery 
N 
Nucleocapsid 
NCS 
No clinical significance 
NIPPV 
Non-invasive positive pressure ventilation 
NIV 
Non-invasive ventilation 
NP 
Nasopharyngeal 
NOCI 
New Onset of Chronic Illness 
PaO2 
Partial pressure of oxygen 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
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PE 
Pulmonary embolism 
PF4 Antibody ELISA 
Platelet Factor 4 antibody ELISA 
aPPT 
Partial Thromboplastin Time  
PT/INR 
Prothrombin time and international normalized ratio 
rAd5 
Recombinant adenovirus serotype 5 
RBD 
Receptor binding domain 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcription polymerase chain reaction 
RTSM 
Randomization and Trial Supply Management  
S 
Spike 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS  
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure  
SpO2 
Peripheral hemoglobin oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction  
TEAE 
Treatment-emergent adverse event 
TLR3 
Toll-like receptor 3 
TTS 
Thrombolytic and thrombocytopenic syndrome 
U.S. 
United States 
VAAST™ 
Vector adjuvant antigen standard technology 
VAED 
Vaccine-associated enhanced disease  
VE 
Vaccine efficacy 
WOCBP 
Women of childbearing potential  
 
  
 
 
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9.7. 
Appendix 7: Summary of Changes to Protocol 
 
  PROTOCOL VXA-COV2-101 HISTORY: 
  Document  
 Date  
Protocol Amendment 4, Version 5.0  
04 August 2022 
Protocol Amendment 3, Version 4.0 
 09 November 2021 
Protocol Amendment 2, Version 3.0 
 17 August 2021 
Protocol Amendment 1; Version 2.0  
06 July 2021 
Original Protocol; Version 1.0  
27 May 2021 
 
VXA -COV2-201 Protocol Amendment 4 (Vers. 5.0) 04 August 2022 
The changes incorporated into Amendment 4 are all of the clarifications that were noted and 
instructed to sites to perform during the conduct of the part 1 of the trial.  The protocol has been 
amended to include the following; 
Clarification that for subjects with suspected COVID-19 illness or exposure during the study 
period (Section 7.1.1): 
a. Any FDA Authorized rapid molecular test (e.g. LUCIRA COVID-19 Test) can be 
used for home or on-site testing for monitoring COVID-19 infection  
b. The duration of q2day testing post confirmed SARS-CoV-2 infection should end after 
10 days if still testing positive at that time  
2. Add an onsite rapid molecular COVID-19 Test at Day 1 and 29 Visits, prior to study vaccine 
administration. This testing is needed given the high rates of COVID-19 being observed at 
clinical sites with the spread of the Omicron variant. 
 3. Clarify that all women who participate in the study should have a pregnancy test at Screening 
(serum) and Days 1 and 29 pre-dose (urine). Currently the protocol is inconsistent with the 
requirement across different sections. 
 4. Clarify that for subjects in the higher range of BMI (30 – 32), investigators must ensure that 
these subjects do not have any additional risk factors for severe COVID-19, per the CDC’s 
guidelines, as listed under exclusion criterion #3 in Section 3.3.2. The higher risk to subjects 
with BMI of 30 – 32 will also be added to the ICF. This clarification was requested by the FDA 
per their review of the current version of the protocol (Amendment 3). 
 5. Clarify that abnormal lab values should be graded using the site’s testing lab reference range 
for guidance, whether local or central. Only abnormal labs that are clinically significant, per the 
judgement of the investigator, should be reported as treatment-emergent adverse events, which 
should be graded based on the clinical scenario. Further, the grading of these adverse events 
should be based on guidance provided in protocol Section 9.3.4.1 – Grading the Severity of 
TEAEs 
 
 
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Additional minor changes have also been incorporated for added clarity and consistency. A 
description of the changes as well as well as a brief rationale for each is presented within the 
table below. 
 
Section No. & Title 
Description of Change  
Brief Rationale 
1.1 Synopsis Part 1 and 
part 2 
3.1 Part 1 Objectives 
and Endpoints 
Secondary endpoints, key 
immunogenictiy endpoints (Antibody 
secreting cells (ASC) IgG in peripheral 
blood mononuclear cells (PBMCs) 
removed 
To align and reflect with the 
assessments that were actually 
collected and the SAP. 
 
Additional immunogenicity endpoints 
(Immunophenotyping by Flow or Mass 
Cytometry (Cytof) removed 
To clarify the additional 
immunogenicity samples collected 
Overall Study Design 
8.5.2 IDMC 
Independent Data Monitoring 
Committee table 1 revised  
Language revised to align with the 
IDMC meeting for part 1  
3.2.3 Part 1: Scientific 
Rational for Study 
Design 
8.1 Sample Size 
Determination 
High dose cohorts removed for the 
elderly population  
Planned sample size decreased from 96 
to 72.  Each cohort size was decrease 
to 36 instead of 48 
Enrollment goals adjusted to 
account for challenges in recruiting 
appropriate vaccine- and covid 
infection- naïve subjects for the last 
cohorts. Data collected without this 
group is felt to be adequate for 
informing future Part 2 dosing. 
3.2.2 Part 1: Eligibility 
for Second Vaccination Presence of acute illness or significant 
new medical condition” added |” 
including positive SARS-COV-2 
rapid molecular test prior to dosing” 
 
Added to align with clarification 
memo issued to sites 
 
The duration of q2day testing post 
confirmed SARS-CoV-2 infection 
should end after 10 days if still testing 
positive at that time. Any FDA 
Authorized rapid molecular test (e.g. 
LUCIRA COVID-19 Test) can be used 
for home or on-site testing for 
monitoring COVID-19 infection  
Added to align with clarification 
memo issued to sites 
1.2 Schedule of 
Activities 
Pregnancy Testing- Pregnancy testing 
should include serum hCG at screening. Sites 
should confirm negative urine pregnancy test 
for all women on Days 1 and 29 prior to 
dosing  
Clarifying that all women (not just 
WOCBP) should be tested. 
3.2.2 Part 1: Eligibility 
for Second Vaccination 
SARS=CoV-2 Rapid Molecular Test 
added 
Added to confirm that rapid 
molecular test to be used only for 
home or on-site testing for 
monitoring COVID-19 infection 
refer to section 7.1.1 
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7.1 Efficacy and 
Immunogenicity 
Assessments 
 
 
Immunophenotyping by Flow or Cytof 
removed  
To Clarify and specify fixed whole 
blood which includes the 
immunophenotyping  
 
Optional added to the Anti Ad5 
antibodies (serum) 
To align with clarification memo 
issued to sites 
3.2.2 Part 1: Eligibility 
for Second Vaccination 
Participants with confirmed SARS-
CoV-2 infection, at any time during 
the study period will be asked to 
provide a nasal swab sample every two 
days after their confirmatory COVID-
19 test, until they test negative, to 
monitor for duration of infection. The 
duration of q2day testing post 
confirmed SARS-CoV-2 infection 
should end after 10 days if still testing 
positive at that time. Any FDA 
Authorized rapid molecular test (e.g. 
LUCIRA COVID-19 Test) can be used 
for home or on-site testing for 
monitoring COVID-19 infection 
Updated to align with clarification 
memo 
3.3 Eligibility Criteria 
Eligibility criterion #6 Body mass 
index (BMI) between 17 and 32 kg/m2 
at screening. Investigators must ensure 
subjects with BMI between 30-32 do 
not have any additional risk factors for 
severe COVID-19, per the CDCs 
guidelines as listed under exclusion 
criteria #3. 
 
Clarification of the eligibility 
criteria to sites 
7.2.3 Clinical Safety 
Laboratory 
Only abnormal labs that are clinically 
significant, per the judgement of the 
investigator, should be reported as 
treatment-emergent adverse events, 
which should be graded based on the 
clinical scenario. Further, the grading 
of these adverse events should be 
based on guidance provided in 
protocol Section 9.3.4.1 for events not 
included in the protocol-defined 
grading system.– Grading the Severity 
of TEAEs, 
 
 
Post-screening abnormal lab results 
with toxicity grade 3 or above that are 
 
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deemed not clinically significant by 
the investigator and not captured as 
adverse events will be included 
separately in the clinical study report.   
 
Pregnancy testing should include 
serum hHCG may be utilized at 
screening. Negative urine pregnancy 
test should be confirmed on Days 1 
and 29 prior to dosing., per the 
discretion of the Investigator. 
Added to incorporate clarification 
memo language. 
8.3.1 Statistical Analysis • The following were removed from 
the Secondary Immunogenicity 
Endpoints;                                     
Antibody secreting cells (ASC) IgG 
and IgA, in peripheral blood 
mononuclear cells (PBMCs) 
• Additional Endpoint 
Immunophenotyping by Flow or 
Mass Cytometry (Cytof ) 
• 
Language update to reflect S binding 
IgG and IgA levels along with other 
antigens will be provided by the 
treatment groups. 
• 
Timepoints for the Additional 
Endpoints are updated to reflect that 
Months 7 and 13 as optional 
GMRs and ASC response were removed 
To align with secondary endpoints 
collected during the trial 
9.3.4.1.2 Grading 
Laboratory 
Abnormalities 
Only abnormal labs that are clinically 
significant, per the judgement of the 
investigator, should be reported as 
treatment-emergent adverse events, 
which should be graded based on the 
clinical scenario. Further, the grading 
of these adverse events should be 
based on guidance provided in 
protocol Section 9.3.4.1 for events not 
included in the protocol-defined 
grading system. 
Tables 10 (serum chemistry), 11 
(hematology) and 12 (urinalysis) 
present FDA toxicity grading 
information for vaccine studies, which 
include guidance to consider 
institutional normal ranges in 
determining lab toxicity grade.  For 
safety analysis, lab abnormalities will 
Further clarification of abnormal 
lab toxicity grading and clinically 
significant lab-related adverse event 
severity grading  
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be graded by these tables while using 
the site’s testing lab reference range 
for guidance, whether local or 
central.  Only post-screening safety 
laboratory tests will have toxicity 
grades assessed in Part 1 
analysis. Post-screening abnormal lab 
results with toxicity grade 3 or above 
that are not deemed clinically 
significant by the investigator and not 
captured as adverse events will be 
included separately in the clinical 
study report. 
 
9.5 
MAAEs are defined as TEAEs with 
medically-attended visits including 
hospital, emergency room, urgent care 
clinic, or other visits to or from 
medical personnel for any reason. New 
onset of chronic illness/diseases 
(NOCI) and AEs of Special Interest 
(AESIs) will be collected as part of the 
MAAEs   
Clarification to the MAAEs 
definition 
 
VXA-COV2-201 Protocol Amendment 3 (Vers. 4.0), 09 November 2021 
The changes incorporated into Amendment 3 are following the initiation of enrollment under the 
prior VXA-COV2-201 Amendment 2 (Vers. 3).  The modifications made were based on 
learnings from screening / enrollment activities and feedback from clinical sites. As the 
percentage of the adult population receiving vaccines against COVID-19, both primary and boost 
doses, continues to rise, the availability of suitable vaccine naïve subjects continues to decrease.  
The Sponsor has reviewed the eligibility criteria with site investigators and the study Medical 
Monitors and implemented modifications with the intent to aid in enrollment of eligible subjects 
without impacting subject safety. These modifications are summarized in the table below. 
 
 Additional minor changes have also been incorporated for added clarity and consistency. A 
description of the changes as well as well as a brief rationale for each is presented within the 
table below. 
 
Section No. & Title 
Description of Change  
Brief Rationale 
Schedule of 
Activities (Table 3 
and 4) 
Clarified that the SARS-CoV-2 rapid 
Ab test is only for required for naïve 
subjects that are being screened for 
participation in Cohort 1 (no prior 
vaccination against SARS-CoV-2 
infection and no history of prior 
COVID-19 or SARS-CoV-2 infection). 
The rapid Ab test to determine prior exposure 
to SARS-CoV-2 is only needed to confirm 
eligibility within Cohort 1 (vaccine and 
COVID-19 naïve subjects). The schedule of 
activities did not clarify that this test was not 
needed in the prior vaccinated subjects to be 
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enrolled within Cohort 2. This point has been 
clarified within the current amendment. 
Section 3.3.1 
(Inclusion Criteria), 
Appendix 2: Safety 
Clinical Laboratory 
Tests (Table 8)  
Safety labs testing panels have been 
modified to be more clinically relevant 
and applicable for the study population.
 
Serum Chemistry will include ALT, 
AST, total bilirubin, BUN, creatinine, 
random glucose, potassium and 
sodium. 
 
Urinalysis will include protein, glucose 
ketones and hemoglobin 
 
Coagulation Tests at screening will 
include PT/INR, APTT and fibrinogen 
The general safety lab panel within the prior 
amendment included analytes that were not 
deemed clinically significant to evaluate for the 
healthy subject population being enrolled in the 
study. The extra tests were leading to long 
turnaround times and the need for repeat tests 
for clinically insignificant results.  Therefore, 
the testing panel was reviewed by the medical 
monitors and revised for added trial efficiency.  
Sections 3.3.1 and 
4.3.1 (Inclusion 
Criteria) 
 
Modified the eligibility criterion for 
BMI from between 17 - 30 kg/m2 to 
between 17 - 32 kg/m2 at screening 
BMIs above 30 kg/m2 was the prime reason for 
screen failures observed in the study to date. 
The Study Medical Monitors reviewed the data 
and concluded that subjects with a BMI slightly 
higher than 30 kg/m2 were presenting in 
otherwise good health without additional risk 
factors of developing severe COVID if they 
were to contract COVID-19 during the study 
period. Therefore, the recommendation to 
slightly broaden the BMI range was proposed.  
Investigators will be advised to closely 
evaluate subjects with BMI values between 30 
– 32 kg/m2 for comorbidities prior to 
enrollment to ensure they are appropriate for 
study participation.  
Section 3.3.2: Part 1 
Exclusion Criteria 
The exclusion for occult blood, via 
collection and testing of a stool sample, 
has been removed from the screening 
assessments. A new exclusion criterion 
of history of gastrointestinal (GI) 
bleeding (melena or hematochezia) has 
been added. 
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. 
Section 3.3.2: Part 1 
Exclusion Criteria 
Exclusion criterion #11 has removed 
“any prescriptive medications for the 
prevention of COVID-19 ” language, 
and the updated exclusion will read 
“Use of antiviral medications or anti-
retrovirals within 1 week before 
vaccination or planned use during the 
active study period.” The exclusion of 
prior medications (prevention and 
treatment) for COVID-19 is explained 
within exclusion criterion #2. 
This change has been implemented for 
increased clarity and consistency. 
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Section 8.3 
Statistical analysis 
Within this section the reporting of 
AEs using a 3-tier classification 
approach has been removed. 
All TEAEs will be presenting in listings and 
tables by treatment group, severity, relationship 
and impact on study drug administration.  The 
tiering approached may be used in later stage 
trials where there is more data if what events 
are expected with the VXA-CoV2-1.1-S 
vaccine. 
 
 
 
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VXA-COV2-201 Protocol Amendment 2 (Vers. 3.0), 17 August 2021 
 
Overall Rationale for the Amendment:  
 
Recent advances in Vaxart’s manufacturing process indicate that the per tablet potency (I.U. 
content) for upcoming GMP drug product lots of the VXA-CoV2-1.1-S vaccine will be in the 
range of 1 to 2x1010 I.U/tablet. Since the protocol defines a low dose of 1x1010 ± 0.5 log I.U., the 
difference from a medium dose of 3x1010 I.U would not be significantly different or as 
informative as previously anticipated with a lower I.U per tablet DP lot yield. Therefore, the 
protocol has been modified to remove the mid dose and include just two dose levels: the low 
dose (a single tablet dose) and the higher dose, which will be composed of multiple tablets to 
deliver a 1x1011 I.U. dose. As there is prior clinical experience with doses up to 5x1010 I.U. with 
a prior COVID-19 oral vaccine candidate (VXA-CoV2-1 under Protocol VXA-COV2-101), and 
with repeat doses of up to 1x1011 I.U. in multiple trials with other Vaxart oral Ad5 tableted 
vaccines, removal of the mid dose will allow the trial to progress to Part 2 more efficiently 
without adding undue safety risk. Ongoing oversight and data reviews between cohorts by the 
IDMC will further ensure a safe progression from the low dose to the high dose vaccine for each 
age group. 
 
Another key change incorporated into Amendment 2 is the inclusion of participants that have 
received prior vaccinations with an mRNA vaccine for the prevention of COVID-19. These 
subjects (N=48) will be enrolled within Cohort 2 and mirror the 4 subgroups (low and high dose 
in younger and older adults) that will be enrolled in Cohort 1, the COVID-19 and vaccine naïve 
participants. Adding in the prior exposed subjects will allow the collection of safety and 
immunogenicity data in this population in an expeditious manner.   
 
 Additional changes have also been incorporated for added clarity and consistency. The changes 
are presented within the table below in the order of initial appearance within the document:   
 
Section No. & Title 
Description of Change  
Brief Rationale 
1.1 Synopsis 
2.1 Study Rationale 
3.2 Part 1 Study 
Design 
7.1 Efficacy and 
Immunogenicity 
Assessments 
8. Statistical 
Determination 
 
 
The protocol design for Part 1 has 
been modified to remove the two 
medium dose (3x1010 I.U.) cohorts in 
naïve subjects.  Additionally, 4 
cohorts have been added to include 
enrollment of subjects that have 
received prior vaccinations with an 
EUA or FDA approved mRNA 
vaccine.  Therefore, the total Part 1 
enrollment has increased from 72 to 
96 total participants. 
As the single tablet I.U. is expected to be a slightly 
higher than 1x1010 I.U., the nominal low dose will 
comprise of a single tablet of 1x1010 ± 0.5 log I.U. 
Therefore, the protocol has been modified to 
remove the medium dose of 3x1010 ± 0.5 log I.U.   
as this would not be meaningfully different than 
the low dose and not yield useful information.  
Cohort 2 (N=48) had been added to evaluate the 
vaccine’s ability to boost immune responses in 
prior vaccinated persons. Dose and age escalation 
will be conducted in a stepwise manner with 
IDMC review of reactogenicity/safety data 
between cohorts. 
1.1 Synopsis 
2.1 Study Rationale 
Language has been added to clarify 
that data from Part 1 will be 
submitted to FDA for review prior to 
initiation of Part 2. 
This Part 1 data review was added based on 
feedback received from FDA on the initial IND 
submission.  The Part 1 safety and early 
immunogenicity data provided to the IDMC, and 
the rationale for the proposed dose for Part 2, will 
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be submitted to FDA for review and consensus 
before initiation of enrollment under Part 2. 
1.1 Synopsis 
4.3 Part 2 
Objectives and 
Endpoints 
8.3 Statistical 
Analyses 
 
The secondary endpoint for 
evaluation for long term safety was 
added as a separate endpoint in Part 
2: Frequency, duration, and severity 
of all SAEs, and MAAEs including 
monitoring for COVID-19, VAED, 
AESIs and NOCIs through one year 
post last dose. 
Though the prior version of the protocol also 
monitored safety through the safety follow-up 
period, this endpoint was inadvertently omitted for 
Part 2 in prior versions of the protocol. This 
inconsistency has been corrected in the current 
version. 
1.2 Schedule of 
Events 
Note added to clarify that 
coagulation tests will be part of the 
screening safety laboratory tests  
Incorporated to add clarity to the schedule of 
events.  Did not impact study conduct from prior 
version of the protocol. 
2.2 Background 
The figures for COVID-19 infections 
and deaths have been updated. 
Information modified to current rates to provide 
more undated information within protocol. 
3.3 Part 1 
Eligibility 
Eligibility criteria for type of 
participant modified into 2 separate 
criteria for Cohort 1 (naïve) and 
Cohort 2 (prior vaccinated). 
Cohort 1 ONLY –  
Naive of any prior vaccination for 
the prevention of COVID-19 (tested 
using a rapid antibody test) at 
screening and within 7 days prior to 
the enrollment (Day 1). 
Cohort 2 ONLY –  
Have received prior immunizations 
(both doses) with an EUA or FDA 
approved mRNA vaccine for the 
prevention of COVID-19, at least 6 
months prior to enrollment (Day 1).  
Exclusion criterion #2 has been 
modified to allow subjects with 
prior vaccinations in Cohort 2. 
Modification incorporated to accommodate 
enrollment of Cohort 2 subjects with prior 
vaccinations with an mRNA vaccine. 
3.2 Part 1 Study 
Design 
7.2 Safety 
Assessments 
Protocol language has been modified 
to clarify that any subjects who 
experience COVID-19 will also be 
monitored for potential vaccine-
associated enhanced disease (VAED) 
 
8.3.1 Part 1 Lead-in 
Phase 
The method for categorization of 
AEs under the primary safety 
endpoint was clarified to remove 
errors in last protocol version. 
A description of the approach for 
evaluating ASC Responses was 
added under Secondary Endpoints. 
The prior protocol included language on analysis 
of AEs between active and placebo groups, which 
was not pertinent to Part 1, the open-label portion 
of the trial. Erroneous wording was removed from 
the Part 1 statistical sections within the protocol.  
 
ASC response analysis information was 
inadvertently left out of prior versions of the 
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protocol; it has been added for completeness and 
clarity. 
8.4 Interim 
Analysis 
A sentence has been added to clarify 
that for Part 1, following completion 
of the Active Period by all Cohorts, 
the database will be cleaned and 
locked. 
 
Information added for sake of completeness and 
clarity. 
Appendix 2: Safety 
Clinical Laboratory 
Tests 
Coagulation Tests have been listed 
out as separately from the Serum 
Chemistry Tests 
Modification incorporated to increase clarity in lab 
testing schedule for Part 1. No change in testing 
schedule made from prior protocol version. 
 
 
VXA-COV2-201 Protocol Amendment 1 (Vers. 2.0), 06 July 2021 
 
Overall Rationale for the Amendment:  
 
Per the request of the FDA, Vaxart has amended this clinical protocol to incorporate information 
on the risk of Thrombosis with Thrombocytopenia Syndrome (TTS) that has been reported with 
administration of two injected adenovirus-vectored COVID-19 vaccines being used under EUA. 
The eligibility criteria within this protocol have been modified to screen for and exclude 
individuals at high risk of TTS from study participation.   
 
Additionally, the study Halting Rules have been modified to clarify that they are applicable to 
the observance of similar AEs and not just identical AEs, and also to clarify that they are 
applicable during the entire study period, not just the 7 days post each vaccination.   
 
Additional changes have also been incorporated for added clarity and consistency. The changes 
are presented within the table below in the order of initial appearance within the document:   
 
Section No. & Title 
Description of Change  
Brief Rationale 
1.2 Synopsis 
 
 
8.5.2 Independent 
Data Monitoring 
Committee (IDMC) 
The criteria for advancing from study Part 1 
to Part 2 have been modified to include an 
FDA review of preliminary Part 1 summary 
safety and immunogenicity information, and 
the Agency’s agreement on the proposed 
approach prior to initiation of Part 2 
enrollment. 
As the specific criteria for advancing from 
Part 1 to Part 2 are not well defined within 
the protocol, FDA has offered this 
approach as a path that allows gaining 
timely consensus on the best path forward 
from Part 1 to Part 2 of the study. 
1.1 Synopsis 
 
3.2.2. Part 1: 
Eligibility for 
Second Vaccine 
 
4.2.2 Part 2: 
Eligibility for 
Second Dose of 
Study Drug 
The assessments and criteria that participants 
must meet at Week 4 to be eligible to receive 
their second vaccination/study drug 
administration has been described in 
additional detail for both Part 1 and Part 2. 
 
Exclusion Criteria for Second Vaccine Dose: 
• Positive pregnancy test at Day 29 (female 
participants), 
• Occurrence of any possibly, probably or 
definitely treatment-related Grade 3 or 4 AE 
or SAE following the initial vaccination  
The additional detail regarding eligibility 
for the second dose was incorporated at 
the request of FDA.   
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• Occurrence of any Grade 3 or 4 AE or SAE 
following the initial vaccination without 
plausible alternative explanation 
• 
Presence of acute illness or significant new 
medical condition  
 
Tables 3 and 4: 
Schedule of Events, 
Part 1 and Part 2, 
respectively 
 
Tables 3 and 4 have been updated to include 
allocation of an aliquot of serum collected at 
baseline to be stored for testing (e.g. PF4 
antibody ELISA) should an AESI related to 
blood clots be reported anytime during the 
study period. 
 
Per the direction of the FDA, a blood 
sample will be collected at baseline and 
stored for analysis should a participant 
experience a clotting adverse event. 
2.3.1 Risk 
Assessment 
The risk section has been updated to include 
language describing the AEs reported with 
two injected adenovirus-vectored vaccines 
(thromboembolism and/or 
thrombocytopenia), as well as with general 
information on how to monitor for and 
report the events should they occur in study 
participants. 
Because Vaxart’s VXA-CoV2-1 
investigational vaccine utilizes an 
adenovirus vectored design, and per the 
director of the FDA, information on the 
risks of thromboembolism and /or 
thrombocytopenia have been added to 
Section 2.3.1 of the protocol. 
3.3 Part 1 
Eligibility 
4.3 Part 2 
Eligibility 
Table 9: Protocol-
Required Safety 
Laboratory 
Assessments 
The eligibility criteria for both Part 1 and 
Part 2 have been modified to provide more 
granular information on abnormal tests, 
medical history and current conditions 
which are exclusionary due to potential risk 
of TTS. 
 
Safety Laboratory tests that may be 
utilized to identify the potential for 
higher risk of TTS, as well as 
assessments of medical history and 
current medical conditions have been 
added to the study protocol under 
Amendment 1 to mitigate potential risks 
with Ad vaccines and TTS. 
3.3 Part 1 
Eligibility 
 
4.3 Part 2 
Eligibility 
The eligibility criteria for both Part 1 and 
Part 2 have been modified to provide 
additional clarify those females who are 
breast-feeding are ineligible for study 
participation. 
 
Though the breast-feeding exclusion was 
already present within the original 
protocol, it was described somewhat 
inconsistently at places.  Per the request 
of FDA, this exclusionary criterion has 
been described more consistently 
throughout the revised protocol. 
6.1. Study Halting 
Rules 
 
 
The Halting Rules for both Part 1 and Part 2 
have been updated to clarify that the rules 
are applicable to the observance of similar 
AEs (not just the same AEs) that are 
deemed as possibly, probably or definitely 
not related. 
The additional detail regarding the 
Halting Rules was incorporated at the 
request of FDA.   
9.1.3 Informed 
Consent Process 
Wording in Section 9.1.3 indicating that a 
separate ICF would be utilized to collect 
consent for exploratory endpoint analyses 
has been removed. 
As the evaluation of a wide range of 
exploratory assays is key to 
understanding the mechanism of action 
for Vaxart’s oral vaccine candidates, 
enrollment will be focused on those 
participants that are willing to provide 
samples for exploratory assays.  
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9.5. Appendix 5: 
Medically Attended 
Adverse Events 
The List of Medically Attended Adverse 
Events (MAAEs) including AEs of special 
interest has been updated to include events 
to be monitored under the category of 
Coagulopathy 
 
Per the guidance of the FDA, the list of 
MAAEs of special interest have been 
updated to allow sites to monitor study 
participants for the occurrence of TTS 
events. 
 
 
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10. 
REFERENCES 
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