Phase 2 Clinical Trial to Optimize Immune Coverage of SARS-CoV-2 Existing and Emerging Variants
Phase: PHASE2
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
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Phase 2 Clinical Trial to Optimize Immune Coverage of SARS-CoV-2 Existing and 
Emerging Variants 
 
COVID-19 VAriant Immunologic Landscape Trial 
(COVAIL Trial) 
 
DMID Protocol Number: 22-0004 
 
IND Sponsor: Division of Microbiology and Infectious Diseases (DMID) 
 
Version Number: 5.0 
 
21 September 2022 
 
 

 
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STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federal wide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB)/Independent or Institutional Ethics Committee (IEC) must be 
registered with OHRP as applicable to the research. 
 
The study will be carried out in accordance with the following as applicable: 
• United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (IRBs), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New Drug 
Application), and/or 21 CFR 812 (Investigational Device Exemptions) 
• The International Council for Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice 
(GCP), and the Belmont Report: Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research, Report of the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research 
• The policies and procedures of National Institutes of Health (NIH) Office of Extramural 
Research and Division of Microbiology and Infectious Diseases (DMID) 
• The National Institute of Allergy and Infectious Diseases (NIAID) Terms of Award 
• Any additional Federal, State, and Local Regulations and Guidance 
 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol, including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Name, Credentials 
Title 
 
 
 

 
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TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ........................................................................................................................ 8 
1. 
PROTOCOL SUMMARY ...................................................................................................... 9 
1.1 
Synopsis .......................................................................................................................... 9 
1.2 
Schedule of Activities (SOA) ....................................................................................... 15 
2. 
INTRODUCTION ................................................................................................................ 20 
2.1 
Background and Study Rationale.................................................................................. 20 
2.1.1 
Public Readiness and Emergency Preparedness Act ............................................ 23 
2.2 
Risk/Benefit Assessment .............................................................................................. 24 
2.2.1 
Known Potential Risks .......................................................................................... 24 
2.2.2 
Known Potential Benefits ..................................................................................... 28 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 30 
4. 
STUDY DESIGN.................................................................................................................. 32 
4.1 
Overall Design .............................................................................................................. 32 
4.2 
Scientific Rationale for Study Design........................................................................... 32 
4.3 
Justification for Doses................................................................................................... 33 
5. 
STUDY POPULATION ....................................................................................................... 34 
5.1 
Inclusion Criteria .......................................................................................................... 34 
5.2 
Exclusion Criteria ......................................................................................................... 34 
5.2.1 
Exclusion of specific populations ......................................................................... 34 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 34 
5.4 
Lifestyle Considerations ............................................................................................... 34 
5.5 
Screen Failures .............................................................................................................. 35 
5.5.1 
Strategies for Recruitment and Retention ............................................................. 35 
5.5.2 
Retention ............................................................................................................... 35 
5.5.3 
Compensation Plan for Subjects ........................................................................... 35 

 
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5.5.4 
Costs ...................................................................................................................... 35 
6. 
STUDY PRODUCT.............................................................................................................. 36 
6.1 
Study Product(s) and Administration............................................................................ 36 
6.1.1 
Study Product Description .................................................................................... 36 
6.1.2 
Dosing and Administration ................................................................................... 37 
6.1.3 
Dose Modifications ............................................................................................... 38 
6.2 
Accountability/Handling/Storage/Preparation .............................................................. 38 
6.2.1 
Acquisition and Accountability ............................................................................ 38 
6.2.2 
Formulation and Appearance ................................................................................ 39 
6.2.3 
Product Storage and Stability................................................................................ 39 
6.2.4 
Preparation ............................................................................................................ 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 40 
6.3.1 
Treatment Assignment Procedures ....................................................................... 40 
6.3.2 
Randomization and Blinding ................................................................................ 40 
6.3.3 
Blinding and Masking Procedures ........................................................................ 41 
6.4 
Study Intervention Compliance .................................................................................... 41 
6.5 
Concomitant Therapy.................................................................................................... 41 
6.5.1 
Rescue Medicine ................................................................................................... 41 
6.5.2 
Non-Research Standard of Care............................................................................ 41 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 42 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 42 
7.1.1 
Halting Criteria ..................................................................................................... 42 
7.1.2 
Criteria for Continuation of Dosing and Redosing ............................................... 42 
7.1.3 
Discontinuation of Study Intervention .................................................................. 42 
7.1.3.1 
Delay of Study Vaccination .............................................................................. 43 
7.1.4 
Follow-up for Subjects that Discontinued Study Intervention ............................. 43 
7.1.5 
Follow up for Subjects with a Suspicion for Myocarditis and/or Pericarditis ...... 43 
7.1.5.1 
Probable Case of Acute Myocarditis ................................................................ 44 
7.1.5.2 
Confirmed Case of Acute Myocarditis ............................................................. 44 
7.1.5.3 
Acute Pericarditis Case Definition.................................................................... 44 

 
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7.1.5.4 
Myopericarditis Case Definition ....................................................................... 45 
7.2 
Subject Withdrawal from the Study and Replacement ................................................. 45 
7.3 
Lost to Follow-Up ......................................................................................................... 46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 47 
8.1 
Screening and Immunogenicity Assessments ............................................................... 47 
8.1.1 
Screening or Enrollment/Baseline Procedures...................................................... 47 
8.1.2 
Immunogenicity Evaluations ................................................................................ 48 
8.1.3 
Samples for Suspected SARS-CoV-2 infection .................................................... 49 
8.1.4 
Samples for Genetic/Genomic Analysis ............................................................... 49 
8.1.4.1 
Genetic/Genomic Analysis ............................................................................... 49 
8.1.4.2 
Genetic Privacy and Confidentiality ................................................................. 49 
8.1.4.3 
Management of Results..................................................................................... 49 
8.1.5 
SARS-CoV-2 infection ......................................................................................... 49 
8.1.6. 
Retained Samples for Biomarker Testing ............................................................. 50 
8.2 
Safety and Other Assessments ...................................................................................... 50 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 50 
8.3.1 
Definition of Adverse Event (AE) ........................................................................ 50 
8.3.1.1 
Solicited Adverse Events .................................................................................. 51 
8.3.1.2 
Unsolicited Adverse Events .............................................................................. 52 
8.3.2 
Definition of Serious Adverse Event (SAE) ......................................................... 52 
8.3.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR).............................. 52 
8.3.4 
Classification of an Adverse Event ....................................................................... 53 
8.3.4.1 
Severity of Adverse Events ............................................................................... 53 
8.3.4.2 
Relationship to Study Intervention ................................................................... 53 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 54 
8.3.6 
Adverse Event Reporting ...................................................................................... 54 
8.3.6.1 
Investigators Reporting of AEs ......................................................................... 54 
8.3.7 
Serious Adverse Event Reporting ......................................................................... 54 
8.3.7.1 
Investigators Reporting of SAEs ...................................................................... 54 
8.3.7.2 
Regulatory Reporting of SAEs ......................................................................... 55 

 
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8.3.8 
Reporting Events to Subjects ................................................................................ 55 
8.3.9 
Adverse Events of Special Interest (AESIs), New Onset of Chronic Medical 
Conditions (NOCMCs) and Medically Attended Adverse Events (MAAEs) ...................... 55 
8.3.10 
Reporting of Pregnancy ........................................................................................ 56 
8.4 
Unanticipated Problems ................................................................................................ 56 
8.4.1 
Definition of Unanticipated Problems (UPs) ........................................................ 56 
8.4.2 
Unanticipated Problem Reporting......................................................................... 57 
8.4.3 
Reporting Unanticipated Problems to Subjects .................................................... 57 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 58 
9.1 
Statistical Hypotheses ................................................................................................... 58 
9.2 
Sample Size Determination........................................................................................... 58 
9.2.1 
Sample Size Calculation for the Safety Endpoint ................................................. 58 
9.2.2 
Sample Size Calculation for the Immunogenicity Endpoints ............................... 59 
9.3 
Populations for Analyses .............................................................................................. 60 
9.4 
Statistical Analyses ....................................................................................................... 60 
9.4.1 
General Approach ................................................................................................. 60 
9.4.2 
Analysis of the Primary Endpoint(s)..................................................................... 61 
9.4.3 
Analysis of the Secondary Endpoints ................................................................... 61 
9.4.4 
Safety Analyses ..................................................................................................... 61 
9.4.5 
Baseline Descriptive Statistics .............................................................................. 61 
9.4.6 
Planned Interim and Early Analyses ..................................................................... 61 
9.4.6.1 
Interim Safety Analyses .................................................................................... 62 
9.4.6.2 
Interim Immunogenicity Review ...................................................................... 62 
9.4.6.3 
Interim Immunogenicity and Safety Review .................................................... 62 
9.4.7 
Sub-Group Analyses ............................................................................................. 62 
9.4.8 
Tabulation of Individual Subject Data .................................................................. 62 
9.4.9 
Exploratory Analyses ............................................................................................ 62 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 63 
10.1 
Regulatory, Ethical, and Study Oversight Considerations............................................ 63 
10.1.1 
Informed Consent Process .................................................................................... 63 

 
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10.1.1.1 
Requirements for Permission by Parents/Guardians and Assent by Children 
(in case of a minor) ........................................................................................................... 64 
10.1.1.2 
Other Informed Consent Procedures ............................................................. 64 
10.1.2 
Study Termination and Closure ............................................................................ 66 
10.1.3 
Confidentiality and Privacy .................................................................................. 66 
10.1.4 
Secondary Use of Stored Specimens and Data ..................................................... 67 
10.1.4.1 
Samples for Secondary Research .................................................................. 68 
10.1.4.2 
Data Sharing for Secondary Research .......................................................... 68 
10.1.5 
Key Roles and Study Governance ........................................................................ 68 
10.1.6 
Safety Oversight.................................................................................................... 68 
10.1.6.1 
Data Safety Monitoring Board (DSMB) ....................................................... 69 
10.1.7 
Clinical Monitoring ............................................................................................... 69 
10.1.8 
Quality Control (QC) and Quality Assurance (QA) ............................................. 69 
10.1.9 
Data Handling and Record Keeping ..................................................................... 70 
10.1.9.1 
Data Collection and Management Responsibilities ...................................... 70 
10.1.9.2 
Study Record Retention ................................................................................ 70 
10.1.9.3 
Source Records ............................................................................................. 71 
10.1.9.4 
Protocol Deviations ....................................................................................... 71 
10.1.9.5 
Data Sharing Plan ......................................................................................... 71 
10.1.9.6 
Genomic Data Sharing (GDS) Plan .............................................................. 71 
10.1.9.7 
Publication .................................................................................................... 72 
10.1.9.8 
Conflict of Interest Policy ............................................................................. 72 
10.2 
Additional Considerations ............................................................................................ 72 
10.2.1 
Research Related Injuries ..................................................................................... 72 
10.3 
Abbreviations ................................................................................................................ 72 
10.4 
Protocol Amendment History ....................................................................................... 78 
11. REFERENCES ..................................................................................................................... 86 
12. APPENDIX A: Adverse Events of Special Interest (AESIs) Terms .................................... 91 
 
 
 

 
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LIST OF TABLES 
Table 1: Study Arms ..................................................................................................................... 11 
Table 2: SOA for single dose ........................................................................................................ 15 
Table 3: SOA for 2 doses .............................................................................................................. 17 
Table 4: Objectives and Endpoints (Outcome Measures)............................................................. 30 
Table 5: Probability of Observing one or more Adverse Event for Various Event Rates in one 
vaccine group (or strata). .............................................................................................................. 58 
Table 6: Two-sided 95% confidence intervals based on observing a particular average loge-
antibody titer in subjects’ vaccine groups and potential strata sizes ............................................ 59 
Table 7: Abbreviations .................................................................................................................. 72 
 
LIST OF FIGURES 
No table of figures entries found. 
 
 

 
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1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
 
Title:  
Phase 2 Clinical Trial to Optimize Immune Coverage of SARS-CoV-2 Existing 
and Emerging Variants  
 
Short title: 
COVID-19 Adaptive VAriant Immunologic Landscape Trial (COVAIL Trial) 
 
Phase:  
Phase 2 
 
Population:  Approximately 1,500 healthy individuals aged ≥ 18 years  
 
Sites:   
Up to 30 US clinical research sites  
 
Rationale: 
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), causative agent of the 
coronavirus disease of 2019 (COVID-19) pandemic, has infected close to 600 million people 
worldwide and resulted in more than 6 million deaths, including 1 million deaths  in the United 
States (August 18, 2022 WHO; www.who.int). As of September 2022, there are four approved or 
authorized vaccines in the U.S.: two using mRNA-based technology (Pfizer BioNTech 
[BNT162b2] and Moderna [mRNA-1273]), one using a non-replicating viral vector vaccine 
(Johnson and Johnson adenovirus Ad26), and one using protein adjuvanted vaccine (Novavax) all 
encoding the spike protein of the ancestral strain.  A fifth manufacturer Sanofi has another 
adjuvanted protein vaccine that showed efficacy in a phase 3 trial. These and other WHO 
authorized vaccines have been an essential countermeasure against the pandemic.  
However, the emergence of many variants of concern with different degrees of immune escape 
challenge the effectiveness of these vaccines. The persistent evolution of the virus leads to the 
consideration of adapting vaccines to antigenically match circulating variants as well as expanding 
and optimizing immune coverage to existing and emerging antigenic variants. Current efforts are 
directed towards modifying the existing vaccines to include the current circulating variant 
Omicron. However, Omicron may not be the circulating variant during the next wave of COVID-
19. It is important to look beyond Omicron and understand the immunologic landscape and how 
we can use prototype and variant vaccines alone or in combination to address emerging variants.  
This phase 2 clinical trial will evaluate the safety and immunogenicity of additional doses of 
prototype and variant (alone or in combination) vaccine candidates in previously vaccinated 
participants with or without prior SARS-CoV-2 infection, and will evaluate innate, cellular, and 

 
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humoral immune responses to inform on how to shift the immune response to cover new variants 
as they emerge. 
 
Objectives:  
Primary:  
  To evaluate humoral immune responses of candidate SARS-CoV-2 variant vaccines, alone or in 
combination.  
Secondary 
1. To evaluate the safety of candidate SARS-CoV-2 variant vaccines, as assessed by:  
• 
Local and systemic solicited Adverse Events for 7 days following each vaccine dose. 
• 
Unsolicited Adverse Events from Dose 1 to 28 days following each vaccine dose.  
• 
SAEs, MAAEs, AESIs, NOCMCs, and AEs leading to withdrawal from the study  
from Dose 1 to 12 months after last vaccine dose.  
Exploratory:  
1. To assess, in at least a subset of samples, the B cell immune response of candidate SARS-
CoV-2 variant vaccines. 
2. To assess, in at least a subset of samples, the SARS-CoV-2 spike protein-specific T cell 
responses of candidate SARS-CoV-2 variant vaccines. 
3. To assess, in at least a subset of samples, the magnitude, phenotype, and percentage of 
innate immune cells with candidate SARS-CoV-2 variant vaccines. 
4. To assess, in at least a subset of samples, the functional potential of SARS-CoV-2 
specific antibodies to mediate Fc-effector functions across candidate SARS-CoV-2 
variant vaccines.  
5. To evaluate breakthrough SARS-CoV-2 infection by sequencing strains for variant spike 
lineage and assessing anti- nucleocapsid serology.  
 
Study Design:  
This is a Phase 2 randomized open label, non-placebo controlled, multi-site, multi-stage clinical 
trial in individuals, 18 years of age and older, who are in stable state of health, have received a 
complete authorized/approved vaccine series (primary series + a booster either with homologous 
or heterologous vaccine products) ≥ 16 weeks prior to enrollment.  
Subjects will be stratified by i) age (18-64 years and ≥ 65 years of age) (however arms 16 and 17 
or stage 4 will only enroll participants between the ages of 18-49 years) and ii) history of confirmed 
prior SARS-CoV-2 infection, and randomly assigned to receive one of several variant vaccines. 
Enrollment will target a goal of approximately 45% of each of the variant vaccine arms to be in 

 
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older adults (≥ 65 years of age) for stages 1, 2 and 3 and approximately 20% to have had confirmed 
COVID-19 for all 4 stages.  
This is an adaptive design and may add arms of new vaccine platforms and/or variant lineage spike 
vaccines as needed. The study arms will be conducted in different stages (that could overlap) 
depending on public health needs and availability of study products (starting with the available 
mRNA vaccines).  
Table 1: Study Arms 
 
Arms Vaccine 
Platform 
Samp
le 
Size 
Vaccine Candidate 
Interval 
(weeks)* 
Timing 
of First 
Dose  
Timing of 
Second Dose 
Stage 1 
1 
Moderna 
mRNA-1273 
100 
Prototype 
≥16 
D1 
NA 
2 
100 
Beta + Omicron  
≥16 
D1 
NA 
3 
100 
Beta + Omicron  
≥16 
D1 
D57 
4 
100 
Delta + Omicron  
≥16 
D1 
NA 
5 
100 
Omicron  
≥16 
D1 
NA 
6 
100 
Omicron + Prototype  
≥16 
D1 
NA 
 
Stage 2 
7 
Pfizer/ 
BioNTech 
BNT162b2 
50 
Wildtype (Prototype) 
≥16 
D1 
NA 
8 
50 
Beta + Omicron  
≥16 
D1 
NA 
9 
50 
Omicron  
≥16 
D1 
NA 
10 
50 
Beta  
≥16 
D1 
NA 
11 
50 
Beta + Wildtype  
≥16 
D1 
NA 
12 
50 
Omicron + Wildtype  
≥16 
D1 
NA 
 
Stage 3 
13 
Sanofi 
CoV2 preS 
dTM-AS03 
50 
Prototype 
≥16 
D1 
NA 
14 
50 
Beta  
≥16 
D1 
NA 
15 
50 
Beta+ Prototype 
≥16 
D1 
NA 
 
Stage 4 
16^ 
Pfizer/ 
BioNTech 
BNT162b2 
bivalent 
100 
Omicron BA.1 + 
Wildtype (Prototype) 
≥16 
D1 
NA 
17^ 
100 
Omicron BA.4/BA.5 + 
Wildtype (Prototype) 
≥16 
D1 
NA 
 
Two age strata:  
• 
18-64 years 
• 
≥ 65 years (~45% in ≥ 65 years). 
^For arms 16 and 17 or stage 4, only participants between the ages of 18 to 49 years will be enrolled. 
 
Two infection strata:  
• 
Confirmed prior SARS-CoV-2 infection (~20%) 
• 
No known history of prior infection.   

 
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*interval (in weeks) since last exposure to SARS-CoV-2 infection or vaccination 
 
Duration of Study:   Up to 4 years  
 
Duration of participation per subject: Up to 2 years (approximately 12 months after last 
inoculation)  
 
Criteria for Inclusion/Exclusion:  
Inclusion Criteria: 
Participants must meet all of the following criteria to be eligible to participate in this study: 
1. Individuals ≥ 18 years of age at the time of consent (18-49 years for stage 4).  
2. Confirmed receipt of a complete primary and booster COVID-19 vaccine series, either 
homologous or heterologous, with an FDA authorized/approved vaccine at least 16 weeks 
prior to study vaccine dose 1. 
3. Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests 
and other study procedures.  
4. Determined by medical history, targeted physical examination and clinical judgement of 
the investigator to be in stable state of health.  
Note: Participants with pre-existing stable chronic medical conditions defined as 
condition not requiring significant change in therapy or hospitalization for worsening 
disease within 4 weeks from enrollment, can be included at the discretion of the 
investigator. 
Exclusion Criteria:  
Participants meeting any of the following criteria will be excluded from the study:  
1. Confirmed SARS-CoV-2 infection < 16 weeks prior to any study vaccine dose.  
2. Pregnant and breastfeeding participants. 
3. Prior administration of an investigational coronavirus vaccine at any time or SARS-CoV-
2 immunoglobulin, monoclonal antibody or plasma antibody therapy in the preceding 3 
months. 
Note: subjects that participated in clinical trials of products that are now FDA 
approved/authorized are allowed to participate. 
4. Current/planned simultaneous participation in another interventional study or receipt of 
any investigational study product within 28 days prior to vaccine study dose(s). 

 
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5. A history of anaphylaxis, urticaria, or other significant adverse reaction requiring medical 
intervention after receipt of a vaccine, polyethylene glycol (PEG), polysorbate or nanolipid 
particles. 
6. A history of myocarditis or pericarditis at any time prior to enrollment (for subjects in 
stages 1, 2 and 4).   
7. Received or plans to receive a vaccine within 28 days prior to or after any dose of study 
vaccine. 
Note: Receipt of seasonal influenza vaccine is allowed at any time.   
8. Bleeding disorder diagnosed by a healthcare provider (e.g., factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or bleeding difficulties with 
intramuscular injections or blood draws.   
9. Current or previous diagnosis of an immunocompromising condition or other 
immunosuppressive condition. 
10. Advanced liver or kidney diseases. 
11. Advanced (CD4 count < 200) and/or untreated HIV, untreated Hepatitis B or untreated 
Hepatitis C. 
12. Received oral, intramuscular or intravenous systemic immunosuppressants, or immune-
modifying drugs for >14 days in total within 6 months prior to any study vaccine dose (for 
corticosteroids ≥ 20 mg/day of prednisone equivalent).  
Note: Topical medications are allowed.   
13. Received immunoglobulin or blood-derived products, within 3 months prior any study 
vaccine dose.   
14. Received chemotherapy, immunotherapy or radiation therapy within 6 months prior to 
any study vaccine dose. 
15. Study personnel or an immediate family member or household member of study 
personnel.   
16. Is acutely ill or febrile 72 hours prior to or at vaccine dosing (fever defined as ≥ 
38.0°C/100.4°F). Participants meeting this criterion may be rescheduled within the relevant 
window periods.  
Note: Afebrile participants with minor illnesses can be enrolled at the discretion of the 
Investigator, as long as the illness is not suggestive of COVID-19. 
17. Plan to receive a COVID-19 booster vaccine outside of the study within the next 180 
days. (for subjects in Stage 4 only) 
 
Safety 
• 
Solicited Adverse Events will be collected for 7 days following each vaccine dose. 

 
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• 
Unsolicited Adverse Events will be collected from Dose 1 to 28 days following each 
vaccine dose.  
• 
SAEs, MAAEs, AESIs, NOCMCs, and AEs leading to withdrawal from the study will be 
collected from Dose 1 to 12 months after last vaccine dose.  
• 
The study will use halting rules for vaccination. See Section 7.1 for details. 

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1.2 
Schedule of Activities (SOA) 
Table 2: SOA for single dose 
Study Day 
D-28 
to 
D-1 
1 
4 
8
b 
15 
29 
91 
181 
271 
366 
Illness/ 
Unsche
duled 
Visitk,m 
Early 
Terminati
on Visit 
Visit Number 
00
a 
1 
1A 
2 
3 
4 
5 
6 
7 
8 
 
 
Window (+/-) 
 
0 
1 
1 
2 
2 
7m 
14m 
14m 
28m 
 
 
Informed Consent
a 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Interim History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examc - Targeted 
X 
X 
 
 
 
 
 
 
 
 
(X) 
 
Vital Signs
c 
X 
X 
 
 
 
 
 
 
 
 
(X) 
 
Height/Weight (BMI)
a 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine β-HCG
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
Memory Aide 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Solicited AEs 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
MAAEs, SAEs, NOCMCs, AEs leading 
to withdrawal from the study and AESIs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nasal swab for PCR & Sequencingf 
 
 
 
 
 
 
 
 
 
 
(X) 
 
Assays 
Serum for Serological Immunogenicity 
Assaysg and Biomarker Testingl 
 
34l 
 
4l 
 
34 
34 
34 
34 
34 
34 
4l-34m 
34 
PBMC Cellular Assays & Plasmag,h 
 
64-70 
 
 
64-70 
 
64-70 64-70 64-70 
 
64-70m 
64-70 

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(select sites only) 
Daily Volume (mL)g,i 
 
98-
104 
4 
 
98-
104 
34 
98-
104 
98-
104 
98-
104 
34 
4-104 
98-104 
Cumulative Volume (mL) over 56 day-
periodg,i 
 
98-
104 
102-
108 
 
200-
212 
234-
246 
132-
138 
98-
104 
98-
104 
132-
138 
 
 
Total Cumulative Volume (mL)g,i 
 
98-
104 
102-
108 
 
200-
212 
234-
246 
332-
350 
430-
454 
528-
558 
562-
592 
 
 
a Optional screening visit – informed consent and screening activities can be a separate visit or combined with Day 1. 
b Telephone visit 
c Vital signs and targeted physical exam will be performed on screening and before vaccination otherwise, only as clinically indicated or based on interim medical 
history. 
d For subjects of childbearing potential, a urine pregnancy will be performed at screening. If enrollment occurs on a separate day, a repeat urine pregnancy test will 
be done within 24 hours of study vaccine administration and negative results confirmed prior to dosing.  
e  The memory aid will be distributed at the Day 1 visit, queried for completion at the Day 8 telephone call and reviewed during an interview with the subject at the 
D15 visit and confirmed data recorded on the DCF. 
fCollect nasal swab for PCR (1-2). Swabs can be self-collected and visit done by phone. Sequencing will be performed on all Illness visit-confirmed SARS-CoV-
2 specimens. 
g Inability (e.g., failure of venipuncture) to collect all baseline samples on Day 1 will not exclude the subject from further participation in this study as long as a 
minimum of baseline blood volume is collected (refer to the MOP for the protocol defined minimum number of required aliquots). Blood volume for PBMC varies 
depending on the type of tubes used for blood collection (refer to the MOP). 
h Selected sites will perform PBMC separation on selected subjects (refer to MOP for more guidance). 
i Blood volumes for early termination visit are not included in the blood volume totals. 
j After vaccination on Day 1, immunosuppressant drugs, COVID-19 related prophylaxis and therapies as well as vaccines will be recorded. For any SAE occurring 
at any time during the study, all medications will be recorded. 
k If an unscheduled visit is performed to evaluate an adverse event, vital signs and targeted physical exam will be performed, as indicated. If, in the judgement of 
the site investigator, the event, occurring within 4 weeks after vaccination, is a case of suspected myocarditis and/or pericarditis, the site will coordinate an 
appropriate diagnostic workup to make a determination of probable or confirmed myocarditis and/or pericarditis which may include, but is not limited to, an ECG, 
cardiac troponin testing and referral to a cardiologist (directly, or through the emergency department or primary care clinic). The suspected myocarditis and/or 
pericarditis case should be reported to the DMID Medical Monitor within 24 hours of site awareness.  
lSerum for biomarker testing will be collected on Day 4 and stored for potential biomarker testing at a central laboratory and compared to testing of an aliquot from 
serum obtained on Day 1.  If an unscheduled visit is related to a concern for myocarditis and/or pericarditis within 4 weeks after vaccination, a 4 mL SST will be 
collected and stored for potential biomarker testing at a central laboratory.  
mIf a participant is planning to receive a COVID-19 booster outside the study, an unscheduled visit will be performed where safety and immunogenicity (collection 
of sera, plasma and PBMC) assessments will be performed. However, if that planned visit falls within twice the window for an upcoming visit ( e.g +/- 14 days for 

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D 91, +/-28 days for D 181 and D 271, +/- 56 days for D 366) then it will occur  and be documented as out of window for the planned upcoming scheduled visit 
(refer to MOP for more guidance).  
 
Table 3: SOA for 2 doses  
Study Day 
D-28 
to 
D-1 
1 
4 
8b 
15 
29 
57 
60 
64b 
71 
85 
147 
237 
327 
422 
Illness/ 
Unsche
duled 
Visitk,m 
Early 
Termi
nation 
Visit 
Visit Number 
00a 
1 
1A 
2 
3 
4 
5 
5A 
6 
7 
8 
9 
10 
11 
12 
  
  
Window (+/-) 
  
0 
1 
1 
2 
2 
3 
1 
1 
2 
2 
7m 
14m 
14m 
28m 
  
  
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Interim History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examc – 
Targeted 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
(X) 
 
Vital Signsc 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
(X) 
 
Height/Weight (BMI)a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-HCG
d 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Memory Aide 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Solicited AEs 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
MAAEs, SAEs, 
NOCMCs, AEs leading 
to withdrawal from the 
study and AESIs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Nasal swab for PCR & 
Sequencingf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
 
Assays 
Serum for Serological 
Immunogenicity Assaysg 
and Biomarker Testingl 
 
34l 
 
4l 
 
34 
34 
34l 
 
4l 
 
34 
34 
34 
34 
34 
34 
4l-34m 
34 
PBMC Cellular Assays & 
Plasmag,h 
(select sites only) 
 
64-
70 
 
 
64-
70 
 
64-
70 
 
 
64-
70 
 
64-
70 
64-
70 
64-
70 
 
64-70m 
64-70 
Daily Volume (mL)g,i 
 
98-
104 
4 
 
98-
104 
34 
98-
104 
4 
 
98-
104 
34 
98-
104 
98-
104 
98-
104 
34 
4-104 
98-104 
Cumulative Volume (mL) 
over 56 day-periodg.i 
 
98-
104 
102
-
108 
 
200
-
212 
234
-
246 
332
-
350 
238
-
250 
 
336
-
354 
268
-
280 
132-
138 
98-
104 
98-
104 
132
-
138 
 
 
Total Cumulative Volume 
(mL)g,i 
 
98-
104 
102
-
108 
 
200
-
212 
234
-
246 
332
-
350 
336
-
354 
 
434
-
458 
468
-
492 
566-
596 
664
-
700 
762
-
804 
796
-
838 
 
 
a Optional screening visit – informed consent and screening activities can be a separate visit or combined with Day 1. 
b Telephone visit 
c Vital signs and targeted physical exam will be performed on screening and before vaccination otherwise, only as clinically indicated or based on interim medical 
history.  
d For subjects of childbearing potential, a urine pregnancy test will be performed at screening. If enrollment occurs on a separate day as screening, a repeat urine 
pregnancy test will be done within 24 hours of first study vaccine administration and repeated on day 57 prior to second study vaccine administration. Negative 
results must be confirmed prior to each dosing.    
e The memory aid will be distributed at the Day 1 and Day 57 visits, queried for completion at the Day 8 and Day 64 telephone calls and reviewed during an 
interview with the subject at the D15 and Day 71 visits and confirmed data recorded on the DCF. 
f Collect nasal swab for PCR (1-2). Swabs can be self-collected and visit done by phone. Sequencing will be performed on all Illness visit-confirmed SARS-CoV-
2 specimens. 
g Inability (e.g., failure of venipuncture) to collect all baseline samples on Day 1 will not exclude the subject from further participation in this study as long as a 
minimum of baseline blood volume is collected (refer to the MOP for the protocol defined minimum number of required aliquots). Blood volume for PBMC varies 
depending on the type of tubes used for the blood collection (refer to the MOP). 
h Selected sites will perform PBMC separation on selected subjects (refer to MOP for more guidance). 
i Blood volumes for early termination visit are not included in the blood volume totals. 

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j After vaccination on Day 1, immunosuppressant drugs, COVID-19 related prophylaxis and therapies as well as vaccines will be recorded. For any SAE occurring 
at any time during the study, all medications will be recorded. 
k If an unscheduled visit is performed to evaluate an adverse event, vital signs and targeted physical exam will be performed, as indicated. If, in the judgement of 
the site investigator, the event, occurring within 4 weeks after each vaccination, is a case of suspected myocarditis and/or pericarditis, the site will coordinate an 
appropriate diagnostic workup to make a determination of probable or confirmed myocarditis and/or pericarditis which may include, but is not limited to, an ECG, 
cardiac troponin testing and referral to a cardiologist (directly, or through the emergency department or primary care clinic). The suspected myocarditis and/or 
pericarditis case should be reported to the DMID Medical Monitor within 24 hours of site awareness. 
lSerum for biomarker testing will be collected on Days 4 and 60 and stored for potential biomarker testing at a central laboratory and compared to testing of an 
aliquot of serum obtained on Days 1 and 57, respectively.  If an unscheduled visit is related to a concern for myocarditis and/or pericarditis within 4 weeks after 
vaccination, a 4 mL SST will be collected and stored for potential biomarker testing at a central laboratory. 
mIf a participant is planning to receive a COVID-19 booster outside the study, an unscheduled visit will be performed where safety and immunogenicity (collection 
of sera, plasma and PBMC) assessments will be performed. However, if that planned visit falls within twice the window for an upcoming visit ( e.g +/- 14 days for 
D 147, +/-28 days for D 237 and D 327, +/- 56 days for D 422) then it will occur and be documented as out of window for the planned upcoming scheduled visit 
(refer to MOP for more guidance).  
 
Note Windows for subsequent visits should be based off the preceding vaccination visit. 
If intercurrent SARS- CoV-2 infection occurs between the first and prior to the planned second study dose or if a COVID-19 vaccine is given outside the study 
between the first and prior to the planned second study dose, no second vaccination will be given. Participants who do not receive a second dose will revert to the 
schedule of activities for single dose participants. 

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2. 
INTRODUCTION 
2.1 
Background and Study Rationale  
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first detected in 
Wuhan, Hubei Province, China in December 2019. The corresponding illness designation, 
coronavirus disease 2019 (COVID-19), was declared as a pandemic respiratory illness in March 
2020.1 As of 18 August 2022, it has infected close to 600 million people worldwide and resulted 
in more than 6  million deaths, including 1 million in the United States.1,2  
Six Phase 3 efficacy trials of SARS-CoV-2 vaccine constructs were conducted and are in long-
term follow-up in the U.S. The ModernaTX, Inc mRNA-1273 and Pfizer/BioNTech BNT162b2 
mRNA platforms encode for the full-length spike (S) protein of SARS-CoV-2, modified to 
introduce 2 proline residues to stabilize the S protein (S-2P) in a prefusion conformation, derived 
from the Wuhan-Hu-1 strain (prototype).3 The Janssen Pharmaceutical/Johnson & Johnson 
COVID-19 Vaccine (Ad26.COV.2) is composed of recombinant, replication-incompetent human 
adenovirus type 26, encoding a prefusion-stabilized SARS-CoV-2 spike antigen.4  Studies of the 
Pfizer and Moderna mRNA vaccines demonstrated high efficacy against all symptomatic and 
severe disease and received Emergency Use Authorization (EUA) on December 12 and 18, 2020, 
respectively and full FDA approval on August 23, 2021 and January 31, 2022. Similarly, Janssen 
Pharmaceuticals reported 66% vaccine efficacy with a single dose and high-level protection 
against severe disease and death. FDA EUA was issued on February 26, 2021. Novavax’s NVX-
CoV2373, a recombinant nanoparticle vaccine containing the full-length spike protein received 
FDA EUA on July 13, 2022.5 AstraZeneca/Oxford’s ChAdOx-2, a recombinant, replication-
incompetent chimpanzee adenovirus vector that expresses the spike protein, , and Sanofi/GSK’s 
adjuvanted recombinant spike protein vaccine are currently not licensed.6,7  
 
Despite widespread vaccine distribution and availability, and high coverage among adults in the 
United States (89.1% of the US population ≥ 18 years of age have received at least one dose)8, 
ongoing waves of the pandemic continue to cause significant disease burden, notable for increasing 
incidence of breakthrough infections in fully vaccinated individuals. Studies have suggested that 
vaccine protection against symptomatic SARS-CoV-2 infection wanes over time though protection 
against severe COVID-19 outcomes remains relatively intact.9-12 However, the evolution of variant 
strains may favor immune escape or reinfection among previously infected or vaccinated 
individuals. A variant first identified in late 2020 (B.1.351), is associated with increased 
transmission, higher viral burden, and possibly increased mortality in infected persons.13  Another 
variant identified in December 2020 (B.1.617.2) is associated with increased transmission, higher 
risk of severe disease and hospitalization than the ancestral strain.14 B.1.617.2 was the dominant 
strain worldwide before being replaced by B.1.1.529 in November 2021 which is characterized by 
a replication advantage, higher re-infection rates and evasion of humoral immunity mediated by 
more than 30 mutations in the spike protein.15  
 
Recent data suggest that a booster dose given as either a third dose for most vaccines (mRNA, 
protein and ChAdOx-2) or a second dose for Janssen improved vaccine effectiveness against new 
variants in the short term.16-18 Data on immunogenicity with booster doses of BNT162b2, mRNA-

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1273, and AD26.COV2.S demonstrated higher antibody titers to D614G after either homologous 
and heterologous prime-boost combinations.19 The result is better neutralizing activity against 
B.1.351,  B.1.617.2 and B.1.1.529.20-22 In an open label phase study of participants who received 
a single 50 mcg booster dose of mRNA-1273 ≥ 6 months after a primary series, a 13 fold rise in 
antibody titers against D614G were noted from pre-boost levels as well as a 17-fold rise in in titers 
against the B.1.617.2 variant.20 In another study, participants boosted with 50 mcg of mRNA-1273 
demonstrated ID50 GMTs against the omicron variant 20 times higher than those described 1 month 
after the second vaccination of the primary series; these titers were 2.9 times lower than titers for 
the D614G variant.21  
 
The Sanofi/GSK adjuvanted recombinant prefusion spike protein vaccine (CoV2 preS dTM-AS03 
[D614]) was developed from an established, platform used for influenza vaccines. A phase 2 study 
showed the safety and immunogenicity of a two-dose primary series of CoV2 preS dTM-AS03 
[D614] in adults who were SARS-CoV-2 naïve and those who were previously infected.23 The 
dose-finding results informed selection of the adjuvanted formulation with 10 mcg antigen as 
primary dose and the adjuvanted formulation with 5 mcg antigen as boost dose for further 
evaluation. Neutralizing antibody titers were higher in non-naïve participants after one dose than 
in naïve participants after two doses. In addition, 5 mcg booster dose increased neutralizing 
antibody titers when used as a heterologous (18-30 times) or homologous (≥ 84 times) boost 
compared to pre boost.24 Interim results from an international phase 3 trial showed 57.9% (95% 
confidence interval 26.5% to 76.7%) efficacy of the two-dose primary series against any 
symptomatic disease and 75% efficacy against moderate or severe COVID-19 with an acceptable 
safety and reactogenicity profile.24   
 
FDA EUA was subsequently issued for a booster 30 ug dose of Pfizer BNT162b2 on September 
24, 2021, 50 ug booster dose of Moderna mRNA-1273 on October 21, 2021, and a 5×1010 viral 
particles booster dose of J&J AD26.COV2 on October 21, 2021. This was recommended for adults 
18 years of age and older who received a FDA authorized and CDC recommended primary booster 
series with an mRNA vaccine at least 5 months prior or a primary series with AD26.COV2 at least 
2 months prior. The Sanofi/GSK vaccine is currently undergoing regulatory review for approval 
of their vaccine candidate for the prevention of COVID-19.   
 
Published reports have also provided some early evidence for the safety and immunogenicity of a 
fourth dose of an mRNA vaccine. An open-label study of healthcare workers in Israel suggests 
that a fourth dose was well-tolerated and restored neutralizing antibody titers for variants to levels 
similar to those after a third dose.25 Notably, this study did not include older adults, and rates of 
infection with B.1.1.529 (omicron) were similar for the control and Pfizer or Moderna 4th dose 
groups. In a retrospective study conducted by the Israeli Ministry of Health, of 1,138,681 adults 
aged 60 to 100 years of age, a fourth dose of mRNA was associated with 2 times lower rate of 
confirmed infection 12 or more days after vaccination compared to those who had only received 3 
doses and the rate of severe illness was lower by a factor of 4.3.26 However, the added protection 
of an additional booster shot is small in absolute terms since less than 0.1% mortality was noted 
after a 3rd dose. Additionally, a separate study of adults age 60 or older suggests that vaccine 
effectiveness of a fourth dose against infection wanes quickly declining from a peak of 64% to 
29% within 2 months though effectiveness of >72% was maintained against severe disease.27  

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On March 29, 2022, the FDA authorized an additional booster dose of an mRNA vaccine for 
adults 50 years of age or older, or for those with immunocompromising conditions (12 years and 
older with immunocompromising conditions could receive a second booster with the Pfizer 
vaccine and 18 years and older could receive a second booster with the Moderna vaccine). 
Subsequent to this authorization, the CDC updated vaccination guidance to permit an additional 
booster dose for these groups in recognition of the increased and ongoing risk for severe disease 
in these populations.   
The emergence of variant strains has raised concerns about the breadth and duration of immunity 
and protection achieved by the current vaccines. Studies of vaccine immunogenicity for early 
variants of concern demonstrated those vaccinated with prototype vaccines may have reduced 
neutralizing activity to the variants.28 For variants like B.1.351, pivotal studies testing both viral 
vector and adjuvanted protein technologies had lower efficacy in regions where B.1.351 was 
known to be circulating.29,30 Moreover, sera from individuals vaccinated with mRNA-based 
vaccines had a 6-to-9-fold lower neutralizing activity against a B.1.351-matched pseudovirion 
relative to a Wuhan-matched pseudovirion.10,11 Similarly, sera from individuals vaccinated with 
mRNA-1273 had an 8-fold lower neutralizing activity against the B.1.617.2 variant compared to 
titers against the D614G variant.21  
Studies have also demonstrated 6.7 fold lower neutralizing activity for Pfizer BNT162b2 against 
B.1.351 with two doses of Pfizer BNT162b2.31 Additionally, in one assessment of sera obtained 
from individuals vaccinated with Pfizer BNT162b2, obtained one month after the second dose, a 
25 fold lower neutralizing antibody geometric mean titers against B.1.1.529 was noted compared 
to the wild-type virus.32 Neutralizing activity has been shown to be partially restored by 
vaccination with a third dose of Pfizer BNT162b2. However, even with three doses, neutralizing 
activity was 4 times lower against B.1.1.529 and 3 times lower against B.1.351 compared to 
B.1.617.2 and 7-8 times lower compared to wild-type virus.33 Thus, additional vaccinations, 
higher doses or variant specific vaccines may improve protection against current and emerging 
variants of concern.  
 
Vaccine manufacturers have performed some trials of candidate variant vaccines. For example, a 
phase 2a open label clinical trial to examine the immunological benefit of boosting subjects 
previously vaccinated 6 months prior with mRNA-1273 with mRNA-1273.351, a B.1.351 strain-
specific mRNA construct (50 mcg), or mRNA-1273.211 (50 mcg) showed 61.6 and 33.7 times 
higher titers against B.1.351 compared to titers from participants one month after the second 
dose of the primary series, with similar titers against B.1.617.2.22 Similar findings were seen 
from a study of a boost with a bivalent mRNA-1273.213 vaccine (a 1:1 mix of beta and delta 
variant mRNA).21  
Similarly, several BNT162b2-based variant vaccines that target these variants are also being 
developed including BNT162b2 (B.1.617.2), BNT162b2 (B.1.351) and BNT162b2 (B.1.1.529).  
In addition, Sanofi has developed a SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant 
(CoV2 preS dTM-AS03 [B.1.351]) monovalent vaccine and a SARS-CoV2 prefusion Spike delta 
TM with AS03 adjuvant bivalent vaccine (D614/B.1.351 (CoV2 preS dTM-AS03 [D614 + 

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B.1.351]). In a nonhuman primate model, these vaccines used as boosters induced cross-
neutralizing antibodies against variants of concern including Delta and Omicron.34 
However, current efforts are directed towards modifying the existing vaccines to include the 
recently  circulating Omicron subvariants (United Kingdom and Canada: Prototype + Omicron 
BA.1 and the US: Prototype + Omicron BA.4/BA.5), though this may not be the circulating variant 
during the next wave of COVID-19. It is therefore important to look beyond Omicron, and 
understand the immunologic landscape and how we can use prototype and variant vaccines alone 
or in combination to address emerging variants.  
For seasonal influenza viruses, the antigenic, viral genetic and epidemiological data guide annual 
updates of the seasonal influenza virus vaccines. Antigenic cartography is a visualization tool 
aimed at understanding the relationship among SARS-CoV-2 variants of concern (VOCs) in terms 
of their ability to induce cross-neutralizing antibodies. A recent study using the antigenic mapping 
approach showed that Omicron represents the first widely circulating new major SARS-CoV-2 
variant.35 Though the dimensions of the cartography, representing new VOCs that could circulate 
in the future, remain largely unknown, a better understanding of diverse immune landscape 
induced by vaccination and natural infection could lead, along with vaccine modification, to more 
durable and broadly protective immunity. The update in vaccine formulations proposed in this 
study will still rely on similar platforms, route of administration and dosing, though will include 
an update of immunogens with VOCs alone or in combination that could result in broadly cross 
reactive serological and cellular immune responses especially in groups with high risk for mortality 
(e.g., older adults).  
This phase 2 clinical trial will evaluate the safety and immunogenicity of additional doses of 
vaccine to expand and optimize immune coverage of the existing and emerging antigenic space. 
Utilizing several prototype and variant specific COVID-19 vaccines based on mRNA and other 
approved platforms, we propose to evaluate innate, cellular, and humoral immune responses 
elicited from different vaccine candidates. As part of an adaptive design, we anticipate adding 
groups with other variant-lineage spike proteins and other vaccine platforms, subject to 
availability. 
2.1.1 
Public Readiness and Emergency Preparedness Act 
The study vaccines and the efforts for this clinical trial are covered under the Public Readiness and 
Emergency Preparedness Act (PREP Act) and the Declaration issued by the Secretary of the U.S. 
Department of Health and Human Services under that Act. Under the PREP Act and the 
Declaration, covered persons (such as manufacturers, distributers, program planners, and other 
qualified persons who prescribe, administer, or dispense study product) are immune from liability 
from the administration, or use of a covered countermeasure. The PREP Act provides immunity 
for covered persons from liability unless the injury was caused by willful misconduct. The 
Declaration invoking the PREP Act for COVID-19 covered countermeasures was made on March 
10, 2020 and is retroactively effective from February 4, 2020.  

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The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries or death that occur as the direct result of the 
administration or use of certain countermeasures. Any requests for compensation must be filed 
within one year of the administration or use of the covered countermeasure. Requests for Benefits 
must be made to the Health Resources and Services Administration’s (HRSA) Countermeasures 
Injury Compensation Program (http://www.hrsa.gov/cicp/) by filing a Request for Benefits Form 
and all required medical records and supporting documentation. Additional information on filing 
a Request for Benefits is available on the CICP’s website at http://www.hrsa.gov/cicp/. 
Compensation may then be available for reasonable and necessary medical benefits, lost wages 
and/or death benefits to eligible individuals for certain injuries in accordance with regulations 
published by the Secretary of HHS (found at 42 CFR part 110).  
If an individual suffers a serious physical injury or death from the administration or use of a 
covered countermeasure in this study, the individual, the individual’s legal or personal 
representative, the administrator/executor of a deceased individual’s estate, or certain survivors 
may request benefits from the CICP. A serious physical injury means an injury that warranted 
hospitalization (whether or not the person was actually hospitalized) or that led to a significant loss 
of function or disability. The CICP is the payer of last resort. This means that it only covers 
expenses or provides benefits that other third-party payers (such as health insurance, the 
Department of Veterans Affairs, or Workers’ Compensation programs) do not have an obligation 
to pay.  
If the Secretary of DHHS does not make a final determination on the individual’s request within 
240 days, or if the individual decides not to accept the compensation, the injured individual or his 
representative may pursue a tort claim in the US District Court for the District of Columbia, but 
only if the claim involves willful misconduct and meets the other requirements for suit under the 
PREP Act. Any award is reduced by any public or private insurance or worker’s compensation 
available to the injured individual. Awards for non-economic damages, such as pain, suffering, 
physical impairment, mental anguish, and loss of consortium are also limited. If the individual 
accepts compensation, or if there is no willful misconduct, then the individual does not have a tort 
claim that can be filed in a US Federal or a State court. 
2.2 
Risk/Benefit Assessment 
2.2.1 
Known Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, IM 
injection, possible reactions to COVID-19 vaccines and breach of confidentiality. 
Risks of blood draw and IM injection 
Drawing blood may cause transient discomfort and fainting. Bruising at the blood draw site may 
occur but can be prevented or lessened by applying pressure to the blood draw site for a few 
minutes after the blood is taken. IM injection may also cause transient discomfort and fainting. 
Vasovagal syncope (fainting) can occur before or after vaccination or blood draw, is usually 
triggered by the pain or anxiety caused by the needlestick and is not related to the substance 

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injected. It is important that standard precautions and procedures be followed to avoid injury from 
fainting. Fainting is usually transient and managed by having the subject lie down and elevate 
his/her legs. 
Drawing blood and IM injection may cause infection. The use of aseptic (sterile) technique will 
make infection at the site where blood will be drawn or where the vaccination will be given 
extremely unlikely. 
Risks of study vaccines  
• mRNA-1273, mRNA-1273.351, mRNA-1273.617.2 and mRNA-1273.529 
mRNA-1273 was granted full FDA approval in 2022 and more than 200 million doses of mRNA-
1273 have been administered in the US alone as of early 2022.36 While the other SARS-CoV-2 
mRNA vaccine candidates manufactured by Moderna have been given to a small number of 
individuals in the setting of clinical trials, the safety profile of these vaccine candidates is believed 
to be largely similar to the approved prototype vaccine. The total amount of immunogens within 
any study vaccine will be 50 mcg, similar to the authorized boost dose of mRNA-1273. 
Immediate systemic allergic reactions (e.g., anaphylaxis) can occur following any vaccines. For 
the mRNA-1273 vaccines, the rate of anaphylaxis is around 2.5 cases per million doses 
administered.37 Most of these reactions have onset within 30 minutes of vaccination and most of 
these events occurred in persons with a prior history of allergy. As a precaution, all subjects will 
remain under observation at the study site for at least 30 minutes after injection. Risk management 
also includes exclusion of participants with history of anaphylaxis, urticaria, or other significant 
adverse reaction requiring medical intervention after receipt of a vaccine or nanolipid particle. 
Infrequently, people who have received dermal fillers might experience swelling at or near the site 
of filler injection (usually face or lips) following administration of a dose of an mRNA-1273 
vaccine. The swelling appears to be temporary and resolves with medical treatment, including 
corticosteroid therapy. COVID-19 vaccines can be administered to people who have received 
injectable dermal fillers who have no contraindications or precautions for vaccination.38 
Reactogenicity has been noted after mRNA-1273 vaccination. Local (pain, redness, swelling and 
pruritus) and systemic adverse effects (headache, myalgia, fatigue, joint pain, chills, and fever) are 
relatively common, most are of mild or moderate severity and are limited to the first few days after 
vaccination.39 A small percentage of participants may experience late local inflammatory 
reactions, with onset seven or more days after, usually the first vaccination, and characterized by 
redness in the deltoid area of the upper arm and/or pain or itching.39 These reactions are self-
limited and are not a contraindication to subsequent vaccinations in the vaccination series. 
Laboratory abnormalities (including increases in liver function tests and serum lipase levels) 
following injection were observed in clinical studies with similar mRNA-based vaccines. These 
abnormalities were without clinical symptoms or signs and returned toward baseline, pre-
vaccination (Day 1) values over time. The clinical significance of these observations is unknown. 
Myocarditis and pericarditis have been reported following mRNA vaccines in a younger 
population (mostly in adolescents and young adults), and are more common in males especially 
after the second dose of mRNA-1273 and within a few days following receipt of the vaccines.40 
The rate per million second doses given in a 7-day risk period in individuals between the ages of 

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18-39 years of age is estimated to be around 33 per million.41 Symptoms can include chest pain, 
shortness of breath, or palpitations. Whilst some severe cases have been reported, most cases have 
been associated with full resolution of symptoms in the short term; however, long-term follow-up 
is limited.42 It is not known whether the risk of myocarditis or pericarditis is increased following 
additional doses of the vaccine, though data after a third dose of mRNA vaccine are reassuring 
especially with the extended interval between primary series and booster doses compared to the 
doses given within the primary series.43-45 
There is limited experience with administration of an additional dose of the mRNA COVID-19 
vaccines, and it is possible that this additional dose may be associated with more frequent or more 
severe adverse events. 
Further details are provided in the FDA-approved fact sheet and current IB.  
• BNT162b2, BNT162b2 (B.1.351) BNT162b2 (B.1.1.529) and bivalent vaccines for 
Stage 4 (with BA.1 + Wildtype or BA.4/BA.5 + Wildtype) 
BNT162b2 was granted full FDA approval in 2021 and more than 300 million doses of 
BNT162b2 have been administered in the US alone as of early 2022. While the other SARS-
CoV-2 mRNA vaccine candidates manufactured by Pfizer have been given to a small number of 
individuals in the setting of clinical trials, the safety profile of these vaccine candidates is 
believed to be largely similar to the approved wildtype (prototype) vaccine. The total amount of 
immunogens within any study vaccine will be 30 mcg, similar to the authorized boost dose of 
BNT162b2. 
Immediate systemic allergic reactions (e.g., anaphylaxis) can occur following any vaccines. For 
the BNT162b2 vaccine, the rate of anaphylaxis is around 11 cases per million doses 
administered.46 Most of these reactions have onset within 15 minutes of vaccination and most of 
these events occurred in persons with a prior history of allergy. As a precaution, all subjects will 
remain under observation at the study site for at least 30 minutes after injection. Risk management 
also includes exclusion of participants with history of anaphylaxis, urticaria, or other significant 
adverse reaction requiring medical intervention after receipt of a vaccine or nanolipid particle. 
Reactogenicity has been noted after BNT162b2 vaccination. Local (pain, redness, swelling and 
pruritus) and systemic adverse effects (headache, myalgia, fatigue, lethargy, decreased appetite, 
night sweats, malaise, joint pain, diarrhea, nausea, vomiting, chills, and fever) are relatively 
common, most are of mild or moderate severity and are limited to the first few days after 
vaccination.47  Lymphadenopathy has been reported in < 1% of study participants. A subset from 
Study C4591001 Phase2/3 participants of 306 adults at least 18 through 55 years of age who 
completed the primary BNT162b2 two-dose course, received a booster dose (third dose) of 
BNT162b2 ~6 months (range of 4.8 to 8.0 months) after receiving Dose 2. The most frequent 
reactogenicity in participants 18 through 55 years of age were injection site pain (>80%), fatigue 
(>60%), headache (>40%), myalgia (>30%), chills and arthralgia (>20%). 
Myocarditis and pericarditis have been reported following BNT162b2 vaccines in a younger 
population (mostly in adolescents and young adults), and are more common in males especially 
after the second dose of BNT162b2 and within a few days following receipt of the vaccines.40 
According to one study, the rate in individuals 18-24 years of age is 5 times lower after BNT162b2 
second dose compared to mRNA-1273 second dose. Symptoms can include chest pain, shortness 

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of breath, or palpitations. Whilst some severe cases have been reported, most cases have been 
associated with full resolution of symptoms in the short term; however, long-term follow-up is 
limited.40 It is not known whether the risk of myocarditis or pericarditis is increased following 
additional doses of the vaccine, though data after a third dose of mRNA vaccine are reassuring 
especially with the extended interval between primary series and booster doses compared to the 
doses given within the primary series.40  
There is limited experience with administration of an additional dose of the mRNA COVID-19 
vaccines, and it is possible that this additional dose may be associated with more frequent or more 
severe adverse events.  
Further details are provided in the FDA-approved fact sheet and current IB.  
• CoV2 preS dTM-AS03 [B.1.351]) and CoV2 preS dTM-AS03 [D614 + B.1.351]. 
CoV2 preS dTM-AS03 has been found to have an acceptable safety profile in phase 2 and phase 
3 trials totaling 25,000 participants including more than 13,000 receiving the vaccine.24 The total 
amount of immunogens within any Sanofi-manufactured study vaccine candidates will be 5 mcg. 
Immediate systemic allergic reactions (e.g., anaphylaxis) can occur following any vaccine. In the 
phase 2 trial involving 721 participants who received at least one injection, no anaphylaxis was 
reported.23 In the phase 2 booster cohorts, one participant reported a possible anaphylactic reaction 
among 1276 participants. As a precaution, all subjects will remain under observation at the study 
site for at least 30 minutes after injection. Risk management also includes exclusion of participants 
with history of anaphylaxis, urticaria, or other significant adverse reaction requiring medical 
intervention after receipt of a vaccine.  
Reactogenicity has been noted after CoV2 preS dTM-AS03 vaccination. Local (pain, redness, 
swelling and pruritus) and systemic adverse effects (headache, myalgia, fatigue, lethargy, 
decreased appetite, night sweats, malaise, joint pain, diarrhea, chills, and fever) are relatively 
common, most are of mild or moderate severity and are limited to the first few days after 
vaccination.23 Per the current IB, a similar reactogenicity profile was observed in participants who 
received a booster dose.  
Based on the theoretical concern that vaccination with an adjuvanted vaccine containing potent 
immunostimulants may interfere with immunological self-tolerance, potential Immune-Mediated 
Diseases (pIMDs) are adverse events of special interest (AESIs) undergoing special safety 
monitoring for vaccines containing Adjuvant Systems. pIMDs are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurological disorders of interest which may 
or may not have an autoimmune etiology. One example of pIMD is narcolepsy. An increased risk 
of narcolepsy was noted in some individuals after vaccination with Pandemrix, a different AS03-
adjuvanted vaccine for H1N1 influenza Current data suggest that cases of narcolepsy seen 
immediately following the 2009/2010 pandemic were the result of an immune cascade, triggered 
by CD4 T cell cross-reactivity to HA proteins from the H1N1 virus itself and hypocretin. This 
conclusion is consistent with the position reached by the EMA in 2016 when it concluded that “a 
hypothesis that takes into account the potential role of antigen is more likely to explain the 
increased risk of narcolepsy observed with Pandemrix than hypotheses that are based on a direct 
role for the AS03 adjuvant”.48 Safety concerns regarding narcolepsy have not been identified in 
trials of AS03-adjuvanted SARS-CoV-2 vaccine candidates to date.23,24 

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There is limited experience with administration of an additional dose of COVID-19 vaccines, and 
it is possible that an additional dose may be associated with more frequent or more severe adverse 
events.  
Further details are provided in the current IB. 
Risks to Privacy 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating site. Electronic files will be password 
protected. Only people who are involved in the conduct, oversight, monitoring, or auditing of this 
trial will be allowed access to the PHI that is collected. Any publications from this trial will not 
use information that will identify subjects by name. Organizations that may inspect and/or copy 
research records maintained at the participating site for quality assurance (QA) and data analysis 
include groups such as the IRB, NIAID and the FDA. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This web site will not include information that can identify subjects. 
There may be other risks, discomforts or side effects that are unknown at this time. 
Risks of Genetic Testing 
Any genetic data generated will be kept private. There may be a risk that information resulting 
from research genetic testing could be misused for discriminatory purposes. However, state and 
federal laws provide protections against genetic discrimination. Researchers will need to maintain 
confidentiality in order to be granted access to genetic information. 
2.2.2 
Known Potential Benefits 
On March 29, 2022, the FDA authorized an additional booster dose (fourth dose) of mRNA 
vaccine for adults 50 years of age or older and adults with immunocompromising conditions. 
Subsequent to this authorization, the CDC updated its guidance to permit an additional booster 
dose for these groups, acknowledging the potential benefit of a second booster for those at risk for 
severe COVID-19 illnesses as well as for those who received two doses of the Johnson & Johnson 
vaccine. The exact benefit of this second booster dose is difficult to ascertain given the design of 
the studies supporting these recommendations. Variant specific mRNA vaccine candidates have 
been shown to induce similar D614G antibody responses as the prototype mRNA vaccine (i.e. 
back boost). Therefore, receipt of a variant vaccine in this study is not expected to be inferior to 
any benefits received from a second booster dose of a Pfizer or Moderna mRNA vaccine obtained 
outside this trial (i.e. is not inferior to standard care). The Sanofi/GSK COVID-19 vaccine is not 
yet FDA authorized; the potential benefit of a booster dose is unknown.  
On August 31th, 2022, the  FDA amended the EUAs of the Moderna COVID-19 Vaccine and the 
Pfizer-BioNTech COVID-19 Vaccine to authorize bivalent formulations of the vaccines for use as 
a single booster dose at least two months following primary or booster vaccination. The updated 
bivalent booster vaccines contain two mRNA components  that code for 2 different Spike proteins 
of SARS-CoV-2 virus, one for the original or “prototype” strain Spike protein, and the other for 

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the S protein variant common in o BA.4 and BA.5 lineages of the Omicron variant of SARS-CoV-
2. Roll-out of a different bivalent vaccine, Prototype + Omicron BA.1 for use as a booster dose 
,will occur in other countries including the United Kingdom and Canada.49,50 We do know from 
this study and others conducted by the companies that antibody levels to various variants can be 
significantly increased by a fourth booster dose.  Also based on the current study and studies 
conducted by the companies,  a Prototype + Omicron BA.1 bivalent booster does increase the 
overall levels of antibody to various variants. However, there are no data to determine if one of 
these bivalent variant vaccines will provide better protection against symptomatic disease and a 
more robust immune response. Knowing that the highest risk of severe disease is still seen in the 
older population andto minimize the risk for participants in arms 16 and 17 (stage 4)  we will limit 
enrollment to individuals between the ages of 18 to 49 years.  
There may be benefit to society resulting from insights gained from participation in this study due 
to the emerging threat of the SARS-CoV-2 variants.  
 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 4: Objectives and Endpoints (Outcome Measures) 
OBJECTIVES 
ENDPOINTS  (OUTCOME MEASURES) 
Primary 
 
• 
To evaluate humoral immune responses of 
candidate SARS-CoV-2 variant vaccines.  
 
Response rate, and magnitude of SARS-CoV-2-specific 
antibody binding and neutralization titers in serum 
samples as assessed via a range of assays at all 
timepoints. 
Secondary 
 
• 
To evaluate the safety of candidate SARS-
CoV-2 variant vaccines 
• 
Local and systemic solicited Adverse Events for 7 days 
following each vaccine dose. 
• 
Unsolicited Adverse Events from Dose 1 to 28 days 
following each vaccine dose. 
• 
SAEs, MAAEs, NOCMCs, AESIs, and AEs leading to 
withdrawal from the study from Dose 1 to 12 months 
after last vaccine dose. 
Exploratory 
 
• 
To assess, in at least a subset of samples, the 
B cell immune response of candidate SARS-
CoV-2 variant vaccines. 
• 
Magnitude, phenotype and percentage of SARS-CoV-2 
specific B cells, as measured by flow cytometry and 
targeted B cell subset analysis at selected time points 
post-vaccination. 
• 
To assess, in at least a subset of samples, the 
SARS-CoV-2 spike protein-specific T cell 
responses of candidate SARS-CoV-2 variant 
vaccines. 
• 
Magnitude, phenotype, and percentage of cytokine 
producing S protein T cells as measured by flow 
cytometry at selected time points post-vaccination. 
• 
To assess, in at least a subset of samples, the 
magnitude, phenotype, and percentage of 
innate immune cells with candidate SARS-
CoV-2 variant vaccines. 
• 
Magnitude, phenotype, and percentage of innate 
immune cells as measured by flow cytometry at D1 and 
14 days after each vaccination.  

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OBJECTIVES 
ENDPOINTS  (OUTCOME MEASURES) 
• 
To assess, in at least a subset of samples, the 
functional potential of SARS-CoV-2 specific 
antibodies to mediate Fc-effector functions 
across candidate SARS-CoV-2 variant 
vaccines.  
 
• 
Characterization of antigen-specific antibody by a) 
subclass, b) isotype, c) ability to interact with Fc 
receptors, d) innate immune receptors, e) lectin-like 
molecules and f) lectins at different times post-
vaccination.  
• 
Functional Fc effector assessments which may include 
quantification of antigen specific antibody-mediated 
NK cell activation (ADCC-NK) levels, antibody-
dependent cellular phagocytosis (ADCP) levels, 
antibody-dependent complement deposition (ADCD) 
and/or antibody-dependent neutrophil 
activation/phagocytosis levels at different times post-
vaccination. 
• 
To evaluate breakthrough SARS-CoV-2 
infection by sequencing strains for variant 
spike lineage and assessing anti- nucleocapsid 
serology. 
• 
Sequence analysis on breakthrough NAAT-confirmed 
SARS-CoV-2 strains at any time post-vaccination 
• 
Anti- nucleocapsid immunoassay at different times 
post-vaccination. 
 
 
 

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4. 
STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2 randomized, adaptive, open label, non-placebo controlled multi-site, multi-stage 
clinical trial in individuals, 18 years of age and older, who are in stable state of health, have 
received a complete authorized/approved vaccine series (primary series + booster either with 
homologous or heterologous vaccine products) and meet all other eligibility criteria. 
Approximately 1500 subjects will be enrolled at up to 30 clinical research sites. At enrollment, 
subjects will be stratified by i) age (18-64 and ≥ 65 years of age) (however arms 16 and 17 or stage 
4 will only enroll participants between the ages of 18-49 years) and ii) confirmed prior SARS-
CoV-2 infection, and randomly assigned to one of several study arms of variant vaccines. The 
study will target the enrollment of approximately 45% of older adults (≥ 65 years of age) for stages 
1, 2 and 3. Additionally, the study will target to enroll approximately 20% enrollment of 
participants with a history of confirmed SARS-CoV-2 infection. It is estimated that another 10-
30% will have undiagnosed prior infection.  Taken together, we anticipate about 40% of the total 
population will have prior infection. The study team will decide, based on latest epidemiology, if 
enrollment of participants in any particular groups are slowed in order to ensure good 
representation of previously infected and not previously infected.   
The adaptive design of this study will include additional arms, an increase in sample size, or 
additional vaccine doses or different dosing and provide rapid information about the 
immunogenicity and the safety of candidate SARS-CoV-2 variant vaccines to inform near term 
public health policy. This trial will provide proof of concept on how variant vaccines could shift 
the immune response to become more specific to the VOCs’ antigens or broaden the antigenic 
landscape for emergent variants.   
Study arms and stages are described in Section 1.1.  
Screening can occur up to 28 days prior to the first dose of study product or on Day 1 prior to 
administration of Dose 1. Safety will be assessed during the study and blood will be drawn for 
immunogenicity assays at enrollment and in-person follow-up visits. Swabs will be self-collected 
or collected by staff at unscheduled illness visits to evaluate breakthrough SARS-CoV-2 infection 
(symptomatic infection or asymptomatic infection with a positive SARS-CoV-2 test outside the 
study).  
Schedules of assessments are found in Section 1.2. 
4.2 
Scientific Rationale for Study Design 
An open-label study will facilitate the need for rapid review and dissemination of study data for 
public health reasons. Safety findings are not expected to be dissimilar from Phase 1/2/3 studies 
conducted for similar vaccine constructs. Randomization will improve comparisons between the 
different arms. Each stage will contain an arm with the prototype vaccine with the exception of 
stage 4.  

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Selected arms will assess 2 study doses of vaccine candidates to assess if 2 doses provide a more 
durable response and more specific to variant viruses.  
We chose the interval of 4 months since a recent study performed by our investigators showed that 
an interval of 3 months between primary series and boost had acceptable safety and 
immunogenicity responses.19  
4.3 
Justification for Doses 
The dosages of mRNA vaccines selected are those authorized for booster doses under EUA, and 
previously shown in prior studies to elicit good immune responses with no major safety concerns. 
In an open label study of participants in the Moderna Phase 3 clinical trial who received a single 
50 mcg booster dose of mRNA-1273 ≥ 6 months after a primary series, a 13 fold rise in antibody 
titers against D614G was noted from pre-boost levels as well as a 17-fold rise in in titers against 
the B.1.617.2 variant.20 This is now the CDC recommended dose for booster vaccinations with the 
Moderna mRNA-1273 product in immunocompetent adults, to be given at least 5 months from the 
last inoculation in the primary series.51 Similarly, in a recent study, boosting with a 50 mcg total 
antigen dose of a bivalent mRNA-1273.213 vaccine (a 1:1 mix of beta and delta variant mRNA) 
produced only modestly lower antibody titers than using a 100 mcg booster dose.21 A separate 
study evaluating safety and immunogenicity of multiple boost strategies suggests that a 
heterologous boost strategy generates antibody and neutralizing responses and that 100 mcg of 
mRNA-1273 (the authorized dose at the time) is likely higher than needed for a booster dose after 
primary mRNA series.52 In addition, surveillance data indicate that following an mRNA boost, 
local and systemic reactions are less common and myocarditis is rarely reported, suggesting that 
the currently authorized doses are safe.45 These findings support the evaluation of mRNA-1273, 
mRNA-1273.351, mRNA-1273.617.2 and mRNA-1273.529 at total dosages of 50 mcg per 
vaccination.  
For BNT162b2, the dose is the same for primary or booster doses in adults. In an open-label 
clinical study, immunogenicity and safety of a fourth dose of either 30 mcg of BNT162b2 (Pfizer–
BioNTech) or 50 mcg of mRNA-1273 (Moderna) administered 4 months after the third dose was 
assessed in 154 and 120 health care workers, respectively.25 After the fourth dose, both messenger 
RNA (mRNA) vaccines increased neutralizing antibody titers to D614G, B.1.617.2 and B.1.1.529 
by a factor of 9 to 10 and were slightly higher than those achieved after the third dose.25 There 
were no significant adverse events with only mild system and local reactogenicity reported which 
was comparable with previous doses of mRNA vaccines. The bivalent booster of BNT162b2  was 
authorized by the FDA based  on pre-clinical data (Omicron BA.4/BA.5 + prototype).53  
For CoV2 preS dTM-AS03 vaccines, none is currently approved. The dose used for booster 
vaccination is as established in the phase 2 trial and is the adjuvanted formulation with 5 mcg for 
any variant vaccine candidate in stage 3.24 That booster dose increased neutralizing antibody titers 
when used as a heterologous (18-30 times) or homologous (≥ 84 times) boost.24 However, no data 
exist on CoV2 preS dTM-AS03 vaccines as a second boost after primary series with mRNA or 
adenoviral vectored vaccines. 

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5. 
STUDY POPULATION 
All participants will have received a complete (primary and booster) US approved/authorized 
vaccine series. The US population has received either homologous primary series and boost (i.e. 
Moderna mRNA-1273 for 1st dose, second dose, and booster), or heterologous boosters, and 
some were infected with SARS-CoV-2 either prior to or after vaccination. This trial will enroll 
this immunologically diverse population, to ensure any findings are applicable to the larger 
population.  
Based on CDC data about use of primary vaccine or boost (https://covid.cdc.gov/covid-data-
tracker/#vaccinations_vacc-total-admin-rate-total), it is estimated that of people in the US that 
have received a primary vaccine series and booster: 
50% will have received Pfizer primary series and Pfizer boost, 
37% will have received Moderna primary series and Moderna boost, 
4% will have received Pfizer primary series and Moderna boost, 
3% will have received Moderna primary series and Pfizer boost, 
1% will have received Janssen primary series and Janssen boost, 
2% will have received Janssen primary series and Moderna boost, 
2% will have received Janssen primary series and Pfizer boost. 
Additionally, approximately 20% of the US population has been infected with SARS-CoV-2, 
likely higher with asymptomatic infections.54 
It is anticipated the enrollment into this trial will be similar to these proportions.  
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician, licensed to 
make medical diagnoses and listed on the Form FDA 1572. No exemptions are granted on 
Subject Inclusion or Exclusion Criteria in DMID-sponsored studies. 
5.1 
Inclusion Criteria 
See Inclusion Criteria in Section 1.1.  
5.2 
Exclusion Criteria 
See Exclusion Criteria in Section 1.1. 
5.2.1 
Exclusion of specific populations 
The effects of SARS-CoV-2 vaccines on the developing fetus are not known, though there are 
data to suggest that mRNA vaccines are safe. Pregnant subjects will not be eligible for the trial as 
the immune responses to vaccines can be different than non-pregnant subjects. Children will not 
be included in this trial as presently there are limited safety data in adults for the variant strains.  
5.3 
Inclusion of Vulnerable Subjects 
No vulnerable subjects will be enrolled in this trial.  
5.4 
Lifestyle Considerations 
During this study subjects are asked to: 

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• Follow public health guidance on preventing SARS-CoV-2 infection. 
5.5 
Screen Failures 
Screening and enrollment visits may be combined. However, the participating site PI or qualified 
designee is to review the inclusion and exclusion criteria and determine the subject’s eligibility 
for the study. Individuals who do not meet the criteria for participation in the study (screen 
failure) can be rescreened if the exclusionary condition is considered to be temporary in nature 
by the investigator.  
Only the following information will be collected on screen failures: demographics (age, screen 
number, sex, ethnicity, and race) and reason for ineligibility. Subjects who are found to be 
ineligible will be told the reason for ineligibility. 
5.5.1 
Strategies for Recruitment and Retention 
The study will target recruitment of racial and ethnic diversity of the community in which the study 
will be conducted. Potential subjects will learn about the study via IRB-approved recruitment 
strategies, including direct mailing, recruitment from an IRB-approved trial registry, press 
releases, social media and local advertisements/flyers. Screening will begin with a brief approved 
telephone call from study staff. Information about the study will be presented to potential subjects 
and questions about their health and ability to comply with the study visit schedule will be asked 
of potential subjects to presumptively determine eligibility. Appointments will be made at the 
research clinic for potential subjects who are interested in the study for further screening 
procedures and additional protocol-specific information. 
5.5.2 
Retention 
Study retention strategies will include education and explanation of the study schedule and 
procedures during screening and enrollment/baseline visits and restriction of enrollment to 
persons who can attend all study visits. Participating subjects will be reminded of subsequent 
visits during each visit, and study staff will contact subjects prior to appointments. Study staff 
will contact subjects who miss appointments to encourage them to return for completion of 
safety evaluations. 
5.5.3 
Compensation Plan for Subjects 
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with local IRB requirements, and subject to local IRB approval. Reimbursements will 
be disbursed at specific timepoints during the study with the amount contingent on completing 
study procedures. 
5.5.4 
Costs 
There is no cost to subjects for the research tests, procedures/evaluations or study product while 
taking part in this trial. Procedures and treatment for clinical care may be billed to the subject, 
subject’s insurance or third party.

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6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration 
6.1.1 
Study Product Description 
mRNA-1273 (prototype), mRNA-1273.351 (Beta), mRNA-1273.617.2 (Delta) and mRNA-
1273.529 (Omicron) 
mRNA-1273 (0.2 mg/mL) is an LNP dispersion containing an mRNA that encodes for the pre 
fusion stabilized S protein of the Wuhan-Hu-1 strain of SARS-CoV-2. mRNA-1273 consists of 
an mRNA Drug Substance that is manufactured into LNPs composed of the proprietary ionizable 
lipid, SM-102, and 3 commercially available lipids, cholesterol, 1,2-distearoyl-sn-glycero-3-
phosphocholine (DSPC), and PEG2000 DMG. 
mRNA-1273.351 (0.1 mg/mL) is formulated in the same way but contains mRNA that encodes 
for the prefusion stabilized S protein of the B.1.351 (Beta) variant SARS-CoV-2 strain. 
mRNA-1273.617.2 (0.2 mg/mL) is formulated in the same way but contains mRNA that 
encodes for the prefusion stabilized S protein of the B.1.617.2 (Delta) variant SARS-CoV-2 
strain. 
mRNA-1273.529 (0.2 mg/mL) is formulated in the same way but contains mRNA that encodes 
for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain. 
BNT162b2 (wildtype), BNT162b2 (B.1.351, Beta), BNT162b2 (B1.1.529, Omicron), 
BNT162b2 bivalent  (wildtype and  Omicron BA.1) and BNT162b2 bivalent (wildtype and 
Omicron BA.4/BA.5) 
BNT162b2 (500 mcg/mL for stage 2) is a preservative-free, sterile dispersion of RNA 
formulated in LNP in aqueous cryoprotectant buffer. mRNA encodes for the pre fusion stabilized 
S protein of the ancestral strain of SARS-CoV-2.  
BNT162b2 (B.1.351) (500 mcg/mL for stage 2) is formulated in the same way but contains 
mRNA that encodes for the prefusion stabilized S protein of the B.1.351 (Beta) variant SARS-
CoV-2 strain. 
BNT162b2 (B.1.1.529)(500 mcg/mL for stage 2) is formulated in the same way but contains 
mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant 
SARS-CoV-2 strain. 
BNT162b2 bivalent (wildtype and  Omicron BA.1 100mcg/mL for stage 4) is formulated in 
the same way but contains mRNA that encodes for the prefusion stabilized S protein of the 
Omicron BA.1 variant SARS-CoV-2 strain and the ancestral strain of SARS-CoV-2.. 
BNT162b2 bivalent (wildtype and  Omicron BA.4/BA.5 100mcg/mL for stage 4) is 
formulated in the same way but contains mRNA that encodes for the prefusion stabilized S 
protein of the Omicron BA.4/BA.5 variant SARS-CoV-2 strain and the ancestral strain of SARS-
CoV-2. 
 

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CoV2 preS dTM-AS03 [D614] (prototype), CoV2 preS dTM-AS03 [B.1.351] (Beta), and 
CoV2 preS dTM-AS03 [D614 + B.1.351] (prototype + Beta) 
CoV2 preS dTM-AS03 [D614] (Recombinant COVID-19 Vaccine 20 mcg/mL + AS03) is a 
liquid formulation made of recombinant protein placed in a formulation buffer and to be mixed 
with equal volumes of AS03 adjuvant (supplied separately) at the study site before 
administration. The antigen solution contains the Spike protein sequence of the ancestral strain of 
SARS-CoV-2.  AS03 is an adjuvant system containing α-tocopherol and squalene in an oil/water 
emulsion. For this formulation, the antigen and AS03 vials are not packaged in a carton box 
together but are supplied as individual vials. 
CoV2 preS dTM-AS03 [B.1.351] (Recombinant COVID-19 Vaccine B1.351 20 mcg/mL+ 
AS03) is formulated in the same way but contains the Spike protein sequence of the B.1.351 
(Beta) variant SARS-CoV-2 strain.  Both antigen and AS03 vials are packaged in a carton box. 
CoV2 preS dTM-AS03 [D614 + B.1.351] (Recombinant COVID-19 Bivalent Vaccine 10/10 
mcg/mL + AS03) is formulated in the same way but contains the Spike protein sequences of the 
ancestral and B.1.351 (Beta) variant SARS-CoV-2 strains.  Both antigen and AS03 vials are 
packaged in a carton box.Diluent: 0.9% NaCl for injection, USP 
The USP grade 0.9% NaCl or normal saline for injection is a sterile, nonpyrogenic, isotonic 
solution; each mL contains NaCl 9 mg. It contains no bacteriostatic agent, antimicrobial agent, 
preservatives, or added buffer and is supplied only in single-dose containers. This product should 
be used to dilute the vaccine to the desired concentration. 
6.1.2 
Dosing and Administration 
 mRNA-1273, mRNA-1273.351, mRNA-1273.617.2 and mRNA-1273.529 
mRNA-1273 (0.2 mg/mL), mRNA-1273.351 (0.1 mg/mL), mRNA-1273.529 (0.2 mg/mL), and 
mRNA-1273.617.2 (0.2 mg/mL).   
Products will be used alone or in combination as specified in Table 1, and will be diluted in 0.9% 
NaCl for injection, USP to obtain an antigen content of 50 mcg in a 0.5 mL dose. Each dose will 
be administered via IM injection into the deltoid muscle. 
The expiration time of the dosing syringe containing the prepared study vaccine is 8 hours at room 
temperature after the solution is drawn into the dosing syringe. 
When applicable, the second dose of study vaccine can be administered in either arm regardless of 
the arm that previously administered.  
BNT162b2, BNT162b2 (B.1.351), BNT162b2 (B1.1.529, Omicron), BNT162b2 bivalent 
(wildtype and  Omicron BA.1) and BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5) 
BNT162b2, BNT162b2 (B.1.351) and BNT162b2 (B.1.1.529 Omicron) at 500 mcg/mL 
concentration for stage 2 and  will be used alone or in combination as specified in Table 1 and will 
be diluted in 0.9% NaCl for injection, USP to obtain an antigen content of 30 mcg in a 0.3 mL 
dose. Each dose will be administered via IM injection into the deltoid muscle. 

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For stage 4, BNT162b2 bivalent (wildtype and Omicron BA.1 or wildtype and BA.4/BA.5) are 
provided at 100 mcg/mL concentration and neither dilution nor mixing are needed for these 
formulations. 
CoV2 preS dTM-AS03 [D614], CoV2 preS dTM-AS03 [B.1.351], and CoV2 preS dTM-AS03 
[D614 + B.1.351] 
The multi-dose vial of CoV2 preS dTM antigen, either monovalent or bivalent antigen, will be 
mixed with the multi-dose vial of AS03 adjuvant prior to administration to obtain an antigen 
content of 5 mcg in a 0.5 mL dose. Vaccine formulations will be prepared in the CoV2 preS dTM 
antigen vials by adding an equal volume of adjuvant. A maximum of 10 doses can be used from a 
single prepared investigational vaccine final product. 
After mixing the investigational product, the combined final product can be held for up to 12 hours 
post preparation at 2 to 8 °C or at controlled room temperatures (up to 23 to 27 °C) and must be 
protected from light. Syringes containing the final product should be covered to limit exposure to 
light as well. 
 
For all stages , the pharmacist will prepare a single dose for each subject based on study arm 
assignment.  
See the protocol-specific Manual of Procedures (MOP) for detailed information on the preparation, 
labeling, storage, and administration of vaccine for each cohort. Vaccine preparation will be 
performed by the participating site’s research pharmacist on the same day of vaccine 
administration to the subject. 
Subjects will be observed in the clinic for at least 30 minutes post each vaccination. Any AEs will 
be recorded on the appropriate DCF prior to discharge from the clinic 
6.1.3 
Dose Modifications 
Not applicable. 
6.2 
Accountability/Handling/Storage/Preparation 
6.2.1 
Acquisition and Accountability 
All the vaccines (and diluents as needed) will be provided by the DMID repository: 
DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com 
All study products will be shipped to the clinical research site upon request and approval from 
DMID. 
Accountability 

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The participating site PI is responsible for study product distribution and disposition and has 
ultimate responsibility for study product accountability. The participating site PI may delegate to 
the participating site’s research pharmacist responsibility for study product accountability. The 
participating site’s research pharmacist will be responsible for maintaining complete records and 
documentation of study product receipt, accountability, dispensation, storage conditions, and final 
disposition of the study product(s).  
Destruction 
After the study treatment period has ended or as appropriate over the course of the study after 
study product accountability has been performed, disposition of unused and used study product 
vials should occur as noted: 
Unused and used study product vials: 
Should be destroyed on-site following applicable site procedures or by the site’s selected 
destruction vendor. Following the site’s procedure for the destruction of hazardous 
material or study product destruction policy/SOP when destroying used and unused items 
with a second staff member’s observation and signed verification (two signatures) that 
the vials were discarded. 
A certificate of destruction or documentation of destruction should be provided to the 
sponsor and retained in the Pharmacy Binder once completed. 
Used syringes may be destroyed in accordance with site-specific SOPs. 
6.2.2 
Formulation and Appearance 
mRNA-1273, mRNA-1273.351, mRNA-1273.617.2 and mRNA-1273.529 are provided as a 
sterile liquid for injection, white to off-white suspension in appearance. 
BNT162b2, BNT162b2 (B.1.351) and BNT162b2 (B.1.1.529 Omicron) and BNT162b2 bivalent 
(wildtype and Omicron BA.1 or wildtype and  Omicron BA.4/BA.5) are provided as a sterile, 
clear colorless liquid for injection. 
CoV2 preS dTM-AS03 [D614], CoV2 preS dTM-AS03 [B.1.351], and CoV2 preS dTM-AS03 
[D614 + B.1.351] antigen formulations are provided as a sterile, clear, colorless solution of 
SARS-CoV-2 prefusion S proteins. The antigen solutions can contain endogenous particles. If 
present, these light-colored particles are slow sinking and suspended in solution. AS03 adjuvant 
is a whitish to yellowish homogenous milky liquid emulsion. After mixing, the vaccine is a 
whitish to yellowish homogeneous milky liquid emulsion. 
Diluent: 0.9% NaCl for injection, USP 
The USP grade 0.9% NaCl or normal saline for injection is a sterile, nonpyrogenic, isotonic 
solution; each mL contains NaCl 9 mg. It contains no bacteriostatic agent, antimicrobial agent, 
preservatives, or added buffer and is supplied only in single-dose containers.  
Each of the study products will be labeled according to manufacturer specifications and include 
the statement “Caution: New Drug Limited by Federal Law to Investigational Use.” 
6.2.3 
Product Storage and Stability 

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The storage of mRNA-1273,BNT162b2, and CoV2 preS dTM-AS03 vials depend on the 
presentation (i.e. commercial lots have different storage conditions from investigational lots).  For 
these reasons, refer to the MOP for storage conditions for vaccine candidates as well as storage of 
diluent.  
Prepared doses are stable for clinical in-use for:  
• mRNA-1273, mRNA-1273.351, mRNA-1273.617.2 and mRNA-1273.529: up to 8 hours 
at room temperature  
•  BNT162b2 bivalent (wildtype and Omicron BA.1 or wildtype and Omicron BA.4/BA.5): 
up to 12 hours between 2 and 30C (35 to 86F)  after vial is first punctured. 
• BNT162b2, BNT162b2 (B.1.351) and BNT162b2 (B.1.1.529 Omicron BA.1 and 
BA.4/BA.5): up to 6 hours at room temperature after 1st vial is punctured. 
• CoV2 preS dTM-AS03 [D614], CoV2 preS dTM-AS03 [B.1.351], and CoV2 preS dTM-
AS03 [D614 + B.1.351]: up to 12 hours post preparation at 2 to 8 °C or at controlled room 
temperatures (up to 23 to 27 °C) and must be protected from light 
 
Study Product Temperature Accountability 
The temperature of the storage unit must be manually recorded daily (excluding non-business days 
and holidays, as applicable) and continuously monitored and recorded during the course of this 
trial per site-specific SOPs, and documentation will be maintained. If the temperature fluctuates 
outside of the required range, the affected study product(s) must be quarantined at the correct 
storage temperature and labeled as ‘Do Not Use’ (until further notice).  
Study product must be stored in a secure area with limited access (pharmacy staff only) and must 
be stored as above.  
6.2.4 
Preparation 
Refer to the protocol-specific MOP for details about preparation. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Treatment Assignment Procedures 
Per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) guideline E6: GCP, screening records will be kept at the participating site to 
document the reason why an individual was screened, but failed trial entry criteria. The reasons 
why individuals failed screening will be recorded in Advantage eClinical, the electronic data 
capture (EDC) system that the Statistical and Data Coordinating Center (SDCC) develops and 
manages.  
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subjects will be enrolled. 
6.3.2 
Randomization and Blinding 
Subjects will be randomized to study intervention in an equal allocation ratio for each stage.  The 
study will be open label and study sites will administer product to a subject according to which 
study arm the subject has been assigned. Sites will be asked to recruit for all arms within a stage. 

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6.3.3 
Blinding and Masking Procedures 
This study is unblinded. 
6.4 
Study Intervention Compliance 
Each dose of study product will be administered by a member of the clinical research team that is 
qualified and licensed to administer the study product. Administration and date, time, and 
location of injection will be recorded on the appropriate DCF. 
6.5 
Concomitant Therapy 
Concomitant medications include prescription medications and vaccinations taken within 28 
days of screening or Day 1. Topical, ophthalmic and otic medications, herbal supplements and 
vitamins will not be collected. This information is asked to assess eligibility. Only COVID-19 
vaccination received at any time in the past will be captured in the trial database.  After 
enrollment, immunosuppressant drugs, COVID-19 vaccines received outside of the study as well 
as COVID-19 related treatment and prophylaxis should be reported at any time during study 
participation and captured in the trial database. At each study visit, if there are new SAEs, 
concomitant medications should be recorded on the appropriate DCF and not included in the 
database unless these are immunosuppressant drugs, COVID-19 vaccines received outside of the 
study or COVID-19 related treatment and prophylaxis. 
6.5.1 
Rescue Medicine 
Not Applicable. 
6.5.2 
Non-Research Standard of Care 
Not Applicable. 

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7. 
STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1 
Halting Criteria 
The study will be halted in a given arm if any of the following events occur following any dose: 
1- Any subject experiences an SAE after administration of the vaccine that is considered 
related to vaccine. 
2- Any subject experiences laryngospasm, bronchospasm or anaphylaxis within 24 hours 
after administration of vaccine that is considered related to vaccine. 
3- Any subject experiences ulceration, abscess or necrosis at the injection site that is 
considered related to vaccine administration. 
4- Two (2) or more subjects experience an immediate IgE-mediated allergic reaction such as 
generalized urticaria (defined as occurring at three or more body parts) that is considered 
related to vaccine. 
5- Three (3) or more subjects experience a Grade 3 AE (unsolicited) related to vaccine 
administration, in the same Preferred Terms based on the Medical Dictionary for 
Regulatory Activities (MedDRA) coding. 
6- One (1) or more participant with myocarditis and/or pericarditis meeting the CDC case 
definition that is considered related to study vaccine. 
7.1.2 
Criteria for Continuation of Dosing and Redosing 
In the event a halting rule is met: 
An unscheduled safety analysis by the DSMB will be required for approval of further enrollment 
Further administration of any study vaccine boost arms will be suspended until an assessment by 
the DSMB takes place. 
7.1.3 
Discontinuation of Study Intervention 
For any arm of the study where participants will receive more than a single dose, subjects will 
need to be reassessed prior to the second dose. The following events constitute contraindications 
to any further administration of study vaccines. If any of these events occur during the study 
prior to the next vaccination, the subject will not receive the next vaccination but will be 
encouraged to continue study participation for safety and immunogenicity evaluations as per the 
Schedule of Activities for subjects receiving a single dose of vaccine.  
• Any clinically significant medical condition that, in the opinion of the participating site 
PI or appropriate sub-investigator, poses an additional risk to the subject if he/she 
continues to participate in the study. 
• Receipt of SARS-CoV-2 vaccine outside of the study or SARS-CoV-2 immunoglobulin, 
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• Confirmed symptomatic or asymptomatic SARS-CoV-2 infection after entry. 
• Anaphylaxis or unexpected systemic hypersensitivity reaction following the 
administration of a prior study vaccination. 
• Any SAE judged to be related to vaccine. 
• Pregnancy. 
• New information becomes available that makes further participation unsafe or interferes 
with the evaluation of responses. 
• 
Termination of this trial. 
7.1.3.1 
Delay of Study Vaccination 
If any of these events occur at the time scheduled for vaccination, the subject may be vaccinated 
at a later date. 
• 
Acute moderate or severe infection with or without fever at the time of vaccination. 
• 
Fever, defined as oral temperature ≥38.0°C (100.4°F) at the time of vaccination. 
Subjects with a minor illness without fever, as assessed by the participating site PI or appropriate 
sub-investigator, can be administered vaccines. Subjects with an oral temperature of 38.0°C 
(100.4°F) or higher will be re-contacted within the window specified in the SOA and re-
evaluated. 
For subjects for whom a second dose is planned, it is preferred that the vaccination still occur 
within the window specified in the SOA if possible but delays outside the windows are permitted 
(would still be a protocol deviation).  If intercurrent SARS- CoV-2 infection occurs between the 
first and prior to the planned second study dose, no second vaccination will be given. 
7.1.4 
Follow-up for Subjects that Discontinued Study Intervention 
Discontinuation of study intervention does not require discontinuation from the study, and the 
remaining study procedures should be completed. Participants who do not receive a second dose 
will revert to the schedule of activities (SOA) for single dose participants.   
If a clinically significant finding is identified, including, but not limited to, changes from 
baseline, after enrollment, the participating site PI or qualified designee will determine if any 
change in subject management is needed (Table 3).  
7.1.5 
Follow up for Subjects with a Suspicion for Myocarditis and/or Pericarditis 
In the event that a subject develops symptoms which in the judgement of the investigator, is 
consistent with a case of suspected myocarditis and/or pericarditis within 4 weeks from 
vaccination, the site will conduct an unscheduled illness visit. Additionally, a serum sample will 
be obtained and stored for potential biomarker testing at a central laboratory. The site will 
coordinate an appropriate diagnostic workup to make a determination of probable or confirmed 
myocarditis and/or pericarditis which may include, but is not limited to, an ECG, cardiac 
troponin testing (T or I) and referral to a cardiologist (directly, or through the emergency 
department or primary care clinic). The suspected myocarditis and/or pericarditis case should be 
reported to the DMID Medical Monitor within 24 hours of site awareness. 

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The definitions below are intended to serve as a guide to help in the reporting of suspected cases 
of myocarditis and/or pericarditis; however, the diagnosis of suspected cases is left to the 
investigator’s clinical judgement.  
7.1.5.1 
Probable Case of Acute Myocarditis 
Presence of ≥ 1 new or worsening of the following clinical symptoms:  
• Chest pain/pressure/discomfort  
• Dyspnea/shortness of breath/pain with breathing  
• Palpitations  
• Syncope  
AND  
Presence of ≥ 1 new finding of the following:  
• Troponin level above upper limit of normal (any type of troponin)  
• Abnormal electrocardiogram (ECG or EKG) or rhythm monitoring findings consistent with 
myocarditis which includes at least one of the following:  
▪ ST segment or T-wave abnormalities  
▪ Paroxysmal or sustained atrial, supraventricular, or ventricular arrhythmias  
▪ AV nodal conduction delays or intraventricular conduction defects  
• Abnormal cardiac function or wall motion abnormalities on echocardiogram  
• Cardiac magnetic resonance imaging (cMRI) finding consistent with myocarditis55  
AND  
• No other identifiable cause of the symptoms and findings 
 
7.1.5.2 
Confirmed Case of Acute Myocarditis  
Meets the case definition for a probable case  
AND 
• Histopathologic confirmation of myocarditis (using Dallas criteria)56 OR 
• cMRI findings consistent with myocarditis in the presence of troponin level above upper limit 
of normal (any type of troponin)  
AND 
• No other identifiable cause of the symptoms and findings  
7.1.5.3 
Acute Pericarditis Case Definition  
Presence of ≥ 2 new or worsening of the following clinical features57:  

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• Acute chest pain (Typically described as pain made worse by lying down, deep inspiration, or 
cough; and relieved by sitting up or leaning forward, although other types of chest pain may 
occur)  
• Pericardial rub on examination  
• New ST-elevation or PR-depression on EKG  
• New or worsening pericardial effusion on echocardiogram or magnetic resonance imaging  
 
7.1.5.4 
Myopericarditis Case Definition  
Participants who meet criteria for both myocarditis and pericarditis may be described under 
myopericarditis. 
 
7.2 
Subject Withdrawal from the Study and Replacement 
Subjects are free to withdraw from participation in the study at any time upon request, without 
any consequence. 
A study subject will be discontinued from participation in the study if any of the following 
reasons occur prior to initial dosing: 
• Request by the subject to terminate participation. 
• Initial vaccine is not administered. 
A subject may be removed from the study for the following reasons post initial dosing; however, 
whenever possible the subject should be followed for safety and immunogenicity evaluations per 
protocol: 
• Subject becomes pregnant before receiving the additional dose of vaccine. 
• Study non-compliance to protocol requirements that in the opinion of the participating 
site PI or appropriate sub-investigator poses an increased risk or compromises the validity 
of the data. 
• Lost to follow-up. 
• If the subject met an exclusion criterion for participation in the study (either newly 
developed or not previously recognized) that precludes further study participation. 
• Request of primary care provider, the IRB, FDA, or NIAID. 
• Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the participating site PI or appropriate sub-investigator 
might compromise the safety of the subject, interferes with the subject’s successful 
completion of this study, or interferes with the evaluation of responses. 
• If any AE or situation occurs such that continued participation in the study would not be 
in the best interest of the subject. 

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• Any SAE judged to be related to vaccine. 
If the subject agrees, every attempt will be made to follow all AEs through resolution or 
stabilization. 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after signing 
the informed consent form (ICF) and administration of the study product will not be replaced. 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after signing 
the ICF but before administration of the first study product may be replaced. 
The reason for subject discontinuation or withdrawal from the study will be recorded on the 
appropriate DCF. 
7.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to appear for a follow-up 
assessment. Extensive effort (i.e., generally three documented contact attempts via telephone 
calls, e-mail, etc., made on separate occasions) will be made to locate or recall the subject, or at 
least to determine the subject’s health status. These efforts will be documented in the subject’s 
study file. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Immunogenicity Assessments 
8.1.1 
Screening or Enrollment/Baseline Procedures 
There is a small amount of risk to subjects who report that they are in stable state of health but 
have an unknown health problem at the time of the enrollment/baseline visit. Screening 
assessments can occur up to 28 days before or at the subject’s first vaccination visit (Day 1). At 
the screening (optional) or enrollment visit, and prior to any other study-related activities, the 
participating site PI or appropriate designee will provide the subject with detailed study 
information and will obtain written informed consent. 
Some or all of the following assessments are performed during the screening (optional) or 
enrollment visit to determine eligibility requirements as specified in the inclusion and exclusion 
criteria: 
• 
Obtain a complete medical history. 
• 
Demographic information. 
• 
Review pre-study medications at screening and record on the appropriate DCF (refer to 
Section 6.5). Review all licensed/approved and any experimental vaccines (the review of 
licensed/approved vaccines other than COVID-19 vaccines is limited to 28 days prior to 
screening/enrollment). 
• 
Review any participation in investigational trials in the last 28 days. 
• 
Measure vital signs (HR, BP, and oral temperature), and height and weight for 
determination of BMI. 
• 
Targeted physical examination.  A targeted exam is one that is targeted to assess any 
symptoms or medical conditions.  The site PI (or designee) determines what exam is 
needed. An individual with no symptoms and no relevant medical history (or a medical 
history that is unlikely to reveal anything on medical exam) may not need any physical 
exam. 
• Urine pregnancy test (in subjects of childbearing potential). If urine pregnancy is done at 
separate screening visit, repeat urine pregnancy test will be done within 24 hours of study 
vaccine administration. 
• 
Review inclusion and exclusion criteria. 
The screening process can be suspended prior to complete assessment at any time if exclusions are 
identified by the study team. 
Study subjects who qualify for inclusion will be contacted and scheduled for enrollment and first 
vaccination within the window for enrollment unless the screening and vaccination are scheduled 
on the same day. 
If a physiologic parameter, e.g., vital signs, is abnormal and potentially clinically significant, then 
the measurement may be repeated if, in the judgment of the participating site PI or appropriate 
designee, the abnormality is the result of an acute, short-term, rapidly reversible condition (e.g., 

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stress, anxiety or “white coat syndrome”) or other source of error. A physiologic parameter may 
also be repeated if there is a technical problem with the measurement caused by malfunctioning, 
or an inappropriate measuring device (i.e., inappropriate-sized BP cuff). 
A subject may be re-screened if there is a transient disease status (e.g., subject complained of a 
“cold or fever” and met a temporary delaying enrollment criterion of acute illness or fever), or if 
a protocol eligibility criterion that is not met at the initial time of screening, will be met by 
rescreening at a later date (e.g., a medication taken within exclusionary window at the time of first 
screening that would not be within exclusionary window at a later rescreen). 
Subjects will be provided the results of abnormal clinical findings necessitating follow-up at the 
discretion of the participating site PI or appropriate designee. Research laboratory results will not 
be provided to the subject with the exception of urine pregnancy test and SARS-CoV-2 local 
testing results.  
The screening and first vaccination procedures both can be conducted at the enrollment visit. 
8.1.2 
Immunogenicity Evaluations 
Humoral Immunogenicity Assays: 
The following humoral immunogenicity assays may be performed: 
• IgG ELISA or Multiplex MSD antibody binding assays to SARS-CoV-2 proteins (may 
include nucleocapsid protein, and multiple variant Receptor binding domains and variant 
spike proteins). 
• Neutralization assays using SARS-CoV-2 variant specific S-pseudotyped viruses. 
• Neutralization assay using different strains of live SARS-CoV-2. 
• Characterization of antigen-specific antibody by a) subclass, b) isotype, c) ability to 
interact with Fc receptors, d) innate immune receptors, e) lectin-like molecules and f) 
lectins at different times post-vaccination.   
• Functional Fc effector assays which may include quantification of antigen specific 
antibody-mediated NK cell activation (ADCC-NK) levels, antibody-dependent cellular 
phagocytosis (ADCP) activity, Antibody-dependent complement deposition (ADCD) 
and/or Antibody-dependent neutrophil activation/phagocytosis activity.  
Preparation of blood samples and shipping instructions for serological immunogenicity assays are 
outlined in the protocol-specific MOP. Inability (e.g., failure of venipuncture) to collect all 
baseline samples on Day 1 will not exclude the subject from further participation in this study as 
long as a minimum of baseline serum for serological immunogenicity assays is collected (refer to 
protocol-specific MOP). 
Cellular Immunology Assays: 
This trial may also investigate innate, B and T cell immune responses using multiparametric flow 
cytometry. Refer to the protocol-specific immune monitoring plan for details. 
Preparation of blood samples and shipping instructions for cellular immunology assays are 
outlined in the protocol-specific MOP. 

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The volume of venous blood to be collected for immunogenicity evaluations is presented in Table 
2 and Table 3. 
8.1.3 
Samples for Suspected SARS-CoV-2 infection 
In the event that a subject develops symptoms compatible with COVID-19, the site will follow 
with an unscheduled Illness Visit in person or by phone (with the participant self-collecting the 
swab). If a participant is asymptomatic but tests positive for COVID-19 outside the study, the 
site will follow the same procedure. Wide discretion is given to sites for the assessment of 
COVID-19 illness. Guidance can be found at the CDC website (2021 Case Definition):  
Coronavirus Disease 2019 (COVID-19) 2021 Case Definition | CDC 
The following intervention will be performed in the event of an illness visit: 
• Nasal swabs for PCR and sequencing 
One to two nasal swabs will be obtained for the purposes of 1) conducting qualitative analysis to 
assess for the presence of SARS-CoV-2 virus, and 2) conducting PCR quantitation/sequencing in 
the event that nasal swab #1 is positive for SARS-CoV-2. If a test outside the study was found to 
be positive only one swab is needed for sequencing. 
The first nasal swab, as applicable, will be processed at the local level with results informing the 
disposition of the second nasal swab. The sites will freeze and store the second swab (refer to 
MOP for labeling, storage, and shipping instructions) for potential shipment to the central 
repository for testing. 
8.1.4 
Samples for Genetic/Genomic Analysis 
8.1.4.1 
Genetic/Genomic Analysis 
DNA obtained from B-cells may be sequenced to identify B cell receptors and monoclonal 
antibodies. The DNA data may be used to synthesize antigen-specific antibodies to characterize 
antibody binding. Secondary research samples may also be used for other genomic analysis, 
including, but not limited to, single nucleotide polymorphisms (SNP) arrays, human leukocyte 
antigen (HLA) typing, transcriptomic analysis, evaluation of the immune response to the 
vaccine, and/or evaluation of any AE from the vaccine. 
8.1.4.2 
Genetic Privacy and Confidentiality 
Any genetic data generated will be kept private. Informed consent permitting data sharing will be 
part of the consent process. Subjects will be informed that the evolution of genomic technology 
and analytical methods raises the risk of re-identification, even when specimens are de-
identified. No data that may identify specific subjects will be kept with the genetic data. 
8.1.4.3 
Management of Results 
All genetic testing in this protocol will be performed for research purposes only and is not 
performed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. 
Therefore, results will not be shared with the subjects. 
8.1.5 
SARS-CoV-2 infection  

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Confirmed SARS-CoV-2 infection at any time during the study, defined as a positive RT-PCR 
test performed by the site or using a non-site testing method (RT-PCR or antigen test), will be 
documented. While this event would occur on study, it is not a typical AE and therefore captured 
as an exploratory efficacy assessment.   
8.1.6. 
Retained Samples for Biomarker Testing  
For all subjects, sera will be collected at  Day 4 and Day 60 (as applicable) and stored for 
potential biomarker assessment at a central laboratory and comparison to testing of an aliquot of 
sera obtained at Day 1 and Day 57, respectively 
Additionally, in the event that a subject develops symptoms compatible with myocarditis and/or 
pericarditis or the site is notified of a diagnosis of myocarditis and/or pericarditis, occurring 
within 4 weeks from vaccination, the site will follow with an in-person unscheduled illness and 
collect serum for potential biomarker testing at a central laboratory.    
The following sample will be collected: 
• 4 mL SST collection for potential biomarker testing at a central laboratory 
 
8.2 
Safety and Other Assessments 
All safety endpoints for this trial are obtained by reporting of adverse events. 
• New symptoms will be queried with both broad open-ended questions at the Day 8 
telephone call and by specifically asking about symptoms of chest pain, shortness of 
breath or palpitations that may represent myocarditis and/or pericarditis. 
• Data on new medical conditions, doctors' office visits (outside of routine care), 
emergency room visits, and hospitalizations will be collected. 
• Memory Aid: All subjects will complete a Memory Aid from the time of each 
vaccination through 7 days after each vaccination. Subjects will be asked to confirm 
completion of the Memory Aid and will be queried on the presence of any grade 3 
symptoms. Based on the information provided, subjects may be asked to return to the 
clinic for evaluation. Fourteen days after each vaccination, Memory Aids are reviewed 
thoroughly with the subject and confirmed data recorded in the CRF.   
 
As these are similar to licensed vaccines, there are no laboratory assessments for safety that will 
be done for this trial. 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related [21 CFR 312.32 (a)]. An AE can therefore be any 
unfavorable and unintended sign, symptom or disease temporally associated with the use of 
medicinal (investigational) product. 

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Any medical condition that is present at the time that the subject is screened will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing medical condition 
increases, it should be recorded as an AE. 
AEs can be further divided into solicited AEs and unsolicited AEs. Solicited AEs are those that 
are described in the package insert as local or systemic reactogenicity occurring in the first 7 days 
after vaccination. Unsolicited AEs are those events that the subject reports occurring without being 
queried about the specific event.  
AEs will be assessed for severity and relationship to study intervention (Section 8.3.4). Reporting 
of all AEs, solicited and unsolicited, will occur during the period from study product 
administration on Day 1 through 28 days after each vaccination. After 28 days post last vaccination 
through the end of study, only SAEs, Protocol Specified AESIs, MAAEs, NOCMCs, and AEs 
leading to withdrawal from the study will be reported. 
All AEs, solicited and unsolicited, will be captured on the appropriate DCF. Solicited AEs will be 
regarded as related to the study product and will not require separate entry into the AE log. 
Information to be collected for unsolicited AEs includes event description, date of onset, 
assessment of severity, relationship to study product and alternate etiology (assessed only by those 
with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the 
participating site PI or appropriate sub-investigator), date of resolution, seriousness, and outcome. 
AEs occurring during the study-collection and reporting period will be documented appropriately 
regardless of relationship. 
AEs will be followed to resolution or stabilization. 
8.3.1.1 
Solicited Adverse Events 
Solicited AEs are anticipated local and systemic AEs for which consistent collection of 
information is desired. Study clinicians will follow and collect resolution information for any 
reactogenicity symptoms that are not resolved within 7 days. 
Solicited AEs (i.e., reactogenicity) will be collected using a memory aid and confirmed data 
recorded on the appropriate DCF from the time of each vaccination through 7 days post each 
vaccination. 
For this study, solicited AEs will be: 
• Injection site Pain 
• Injection site Erythema 
• Injection site Edema/Induration 
• Headache 
• Fatigue 
• Myalgia 
• Arthralgia 
• Nausea 
• Fever 
• Chills 

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8.3.1.2 
Unsolicited Adverse Events 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
staff or revealed by observation, physical examination or other diagnostic procedures must be 
recorded on the appropriate DCF. 
Unsolicited AEs of all severities will be reported from the time of study product administration 
through 28 days post each vaccination. 
After 28 days post last vaccination through the end of study, only SAEs, AESIs, NOCMCs,  
MAAEs, and AEs leading to withdrawal from the study (as detailed in Section 8.3.7 and 8.3.9) 
will be reported. 
8.3.2 
Definition of Serious Adverse Event (SAE) 
An SAE is defined in 21 CFR 312.32 as follows: “An AE or suspected adverse reaction is 
considered serious if, in the view of either the participating site PI or appropriate sub-investigator 
or the sponsor, it results in any of the following outcomes: 
• Death, 
• a life-threatening AE, 
• inpatient hospitalization or prolongation of existing hospitalization, 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.” 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered an SAE. 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
All SAEs will be recorded on the appropriate SAE DCF. 
All SAEs will be followed through resolution or stabilization by a study clinician, licensed to 
make medical diagnoses and listed on the Form FDA 1572 as the participating site PI or 
appropriate sub-investigator. 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review unless related) and IRB/IEC as needed. 
8.3.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 

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A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the Investigator’s Brochure (IB), Package Insert, and/or Summary of 
Product Characteristics. 
8.3.4 
Classification of an Adverse Event 
The determination of seriousness, severity and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs and 
classify AEs based upon medical judgment. This includes, but is not limited to, physicians, 
physician assistants and nurse practitioners. 
8.3.4.1 
Severity of Adverse Events 
All AEs, AESIs, NOCMCs, MAAEs, SAEs, and AEs leading to withdrawal from the study will 
be assessed for severity, according to the toxicity grading scales in the FDA “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. 
For AEs not included in the FDA-defined grading system, the following guidelines will be used 
to describe severity. 
Mild (Grade 1): Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s 
usual activities of daily living. 
Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research subject. 
Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affect 
clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
AEs characterized as intermittent require documentation of onset and duration of each episode. 
The start and stop date of each reported AE will be recorded on the appropriate DCF. Changes in 
the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of intensity. 
8.3.4.2 
Relationship to Study Intervention 
For each reported adverse reaction, the participating site PI or qualified designee must assess the 
relationship of the event to the study product using the following guidelines: 
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 

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Solicited adverse events reported in the 7 days after each vaccination are considered related to 
study product unless they are also recorded as an unsolicited event, in which case the relationship 
to study product will be determined by the PI or qualified designee. 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study: 
• Solicited Adverse Events will be collected for 7 days following each vaccine dose. 
• Unsolicited AEs will be collected until 28 days after each vaccination. 
• AESIs, NOCMCs, MAAEs, SAEs, and AEs leading to withdrawal from the study  will be 
collected from Day 1 through the end of the study. 
8.3.6 
Adverse Event Reporting 
8.3.6.1 
Investigators Reporting of AEs 
Information on reportable AEs should be recorded on the appropriate DCF. All clearly related 
signs, symptoms and results of diagnostic procedures performed because of an AE should be 
grouped together and recorded as a single diagnosis. If the AE is a clinical laboratory abnormality 
that is part of a clinical condition or syndrome, it should be recorded as the syndrome or diagnosis 
rather than the individual clinical laboratory abnormality. Each AE will also be described in terms 
of duration (start and stop date), severity, association with the study product, action(s) taken, and 
outcome. 
8.3.7 
Serious Adverse Event Reporting 
8.3.7.1 
Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as an SAE must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into Advantage eClinical. 
Refer to the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. 

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At any time after completion of the study, if the participating site PI or appropriate sub-investigator 
becomes aware of an SAE that is suspected to be related to study product, the participating site PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
8.3.7.2 
Regulatory Reporting of SAEs 
Following notification from the participating site PI or appropriate sub-investigator, DMID, as the 
IND sponsor, will report any SUSAR in an IND safety report to the FDA and will notify all 
participating site PIs (i.e., all PIs to whom the sponsor is providing drug under its IND(s) or under 
any PI’s IND(s)) of potential serious risks from clinical studies or any other source, as soon as 
possible. DMID will report to the FDA any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible, but in no case later than 7 calendar days after the sponsor’s initial 
receipt of the information. If the event is not fatal or life-threatening, the IND safety report will be 
submitted within 15 calendar days after the sponsor determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32. Relevant follow-up information to an IND safety 
report will be submitted as soon as the information is available. Upon request from FDA, DMID 
will submit to the FDA any additional data or information that the agency deems necessary, as 
soon as possible, but in no case later than 15 calendar days after receiving the request. 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs. 
8.3.8 
Reporting Events to Subjects 
Subjects will be informed of any major safety event that occurs as part of their participation in 
this trial. 
8.3.9 
Adverse Events of Special Interest (AESIs), New Onset of Chronic Medical 
Conditions (NOCMCs) and Medically Attended Adverse Events (MAAEs)  
Adverse Events of Special Interest (AESIs) represent any events for which additional data 
(besides the standard AE data) are desired. An adverse event of special interest (serious or 
nonserious) is one of scientific and medical concern specific to the sponsor’s product or program, 
for which ongoing monitoring and rapid communication by the investigator to the sponsor is 
required. Such an event may require further investigation in order to characterize and understand 
it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties 
(e.g., regulators) may also be required. These may be at the request of the regulatory agency, 
industry partner or DMID, and driven by a regulatory requirement, or known or potential risk from 
the product or class.  
 
Protocol Specified AESIs are listed in Section 12. In addition, for stage 3, AESIs will also include 
a list of pIMD. 
 
Potential Immune-mediated Diseases (pIMDs)  
Potential immune-mediated diseases (pIMDs). pIMDs are a subset of AESIs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may 
or may not have an autoimmune etiology. AESIs that need to be recorded and reported as pIMDs 
for Stage 3 participants are listed in Section 12. 

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However, the investigator will exercise their medical and scientific judgement in deciding whether 
other diseases have an autoimmune origin (that is pathophysiology involving systemic or organ-
specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
 
When there is enough evidence to make any of the diagnoses mentioned in Section 12, the AESI 
must be reported as a pIMD. Symptoms, signs or conditions which might (or might not) 
represent the above diagnoses, should be recorded and reported as AEs but not as pIMDs until 
the final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
New Onset of Chronic Medical Conditions (NOCMCs) are defined as any new ICD diagnosis 
(per current International Statistical Classification of Diseases and Related Health Problems) that 
is applied to the subject during the course of the study, after receipt of the study agent, that is 
expected to continue for at least 3 months and requires continued health care intervention. 
Medically Attended Adverse Events (MAAEs) are defined as a hospitalization < 24 hours, 
emergency room visit or an otherwise unscheduled visit to or from medical personnel for any 
reason; and considered related or possibly related to study product. 
 
All AESIs, MAAEs, NOCMCs, are assessed, recorded, and followed as described above under 
AEs. The following need to be reported to DMID pharmacovigilance: 
All AESIs, MAAEs or NOCMCs that meet SAE criteria (reported within 24 hours); 
Any AESIs even if not SAE (reported within 24 hours); 
MAAEs only when requested by the sponsor; 
NOCMCs only when requested by the sponsor. 
As indicated, these should be reported to DMID Pharmacovigilance Group at the following 
address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
 SAE Email Address: PVG@dmidcroms.com 
8.3.10 
Reporting of Pregnancy 
Pregnancy is not an AE. Pregnancy outcomes will be reported on the appropriate DCF if a new 
pregnancy occurs within 3 months from last study vaccine dose.   If pregnancy is associated with 
an SAE to the mother or fetus (e.g., miscarriage or preeclampsia), the SAE should be reported to 
PVG.   
8.4 
Unanticipated Problems 
8.4.1 
Definition of Unanticipated Problems (UPs) 

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The Department of Health and Human Services (DHHS) OHRP considers unanticipated 
problems involving risks to subjects or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 UPs that are SAEs will be reported to the IRB, to the DMID Pharmacovigilance Group, 
and in the clinical database within 24 hours of the participating site PI or appropriate sub-
investigator becoming aware of the event per the above-described SAE reporting process. 
 UPs that are SAEs will be collected from Day 1 through the end of the study. 
 Any other UP will be reported to the IRB and in the clinical database within 3 days of the 
participating site PI or appropriate sub-investigator becoming aware of the problem. 
8.4.3 
Reporting Unanticipated Problems to Subjects 
Subjects will be informed of any UPs that occur as part of their participation in this trial. 
 

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9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
This is a phase 2, open-label, multi-site clinical trial that is not designed to test a specific 
hypothesis. Rather, it is intended to obtain preliminary estimates in adults of the safety and 
immunogenicity of additional booster doses of SARS-CoV-2 variant vaccines.  
9.2 
Sample Size Determination  
9.2.1 
Sample Size Calculation for the Safety Endpoint 
Rare AEs are not demonstrable in a clinical study of this size; however, the probabilities of 
observing one or more AEs given various true event rates are presented in Table 5. With the 
assumption that all enrolled subjects will likely complete immunizations and safety visits in this 
relatively short duration study, the following statistical considerations apply. With approximately 
100 subjects in each arm there is a greater than 99.9% chance of observing at least one AE of 
probability 10%. With approximately 50 subjects in each of the strata subgroups (or arms), there 
is a 99.5% chance of observing at least one AE of probability 10%. With approximately 25 subjects 
in each of the strata subgroup combinations (assuming equal numbers and 100 per arm), there is a 
92.8% chance of observing at least one AE of probability 10%. Finally, with approximately 15 
subjects in the smallest of the strata subgroup combinations (assuming unequal numbers and 100 
per arm or 50 per arm), there is a 79.4% chance of observing at least one AE of probability 10%. 
Therefore, if no AEs of a given type occur in a group (or strata), we can be relatively confident 
that they will occur in fewer than 10% of people if the vaccine is implemented.  
 Table 5: Probability of Observing one or more Adverse Event for Various Event Rates in 
one vaccine group (or strata).  
N 
“True” Event 
Rate 
Probability of Observing ≥ 
1 events (%) 
N 
“True” Event 
Rate 
Probability of Observing ≥ 
1 events (%) 
100 
0.1% 
9.5 
50 
0.1% 
4.9 
0.5% 
39.4 
0.5% 
22.2 
1.0% 
63.4 
1.0% 
39.5 
2.0% 
86.7 
2.0% 
63.6 
3.0% 
95.2 
3.0% 
78.2 
4.0% 
98.3 
4.0% 
87 
5.0% 
99.4 
5.0% 
92.3 
10.0% 
>99.9 
10.0% 
99.5 
15.0% 
>99.9 
15.0% 
>99.9 
20.0% 
>99.9 
20.0% 
>99.9 
30.0% 
>99.9 
30.0% 
>99.9 

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N 
“True” Event 
Rate 
Probability of Observing ≥ 
1 events (%) 
N 
“True” Event 
Rate 
Probability of Observing ≥ 
1 events (%) 
25 
0.1% 
2.5 
15 
0.1% 
1.5 
0.5% 
11.8 
0.5% 
7.2 
1.0% 
22.2 
1.0% 
14 
2.0% 
39.7 
2.0% 
26.1 
3.0% 
53.3 
3.0% 
36.7 
4.0% 
64.0 
4.0% 
45.8 
5.0% 
72.3 
5.0% 
53.7 
10.0% 
92.8 
10.0% 
79.4 
15.0% 
98.3 
15.0% 
91.3 
20.0% 
99.6 
20.0% 
96.5 
30.0% 
>99.9 
30.0% 
99.5 
9.2.2 
Sample Size Calculation for the Immunogenicity Endpoints 
The primary objective of this study is to evaluate the magnitude and durability of SARS-CoV-2 
specific antibody titers in serum samples. This objective is descriptive in nature and will be 
accomplished by estimating 95% confidence intervals (CI) for the geometric mean titer (GMT) 
at each timepoint when samples are collected. 
The precision with which the GMT can be estimated from observed data depends on the standard 
deviation (SD) of the measurements, on the logarithmic scale, and the sample size. Table 6 
displays two-sided 95% confidence intervals for the GMT for several values of the observed 
antibody titer. Table 6 also shows results assuming up to 10% attrition. 
Table 6: Two-sided 95% confidence intervals based on observing a particular average loge-
antibody titer in subjects’ vaccine groups and potential strata sizes  
Observed 
average loge 
antibody titer 
SD of loge 
antibody 
titer 
95% confidence interval of  
GMT in vaccine groups and strata 
N = 100 
N = 50 
N = 25 
N = 15 
loge (5) 
0.5 
(4.5, 5.5) 
(4.3, 5.8) 
(4.1, 6.1) 
(3.8, 6.6) 
loge (20) 
(18.1, 22.1) 
(17.4, 23.1) 
(16.3, 24.6) 
(15.2, 26.4) 
loge (50) 
(45.3, 55.2) 
(43.4, 57.6) 
(40.7, 61.5) 
(37.9, 66) 
loge (100) 
(90.6, 110.4) 
(86.8, 115.3) 
(81.4, 122.9) 
(75.8, 131.9) 
loge (250) 
(226.4, 276.1) 
(216.9, 288.2) 
(203.4, 307.3) 
(189.5, 329.8) 
loge (500) 
(452.8, 552.1) 
(433.8, 576.3) 
(406.8, 614.6) 
(379.1, 659.5) 
loge (1000) 
(905.6, 1104.3) 
(867.5, 1152.7) 
(813.5, 1229.2) 
(758.1, 1319) 
loge (5) 
1.0 
(4.1, 6.1) 
(3.8, 6.6) 
(3.3, 7.6) 
(2.9, 8.7) 

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Observed 
average loge 
antibody titer 
SD of loge 
antibody 
titer 
95% confidence interval of  
GMT in vaccine groups and strata 
N = 100 
N = 50 
N = 25 
N = 15 
loge (20) 
(16.4, 24.4) 
(15.1, 26.6) 
(13.2, 30.2) 
(11.5, 34.8) 
loge (50) 
(41, 61) 
(37.6, 66.4) 
(33.1, 75.6) 
(28.7, 87) 
loge (100) 
(82, 121.9) 
(75.3, 132.9) 
(66.2, 151.1) 
(57.5, 174) 
loge (250) 
(205, 304.9) 
(188.2, 332.2) 
(165.5, 377.8) 
(143.7, 435) 
loge (500) 
(410, 609.7) 
(376.3, 664.3) 
(330.9, 755.5) 
(287.4, 869.9) 
loge (1000) 
(820, 1219.5) 
(752.6, 1328.7) 
(661.8, 1511) 
(574.8, 1739.8) 
*  Assumes approximately 10% attrition. 
9.3 
Populations for Analyses 
The safety analysis population includes all enrolled subjects who received at least one dose of 
study vaccine. Analyses for the safety population will include safety reported through the end of 
the study. The modified intent-to-treat (mITT) population includes all subjects who received at 
least one dose of vaccine and contributed both pre- and at least one post-vaccination venous 
blood sample for immunogenicity testing for which valid results were reported. 
In the final analysis, protocol deviations will be reviewed to determine which protocol deviations 
may affect the analysis. The per protocol (PP) population will then be defined – and this includes 
all subjects in the mITT subset with the following exclusions: 
• 
Data from all available visits for subjects found to be ineligible at baseline. 
• 
Data from all visits subsequent to the protocol deviations that are considered to affect the 
science. 
• 
Data from any visit that occurs substantially out of window. 
9.4 
Statistical Analyses 
Interim analyses of safety and immunologic response data will be done, as needed. 
The final analysis will be performed after the final data lock and clinical study report (CSR) 
completed when all primary safety endpoint data and all secondary immunogenicity endpoint data 
are available and received by the SDCC. Any available data from the exploratory immunogenicity 
endpoints may also be included in the CSR. Remaining exploratory immunogenicity endpoint data 
may be included in an addendum to the CSR, publication of manuscript(s), or other report(s). 
Abbreviated analysis plans that describe planned analyses to facilitate dissemination of study data 
for public health reasons, including manuscript publication(s), will be developed by the SDCC as 
needed. A full statistical analysis plan (SAP) will be developed by the SDCC and finalized prior 
to the primary data lock.  
9.4.1 
General Approach 

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Unless otherwise noted in the SAP, continuous variables will be summarized using the following 
descriptive statistics: n (non-missing sample size), mean, standard deviation, median, maximum 
and minimum. The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures. 
9.4.2 
Analysis of the Primary Endpoint(s) 
Descriptive summaries of immunogenicity data will be presented for the mITT population. If 
there are protocol deviations which may affect the analysis, a per-protocol (PP) analysis may 
also be performed. 
Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) from baseline of SARS-
CoV-2 specific antibody binding and neutralization titers will be calculated, along with 95% CIs, 
for all groups, at each timepoint. Summaries will also be displayed graphically. Geometric Mean 
Ratio (GMRD614G) is defined as the ratio of a variant of concern to D614G ( i.e Beta to D614G) 
will also be reported for all groups, at each timepoint, along with 95% CIs.  
9.4.3 
Analysis of the Secondary Endpoints 
Section 9.4.4 describes the analyses of Safety Endpoints, which is the secondary endpoint of this 
protocol.  
9.4.4 
Safety Analyses 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. 
Solicited non serious AEs will be collected from the time of each vaccination until 7 days after. 
Solicited AEs will be summarized by severity for each day post vaccination (Days 1-8) and as the 
maximum severity over all 8 days. Additionally, solicited AEs will be analyzed using standard 
techniques, such as exact confidence intervals (CI), to summarize the proportion of subjects 
reporting each symptom, any application site symptom, and any systemic symptom.  
Unsolicited non-serious AEs will be collected from the time of first vaccination through 28 days 
after each vaccination. Unsolicited AEs will be coded by MedDRA for preferred term and system 
organ class (SOC). SAEs, MAAEs, NOCMCs, AESIs, and AEs leading to withdrawal from the 
study will be collected from the time of first vaccination through 12 months after the last vaccine 
dose. The numbers of SAEs, MAAEs, NOCMCS, AESIs, and AEs leading to withdrawal from the 
study will be reported by detailed listings showing the event description, MedDRA preferred term 
and SOC, relevant dates (vaccinations and AEs), severity, relatedness, and outcome for each event. 
Non-serious unsolicited AEs will be summarized as number and percentage of subjects reporting 
at least one event in each MedDRA preferred term and SOC, cross tabulated by severity and 
relationship to study product. Additionally, the proportion of subjects and exact 95% CIs of AEs 
in aggregate and by MedDRA categories will be computed.  
9.4.5 
Baseline Descriptive Statistics 
Summaries of demographic variables such as age, sex, ethnicity, race, and prior infection status 
will be presented by vaccination arm and overall.  
9.4.6 
Planned Interim and Early Analyses 

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Data may be disseminated to public health officials and partners as needed and included in 
publications and presentations to inform the global scientific community. Early analyses will 
include safety and immunogenicity as described in Sections 9.4.6.1, 9.4.6.2, and 9.4.6.3. Further, 
the protocol team will review data periodically to confirm no halting criteria have been met as 
described in Section 7.1.1. 
Cumulative safety information, study status, and primary endpoint results may be published, 
presented at a public forum, or presented as summaries aggregated by study arm at the discretion 
of the sponsor while the study is ongoing. None of the interim analyses will include any formal 
statistical hypothesis testing; therefore, p value adjustment will not be made to any analyses.  
9.4.6.1 
Interim Safety Analyses 
Given the need for rapid review and dissemination of study data for public health reasons, AEs 
and SAEs may be reviewed as necessary outside of DSMB reviews. The DSMB may not need to 
meet (unless halting rules are met), and materials will be provided electronically. Documentation 
of review and any concerns noted will be solicited electronically. 
The DSMB will review separate cumulative AE data reports for all subjects within each arm.  
Given the safety database known for authorized/approved vaccines, there is no routine mandatory 
review by the DSMB unless halting rules are triggered.  
9.4.6.2 
Interim Immunogenicity Review 
Interim data review of immunogenicity will be performed as often as needed to inform public 
health decisions. 
Statistical analyses of immunogenicity endpoints, by vaccine arm, may be performed when 
subjects have completed key immunogenicity visits. Immunogenicity reviews may be shared with 
the DSMB, as determined by DMID. 
Data may be disseminated to public health officials and partners as needed and included in 
publications and presentations to inform the global scientific community. 
9.4.6.3 
Interim Immunogenicity and Safety Review 
Interim analyses of safety, reactogenicity, and immunologic response data may be done, as 
needed. 
9.4.7 
Sub-Group Analyses 
Subgroup analyses, by age group and infection status, may be performed. Detailed information 
will be provided in the Statistical Analysis Plan.  
9.4.8 
Tabulation of Individual Subject Data 
In general, all data will be listed, sorted by vaccine arm and subject, and when appropriate by 
visit number within subject. 
9.4.9 
Exploratory Analyses 
Summaries and analysis of immunologic assay data will be presented for the mITT population. If 
there are protocol deviations which may affect the analysis, a PP analysis may also be performed. 

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10. 
SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
This study will be conducted in conformity with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research; April 18, 1979), and the federal policy for the Protection of Human Subjects codified 
in 45 CFR Part 46, 21 CFR Part 50 (Protection of Human Subjects), and the ICH E6(R2). 
An OHRP-registered IRB will review and approve this protocol, associated informed consent 
documents, recruitment materials, and handouts or surveys intended for the subjects, prior to the 
recruitment, screening and enrollment of subjects. The IRB review shall be in accordance with 
45 CFR 46 and 21 CFR 50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and 
policies, as applicable. 
Each institution engaged in this research will hold an OHRP-approved FWA. 
Any amendments to the protocol or informed consent documents will be approved by the IRB 
before they are implemented. IRB review and approval will occur at least annually throughout 
the duration of the study. The participating site PI will notify the IRB of deviations from the 
protocol and reportable SAEs, as applicable to the IRB policy. 
DMID must receive the documentation that verifies IRB approval for this protocol, informed 
consent documents and associated documents, prior to the recruitment, screening and enrollment 
of subjects, and any IRB approvals for continuing review or amendments as required by the 
DMID. 
10.1.1 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Investigators or designated 
research staff will obtain a subject’s informed consent in accordance with the requirements of 45 
CFR 46, 21 CFR 50 and 21 CFR 56 for FDA-regulated studies, state and local regulations and 
policy, and ICH E6 GCP before any study procedures or data collection are performed. The 
participating site PI or other study staff may obtain oral or written information for the purpose of 
screening, recruiting, or determining the eligibility of prospective subjects without the informed 
consent of the prospective subject if the process is approved by the IRB. 
At the first study visit, informed consent will be obtained and documented before any study 
procedures are performed. Subjects will receive a concise and focused presentation of key 
information about the clinical trial, verbally and with a written consent form. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
study interventions/products, risks and discomforts, the expected duration of the subject’s 
participation in the trial, any expected benefits to the subject, and alternative treatments and 
procedures that may be available to the subject. The explanation will be organized and presented 
in lay terminology and language that facilitates understanding why one might or might not want 
to participate. 

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Subjects will receive an explanation as to whether any compensation and any medical treatments 
are available if injury occurs, and, if so, what they consist of, or where further information may 
be obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the participating site 
PI) for answers to any questions relating to the research project. Information will also include the 
foreseeable circumstances and/or reasons under which the subject’s participation in the trial may 
be terminated. The subjects will be informed that participation is voluntary and that they are free 
to withdraw from the study for any reason at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. Subjects will be allowed sufficient time to consider 
participation in this research trial and have the opportunity to discuss this trial with their family, 
friends or legally authorized representative, or think about it prior to agreeing to participate. 
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the trial are published, the subject’s identity will remain confidential. 
Subjects will be informed, even if identifiers are removed, that information collected from this 
research and/or specimens may be used for secondary research, including the sharing of 
deidentified data. 
Subjects will be informed that the monitor(s), auditors(s), IRB, NIAID, and regulatory 
authority(ies) will be granted direct access to the subject’s original medical records for 
verification of clinical trial procedures and/or data without violating the confidentiality of the 
subject, to the extent permitted by the applicable laws and regulations, and that, by signing a 
written ICF, the subject is authorizing such access. 
ICFs will be IRB-approved, and subjects will be asked to read and review the consent form. 
Subjects must sign the ICF prior to starting any study procedures being done specifically for this 
trial. Once signed, a copy of the ICF will be given to the subject for their records. 
New information will be communicated by the participating site PI or designee to subjects who 
consent to participate in this trial in accordance with IRB requirements. The informed consent 
document will be updated, and subjects will be re-consented per IRB requirements, if necessary. 
10.1.1.1 
Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor) 
Not Applicable 
10.1.1.2 
Other Informed Consent Procedures 
The rights and privacy of human subjects who participate in genomic or phenotypic research 
studies will be protected at all times. The consent process, including relevant language in the ICF, 
will provide an explanation of the potential risks to the individual study subjects and their families. 
Clinical metadata, genomic, or other datasets or a subset of the clinical and other metadata that 
may potentially identify human subjects will not be released in unrestricted databases. Subjects 
will be informed that the evolution of genomic technology and analytical methods raises the risk 
of re-identification, even when specimens are de-identified. 

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Subjects will be asked for consent to collect additional blood, nasal swabs, the use of residual 
specimens, and the sharing of genetic information and samples for secondary research. This 
extra/residual blood and corresponding serum, plasma and PBMCs will be used as back-up 
specimens for PP defined assays or designated for secondary research use and stored indefinitely 
at a designated storage facility. 
Subjects will be asked to consent specifically to genetic testing on primary and secondary research 
samples, including but not limited to transcriptomics and DNA sequencing. DNA sequencing data 
will be kept private. DNA data may be used to produce commercial antibody-based therapeutics. 
Subjects will not share in profits or commercial rights to those products. 
If subjects choose not to provide permission for extra blood and secondary research use, they will 
not be eligible for enrollment into the study. 
Collection of extra/residual samples during the course of the study will help facilitate rapid follow-
on analyses, if warranted, to provide more comprehensive scientific insights into the impact (safety 
and immunological) of the vaccine on the host response to vaccination. To maintain statistical 
power in follow-on analyses it is important that extra blood collection and secondary research use 
be included in as many subjects as possible, due to the limited sample size per treatment arm. 
The stored samples will be labeled with barcodes to maintain confidentiality. Research with 
identifiable samples and data may occur as needed, however, subject confidentiality will be 
maintained as described for this protocol and with IRB approval. 
Samples designated for secondary research use may be used for additional immunological 
assessments that may include but are not limited to antibody epitope mapping, B and T cell 
repertoire determination, non-traditional immune assay development, determination of innate 
immune factors and the ability of vaccine-induced antibodies to cross-react to different proteins 
and virus strains. These blood samples might be used in new or different immunological laboratory 
tests, to provide information for the development of new vaccines or therapeutics, or for the studies 
of SARS-CoV-2 or other infections. Secondary research using DNA may also be warranted to 
understand genetic factors involved in vaccination failures. 
Samples will not be sold for commercial profit. Although the results of any future research may 
be patentable or have commercial profit, subjects will have no legal or financial interest in any 
commercial development resulting from any future research. 
There are no direct benefits to the subject for extra specimens collected or from the secondary 
research. No results from secondary research will be entered into the subject’s medical record. 
Incidental findings will not be shared with the subject, including medically actionable incidental 
findings, unless required by law. 
Risks are associated with the additional volume of blood collected, such as anemia. Risks for loss 
of privacy and confidentiality are described below. 
Subjects may withdraw permission to use samples for secondary use at any time. They will need 
to contact the participating site and the samples will be removed from the study repository after 
this study is completed and documentation will be completed that outlines the reason for 
withdrawal of permission for secondary use of samples. Subjects who withdraw consent before 
the last visit will not have the extra blood drawn for secondary use. 

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Human Genetic Testing 
The research staff will seek the subjects’ consent for extra and residual specimens to be stored and 
used for secondary research, including genetic research, evaluating human genomic and 
phenotypic markers. The rights and privacy of human subjects who participate in genomic or 
phenotypic research studies will be protected at all times. 
The consent process will include an explanation of the potential risks to the individual subjects 
and their families associated with data submitted to an NIH data repository and subsequent sharing. 
Data that may potentially identify human subjects will not be released in unrestricted databases. 
Subjects will be informed that the evolution of genomic technology and analytical methods raises 
the risk of re-identification, even when specimens are de-identified. The consent will include 
whether individual subject data will be shared through a NIH controlled access data repository. 
Data for genomic or phenotypic research will be submitted to a controlled access data repository, 
therefore, informed consent permitting the data sharing must be documented, even if the specimens 
are de-identified. 
10.1.2 
Study Termination and Closure 
In Section 7, Study Intervention Discontinuation and Subject Discontinuation/Withdrawal, 
describes the temporary halting of the study. 
This study may be prematurely terminated if there is sufficient reasonable cause, including, but 
not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Results of interim analysis 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or not evaluable 
• Regulatory authorities 
If the study is prematurely terminated, the PI or designee will promptly inform study subjects 
and the IRB will be notified. The PI will assure appropriate follow-up for the subjects, as 
necessary. 
The sponsor will notify regulatory authorities as applicable. 
10.1.3 
Confidentiality and Privacy 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover clinical information relating 
to subjects, test results of biological samples and genetic tests, and all other information generated 
during participation in the study. No identifiable information concerning subjects in the study will 
be released to any unauthorized third party. Subject confidentiality will be maintained when study 
results are published or discussed in conferences. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
and/or regulatory agencies may inspect all documents and records required to be maintained by 
the participating site PI, including, but not limited to, medical records (office, clinic, or hospital) 

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and pharmacy records for the subjects in this study. The participating site will permit access to 
such records. 
All source records, including electronic data, will be stored in secured systems in accordance with 
institutional policies and federal regulations. 
All study data and research specimens that leave the participating site (including any electronic 
transmission of data) will be identified only by a coded number that is linked to a subject through 
a code key maintained at the participating site. Names or readily identifying information will not 
be released unless DMID approves and it aligns with the consent form, or according to laws for 
required reporting. 
Because it may be possible to re-identify de-identified genomic data, even if access to data is 
controlled and data security standards are met, confidentiality cannot be guaranteed, and re-
identified data could potentially be used to discriminate against or stigmatize subjects, their 
families, or groups. In addition, there may be unknown risks. 
As this research is funded by the NIH, it is covered by NIH policy which effectively issues the 
research a Certificate of Confidentiality (COC). By this policy, researchers cannot be forced to 
disclose or provide, in any Federal, State, or local civil, criminal, administrative, legislative, or 
other proceeding, the name of such individual or any such information, document, or biospecimen 
that contains identifiable, sensitive information about the individual and that was created or 
compiled for purposes of the research, unless such disclosure or use is made with the consent of 
the individual to whom the information, document, or biospecimen pertains. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the FDA. 
A COC does not prevent subjects from voluntarily releasing information about themselves or their 
involvement in this research. If any person or agency obtains a written consent to receive research 
information, then the researchers may not use the Certificate to withhold that information. 
The COC does not prevent the researchers from reporting, without the subject’s consent, 
information that would identify the subject as a subject in the research project in the case of matters 
that must be legally reported, including child and elder abuse, sexual abuse, or wanting to harm 
themselves or others. 
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or that the release is in compliance with applicable Federal regulations governing the 
protection of human subjects in research. 
10.1.4 
Secondary Use of Stored Specimens and Data 
Secondary Human Subject Research is the re-use of identifiable data or identifiable biospecimens 
that were collected from some other ‘‘primary’’ or ‘‘initial’’ activity, such as the data and samples 
collected in this protocol. This section will detail the samples and data available for secondary 
research. Any use of the secondary sample or data, however, will be presented in a separate 
protocol and require separate IRB approval. 

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10.1.4.1 
Samples for Secondary Research 
The following types of samples will be stored and used for secondary research: 
Residual Research Sample: Any leftover Primary Research Sample after the laboratory testing 
specified in this protocol is completed will be stored for future studies with the subject’s consent. 
Repository Research Sample: Samples will be collected with the subject’s consent in this 
protocol with the intent to store for additional research (i.e., samples collected beyond those 
needed for primary research) and will be used in future studies. Amendments to this protocol 
with additional assays may use repository research samples. 
Samples will be stored indefinitely at a DMID-designated storage facility. Each sample will be 
encoded (labeled) only with a barcode and a unique tracking number to protect subject 
confidentiality. Secondary research with coded samples and data may occur, however, subject 
confidentiality will be maintained as described for this protocol. An IRB review of the secondary 
research using coded specimens is required. 
Residual/Repository Research Samples, upon written request and approval from DMID and any 
approvals required by the site or network, may be shared for secondary research with investigators 
at the participating site, with researchers at other sites or other institutions, or company-designated 
research laboratories. The samples will not be sold or used directly for production of any 
commercial product. DMID will authorize shipment from the DMID CMS. 
The subject’s decision can be changed at any time by notifying the study doctors or nurses in 
writing. To participate in this study, subjects must consent for storage of samples for secondary 
use. If the subject subsequently changes his/her decision, the samples will be destroyed if the 
samples have not been used for research or released for a specific research project. 
10.1.4.2 
Data Sharing for Secondary Research 
Data from this study may be used for secondary research. All of the individual subject data 
collected during this study will be made available after de-identification. The SAP and Analytic 
Code will also be made available. Data will be available immediately following publication, with 
no end date. Upon written request, with provision of a methodologically sound proposal, and 
approval from DMID and any approvals required by the site or network, data may be shared for 
secondary research with investigators/researchers. The data will be available for only the purpose 
outlined in the approved proposal. 
For access to genomic data in the NIH designated controlled access database, an investigator (or 
data requestor) must submit a Data Access Request which certifies adherence to the NIH Security 
Best Practices for Controlled-Access data subject to the NIH Genomic Data Sharing (GDS) Policy. 
The participating site PI may request removal of data on individual study subjects from NIH data 
repositories in the event that a research subject withdraws or changes his or her consent. 
However, some data that have been distributed for approved research use cannot be retrieved. 
10.1.5 
Key Roles and Study Governance 
This study is sponsored by DMID. Key Roles are noted in the protocol-specific MOP. 
10.1.6 
Safety Oversight 

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10.1.6.1 
Data Safety Monitoring Board (DSMB) 
The DSMB is an independent group of at least three experts that monitors subject safety and 
advises DMID. DSMB members will be separate and independent of study staff participating in 
this trial and should not have scientific, financial, or other conflicts of interest related to this trial. 
The DSMB will consist of members with appropriate expertise to contribute to the interpretation 
of data from this trial. A quorum will consist of a simple majority. 
The DSMB will hold an organizational meeting or electronic review prior to enrollment. At this 
meeting, the DSMB will review the charter, protocol, ICF, IBs, and safety report templates. 
The DSMB will not need to meet unless halting rules are met.  The DSMB will be provided 
periodic updates on enrollment, safety, and immunogenicity. Documentation of review and any 
concerns noted will be solicited electronically. 
Ad hoc reviews will occur when trial halting criteria are met, or as requested by the sponsor or 
PI. 
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will 
review applicable data, including, but not limited to, enrollment, demographics, dosing data, 
clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the 
DSMB charter. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. As an outcome of each review/meeting, the 
DSMB will make a recommendation as to the advisability of proceeding with study product 
administration, and to continue, modify, or terminate this trial. 
10.1.7 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are 
protected, that the reported trial data are accurate, complete, and verifiable. Clinical Monitoring 
also ensures conduct of the trial is in compliance with the currently approved protocol/ 
amendment(s), ICH, GCP, and with applicable regulatory requirement(s) and sponsor 
requirements. Clinical monitoring will also verify that any critical study procedures are completed 
following specific instructions in the protocol-specific MOP. 
Monitoring for this study will be performed by DMID. Details of clinical site monitoring are 
documented in a CMP. The CMP describes in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, electronic case report forms (eCRFs), ICFs, medical and 
laboratory reports, site study intervention storage records, training records, and protocol and GCP 
compliance. Site monitors will have access to each participating site, study staff and all study 
documentation according to the DMID-approved CMP. Study monitors will meet with all 
participating site PIs to discuss any problems and outstanding issues and will document site visit 
findings and discussions. 
10.1.8 
Quality Control (QC) and Quality Assurance (QA) 

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To ensure the reliability of study data, each participating site will develop a Clinical Quality 
Management Plan (CQMP). The CQMP will describe: 
• routine internal QC and QA activities for the purposes of measuring, documenting and 
reporting study conduct, protocol adherence, human subjects’ protections, and reliability 
of the protocol-driven data collected and independent of sponsor site monitoring. 
• a process for addressing data quality issues (i.e., collecting, recording) or systemic issues 
(i.e., protocol conduct, non-compliance, human subject protections), and implementation 
and evaluation of Corrective and Preventative Action Plan (CAPA) procedures as needed. 
10.1.9 
Data Handling and Record Keeping 
10.1.9.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the study staff at the participating site under the 
supervision of the participating site PI. The participating site PI must maintain complete and 
accurate source documentation. 
Clinical research data from source documentation, including, but not limited to, AEs/SAEs, 
concomitant medications, medical history, physical assessments, and clinical laboratory data, 
will be entered by the participating site into eCRFs via a 21 CFR Part 11-compliant internet data 
entry system provided by Emmes. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. AEs and concomitant medications will be coded according to the most 
current versions of MedDRA and WhoDrug, respectively. 
The SDCC will be responsible for data management, quality review, analysis, and reporting of 
the study data. 
The IND sponsor is responsible for review of data collection tools and processes, and review of 
data and reports. 
AEs will be coded according to the MedDRA dictionary version 23.0 or higher. 
A separate study specific Study Data Standardization Plan (SDSP) appendix will be developed 
which describes the technical recommendations for the submission of human study data and 
related information in a standardized electronic format throughout product development. 
At the end of the study, a copy of all datasets, including annotated CRFs and data dictionary, will 
be provided to DMID. 
10.1.9.2 
Study Record Retention 
Study-related records, including the regulatory file, study product accountability records, consent 
forms, subject source documents and electronic records, should be maintained for a period of 2 
years following the date a marketing application is approved for the investigational product for the 
indication for which it is being investigated; or, if no application is to be filed or if the application 
is not approved for such indication, until 2 years after the investigation is discontinued and FDA 
is notified. These documents should be retained for a longer period, however, if required by local 
policies or regulations. No records will be destroyed without the written consent of DMID. 
Consent forms with specimen retention linked to identifiable specimens will be maintained for as 

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long as the specimens remain in identifiable format, and a minimum of three years after use of the 
identifiable specimens in nonexempt human subject research. 
10.1.9.3 
Source Records 
Source data are all information in original records (and certified copies of original records) of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Each participating site will maintain 
appropriate medical and research records for this trial, in compliance with ICH GCP, regulatory, 
and institutional requirements. Study data will be collected on paper CRFs and entered the eCRF 
or data will be entered directly into the eCRF. Data recorded in the eCRF derived from source 
documents should be consistent with the data recorded on the source documents. Data entered 
directly into the eCRFs will be considered the source document. 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
10.1.9.4 
Protocol Deviations 
A protocol deviation is any non-compliance with the clinical trial protocol, any process that is 
noted in the protocol and refers to details in the protocol-specific MOP or GCP requirements, or 
any critical study procedures with specific instructions in ancillary documents referenced in the 
protocol such as a protocol-specific MOP. 
The non-compliance may be either on the part of the subject, the participating site PI or the study 
staff. Following a deviation(s), corrective actions should be developed by the participating site and 
implemented promptly. All individual protocol deviations will be addressed in subject study 
records. 
It is the responsibility of the participating site PI and study staff to use continuous vigilance to 
identify and report deviations within five working days of identification of the protocol deviation, 
or within five working days of the scheduled protocol-required activity. All deviations must be 
promptly reported to DMID per the protocol deviation reporting procedures. Protocol deviations 
must be sent to the local IRB/IEC per their guidelines. The participating site PI and study staff are 
responsible for knowing and adhering to their IRB requirements. A completed copy of the DMID 
Protocol Deviation Form must be maintained in the Regulatory File, as well as in the subject’s 
chart if the deviation is subject specific. 
10.1.9.5 
Data Sharing Plan 
Data will be available immediately following publication, with no end date, with data sharing at 
the discretion of the PI.  
10.1.9.6 
Genomic Data Sharing (GDS) Plan 
This study will comply with the NIH GDS Policy, which applies to all NIH-funded research that 
generates large-scale human or non-human genomic data, as well as the use of these data for 
subsequent research. Large-scale data include genome-wide association studies (GWAS), SNP 
arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data. 

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10.1.9.7 
Publication 
At intervals throughout the study at the discretion of the sponsor and following completion of the 
study, the results of this research will be published in a scientific journal. This study will adhere 
to the NIH Public Access Policy, which ensures that the public has access to the published results 
of NIH funded research. As such, the final peer-reviewed journal manuscripts will be accessible 
to the public on PubMed Central no later than 12 months after publication. 
10.1.9.8 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. DMID has established policies and procedures for all study team members 
to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
10.2 
Additional Considerations 
10.2.1 
Research Related Injuries 
For any potential research related injury, the participating site PI or designee will assess the 
subject. Study staff will try to reduce, control and treat any complications from this trial. 
Immediate medical treatment may be provided by the participating site, such as giving 
emergency medications to stop immediate allergic reactions to the vaccine. As needed, referrals 
to appropriate health care facilities will be provided to the subject. The participating site PI 
should then determine if an injury occurred as a direct result of the tests or treatments that are 
done for this trial. 
If it is determined by the participating site PI that an injury occurred to a subject as a direct result 
of the tests or treatments that are done for this trial, then referrals to appropriate health care 
facilities will be provided to the subject. Study staff will try to reduce, control and treat any 
complications from this trial. Immediate medical treatment may be provided by the participating 
site, such as giving emergency medications to stop immediate allergic reactions to the vaccine. No 
financial compensation will be provided to the subject by NIAID, NIH, the vaccine manufacturer, 
or the participating site for any injury suffered due to participation in this trial. 
For this protocol, the study vaccines are covered under the PREP Act, as described in Section 
2.1.1. 
10.3 
Abbreviations 
Table 7: Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
Ad 
Adenovirus 

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ADCC-NK 
Antibody-Mediated Natural Killer 
ADCD 
Antibody-Dependent Complement Deposition 
ADCP 
Antibody-Dependent Cellular Phagocytosis 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
PBMC 
Peripheral Blood Mononuclear Cell  
BMI 
Body Mass Index 
BP 
Blood Pressure 
°C 
Degrees Celsius 
CAPA 
Corrective and Preventative Action Plan 
CD4 
Cluster of Differentiation 4 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CICP 
Countermeasures Injury Compensation Program 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Clinical Material Services 
COC 
Certificate of Confidentiality 
CoV 
Coronavirus 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 

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CSR 
Clinical Study Report 
CQMP 
Clinical Quality Management Plan 
DCF 
Data Collection Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EKG 
Electrocardiogram 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EUA 
Emergency Use Authorization 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GDS 
Genomic Data Sharing 
GMFR 
Geometric Mean Fold Rise 
GMT 
Geometric Mean Titer 
GWAS 
Genome-Wide Association Studies 
β-HCG 
β Human Chorionic Gonadotropin 

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HHS 
Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HR 
Heart Rate 
HRSA 
Health Resources and Services Administration 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDCRC 
Infectious Disease Clinical Research Consortium 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LNP 
Lipid Nanoparticle 
MAAE 
Medically Attended Adverse Event 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
min 
Minute 

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mITT 
Modified Intent-To-Treat 
mL 
Milliliter 
MOP 
Manual of Procedures 
mRNA 
Messenger Ribonucleic Acid 
MSD 
Meso Scale Discovery 
N 
Number (typically refers to subjects) 
NAAT 
Nucleic Acid Amplification Test 
NaCl 
Sodium Chloride 
NDA 
New Drug Application 
NEUT 
Neutralizing 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NOCMC 
New Onset Chronic Medical Condition 
OHRP 
Office for Human Research Protections 
pIMD 
Potential Immune Mediated Diseases 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction  
PEG 
Polyethylene Glycol 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PREP Act 
Public Readiness and Emergency Preparedness Act 
QA 
Quality Assurance 

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QC 
Quality Control 
RNA 
Ribonucleic Acid 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV 
SARS Coronavirus 
SARS-CoV-2 
SARS Coronavirus 2 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SDSP 
Study Data Standardization Plan 
SNP 
Single Nucleotide Polymorphisms 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SST 
Serum Separator Tube 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Th 
T helper 
TTS 
Thrombosis with Thrombocytopenia Syndrome 
UP 
Unanticipated Problem 
US 
United States 
USP 
United States Pharmacopeia 
VOC 
Variants Of Concern 

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VRC 
Vaccine Research Center 
WHO 
World Health Organization 
WIV1 
Chinese Horseshoe Bat Coronavirus WIV1 
 
10.4 
Protocol Amendment History 
Protocol Amendment History 
Version, Date 
Section 
Description of Change 
Brief Rationale 
Version 2.0, 15, April 
2022 
Throughout 
Administrative. 
Advanced version 
and date. 
 
1.2, 7.1.5, 8.1.6 
4 cc will be stored and 
sent to central lab for 
potential biomarker 
testing at Day 4 and 
Day 60 (new visits 
added), and at 
unscheduled visit for 
suspected case 
myocarditis or 
pericarditis 
To address FDA 
comment. 
 
1.1 
Exploratory Objective 
5 addition of assessing 
anti-nucleocapsid 
serology 
To assess for 
asymptomic SARS-
CoV2 infections. 
 
1.1, 4.1 and 5 
Changed “35%” of 
confirmed infection to 
“20%” confirmed 
infection. 
To reflect a realistic 
percentage of 
participants with 
confirmed infection 
enrolling in the study 
based on US 
serologic data54  
 
1.1 
“A history of 
myocarditis or 
pericarditis at any time 
prior to enrollment” 
added as an exclusion 
criteria. 
To address FDA 
comment. 

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1.2 
Blood volume updated 
for 2 extra cc of sera 
collected at any in-
person scheduled visit 
or early termination 
visit. 
As the volume of 
blood per SST is 8.5 
cc rather than 8 cc. 
 
1.2, 7.1.5, 8.1.6 
Added information on 
management of 
suspected cases of 
myocarditis and/or 
pericarditis. 
To address FDA 
comment. 
 
1.2 
Added clarification 
that pregnancy testing 
is conducted at 
screening as well as 
prior to each 
vaccination.  
Clarification. 
 
1.2, 8.2, 8.3.1.1 
Added clarifications 
regarding confirmation 
of information 
collected in the 
Memory Aid. 
Clarification.  
 
2.1 and 2.2.2 
Added additional 
information relevant to 
the second booster 
currently part of 
standard of care. 
Provided justification 
on how the receipt of 
a variant vaccine in 
the study is not 
expected to be 
inferior to any 
benefits received 
from a second 
booster dose of a 
Pfizer or Moderna 
mRNA vaccine 
obtained outside this 
trial. 
 
Throughout 
“Women” was 
changed to “subjects”. 
To maintain gender 
neutrality.  

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6.5 and 8.1.1 
Non COVID-19 
approved/authorized 
vaccinations are only 
recorded if received 28 
days prior to first dose. 
Clarification.  
 
7.1.1 
Added “immediate IgE 
mediated” to halting 
criteria relevant to 
allergic reactions 
related to study 
vaccine. 
Clarification. 
 
7.1.1. 
Added halting criteria 
relevant to myocarditis 
and /or pericarditis. 
To address FDA 
comment. 
 
8.1.1 
Description provided 
for targeted physical 
exam. 
Clarification.  
 
8.1.5 and 8.3.9 
SARS-CoV2 is not an 
AE but an exploratory 
efficacy assessment.  
To address 
manufacturer 
comment. 
 
8.3.9 and 12 
Listing of types of 
AEs requiring 
reporting to DMID 
pharmacovigilance. 
To address 
manufacturer 
comment. 
 
11 
Changes in references. 
Updates. 
Version 3.0, 29, April 
2022 
Throughout 
Administrative. 
Advanced version 
and date. 
 
1.1, 2.1 
Changes to number of 
cases and deaths from 
COVID-19. 
Updates. 
 
1.1 
Addition of study 
arms. 
Update to include 
Pfizer/ BioNTech 
BNT162b2 vaccine 
platform. 

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2.1  
Data on 
immunogenicity for 
Pfizer/BioNTech 
BNT162b2 vaccine 
against variants of 
concern and type of  
variant vaccines 
available from 
Pfizer/BioNTech  
Addition of 
information relevant 
to new arms of 
Pfizer/BioNTech 
variant vaccines. 
 
2.2.1 
Information on risks 
associated with 
Pfizer/BioNTech 
BNT162b2 variant 
vaccine candidates. 
Addition of 
information relevant 
to new arms of 
Pfizer/BioNTech 
variant vaccines. 
 
2.2.1 
Additional systemic 
adverse effects listed. 
Addition of 
lethargy, decreased 
appetite, night 
sweats, diarrhea and 
malaise. 
 
4.1 
Addition of stage 2. 
Update. 
 
4.3 
Addition of language 
relevant to dosing 
justification for 
Pfizer/BioNTech 
BNT162b2 variant 
vaccine candidates. 
Addition of 
information relevant 
to new arms of 
Pfizer/BioNTech 
variant vaccines. 
 
6.1.1, 6.1.2,  6.2.2, 
6.2.3 
Addition of language 
relevant to study 
product description, 
dosing, 
administration, 
appearance, 
formulation, stability, 
storage for 
Pfizer/BioNTech 
BNT162b2 variant 
vaccine candidates. 
Addition of 
information relevant 
to new arms of 
Pfizer/BioNTech 
variant vaccines. 
Version 4.0, 19, May 
2022 
Throughout 
Administrative. 
Advanced version 
and date. 
 
Throughout  
Clarifications and 
updates 
Clarifications and 
updates 

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1.1 
Addition of study 
arms. 
Update to include 
Sanofi GSK CoV2 
preS dTM-AS03 
vaccine platform. 
 
1.1 
Update to eligibility 
criteria 
 
Addition of history 
of anaphylaxis, 
urticaria, or other 
significant adverse 
reaction requiring 
medical intervention 
after receipt of 
“polysorbate” has 
been added as an 
exclusion criteria. 
 
1.1 
Update to eligibility 
criteria 
Exclusion criterion 
#6 does not apply to 
stage 3. 
 
2.1 
Data on 
immunogenicity  and 
efficacy for Sanofi 
GSK CoV2 preS 
dTM-AS03 vaccine 
against variants of 
concern and type of  
variant vaccines 
available  
Addition of 
information relevant 
to new arms of 
Sanofi GSK variant 
vaccines. 
 
2.2.1 
Information on risks 
associated with 
Sanofi GSK variant 
vaccine candidates. 
Addition of 
information relevant 
to new arms of 
Sanofi GSK variant 
vaccines. 
 
4.3 
Addition of language 
relevant to dosing 
justification for 
Sanofi GSK variant 
vaccine candidates. 
Addition of 
information relevant 
to new arms of 
Sanofi GSK variant 
vaccines 

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6.1.1, 6.1.2,  6.2.2, 
6.2.3 
Addition of language 
relevant to study 
product description, 
dosing, 
administration, 
appearance, 
formulation, stability, 
storage for Sanofi 
GSK variant vaccine 
candidates. 
Addition of 
information relevant 
to new arms of 
Sanofi GSK variant 
vaccines. 
 
8.3.9 
For stage 2, AESIs 
also include a list of 
pIMD. Description of 
pIMD provided.  
Updated safety 
reporting language  
 
12 
List of pIMD 
Updated list of 
AESIs for stage 3 
Version 5.0, 21 
September 2022 
Throughout 
Administrative. 
Advanced version 
and date. 
 
Throughout 
Clarifications and 
updates. 
Clarifications and 
updates. 
 
Throughout 
Replaced “Sanofi 
Pasteur” with 
“Sanofi”, as 
applicable. 
Company name 
updated to reflect 
change made within 
the organization. 
 
1.1 
Addition of study 
arms and stage 4. 
Update to include 
Pfizer BioNTech 
bivalent Prototype + 
Omicron BA.1 and 
Prototype + 
Omicron BA.4/BA.5 
as stage 4. 

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1.1 
Update to eligibility 
criteria. 
Age 18-49 years 
only for arms 16 and 
17 (stage 4). 
Exclusion criteria of 
history of 
pericarditis and 
myocarditis still 
applies to stage 4.   
Only participants 
not willing to 
receive vaccine 
outside the study for 
180 days will be 
enrolled. 
 
 
1.2 
Update for how to 
proceed if participant 
is about to receive a 
COVID-19 vaccine 
outside the study. 
Either plan for an 
unscheduled visit or 
allowing double the 
window for an 
upcoming scheduled 
visit.  
 
1.1 and 2.1 
Update that Novavax 
vaccine received 
FDA EUA. 
Updates to include 
that Novavax 
vaccine received 
FDA EUA on July 
13, 2022. 
 
2.1 and 2.2  
Updates on new 
bivalent boosters that 
will be used in the 
US and the UK and 
Canada in the fall of 
2022. 
Bivalent Prototype+ 
Omicron BA.1 will 
be used as a booster 
vaccine in the UK 
and Canada and 
bivalent Prototype+ 
Omicron BA.4/BA.5 
will be used as a 
booster vaccine in 
the US. 

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2.2.1 
Added nausea, 
vomiting and 
lymphadenopathy as 
side effects of 
Pfizer/BioNTech 
vaccines per IB 
Updates on safety 
 
4.1 and 4.2 
Update to include 
arms 16 and 17. 
Updates to include 
stage 4. 
 
6 
Update to include 
arms 16 and 17. 
Addition of 
information relevant 
to new arms of 
Pfizer/BioNTech 
bivalent variant 
vaccines in stage 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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29. Callaway E, Mallapaty S. Novavax offers first evidence that COVID vaccines protect people 
against variants. Nature 2021;590(7844):17. DOI: 10.1038/d41586-021-00268-9. 
30. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and 
B.1.1.7. Nature 2021;593(7857):130-135. DOI: 10.1038/s41586-021-03398-2. 
31. Muik A, Lui BG, Wallisch AK, et al. Neutralization of SARS-CoV-2 Omicron by 
BNT162b2 mRNA vaccine-elicited human sera. Science 2022;375(6581):678-680. DOI: 
10.1126/science.abn7591. 
32. Cele S, Jackson L, Khoury DS, et al. Omicron extensively but incompletely escapes Pfizer 
BNT162b2 neutralization. Nature 2022;602(7898):654-656. DOI: 10.1038/s41586-021-
04387-1. 
33. Nemet I, Kliker L, Lustig Y, et al. Third BNT162b2 Vaccination Neutralization of SARS-
CoV-2 Omicron Infection. N Engl J Med 2022;386(5):492-494. DOI: 
10.1056/NEJMc2119358. 
34. Pavot V, Berry C, Kishko M, et al. Protein-based SARS-CoV-2 spike vaccine booster 
increases cross-neutralization against SARS-CoV-2 variants of concern in non-human 
primates. Nat Commun 2022;13(1):1699. DOI: 10.1038/s41467-022-29219-2. 
35. van der Straten K, Guerra D, van Gils MJ, et al. Mapping the antigenic diversification of 
SARS-CoV-2. medRxiv 2022:2022.01.03.21268582. DOI: 10.1101/2022.01.03.21268582. 
36. CDC. COVID-19 Vaccinations in the United States. Centers for Disease Control and 
Prevention. (https://covid.cdc.gov/covid-data-tracker/#vaccinations). 
37. Team CC-R, Food, Drug A. Allergic Reactions Including Anaphylaxis After Receipt of the 
First Dose of Moderna COVID-19 Vaccine - United States, December 21, 2020-January 10, 

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2021. MMWR Morb Mortal Wkly Rep 2021;70(4):125-129. DOI: 
10.15585/mmwr.mm7004e1. 
38. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna 
and Pfizer COVID-19 vaccination: A registry-based study of 414 cases. J Am Acad Dermatol 
2021;85(1):46-55. DOI: 10.1016/j.jaad.2021.03.092. 
39. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-
CoV-2 Vaccine. N Engl J Med 2021;384(5):403-416. DOI: 10.1056/NEJMoa2035389. 
40. Oster ME, Shay DK, Su JR, et al. Myocarditis Cases Reported After mRNA-Based COVID-
19 Vaccination in the US From December 2020 to August 2021. JAMA 2022;327(4):331-
340. DOI: 10.1001/jama.2021.24110. 
41. Oliver S. ACIP Meeting: Evidence to Recommendation Framework. 4 Feb 2022 
(https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-04/07-COVID-
Oliver-508.pdf). 
42. Kracalik I. ACIP Meeting: Update on myocarditis outcomes. 4 Feb 2022 
(https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-04/04-COVID-
Kracalic-508.pdf). 
43. Gilboa M, Mandelboim M, Indenbaum V, et al. Early Immunogenicity and safety of the third 
dose of BNT162b2 mRNA Covid-19 vaccine among adults older than 60 years; real world 
experience. J Infect Dis 2021. DOI: 10.1093/infdis/jiab584. 
44. Buchan SA, Seo CY, Johnson C, et al. Epidemiology of myocarditis and pericarditis 
following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval. 
medRxiv 2021:2021.12.02.21267156. DOI: 10.1101/2021.12.02.21267156. 
45. Hause AM, Baggs J, Marquez P, Myers TR. Safety Monitoring of COVID-19 Vaccine 
Booster Doses Among Adults — United States, September 22, 2021–February 6, 2022. 
MMWR Morb Mortal Wkly Rep 2022. DOI: http://dx.doi.org/10.15585/mmwr.mm7107e1. 
46. Team CC-R, Food, Drug A. Allergic Reactions Including Anaphylaxis After Receipt of the 
First Dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020. 
MMWR Morb Mortal Wkly Rep 2021;70(2):46-51. DOI: 10.15585/mmwr.mm7002e1. 
47. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA 
Covid-19 Vaccine. N Engl J Med 2020;383(27):2603-2615. DOI: 10.1056/NEJMoa2034577. 
48. Agency EM. Assessment report: Pandemrix. 28 April 2016. 
(https://www.ema.europa.eu/en/documents/variation-report/pandemrix-h-c-832-ii-0079-epar-
assessment-report-variation_en.pdf). 

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49. Mahase E. Covid-19: UK will roll out Moderna's omicron BA.1 vaccine as part of autumn 
booster programme. BMJ 2022;378:o2038. DOI: 10.1136/bmj.o2038. 
50. (FDA) UFaDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-
19-update-fda-recommends-inclusion-omicron-ba45-component-covid-19-vaccine-booster. 
51. Guidelines CCVB. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-
shot.html?s_cid=11737:cdc covid booster shot 
guidelines:sem.ga:p:RG:GM:gen:PTN:FY22.Accessed February 13, 2022. 
52. Munro APS, Janani L, Cornelius V, et al. Safety and immunogenicity of seven COVID-19 
vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 
in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. 
Lancet 2021;398(10318):2258-2276. DOI: 10.1016/S0140-6736(21)02717-3. 
53. Pfizer asks FDA to greenlight new omicron booster shots, which could arrive this fall. NPR. 
(https://www.npr.org/sections/health-shots/2022/08/22/1118788439/vaccine-maker-asks-fda-
to-greenlight-updated-omicron-booster-shot). 
54. Jones JM, Stone M, Sulaeman H, et al. Estimated US Infection- and Vaccine-Induced SARS-
CoV-2 Seroprevalence Based on Blood Donations, July 2020-May 2021. JAMA 
2021;326(14):1400-1409. DOI: 10.1001/jama.2021.15161. 
55. Ferreira VM, Schulz-Menger J, Holmvang G, et al. Cardiovascular Magnetic Resonance in 
Nonischemic Myocardial Inflammation: Expert Recommendations. J Am Coll Cardiol 
2018;72(24):3158-3176. DOI: 10.1016/j.jacc.2018.09.072. 
56. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol 1987;18(6):619-24. DOI: 
10.1016/s0046-8177(87)80363-5. 
57. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and 
management of pericardial diseases: The Task Force for the Diagnosis and Management of 
Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The 
European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36(42):2921-
2964. DOI: 10.1093/eurheartj/ehv318. 
 
 

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12. 
APPENDIX A: Adverse Events of Special Interest (AESIs) 
Terms 
Investigators should report all events which fall into the following categories as an AESI per the 
reporting processes specified in the protocol. The following AESIs are medical concepts that 
may be related to COVID-19 or are of interest in COVID-19 vaccine safety surveillance. Even if 
the events below occur in the setting of a SARS-CoV-2 infection, the event should still be 
reported as an AESI if it is one of the medical concepts below. SARS-CoV-2 infection will  not 
be reported using the AESI reporting system.  For documentation and medical assessment 
purposes all AESIs will also be reported on an SAE form and must be submitted immediately 
(within 24 hours of site awareness) to the DMID Pharmacovigilance Group; however, when 
applicable, the narrative will indicate that the AESI did not meet SAE criteria. 
 
 
Medical Concept 
Additional Notes 
Anosmia, Ageusia 
• New onset COVID associated or idiopathic events without other 
etiology excluding congenital etiologies or trauma 
Subacute thyroiditis 
• Including but not limited to events of: atrophic thyroiditis, 
autoimmune thyroiditis, immune-mediated thyroiditis, silent 
thyroiditis, thyrotoxicosis and thyroiditis 
Acute pancreatitis 
• Including but not limited to events of: autoimmune pancreatitis, 
immune-mediated pancreatitis, ischemic pancreatitis, edematous 
pancreatitis, pancreatitis, acute pancreatitis, hemorrhagic 
pancreatitis, necrotizing pancreatitis, viral pancreatitis, and 
subacute pancreatitis 
• Excluding known etiologic causes of pancreatitis (alcohol, 
gallstones, trauma, recent invasive procedures) 
Appendicitis 
• Include any event of appendicitis  
Rhabdomyolysis 
• New onset rhabdomyolysis without known etiology such as 
excessive exercise or trauma 
Acute respiratory distress 
syndrome (ARDS) 
• Including but not limited to new events of ARDS and respiratory 
failure 
Coagulation disorders 
• Including but not limited to thromboembolic and bleeding 
disorders, disseminated intravascular coagulation, pulmonary 
embolism, deep vein thrombosis 

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Acute cardiovascular injury 
• Including but not limited to myocarditis, pericarditis, 
microangiopathy, coronary artery disease, arrhythmia, stress 
cardiomyopathy, heart failure, or acute myocardial infarction 
Acute kidney injury 
• Include events with idiopathic or autoimmune etiologies 
• Exclude events with clear alternate etiology (trauma, infection, 
tumor, or iatrogenic causes such as medications or radiocontrast 
etc.) 
• Include all cases that meet the following criteria:  
o Increase in serum creatinine by ≥ 0.3 mg/dl (≥26.5 umol/l) 
within 48 hours; 
o OR Increase in serum creatinine to ≥ 1.5 times baseline, 
known or presumed to have occurred within prior 7 days 
o OR Urine volume ≤0.5 ml/ kg/ hour for 6 hours 
Acute liver injury 
Include events with idiopathic or autoimmune etiologies 
Exclude events with clear alternate etiology (trauma, infection, 
tumor, etc.) 
Include all cases that meet the following criteria 
> 3-fold elevation above the upper normal limit for ALT or 
AST 
OR • > 2-fold elevation above the upper normal limit for total 
serum bilirubin or GGT or ALP 
Dermatologic findings 
• Chilblain-like lesions 
• Single organ cutaneous vasculitis 
• Erythema multiforme 
• Bullous rashes 
• Severe cutaneous adverse reactions including but not limited to: 
Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis 
(TEN), Drug Reaction with Eosinophilia and Systemic Symptoms 
(DRESS) and fixed drug eruptions 
Multisystem inflammatory 
disorders 
Multisystem inflammatory syndrome in adults (MIS-A) 
Multisystem inflammatory syndrome in children (MIS-C) 
Kawasaki’s disease 
Thrombocytopenia and/or 
Thrombosis with 
Thrombocytopenia 
Syndrome (TTS) 
• Platelet counts < 150 x10^9 
• Thrombotic events:  Suspected deep vessel venous or arterial 
thrombotic events 
• Including but not limited to TTS (default operative diagnosis if 
boosted with Ad26.COV2.S), immune thrombocytopenia, platelet 
production decreased, thrombocytopenia, thrombocytopenic 

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purpura, thrombotic thrombocytopenic purpura, or HELLP 
syndrome 
Acute aseptic arthritis 
• New onset aseptic arthritis without clear alternate etiology (e.g., 
gout, osteoarthritis, and trauma) 
New onset of or worsening of 
neurologic disease 
Including but not limited to: 
Guillain-Barre Syndrome 
Acute disseminated encephalomyelitis (ADEM) 
Peripheral facial nerve palsy (Bell’s palsy)  
Transverse myelitis 
Encephalitis/Encephalomyelitis 
Aseptic meningitis 
Febrile seizures 
Generalized seizures/convulsions 
Stroke (Hemorrhagic and non-hemorrhagic) 
Narcolepsy 
Anaphylaxis 
Anaphylaxis is an acute hypersensitivity reaction with multi-
organ-system involvement that can present as, or rapidly 
progress to, a severe life-threatening reaction. It may occur 
following exposure to allergens from a variety of sources. 
Anaphylaxis is a clinical syndrome characterized by: 
o sudden onset AND 
o rapid progression of signs and symptoms AND 
o involving two or more organ systems, as follows: 
o Skin/ mucosal: urticaria (hives), generalized erythema, 
angioedema, generalized pruritus with skin rash, 
generalized prickle sensation, red and itchy eyes 
o Cardiovascular: measured hypotension, clinical diagnosis of 
uncompensated shock, loss of consciousness or decreased 
level of consciousness, evidence of reduced peripheral 
circulation 
o Respiratory: bilateral wheeze (bronchospasm), difficulty 
breathing, stridor, upper airway swelling (lip, tongue, 
throat, uvula, or larynx), respiratory distress, persistent dry 
cough, hoarse voice, sensation of throat closure, sneezing, 
rhinorrhea 
o Gastrointestinal: diarrhea, abdominal pain, nausea, vomiting 
Follow reporting procedures in protocol. 
Myocarditis and/or pericarditis 
Symptoms and diagnostic findings include but are not limited to: 
Chest pain 
Dyspnea 
ST or T wave changes on ECG 
Elevated cardiac enzymes 

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Abnormal echocardiography or other cardiac imaging.  
Other syndromes 
• Fibromyalgia 
• Postural Orthostatic Tachycardia Syndrome 
• Chronic Fatigue Syndrome (Includes Myalgic encephalomyelitis 
and Post viral fatigue syndrome) 
• 
Myasthenia gravis 
 
List of potential Immune-mediated Diseases (pIMDs) for Stage 3  
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid 
syndrome 
 
Autoimmune aplastic 
anemia 
 
Autoimmune hemolytic 
anemia 
• Includes warm antibody hemolytic anemia and cold 
antibody hemolytic anemia 
Autoimmune 
lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune 
pancytopenia 
 
Autoimmune 
thrombocytopenia 
• Frequently used related terms include: “autoimmune 
thrombocytopenic purpura”, “idiopathic thrombocytopenic 
purpura (ITP)”,  “idiopathic immune thrombocytopenia”, 
“primary immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with 
thrombocytopenia 
syndrome (TTS) 
 
Thrombotic 
thrombocytopenic 
purpura 
• Also known as “Moschcowitz-syndrome” or 
“microangiopathic hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 

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Medical Concept 
Additional Notes 
Idiopathic 
Myocarditis/Pericarditis 
Including but not limited to: 
• Autoimmune / Immune-mediated myocarditis 
• Autoimmune / Immune-mediated pericarditis 
• Giant cell myocarditis 
Idiopathic pulmonary 
fibrosis 
Including but not limited to: 
• Idiopathic interstitial pneumonia (frequently used related 
terms include “Interstitial lung disease”, “Pulmonary 
fibrosis”, “Immune-mediated pneumonitis”) 
• Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar 
proteinosis (PAP) 
• Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-
mediated thyroiditis  
Including but not limited to: 
• Hashimoto thyroiditis (autoimmune hypothyroidism, 
lymphocytic thyroiditis) 
• Atrophic thyroiditis  
• Silent thyroiditis  
• Thyrotoxicosis 
Autoimmune diseases of 
the testis and ovary 
• Includes autoimmune oophoritis,  autoimmune ovarian 
failure and autoimmune orchitis 
Autoimmune 
hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s 
disease 
• Includes Marine Lenhart syndrome and Graves' 
ophthalmopathy, also known as thyroid eye disease (TED) 
or endocrine ophthalmopathy 
Insulin autoimmune 
syndrome 
 
Polyglandular 
autoimmune syndrome 
• Includes Polyglandular autoimmune syndrome type I, II and 
III 
Eye disorders 

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Medical Concept 
Additional Notes 
Ocular Autoimmune / 
Immune-mediated 
disorders 
Including but not limited to: 
• Acute macular neuroretinopathy (also known as acute 
macular outer retinopathy) 
• Autoimmune / Immune-mediated retinopathy  
• Autoimmune / Immune-mediated uveitis, including 
idiopathic uveitis and sympathetic ophthalmia  
• Cogan's syndrome: an oculo-audiovestibular disease 
• Ocular pemphigoid 
• Ulcerative keratitis 
• Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-
mediated pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel 
disease  
Including but not limited to:  
• Crohn’s disease  
• Microscopic colitis  
• Terminal ileitis 
• Ulcerative colitis  
• Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing 
cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• Dermatomyositis 
• Inclusion body myositis 
• Immune-mediated necrotizing myopathy 

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Medical Concept 
Additional Notes 
• Polymyositis 
Mixed connective tissue 
disorder 
 
Polymyalgia rheumatica 
(PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• Rheumatoid arthritis associated conditions 
• Juvenile idiopathic arthritis 
• Palindromic rheumatism 
• Still's disease 
• Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to:  
• Ankylosing spondylitis 
• Juvenile spondyloarthritis 
• Keratoderma blenorrhagica 
• Psoriatic spondylitis  
• Reactive Arthritis (Reiter's Syndrome) 
• Undifferentiated spondyloarthritis 
Systemic Lupus 
Erythematosus  
• Includes Lupus associated conditions (e.g. Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such 
as shrinking lung syndrome (SLS) 
Systemic Scleroderma 
(Systemic Sclerosis) 
• Includes Reynolds syndrome (RS), systemic sclerosis with 
diffuse scleroderma and systemic sclerosis with limited 
scleroderma (also known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis 
(ADEM) and other 
inflammatory-
demyelinating variants  
Includes the following: 
• Acute necrotising myelitis 
• Bickerstaff's brainstem encephalitis  
• Disseminated necrotizing leukoencephalopathy (also known 
as Weston-Hurst syndrome, acute hemorrhagic leuko-

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Medical Concept 
Additional Notes 
encephalitis,  or acute necrotizing hemorrhagic 
encephalomyelitis)  
• Myelin oligodendrocyte glycoprotein antibody-associated 
disease 
• Neuromyelitis optica (also known as Devic’s disease) 
• Noninfective encephalitis / encephalomyelitis / myelitis 
• Postimmunization encephalomyelitis  
Guillain-Barré syndrome 
(GBS) 
• Includes variants such as Miller Fisher syndrome and the 
acute motor and sensory axonal neuropathy (AMSAN) 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis) 
Including but not limited to: 
• Cranial nerve neuritis (e.g. Optic neuritis) 
• Idiopathic nerve palsies/paresis (e.g. Bell’s palsy) 
• Melkersson-Rosenthal syndrome 
• Multiple cranial nerve palsies/paresis  
Multiple Sclerosis (MS) 
Includes the following: 
• Clinically isolated syndrome (CIS)  
• Malignant MS (the Marburg type of MS)  
• Primary-progressive MS (PPMS) 
• Radiologically isolated syndrome (RIS) 
• Relapsing-remitting MS (RRMS) 
• Secondary-progressive MS (SPMS) 
• Uhthoff's phenomenon  
Myasthenia gravis 
• Includes ocular myasthenia and Lambert-Eaton myasthenic 
syndrome 
Narcolepsy 
• Includes narcolepsy with or without presence of 
unambiguous cataplexy 
Peripheral inflammatory 
demyelinating 
neuropathies and 
plexopathies 
Including but not limited to: 
• Acute Brachial Radiculitis (also known as Parsonage-
Turner Syndrome or neuralgic amyotrophy) 
• Antibody-mediated demyelinating neuropathy 
• Chronic idiopathic axonal polyneuropathy (CIAP) 
• Chronic Inflammatory Demyelinating 
Polyradiculoneuropathy (CIDP), including atypical CIDP 

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Medical Concept 
Additional Notes 
variants (e.g. multifocal acquired demyelinating sensory 
and motor neuropathy also known as Lewis-Sumner 
syndrome) 
• Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• Includes acute partial transverse myelitis (APTM) and acute 
complete transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-
mediated 
glomerulonephritis  
Including but not limited to: 
• IgA nephropathy 
• IgM nephropathy 
• C1q nephropathy 
• Fibrillary glomerulonephritis 
• Glomerulonephritis rapidly progressive 
• Membranoproliferative glomerulonephritis 
• Membranous glomerulonephritis 
• Mesangioproliferative glomerulonephritis 
• Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / Immune-
mediated blistering 
dermatoses  
Including but not limited to:  
• Bullous Dermatitis 
• Bullous Pemphigoid  
• Dermatitis herpetiformis  
• Epidermolysis bullosa acquisita (EBA)  
• Linear IgA-mediated bullous dermatosis (LABD), also 
known as Linear IgA disease 
• Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Reactive granulomatous 
dermatitis  
Including but not limited to 
• Interstitial granulomatous dermatitis 
• Palisaded neutrophilic granulomatous dermatitis 

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Medical Concept 
Additional Notes 
Lichen planus 
• Includes liquen planopilaris 
Localised Scleroderma 
(Morphoea) 
• Includes Eosinophilic fasciitis (also called Shulman 
syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson 
Syndrome (SJS) 
 
Including but not limited to:  
• Toxic Epidermal Necrolysis (TEN)  
• SJS-TEN overlap 
Sweet’s syndrome 
• Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
• Arteritic anterior ischemic optic neuropathy (AAION or 
arteritic AION) 
• Giant cell arteritis (also called temporal arteritis)  
• Takayasu's arteritis  
Medium sized and/or 
small vessels vasculitis  
Including but not limited to: 
• Anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified)  
• Behcet's syndrome  
• Buerger’s disease (thromboangiitis obliterans) 
• Churg–Strauss syndrome (allergic granulomatous angiitis)  
• Erythema induratum (also known as nodular vasculitis) 
• Henoch-Schonlein purpura (also known as IgA vasculitis) 
• Microscopic polyangiitis 
• Necrotizing vasculitis 
• Polyarteritis nodosa 
• Single organ cutaneous vasculitis, including 
leukocytoclastic vasculitis, hypersensitivity vasculitis and 
acute hemorrhagic edema of infancy (AHEI) 
• Wegener's granulomatosis  
Other (including multisystemic) 

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Medical Concept 
Additional Notes 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• Frequently used related terms include : “systemic capillary 
leak syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• Frequently used related terms include : “pulmonary renal 
syndrome” and “anti-Glomerular Basement Membrane 
disease (anti-GBM disease)” 
Immune-mediated 
enhancement of disease 
• Includes vaccine associated enhanced disease (VAED and 
VAERD). Frequently used related terms include “vaccine-
mediated enhanced disease (VMED)”, “enhanced 
respiratory disease (ERD)”, “vaccine-induced enhancement 
of infection”, “disease enhancement”, “immune 
enhancement”, and “antibody-dependent enhancement 
(ADE) 
Immunoglobulin G4 
related disease 
 
Langerhans' cell 
histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• Kawasaki’s disease 
• Multisystem inflammatory syndrome in adults (MIS-A) 
• Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• Includes Loefgren syndrome 
Susac's syndrome