Additional Recombinant COVID-19 Humoral and Cell-Mediated Immunogenicity in Immunosuppressed Populations
Phase: PHASE2
Conditions: Immunosuppression, COVID-19
Sponsor: University of Wisconsin, Madison

 
 
 
 
Additional Recombinant COVID-19 Humoral and Cell-
Mediated Immunogenicity in Immunosuppressed 
Populations. (ARMOR-COVID) 
 
October 5, 2024 
 
NCT06027229 
 
 
 

Additional Recombinant COVID-19 Humoral and Cell-Mediated Immunogenicity in 
Immunosuppressed Populations. (ARMOR-COVID) 
 
Sponsor- Investigator:  
Freddy Caldera, DO, MS 
Protocol Number: 
 
 
Oncore Protocol number: 235058 
IRB Protocol number: 2023-1208 
 
IND Number:  
 
 
29913 
 
Sub-Investigator: 
 
 
Mary S. Hayney PharmD, MPH 
 
Site Information: 
University of Wisconsin School of Medicine & Public Health  
Department of Medicine, Division of Gastroenterology & 
Hepatology  
 
 
 
 
 
1685 Highland Avenue 
 
 
 
 
 
Madison, WI 53705 
 
 
Contact Information: 
 
Freddy Caldera, DO, MS  
 
 
 
 
 
608-628-8201  
Source of Funding  
 
Novavax  
 
Version Date:  
 
 
October 5, 2024  
 
This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior authorization from the Sponsor or Principal Investigator. 
 
 
 
 
 

 
 
 
 
 
 
 
 
Contents 
1.0 
Statement of Compliance ................................................................................................. 5 
2.0 
List of Abbreviations ......................................................................................................... 6 
3.0 
Synopsis ............................................................................................................................. 7 
4.0 
Key Roles ......................................................................................................................... 11 
5.0 
Introduction ....................................................................................................................... 12 
5.1 
Background and Scientific Rationale ........................................................................ 12 
5.2 
Study Aim and Hypotheses. ...................................................................................... 13 
6.0 
STUDY OBJECTIVES & ENDPOINTS ........................................................................ 14 
6.1 
Primary Objective ........................................................................................................ 14 
6.2 
Secondary objectives .................................................................................................. 14 
6.2.1 
Sustained antibody concentrations of the recombinant booster dose. .........14 
6.2.2 
Seroconversion. .....................................................................................................15 
6.2.3 
Cell-mediated immunity to recombinant COVID-19 booster vaccine. ..........15 
6.2.4 
Sustained cell-mediated immunity to the recombinant COVID-19 booster 
vaccine. .................................................................................................................................15 
6.3 
Describe the safety of the COVID-19 vaccine. ....................................................... 16 
6.4 
Evaluate the disease activity following administration of the booster dose up to 
30 days post-vaccination and during the whole post-vaccination follow-up period. .... 17 
6.5 
Evaluate for solid organ transplant rejection following administration of booster 
dose, up to 30 days post- vaccination and during the whole post-vaccination follow-up 
period. ...................................................................................................................................... 17 
7.0 
STUDY DESIGN.............................................................................................................. 18 
7.1 
Program Type / Scope of Study / Clinical Design / Sites ...................................... 18 
7.2 
Site Responsibilities Overview .................................................................................. 18 
7.3 
Study Population Overview ........................................................................................ 19 
7.4 
Study Duration ............................................................................................................. 19 
7.5 
Ethical and Regulatory Considerations .................................................................... 20 
8.0 
SELECTION AND WITHDRAL OF SUBJECTS ........................................................ 21 

8.1 
Inclusion criteria ........................................................................................................... 21 
8.2 
Exclusion criteria .......................................................................................................... 22 
8.3 
Subject Identification and Recruitment .................................................................... 22 
8.4 
Remuneration for participation .................................................................................. 23 
8.5 
Premature Subject Discontinuation .......................................................................... 23 
9.0 
Study Agent - Novavax COVID-19 Vaccine, Adjuvanted ......................................... 25 
9.1 
Source ........................................................................................................................... 25 
9.2 
Packaging and Labeling ............................................................................................. 25 
9.3 
Preparation ................................................................................................................... 25 
9.4 
Storage and Stability ................................................................................................... 26 
9.5 
Accountability ............................................................................................................... 26 
9.6 
Dosing and Administration ......................................................................................... 26 
10.0 STUDY ASSESSMENT SCHEDULE AND PROCEDURES .................................... 27 
10.1 Study Calendar ............................................................................................................ 27 
10.2 Study Assessments by Visit ....................................................................................... 27 
10.3 Informed Consent Procedures................................................................................... 28 
10.4 Clinical assessments................................................................................................... 29 
10.4.1 
Blood Samples ...................................................................................................29 
10.4.2 
Disease Activity Assessment ...........................................................................30 
10.4.3 
Adverse Events Assessments .........................................................................30 
10.4.4 
Other Measurements ........................................................................................30 
11.0 Data Handling and REcord Keeping ............................................................................ 31 
12.0 Study Analysis ................................................................................................................. 34 
12.1 Number of Subjects (Statistical Justification) .......................................................... 34 
12.2 Statistical Analysis ........................................................ Error! Bookmark not defined. 
13.0 SAFETY REPORTING ................................................................................................... 35 
13.1 Definitions: .................................................................................................................... 35 
13.2 Severity of Event .......................................................................................................... 36 
13.3 Expectedness to Study Intervention ......................................................................... 41 
13.4 Time Period and Frequency for Event Assessment and Follow-Up .................... 41 
13.5 Reporting AEs and SAEs ........................................................................................... 41 
13.5.1 
Reporting AEs ....................................................................................................42 
13.5.2 
Reporting of SAEs .............................................................................................42 
13.5.3 
Additional Reporting Requirements ................................................................42 

13.6 Unanticipated Problems ............................................................................................. 44 
13.7 Safety Oversight and Stopping Rules ...................................................................... 44 
13.8 Study Monitoring .......................................................................................................... 45 
14.0 RISK-BENEFIT ................................................................................................................ 47 
14.1 Risks of Study .............................................................................................................. 47 
14.2 Potential Benefits of Study ......................................................................................... 47 
15.0 Study Feasbility ................................................................................................................. 48 
16.0 Appendices ....................................................................................................................... 49 
16.1 Appendix 1: Short Crohn’s Disease Activity Index (sCDAI) .................................. 49 
16.2 Appendix 2: Simple Clinical Colitis Activity Index ................................................... 49 
16.3 Appendix 3: List of potential Immune-mediated Diseases (pIMDs) .................... 50 
17.0 References ....................................................................................................................... 58 
 

1.0 
STATEMENT OF COMPLIANCE 
I confirm that I have read this protocol. I will comply with the IRB-approved protocol, and 
applicable regulations, guidelines, laws, and institutional policies. 
  
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitment. 
 
Name 
Signature 
Date 
 
 
__________________________________ 
_____________________________ 
______ 
Sponsor-Investigator 
 

2.0 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CMS 
Centralized Monitoring Service 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMP 
Data & Safety Monitoring Plan 
eCRF 
Electronic Case Report Forms 
EHR 
Electronic Health Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
OnCore 
Online Collaborative Research Environment 
PHI 
Protected Health Information 
PI 
Principal Investigator 
pIMDs 
Potential Immune-Mediated Diseases 
PRC 
Pharmaceutical Research Center 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMP 
Study Monitoring Plan 
UP 
Unanticipated Problem 
 

3.0 
SYNOPSIS 
Full Title 
Additional Recombinant COVID-19 Humoral and Cell-Mediated Immunogenicity in 
Immunosuppressed Populations 
Short Title 
ARMOR-COVID 
Protocol Number 
Oncore Protocol number: 235058 
IRB Protocol number: 2023-1208 
ClinicalTrials.gov 
Identifier & 
Summary 
NCT06027229  
To determine whether providing a 2023/2024 (monovalent, XBB containing) Novavax 
COVID-19 vaccine, the Omicron XBB.1.5 vaccine is named BV2601, with the drug product as 
NVX-CoV2601, improves sustained humoral and cell-mediated immunogenicity against 
SARS-CoV-2 in immunosuppressed patients with IBD and/or solid organ transplant 
recipients. 
 
The study will be extended to 2024/2025 season which will determine whether providing a 
2024/2025 (monovalent, XBB containing) Novavax COVID-19 vaccine, the Omicron XBB.1.5 
vaccine is named BV2601, with the drug product as NVX-CoV2024-2025, improves 
sustained humoral and cell-mediated immunogenicity against SARS-CoV-2 in 
immunosuppressed patients with IBD and/or solid organ transplant recipients. 
 
 
Number of 
Site(s) 
One clinical site in the United States. 
Phase 
Phase II 
Main Inclusion 
Criteria 
• 
Patient is between the ages of 18-85 years.  
• 
Patients has a history of ulcerative colitis (UC),  Crohn’s disease, or pouchitis diagnosed 
by standard clinical, radiographic, endoscopic, and histopathologic criteria or solid organ 
transplant recipient.  
• 
Have received at least three doses of a COVID-19 vaccine.  
• 
On systemic immunosuppressive therapy for inflammatory bowel disease or for solid organ 
transplant  
Main Exclusion 
Criteria 
• 
Allergy to recombinant COVID-19 vaccine or any component of it  
• 
Patient cannot or will not provide written informed consent.  
• 
Unable to provide appropriate informed consent because of illiteracy or impairment in 
decision-making capacity.  
• 
Active antibody-mediated or cellular rejection.  
• 
Recent IBD flare requiring initiation of systemic corticosteroids within the past month.  
Objective(s) 
2023-2024 season  
 
Primary Objective  
• 
Humoral Immunogenicity of a NVX-CoV2601 
Secondary Objectives  
• 
Sustained antibody concentrations of the NVX-CoV2601 booster dose.  
• 
Seroconversion. 
• 
Cell-mediated immunity to NVX-CoV2601 booster vaccine 
• 
Sustained cell-mediated immunity to the NVX-CoV2601booster vaccine.  
• 
Describe the safety of the NVX-CoV2601. 

• 
Evaluate the disease activity following administration of the booster dose up to 30 days 
post-last vaccination and during the whole post-vaccination follow-up period. 
• 
Evaluate for solid organ transplant rejection following administration of booster dose, up 
to 30 days post-vaccination and during the whole post-vaccination follow-up period 
 
2024-2025 season  
(The 2024-2025 season activities will not proceed as originally planned due to the withdrawal 
of financial support from our sponsor). 
Primary Objective  
• 
Humoral Immunogenicity of a NVX-CoV2024-2025 booster 
Secondary Objectives  
• 
Sustained antibody concentrations of the NVX-CoV2024-2025 booster.  
• 
Seroconversion. 
• 
Cell-mediated immunity to NVX-CoV2024-2025 booster 
• 
Sustained cell-mediated immunity to the NVX-CoV2024-2025 booster 
• 
Describe the safety of the NVX-CoV2024-2025 booster 
• 
Evaluate the disease activity following administration of the booster dose up to 30 days 
post-last vaccination and during the whole post-vaccination follow-up period. 
• 
Evaluate for solid organ transplant rejection following administration of booster dose, up 
to 30 days post-vaccination and during the whole post-vaccination follow-up period 
 
 
Endpoints 
2023-2024 Season  
 
Primary Endpoint 
• 
Antibody concentrations at V2 are statistically significantly higher than at V1.   
Secondary Endpoints 
• 
Seropositivity rate at V2 and V3 in all participants. 
• 
Individuals who achieve seroconversion at V2 
• 
Interferon gamma responses at V2 compared to V1. 
• 
Interferon gamma responses at V3 compared to V1. 
• 
The number and percentage of subjects reporting solicited and unsolicited AEs, pIMDs, 
and SAEs. 
• 
Number and percentage of participants reporting disease flares of IBD. 
• 
Number and percentage of participants reporting acute rejection of their transplant. 
 
2024-2025 Season  
 
Primary Endpoint 
• 
Antibody concentrations at V2 are statistically significantly higher than at V1.   
Secondary Endpoints 

• 
Seropositivity rate at V2 and V3 in all participants. 
• 
Individuals who achieve seroconversion at V2 
• 
Interferon gamma responses at V2 compared to V1. 
• 
Interferon gamma responses at V3 compared to V1. 
• 
The number and percentage of subjects reporting solicited and unsolicited AEs, pIMDs, 
and SAEs. 
• 
Number and percentage of participants reporting disease flares of IBD. 
• 
Number and percentage of participants reporting acute rejection of their transplant. 
 
Study Design 
 
2023-2024 season  
This will be a single-center, prospective, unblinded, non-randomized study of 120 
immunosuppressed patients who are planning to receive a NVX-CoV2601 COVID-19 vaccine 
booster dose.  
 
2024-2025 season  
 
This will be a single-center, prospective, unblinded, non-randomized study of 120 
immunosuppressed patients who are planning to receive a NVX-CoV2024-2025 COVID-19 
booster 
 
FDA Regulatory 
Overview 
The protocol uses an investigational product, NVX-CoV2601, and is being conducted under 
IND NUMBER 29913 that is held by Dr. Freddy Caldera. 
Study 
Intervention 
NVX-CoV26012023/2024 (monovalent, XBB containing) Novavax COVID-19 vaccine, the 
Omicron XBB.1.5 vaccine is named BV2601 
 
NVX-CoV2024-2025 booster Novavax COVID-19 vaccine, the Omicron XBB.1.5 vaccine is 
named BV2601 
 
Total Number of 
Subjects 
2023-2024 season  
- 
21 patients were enrolled in this season  
2024-2025 season (none will be recruited anymore) (The 2024-2025 season activities will not 
proceed as originally planned due to the withdrawal of financial support from our sponsor). 
 
- 
A total 120 subjects will be enrolled.  
 
 
A total of 141 subjects will be enrolled for this study for both seasons.  
Study Population Male and females aged 18 to 85 with IBD and/or who are solid organ transplant recipients. 
Statistical 
Methodology 
In analyzing the primary endpoint, a paired t-test will be utilized to test whether, on average, 
there is a change of at least 15% antibody blood concentration between the first and second 

blood draws. A test statistics and degrees of freedom, including the 95% confidence intervals 
will be reported. In addition, we will model the post measurement blood draw concentrations 
(i.e., V2 and V3) as the response variable using an ANOVA (i.e., ANOVA-POST), while 
adjusting for the initial responses (V1) and other baseline covariates. 
 
Estimated 
Subject Duration 
The duration of the study for each subject is approximately 6 months.  
Estimated 
Enrollment 
Period & Study 
Duration 
Study enrollment and follow-up will occur over 6 months with the total expected duration of 
the trial to be 24 months. 
 

4.0 
KEY ROLES 
The following is a list of all key personnel and roles: 
 
Sponsor-Investigator 
Freddy Caldera, DO, MS 
University of Wisconsin School of Medicine & 
Public Health  
Department of Medicine, Division of 
Gastroenterology & Hepatology  
1685 Highland Avenue 
Madison, WI 53705 
608-628-8201 
Participating Site(s) 
University of Wisconsin Madison 
1685 Highland Avenue 
Madison, WI 53705 
Medical Monitor 
Mary Hayney PharmD, MPH 
Professor of Pharmacy  
University of Wisconsin School of Pharmacy 
Rennebohm Hall 
777 Highland Avenue 
Madison, WI 53705 
608-265-4666 
mary.hayney@wisc.edu 
Central Laboratory Services 
LabCorp Diagnostics 
4301 Lost Hills Road, Calabasas, CA 91301 
Caldera/Hayney Lab  
Rennebohm Hall 
777 Highland Avenue 
Madison, WI 53705 
Study Monitoring Contact  
Centralized Monitoring Service 
1685 Highland Avenue 
Madison, WI 53705 
Funding Sponsor 
Novavax 
21 Firstfield Road 
Gaithersburg, MD 20878 
Biostatistician 
Emmanuel Sampene, PhD  
WARF Office Building, Room 230 
610 Walnut Street 
Madison, WI 53726 
608-265-8725 
sampene@biostat.wisc.edu 
Data Coordinating Center 
University of North Carolina 
David Seligson 
DATA MANAGEMENT PROGRAMMER 
COLLABORATIVE STUDIES COORDINATING 
CENTER 
dseligso@email.unc.edu 
 

5.0 
INTRODUCTION  
5.1 
Background and Scientific Rationale  
Immunosuppressed populations, which include patients with inflammatory bowel disease 
(IBD) and those with solid organ transplant (such as liver transplant recipients), account for 
approximately 3% of the population in the United States (US).1 They are commonly treated with 
immunosuppressive medications that can increase their risk of respiratory infections such as 
influenza, invasive pneumococcal disease and SARS-CoV-2 all which are potentially vaccine 
preventable diseases.2  Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic 
with greater than 500  million infections and more than 6 million deaths worldwide. 
Immunosuppressed populations are at an increased risk for severe COVID-19 outcomes. Three 
safe and highly efficacious SARS-CoV-2 vaccines are authorized by the Food and Drug 
Administration (FDA) in response to the COVID-19 pandemic.1  Immunosuppressed patients were 
excluded from the original Phase III clinical trials; therefore, the efficacy in this population is 
unknown. These vaccines have been found to be safe in patients with IBD, with similar rates of 
localized and systemic adverse events as found in the general population, with low rates of IBD 
flares following vaccination (2%). 3, 4   Additionally these vaccines are associated with similar rates 
of reactogenicity in solid organ transplant recipients and low rates of acute rejection following 
immunization. 5, 6  
 
Patients with solid organ transplant are less likely to seroconvert after the two-dose 
series.7, 8 The humoral response to COVID-19 vaccines in patients with solid organ transplant has 
been reported to be approximately 50-70%.7, 8  In contrast, it appears that most patients with IBD 
are able to mount an antibody response post immunization.9  In our study HERCULES we found 
that patients with IBD had lower antibody concentrations than healthy controls.9 These studies 
have raised concerns that immunosuppressed patients may be susceptible to breakthrough 
COVID-19 infections and potential complications from COVID-19 disease despite being 
immunized. Our study HERCULES showed robust antibody responses after three doses of 
COVID-19 vaccines in patients with IBD, with antibody concentrations being higher after the third 
dose than after the two doses primary series.10  In contrast, among immunosuppressed solid 
organ transplant recipients, a third dose improves humoral immune response but they are still 
suboptimal when compared to the general population.11  
 
There is evidence of waning humoral immunity in the general population following 
vaccination, especially in those who are immunosuppressed or greater than 65 years.12 A high 
incidence of breakthrough infection among vaccinated healthcare workers has also been 
described.13 As such, the Advisory Committee on Immunization Practice (ACIP) recommended a 
booster mRNA vaccine dose five months after completion of the original two-dose vaccine series 
for all adults. Booster doses have reduced the incidence of infection and severity of illness.14 For 
those who completed a three-dose mRNA vaccine primary series, as recommended by the ACIP 
for those who are moderately to severely immunosuppressed, are now eligible for up to two 
additional booster doses.  
 
Homologous booster strategies have improved vaccine response in the general 
population and immunosuppressed populations. Heterologous prime boost strategies may offer 
immunological advantages to optimize the breadth and longevity of protection achieved with the 
currently available vaccines. A recent study showed that both homologous and heterologous 
boosting strategies resulted in improved humoral immunogenicity in adults.15  Furthermore a large 
population based study showed that heterologous boosting achieved higher vaccines 
effectiveness for many clinical outcomes compared to homologous boosting.16 17 

 
A new COVID-19 vaccine, NVX-CoV2372 (Novavax), made up of a full-length stabilized 
recombinant spike protein, has been found to be safe and effective in preventing COVID-19.18  It 
recently received approval from the FDA for emergency use authorization (EUA). The ACIP also 
recommended the use of this vaccine as a primary series. This recombinant COVID-19 vaccine 
may be an ideal agent to boost, given that it has a different mechanism and has the full length of 
the spike protein compared to mRNA vaccines. Thus, there is a critical need to evaluate whether 
a recombinant COVID-19 vaccine can improve the immune response to COVID-19 vaccines in 
immunosuppressed populations.  The goal of this study to evaluate the immunogenicity of a 
2023/2024 and 2024/2025 (monovalent, XBB containing) Novavax COVID-19 vaccine, the 
Omicron XBB.1.5 vaccine is named BV2601 with the drug product as NVX-CoV2601 and not to 
evaluate the impact of a heterologous boosting strategy. This critical need will be addressed via 
a collaborative study with investigators in expertise in inflammatory bowel disease and 
vaccinology (Freddy Caldera, DO, MS), vaccinology (Mary Hayney, PharmD, MPH), and 
immunology (Keith Knutson, PhD). Whether antibody concentrations will continue to wane after 
booster doses of mRNA vaccines and increase the risk of breakthrough infections in 
immunosuppressed patients remains unknown. Thus, there is a critical need to continue 
investigating ways to improve sustained protection in these populations.   We will help answer 
this critical question with the following aims. 
5.2 
Study Aim and Hypotheses.  
 
Aim 1:  To determine whether providing a NVX-CoV2601 booster COVID-19 vaccine 
improves sustained humoral and cell-mediated immunogenicity against SARS-CoV-2 in 
immunosuppressed patients with IBD and/or solid organ transplant recipients.   
We hypothesize that solid organ transplant recipients receiving a combination of 
immunosuppressive regimens will have lower antibody concentrations than patients with IBD 
because our previous work has shown that patients with IBD have higher rates of seroconversion 
than solid organ transplant recipients.  
 
 
 
 

6.0 
STUDY OBJECTIVES & ENDPOINTS 
 
The vaccine will be evaluated for two seasons separately: 2023/2024 and 2024/2025. Thus, we 
will have two co primary objectives.  
 
• 
2023-2024 season  
The primary objective of this study is to evaluate the immunogenicity of a 2023/2024 
(monovalent, XBB containing) Novavax COVID-19 vaccine, the Omicron XBB.1.5 NVX-
CoV2601 in immunosuppressed populations. 
 
• 
2024-2025 season (The 2024-2025 season activities will not proceed as originally 
planned due to the withdrawal of financial support from our sponsor). 
The primary objective of this study is to evaluate the immunogenicity of a 2024/2025 
(monovalent, XBB containing) Novavax COVID-19 vaccine, the Omicron XBB.1.5 
NVX-CoV2601 in immunosuppressed populations. 
 
6.1 
Primary Objective  
 
The following objective will be evaluated separately based on the season 2023-2024 and 2024-
2025. 
 
 
Humoral Immunogenicity of a NVX-CoV2601/(2024/2025 COVID booster).  
We will evaluate antibody concentrations 1 month after the recombinant vaccine booster (V2) in 
patients with IBD and solid organ transplant recipients compared to their baseline visit (V1). We 
measured antibody concentrations in patients with IBD one-month post-booster and found robust 
responses.10  We will measure anti-receptor binding domain (RBD) antibody levels and 
nucleocapsid antibodies in all participants at baseline and post-immunization.  
 
Success Criterion: The objective of our primary endpoint will be achieved if the antibody 
concentration at V2 is at least 15% higher than at V1.  
6.2 
Secondary objectives  
The vaccine will be evaluated for two seasons, separately: 2023/2024 and 2024/2025. Thus, we 
will have two co-secondary objectives.  
 
6.2.1 Sustained antibody concentrations of NVX-CoV2601 booster dose/(2024/2025 
COVID booster).  
We will evaluate sustained antibody concentrations using a quantitative assay from LabCorp, 
which is currently being used by the Centers for Disease Control and Prevention (CDC) to 
evaluate seroprevalence and study immunity at six months after completion of the booster dose 
(V3).   
 
Endpoint:  
We will evaluate individuals who are seropositive at V2 and V3 in both groups.  

 
Seropositivity rate at V2 and V3 in all participants. 
Seropositive will be defined by positive anti-receptor binding domain (RBD) IgG antibodies 
specific to SARS-CoV-2 performed by Labcorp (greater than 1.0 in μg/mL). 
 
Success Criterion: Descriptive  
6.2.2 Seroconversion.  
Percentages (and 2-sided 95% Cis) of participants who were seronegative (less than 1.0 in 
μg/mL)  at baseline and became seropositive (greater than 1.0 in μg/mL)  after immunization will 
be evaluated for before and after measures.  For initially seropositive subjects at V1, antibody 
concentration at post-vaccination (V2) ≥ 4 fold the pre-vaccination antibody concentration.   
 
Endpoint:  
Individuals who achieve seroconversion at V2.  
 
Success Criterion: Descriptive  
6.2.3 Cell-mediated immunity to NVX-CoV2601/(2024/2025 COVID booster).  COVID-19 
booster vaccine.  
We will evaluate cell-mediated immunity to a booster dose vaccine at baseline (V1) and one 
month after a booster dose (V2) in patients with IBD and solid organ transplant recipients.  IFN-
ϒ ELISpot, which detects both CD4 and CD8 T cell effectors, will be used to detect T-cell immunity 
to the Covid-spike protein or peptides. 
 
 
Endpoint:  
We will evaluate the interferon gamma responses at V2 compared to V1. 
 
An interferon gamma response will be considered any measurable response. 
 
Success Criterion: Descriptive  
            
6.2.4 Sustained cell-mediated immunity to NVX-CoV2601/(2024/2025 COVID booster).  
COVID-19 booster vaccine.  
We will evaluate sustained cell-mediated immunity against Covid-spike proteins approximately 
six months following V1 (V1 + 180 days, +/-30 days) (V3) 
 
 
Endpoint:  
We will evaluate the interferon gamma responses at V3 compared to V1. 
 
Success Criterion: Descriptive  
 
 
The safety of the vaccine boosters will be assessed for both seasons separately. 
This includes section 6.3-6.5. 
 

6.3 
Describe the safety of NVX-CoV2601/(2024/2025 COVID booster).  COVID-19 
vaccine.   
Participants will be asked to fill out their vaccine diary daily for 7 days post immunization.  They 
will record the information daily for 7 days post immunization. 
Participants will be provided a paper vaccine diary on visit 1 to enter their answers.  
 
At follow up visit 1 the research coordinator will remind patients to complete their diary.  If they 
have lost the diary the coordinator will fill out the diary with participant.  
 
At follow up visit 1 they will be asked about any unsolicited or solicited adverse events occurred 
following immunization. The call will involve standardized list of potential adverse effects, 
including fever, injection site reaction, fatigue, myalgia, and other reactions not listed.18    
Participants who do not fill out their vaccine diary or unable to be contacted at FU1 will be 
considered to have missing post immunization data.   This data will be considered non-reported 
data. 
 
 
Participants will be asked about unsolicited and solicited adverse events at all study visits V1, V2, 
and V3.  
 
 
Safety and reactogenicity up to 30 days post-last vaccination and during the whole post-
vaccination follow-up period 
 
Endpoints:  
Solicited Adverse Events (AEs) 
The number and percentage of participants reporting each solicited local AE and each solicited 
systemic AE within seven days (Days 1-7) after the booster dose and overall will be 
summarized for both study groups.  
• 
Solicited local AEs included injection site pain, redness, and swelling.  
• 
Solicited systemic AEs included fatigue, myalgia, arthralgia, headache, shivering/chills, 
fever, and gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain). 
 
Success Criterion:  Descriptive  
 
Unsolicited Adverse Events  
The number and percentage of participants reporting unsolicited AEs within 30 days (Days 1-
30) after the booster dose and overall will be summarized for both the study groups.    
 
Success Criterion: Descriptive  
 
Potential Immune-Mediated Diseases (pIMDs)  
The number and percentage of participants reporting pIMDs from the booster dose to the study 
end will be summarized for both study groups. Please refer to the full list of pIMD’s in Appendix 
3. 
 
Success Criterion: Descriptive  

 
Serious Adverse Events (SAEs) 
The number and percentage of participants reporting SAEs and fatal SAEs from the booster 
dose administration to the study end will be summarized for both the study groups. 
 
Success Criterion: Descriptive  
6.4 
Evaluate the disease activity following administration of the booster dose up to 30 
days post-vaccination and during the whole post-vaccination follow-up period. 
Disease activity will be assessed by monitoring disease activity using the Short Crohn’s Activity 
Index (SCAI)19 for patients with Crohn’s disease or the Simple Clinical Colitis Activity 
Index (SCCAI) questionnaire for patients with Ulcerative colitis at the baseline visit (V1),  V2, 
and V3 visits.  For patients with pouchitis we will use the simplified pouchitis disease activity 
index (PDAI).  The incidence of IBD flares will be evaluated in all patients receiving recombinant 
boosters. This will be quantified by patients who were in clinical remission who develop a 
disease flare after receiving a recombinant COVID-19 booster. 
 
Endpoint: 
The number and percentage of participants reporting disease flares of IBD. 
 
Success Criterion: Descriptive  
6.5 
Evaluate for solid organ transplant rejection following administration of booster 
dose, up to 30 days post- vaccination and during the whole post-vaccination 
follow-up period. 
Participants will be asked if they have been diagnosed with acute rejection after their baseline 
visit (V1).  Episodes of acute rejection will be collected by searching electronic medical records 
and asking patients at each clinic visit (V2 and V3). Acute rejection will be defined as a notation 
of a new episode of acute rejection (cellular or antibody-mediated), a steroid bolus and taper in 
the absence of another indication, or administration of a T or B cell depleting agent or immune 
globulin.20     
 
This will be quantified by patients who develop acute rejection of their transplant after receiving a 
recombinant COVID-19 booster. 
 
Endpoint: 
The number and percentage of participants reporting acute rejection of their transplant. 
 
Success Criterion: Descriptive  
 
 

7.0 
STUDY DESIGN  
7.1 
 Program Type / Scope of Study / Clinical Design / Sites 
This will be a single-center, prospective, unblinded, non-randomized study of 141 
immunosuppressed patients who are planning to receive a NVX-CoV2601  COVID-19 vaccine 
booster dose as standard of care and are willing to participate in the study.   We have paused 
recruitment in 2023-2024 season due to low recruitment.   We are extending the study to enroll 
an additional 120  immunosuppressed patients who are planning to receive a 2024/2025  COVID-
19 vaccine booster dose as standard of care and are willing to participate in the study.    
 
During the 2024/2025 season at least 35 patients will have inflammatory bowel disease and at 
least 35 patients will be a solid organ transplant recipient. After obtaining informed consent, 
individuals who meet the inclusion criteria and none of the exclusion criteria will be invited to 
participate in the study.  Blood samples will be collected from each participant at the baseline visit 
(V1), at 1M post–booster (V2 visit), and 6M post–booster (V3). 
 
Figure 1. Schematic of Visits: 
 
7.2 
 Site Responsibilities Overview 
The University of Wisconsin Hospital and Clinics will be the site of the study and will be 
responsible for coordinating activities, receiving and analyzing samples and data, and developing 
and updating the study protocol as needed. The UNC-developed data/web platform will be used 
to collect subject data and subject data will be stored on UNC platforms.     A Data Transfer Use 
Agreement between UW and UNC will be executed before the sharing of data with UNC begins.  
UNC will obtain their own IRB approval. 
 
V1:Visit 1 Novavax 
Booster
Blood sample #1
FU#1 (Day 7-15)
V2: Visit 2 (Day 28-
65) 
Blood Sample #2
V3: Visit 3 
(V1 + 180 days, +/-30 
days)) 
Blood sample #3

Communication plan: Monthly conferences led by Freddy Caldera, PI, with research staff at 
UW. In this teleconference, the following will be discussed: recruitment, barriers to recruitment, 
and potential future protocol changes.  
 
Adverse events/SAE/Unanticipated problems: All events, including adverse events to 
vaccines, IBD flares, transplant rejection, noncompliance, unanticipated events, protocol 
deviations, protocol violations, or serious adverse events will be reported to the regulatory bodies, 
including the IRB, as appropriate and per posted guidelines. The UW PI will be responsible for 
reporting any adverse events, as described in the Safety Reporting section. 
 
Compliance with protocol: To ensure that no deviations from the protocol occur, the PI will 
review random cases every two months. Any deviations in the protocol will be investigated to 
evaluate the root cause for deviation. Noncompliance, unanticipated events, protocol deviations, 
protocol violations, or serious adverse events will be reported to the IRB per the posted guidelines.  
7.3 
Study Population Overview 
Adults with established IBD on immunosuppression age 18-85 years and/or solid organ transplant 
recipients on systemic immunosuppressive therapy.  
 
Inclusion criteria 
• 
Have received at least three doses of a COVID-19 vaccine.  
• 
On systemic immunosuppressive therapy for inflammatory bowel disease  
o Immunomodulator (e.g. azathioprine, methotrexate) 
o Anti-TNF inhibitor 
o Il 12/23 blocker 
o IL 23 blocker 
o Janus Kinase inhibitor 
o S1P inhibitor  
 
• 
On systemic immunosuppressive therapy for solid organ transplant  
o Mycophenolate 
o Tacrolimus or cyclosporine 
o Sirolimus or everolimus 
o Azathioprine 
o Corticosteroids  
o Belatacept 
 
7.4 
Study Duration 
Major Study Periods 
First Patient In (FPI) to Last Patient In (LPI):                                             6 months 
LPI to Last Patient Out (LPO): 
                                             6 months 
LPO to manuscript                                                                                     4 months  
 
We will publish the first manuscript based on the vaccine response baseline compared to 1 month 
post immunization 4 months after LPI.  
The second manuscript will be published after completion of the study. 
 
 

7.5 
Ethical and Regulatory Considerations 
Prior to initiating the study, IRB approval will be sought from the University of Wisconsin School 
of Medicine and Public Health. 
 
Once approval is obtained, we will start recruitment. UW research staff (such as the PI and 
research coordinator) will hold monthly research conferences to ensure that there are no 
deviations in the protocol. 
 
Compliance with protocol: To assure no deviations from protocol occur, random cases from the 
single-UW enrolling site will be reviewed by the PI to assure no deviations from protocol every 2 
months. Any deviations in the protocol will be investigated to evaluate the root cause of the 
deviation.  
 
The investigation will be conducted in compliance with the requirements for review by the IRB. 

8.0 
SELECTION AND WITHDRAL OF SUBJECTS  
Patients with IBD (at least 35 subjects) and solid organ transplant recipients (at least 35 subjects) 
8.1 
Inclusion criteria  
• 
Patient is between the ages of 18-85 years.  
• 
Patient has a history of ulcerative colitis (UC), Crohn’s disease, pouchitis, or indeterminate 
colitis diagnosed by standard clinical, radiographic, endoscopic, and histopathologic 
criteria.  
And/or patient is a solid organ transplant recipient (e.g. lung, kidney, liver) 
• 
Have received at least three doses of a COVID-19 vaccine.  
o Three mRNA vaccines 
Or  
o One or two viral vector vaccine and one or two mRNA vaccines. 
  
• 
Female participant of non-childbearing potential (pre-menarche, current tubal ligation, 
hysterectomy, oophorectomy or post-menopause) and childbearing potential (if they had: 
practiced adequate contraception (include -IUD or equivalent, hormonal contraceptive 
(e.g. pill, patch, ring, implant or an injection used consistently and that has reached full 
effect prior to the first dose of vaccine), hysterectomy and/or a bilateral tubal ligation or 
bilateral oophorectomy)  for 1 month prior to vaccination and agreement to use such for 
an additional 8 weeks after administration of the Novavax COVID-19 vaccine).  Non-
pregnant females with a negative pregnancy test who are willing to practice adequate 
contraception 8 weeks after administration of the Novavax COVID-19 vaccine. 
 
• 
On one of the following treatment regimens  
o IBD  
 
Thiopurine Therapy Group: on azathioprine at least 2.0mg/kg or 6MP 
1.0mg/kg 
 
Anti-TNF Therapy Group: on maintenance therapy infliximab (at least every 
8 weeks), golimumab (at least monthly), adalimumab (at least every 2 
weeks), or certolizumab (at least monthly) 
 
Anti-TNF Combination Therapy Group: on anti-TNF therapy as described 
above along with either 15mg of methotrexate or azathioprine at least 
1.0mg/kg or 6MP 0.5mg/kg. 
 
Vedolizumab Therapy Group:  either vedolizumab monotherapy at least 
every 8 week dosing or combination therapy Group: on vedolizumab 
therapy at with azathioprine or methotrexate  
 
Ustekinumab Therapy Group: either ustekinumab monotherapy or 
combination therapy with methotrexate or azathioprine. 
 
Tofacitinib Therapy Group: on tofacitinib at least 5mg PO twice daily   
 
Risankizumab Therapy: 360mg at least every 8 weeks  
 
Mirikizumab: 200mg at least every 4 weeks 
 
Upadacitinib Therapy Group: on upadacitinib at least 15mg PO daily 
 
Ozanimod: at least 0.92mg once daily  
 
Etrasimod: at least 2mg once daily  
 
 

o Solid organ transplant recipient (on any dose of the following regimens: patients 
can be on more than one of the regimens below) 
 
Mycophenolate 
 
Tacrolimus or cyclosporine 
 
Sirolimus or everolimus 
 
Azathioprine 
 
Corticosteroids  
 
Belatacept 
8.2 
Exclusion criteria  
A patient will not be eligible for inclusion in this study if they meet any of the following criteria.  
 
• 
Allergy to recombinant COVID-19 vaccine or any component of it  
• 
Patient cannot or will not provide written informed consent.  
• 
Unable to provide appropriate informed consent because of illiteracy or impairment 
in decision-making capacity.  
• 
Active antibody-mediated or cellular rejection within the past six months   
• 
Recent IBD flare requiring initiation of systemic corticosteroids within the past 
month.  
• 
Previous history of myocarditis or pericarditis ever.  
• 
Patients who are pregnant  
• 
Patients who are lactating  
• 
Patients with an active COVID-19 infection 
• 
Patients with a COVID-19 infection within the past two months  
 
 
8.3 
Subject Identification and Recruitment 
Patients will be recruited from the University of Wisconsin Hospital and Clinics if they meet the 
inclusion criteria (see Section 8.0). Patients will be recruited in the following manner. Clinical 
research coordinators will prescreen provider clinic schedules (e.g. Clinics at the Digestive Health 
Center, Transplant Surgery, and etc.) and review medical records to evaluate potential study 
subjects that meet all inclusion criteria. The clinical research coordinator will review potential 
patients with the subspecialist who sees that patient. Any patient planning to receive a 
recombinant COVID-19 vaccine booster as standard of care will be invited to participate. Patients 
will be invited to participate after having any type of clinical contact with their provider or any 
member of their healthcare team. A member of the health team will provide patients with 
information about the study. The research coordinator will further review the information, invite 
participants to participate in the study, and obtain consent either in person or via remote consent.  
 
If study team members are available, subjects would undergo an in-person consent discussion 
and be asked to sign a paper copy of the consent form. Alternatively, a member of the care team 
would obtain subject permission to allow study team members to contact the subject by phone for 
a follow-up discussion, and/or set up a virtual meeting using a HIPAA-compliant virtual platform, 
with subjects providing signed consent using an FDA part 11 compliant electronic signature (i.e., 
DocuSign).  
 

Advertising (study flyers) will be posted throughout UW health entities such as the UW Digestive 
Health Center (DHC), 1 South Park, UW Hospital Ambulatory Center, Transplant Clinic, and other 
clinics throughout UW Health. These flyers will be used on TV screens in waiting room locations.  
 
The study flyer will be shared through social media such as Twitter and tweeted by the PI, inviting 
patients to participate.  
 
We will recruit participants via MyChart, UW Health's patient portal. Participants will be identified 
via a chart review by the Clinical Research Data Service (CRDS). We will obtain all needed 
approvals from UW Health and CRDS and follow the required workflows. We will/have create(d) 
an OnCore study record that is interfaced with Health Link and will track individual level 
recruitment in OnCore. Once approvals are in place, the IRB-approved invitation will be posted to 
invited participants’ Research Studies page in MyChart and patients will initiate contact with study 
team if interested. 
 
The patient-facing MyChart invitation is included with the IRB application for review and approval. 
 
Patients will be recruited from the University of Wisconsin Hospital and Clinics if they meet the 
inclusion criteria (see Section 8.0). Patients will be recruited in the following manner. Clinical 
research coordinators will prescreen using Research Elecetronic Data Capture (REDCap) 
database system from provider clinics (e.g. Clinics at the Digestive Health Center, Transplant 
Surgery, etc.) and review medical records to evaluate potential study subjects that meet all 
inclusion criteria. The clinical research coordinator will review potential patients with the 
subspecialist who sees that patient. Any patient planning to receive a recombinant COVID-19 
vaccine booster as standard of care will be invited to participate. Patients will be invited to 
participate after having any type of clinical contact with their provider or any member of their 
healthcare team. A member of the health team will provide patients with information about the 
study. The research coordinator will further review the information, invite participants to participate 
in the study, and obtain consent either in person or via remote consent. 
 
A phone screening script will be used when contacting potential subjects by phone for recruitment 
or in person to the study flyer.  
8.4 
Remuneration for participation 
Participants will be paid $75 for each completed in-person study visit for a total up to $75, $150, 
and $225, depending on the number of study visits. Payments will be made at the end of the 
study. If subjects choose to leave or are taken off the study before they complete it, they will 
receive payment for the visits completed. 
8.5 
Premature Subject Discontinuation  
Patients will be encouraged to complete the study; however, they may voluntarily withdraw at any 
time. 
 
The Principal Investigator may discontinue or withdraw a subject from the study for the following 
reasons at his/her discretion: 
• 
Subject non-compliance with study requirements (e.g., study intervention non-
compliance, do not complete scheduled visits)  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject 

 
Subjects who sign the informed consent form but do not receive the study intervention will be 
replaced and will not be counted against the enrollment total.   A one-to-one replacement will 
occur. Every patient who does not receive the study intervention will be replaced with another 
participant.  

9.0 
STUDY AGENT - NOVAVAX COVID-19 VACCINE, ADJUVANTED 
The U.S. Food & Drug Administration (FDA) required an investigational new drug (IND) for the 
use of the Novavax Covid-19 Vaccine, Adjuvanted currently available under an Emergency Use 
Authorization (EUA).  
9.1 
Source 
Study drug will be provided free of charge by the manufacturer, Novavax, for the study. 
Novavax will distribute the study drug to the study site. The University of Wisconsin Madison’s 
Pharmaceutical Research Center (PRC) will be responsible for receipt of the product from the 
manufacturer.  
 
Each shipment will include a temperature-monitoring device to verify maintenance of the cold 
chain during transit, as well as a packing slip. On delivery of the product to the site, the person 
in charge of product receipt will follow standard PRC instructions for receipt of product, including 
checking that the cold chain was maintained during shipment (i.e., verification of the 
temperature indicator). The contents of the shipment will then be reviewed and verified against 
the packing slip, and will be documented as instructed at the initiation visit.  
 
If the temperature-monitoring indicator reflects that the cold chain has been broken, the entire 
shipment must be immediately quarantined and further processed consistent with PRC 
operating procedures.  
9.2 
Packaging and Labeling  
The Novavax COVID-19 Vaccine, Adjuvanted will be obtained from the manufacturer in a 
multidose vial containing 5 or 10 doses of 0.5 mL each. Packages will be labeled with the 
statement ““Caution: New Drug—Limited by Federal (or United States) law to investigational 
use.” 
9.3 
Preparation 
The PRC will prepare the suspension for intramuscular injection as follows: 
Inspection of the vial  
• 
The Novavax COVID-19 Vaccine, Adjuvanted (Omicron XBB.1.5) NVX-CoV2601 is a 
colorless to slightly yellow, clear to mildly opalescent suspension, free from visible 
particles.   
• 
The multi-dose vial will be gently swirled before each dose withdrawal. Do not shake.  
• 
Each vial will be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. The vaccine will not be 
administered if either of these conditions exist. 
Handling of Multidose Vial 
• 
The date and time of the first puncture will be recorded on the vial label.  
• 
After the first needle puncture, the vial will be held between 2 to 25°C (36 to 77°F) for up 
to 12 hours.  
• 
The vial will be discarded 12 hours after the first puncture. 
Handling of filled syringe 

• 
The date and time that the syringe was prepared will be recorded on the syringe label 
along with subject ID 
• 
Syringes will be labeled with the statement ““Caution: New Drug—Limited by Federal (or 
United States) law to investigational use.” 
• 
The syringe will be held between 2 to 25°C (36 to 77°F) for up to 12 hours. 
9.4 
Storage and Stability 
Investigational product must be stored separately from normal hospital stocks and must be 
stored in a securely locked area accessible only to authorized trial personnel until dispensed. 
The temperature must be monitored and documented on the appropriate form for the entire time 
that the investigational product is at the trial site. If the storage temperature deviates from the 
permitted range, the investigational product must not be administered, and the sponsor-
investigator should be contacted for additional instruction. 
 
Novavax COVID-19 Vaccine, Adjuvanted unpunctured multi-dose vials may be stored in 
refrigeration between 2 to 8°C (36 to 46°F). Vaccine must not be frozen and must be protected 
from light. After the first needle puncture, the vial may be held between 2 to 25°C (36 to 77°F) 
for up to 12 hours. Discard the vial 12 hours after the first puncture. 
9.5 
Accountability 
The PRC will maintain records of product delivery, site inventory, and product disposal or return. 
The data coordinating center will verify each site’s product accountability records against the 
record of administered doses in the electronic case report forms (eCRFs), the source 
documents, and the communication from the online randomization program. 
9.6 
Dosing and Administration 
Study product will be supplied by the PRC as 0.5 mL single-dose, pre-filled syringes. Administer 
as follows: 
 
• 
Visually inspect the syringe for particulate matter and/or discoloration prior to 
administration. If either of these conditions exist, do not administer. 
• 
Gently shake the prefilled syringe. 
• 
Identify the deltoid muscle (upper arm) and cleanse the injection site with alcohol. 
• 
Insert needle (22 to 25 -gauge 1-inch needle recommended; 1 ½ inch needle 
recommended for those with BMI ≥ 30) at a 90-degree angle to the skin and inject 
entire contents of the syringe intramuscularly. Do not inject the vaccine 
subcutaneously or intravenously. Care should be taken to avoid administering the 
injection into or near blood vessels and nerves. 
• 
Monitor the subject for at least 15 minutes post administration. Monitor for 30 
minutes if allergy-related contraindication to another type of COVID-19 vaccine, non-
severe immediate (onset within 4 hours) allergic reaction after a previous dose of 
COVID-19 vaccine or anaphylaxis after non-COVID-19 vaccines or injectable 
therapies.   
 

10.0 
STUDY ASSESSMENT SCHEDULE AND PROCEDURES  
10.1 
Study Calendar 
 
 
Procedure 
(Visit Window) 
Visit 1 
(V1) 
(Day 
0) 
F/U 
15 
(Day 
7-15) 
Visit 2 
(V2) 
(Day 
28-65) 
Visit 3 (V3) 
(V1 + 180 days 
+/- 30 days) 
Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Concomitant 
Medications 
X 
 
X 
X 
Medical History1 
X 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
Blood draw (Serum & 
CMI) 
X 
 
X 
X 
Standard of Care 
Recombinant 
COVID-19 Vaccine 
Booster  
X 
 
 
 
7-Day Vaccine Diary2 
- - - - - - - -X - - 
- - - - -  
 
SCAI, PDAI, or 
SCCAI 
Questionnaire3 
X 
 
X 
X 
Adverse Event 
Monitoring 
X 
X 
X 
X 
Telephone Contact4 
 
X 
 
 
 
Notes: 
1. Baseline medical history included all IBD diagnoses or solid organ transplant diagnoses, 
medication history, and information in the source documents. 
2. Dispense the 7-day Vaccine Diary at Visit 1 for subjects to complete at home. 
3. SCAI, PDAI, or SCCAI will be administered based on IBD diagnosis at visits 1, 2, and 3.  
4. Between Visit 1 and Visit 2, the study staff will attempt two phone contacts to assess AEs 
and remind them to complete vaccine diaries as well as to assist with subject retention. 
5. Visits can be conducted via telephone calls. Patients who don’t respond to survey will be 
emailed and receive a phone call reminding them to fill out diary.  
10.2 
Study Assessments by Visit  
Visit #1 (V1) Baseline/Enrollment Visit (Day 0) 
• 
Obtain written informed consent or remote consent. 
• 
Review the inclusion and exclusion criteria to confirm eligibility.  
• 
Assign Subject ID number.  
• 
Record demographics (gender, age, race and ethnicity)  

• 
Collect medical history, including vaccination history and medications (ongoing and any 
medications taken during the last 30 days) 
• 
If patient has IBD complete Short Crohn’s Activity Index (SCAI), Simplified Pouchitis 
Disease Activity Index (PDAI), or Simple Clinical Colitis Activity Index (SCCAI) 
• 
Collect a baseline blood sample #1 of approximately 60ml (12 teaspoons)  
• 
Provide study intervention, recombinant NVX-CoV2601 COVID-19 booster.  
• 
If the patient is receiving the standard-of-care blood tests, these additional research 
samples will be collected at the same time as the standard-of-care tests.  
• 
Subjects will be instructed to contact the study team with any concerns or development 
of fever, chills, rash, or other concerning symptoms. 
• 
A paper version of the vaccine diary chart is also provided. 
• 
A paper ruler will be provided to measure any swelling or redness. 
 
Follow up Phone Call (Day 7-15) 
• 
7-15 days after the patient receives the COVID-19 vaccine booster, the patient will be 
contacted by clinical research coordinator  
• 
Collect information to identify any adverse events including fevers or chills, rash and any 
unplanned visits to the emergency room or to their primary care physicians.  
• 
Collect vaccine diary (phone) remind patient to fill out if not already filled out.  
 
Visit #2 (V2) Month 1 (Day 28-65) post COVID-19 booster.  
• 
Collect blood sample #2 of approximately 60ml (12 teaspoons) 
• 
Collect SCAI, PDAI, or SCCAI for patients with IBD. 
• 
Ask solid organ transplant recipients if they have been diagnosed with transplant rejection. 
• 
Collect information to identify any adverse effects, including, fever, chills, rash, and any 
unplanned visits to the emergency room or to their primary care provider.  
 
Visit #3 (V3) (V1 + 180 days +/- 30 days) 
• 
Collect blood sample #3 of approximately 60ml (12 teaspoons) 
• 
Collect SCAI, PDAI, or SCCAI for patients with IBD. 
• 
Ask solid organ transplant recipients if they have been diagnosed with transplant rejection. 
• 
Collect information to identify any adverse effects, including, fever, chills, rash, and any 
unplanned visits to the emergency room or to their primary care provider.  
10.3 
Informed Consent Procedures 
The informed consent process will be conducted following all federal and institutional 
regulations relating to informed consent. Informed consent will be obtained prior to conducting 
any study-related activities. 
 
The informed consent process will be performed as follows: 
• 
Delegated study staff will review the informed consent form and discuss the study in 
detail with the potential research subject. 
• 
Delegated study staff will explain the study, its risks and benefits, what would be 
required of the research subject, and alternatives to participation. 
• 
The research subject will be given the opportunity to take the informed consent form 
home so that they may discuss it with family members, friends, clergy or others when 
possible.  

• 
The subject will have the opportunity to ask questions and have all questions 
answered by the delegated study staff and/or PI. 
• 
The informed consent document must be signed and dated by the research subject. 
• 
Delegated study staff will review the informed consent document to ensure that all 
fields that require a response are complete (i.e., checkbox marked yes or no, etc.) as 
applicable. 
• 
The research subject will be given a copy of the signed and dated informed consent 
form. The original signed informed consent form is kept with the subject records. 
 
A research subject will be defined as “enrolled” in the study when they meet the following 
criteria: 
• 
The subject has been consented by study staff and received the study intervention. 
10.4 
Clinical assessments 
10.4.1 Blood Samples 
All subjects participating in the study will have blood specimens collected at three in-person visits. 
All of these blood specimen collections will be for evaluation of humoral and cell mediated 
immunity to COVID-19 vaccine. To evaluate humoral immunity we will send samples to LabCorp. 
They will use a quantitative assay to determine COVID-19 antibodies. We have used these 
assays in our previous studies evaluating humoral immunogenicity to COVID-19 vaccines. 10, 21 
 
 
Cell-mediated immunity to COVID-19 will be evaluated at UW. Specimens at UW will be labeled 
with the subject’s study ID number and date of collection so that the data collected for this protocol 
can be linked to the sample. Samples will be stored in Rennebohm Hall at the University of 
Wisconsin. Only investigators and key personnel assigned to the laboratory have access to the 
lab. Samples will be coded (labeled with subject ID and date of collection) before they arrive at 
the laboratory. All computers used for data storage and analysis are password protected and 
used exclusively by key personnel. 
 
Blood samples will be stored for future unspecified studies.  Participants may withdraw their 
samples by contacting Dr. Caldera at any time.  Any future studies that will utilize these specimens 
will be done by UW researchers and will be submitted for a separate IRB approval. Only coded 
samples and data will be released for future research. Information linking the samples and data 
to individual participants will not be released. 
 
COVID-19 antibody concentration analysis: These samples will be shipped to LabCorp. They 
will use LabCorp’s Cov2Quant IgG™ assay which uses immunoassay that uses 
electrochemiluminescent technology (ECL) for quantitative determination of anti-receptor binding 
domain (RBD) IgG antibodies specific to SARS-CoV-2. The RDB of the spike protein is the moiety 
that interacts directly with the ACE2 receptor on a host cell to enable viral entry. In addition to 
RBD being a critical player, it is also poorly conserved among other coronaviruses. Therefore, 
RBD represents a promising antigen for detecting SARS- antibodies in humans. There is also a 
strong correlation between levels of RBD-binding antibodies and SARS-COV-2 neutralizing 
antibodies in patient sera. The results of this assay will be shared with patients as positive or 
negative rather than the amount of antibody detected. Patients will be asked to follow up with their 
gastroenterologist or transplant surgeon if they have any questions regarding the test results.   We 
will also use LabCorp Qualitative detection of high affinity antibodies to SARS-CoV-2 
nucleocapsid (N) protein, the virus that causes COVID-19, to aid in identifying individuals with an 

adaptive immune response to SARS-CoV-2, indicating recent or prior infection.  This will be done 
at every time point.  
 
Cell Mediated Immunity to COVID-19 
For each patient, peripheral blood mononuclear cells (PBMCs) will be isolated from green tubes 
or CPT tubes  per study visit, and stored in liquid nitrogen. IFN-ϒ ELISpot, which detects both 
CD4 and CD8 T cell effectors, will be used to detect T-cell immunity to the Covid-spike protein or 
peptides. The plates will be read on an AID ELISpot reader (Cell Technology, Inc., Columbia MD, 
reader software v.3.1.1.). A positive response to antigen will be defined as a frequency that was 
significantly (p < 0.05, two-tailed t test) greater than the mean of control no-antigen wells and 
detectable (i.e., >1:100,000). T cell responses will be correlated to Covid-19 neutralizing antibody 
responses. We have previously evaluated cell-mediated immunogenicity to COVID-19 vaccine in 
patients with IBD. 22 
10.4.2 Disease Activity Assessment 
The Short Crohn’s Activity Index (SCAI), the Simplified Pouchitis Disease Activity Index (PDAI), 
or the Simple Clinical Colitis Activity Index (SCCAI) questionnaire will be used to assess CD, 
Pouchitis, or UC disease activity, respectively (Appendices 1 and 2). These assessments include 
questions about patient overall well-being as well as specific symptoms and complications of CD 
or UC, such as stool frequency and abdominal pain. 
 
Subjects will be questioned at each visit, V1, V2, and V3, regarding their clinical symptoms and 
subsequently scored accordingly. 
 
Transplant Rejection 
Episodes of acute rejection will be collected by searching electronic medical records and asking 
patients at each clinic visit V1, V2, and V3. Acute rejection will be defined as a notation of a new 
episode of acute rejection (cellular or antibody-mediated), a steroid bolus and taper in the 
absence of another indication, or administration of a T or B cell depleting agent or immune 
globulin.  
10.4.3 Adverse Events Assessments  
Adverse events data collection for this study begins at the time the subject signs the informed 
consent. Adverse event assessments included questioning subjects both at the follow-up phone 
call and at the follow-up visit regarding Adverse Events and SAEs. 
 
 
Participants who do not fill out their vaccine diary or unable to be contacted at FU1 will be 
considered to have missing post immunization data.   This data will be considered non-reported 
data. 
 
10.4.4 Other Measurements 
Medical history, including medications used to treat IBD or solid organ transplant, will be obtained 
from the subjects’ medical records and entered into the research records. Medical history included 
all diagnoses and other diseases. 
 

Medication history must be present in the subject’s medical records and recorded in the subject’s 
research records, including all prescription medications and nonprescription therapies taken 
within 30 days prior to the initial visit. 
 
 
 
 
Data Handling and Record Keeping The only identifiers UNC will have access to are Subject ID 
numbers and dates of service and vaccination. They will not have access to linking coded data. 
The link to the subject ID will be maintained by UW research staff. 

11.0 
DATA HANDLING AND RECORD KEEPING 
Data will be stored on a web-based platform to collect all patient-related information, disease 
activity, and other study questionnaires. This web-based platform will be developed by University 
of North Carolina.   They will not be the data safety monitor for the study.  
 
The University of North Carolina will serve as a Data Management Center (DMC) for this study.  
The work will be conducted in the Bioinformatics and Biostatistics Core of the Center for 
Gastrointestinal Biology and Disease (CGIBD). Dr. Millie Long, will lead the DMC for this study. 
The Core has served as the Data Management Center for the Crohn’s and Colitis Foundation 
Clinical Alliance.  In that capacity the DMC has conducted a number of randomized trials and 
observational studies of IBD. They have also served as the Data Management Center for the 
Sinai Helmsley Alliance for Research Excellence which is a multicenter study of patients with IBD. 
The DMC will be charged with creating, managing, and housing the data management system. 
 
The DMC will be responsible for all of the data management needs of the study.  These activities 
will include, but not be limited to the following. They will build applications to collect baseline and 
follow-up data as specified in the protocol, generate reports about recruitment, enrollment, 
compliance, and dropouts, provide barcodes for biological specimens and build tracking programs 
for the specimens, provide data sets for analysis, and participate in data analysis and reporting. 
The only identifiers UNC will have access to are Subject ID numbers and dates of service.  They 
will not have access to linking coded data.  The link to the subject ID will be maintained by UW 
research staff. 
 
Site Coordinators will collect data on source documents and will complete double data entry onto 
electronic CRFs in the data management system created by the DMC.  Participants will collect 
data via direct data capture. All of the data will be maintained, archived, retrieved and distributed 
(except for the source documents completed by the Site Coordinators), by a computer system. 
The use of electronic records will increase the speed of data collection and exchange. Electronic 
records permit economical storage of study data and ease of accessibility and analysis. Data 
management and data quality systems will be built into the system. The DMC will have password-
required access to the data management system where they can export data. UW will have 
password-required access to the data management system as well but they will only have access 
to their site’s data and they will not be permitted to export the data. 
 
The DMC at the CGIBD at the University of North Carolina will track the data collection, provide 
data security, control for confidentiality of study data, maintain computer backups to protect data 
until study closure and archive study data. Electronic signatures will be linked to each entry. 
 
All computer systems and programs will be password protected, and all electronic 
communications of study and other confidential information will be encrypted. Personnel at the 
CGIBD have extensive training and experience using electronic data systems. Good computer 
security practice (restricting physical access to machines, prohibition of password sharing, and 
logging off computers after work hours or when away from the machine) will be required of all 
study personnel. 
 
Standard Operating Procedures exist for users of the DMC. The DMC will be housed on an https 
secure website in order to protect the study participants’ information. Only authorized persons are 
authorized for data entry and access. Data security systems require password protected 
identification codes for data entry and provide protection against data manipulation. The database 
is located on a server protected by firewalls. Access to the database server will not be allowed by 

users on computers outside of the firewall-protected zone. Virus protection software is installed 
on each study machine. System access to computer systems will be audited. Redundant backups 
and off-site backup storage will allow for quick restoration of data in the unlikely event that a 
hardware failure, disaster, or security breach should occur. Servers and backups will be located 
in a secured location with access limited to authorized personnel. 
 
Standardized study management reports will be generated monthly during the recruitment phase 
of the study. These reports will be used to track study progress including patient enrollment, 
randomization, compliance, patient status changes, and study events. The data will be reported 
for each Study Center individually and summarized for the study as a whole. Every six months, a 
standardized report will also be generated for meeting with University of Wisconsin team. This 
report will include additional information on clinical events and adverse events that is coded by 
treatment group. Other than the UW, the study statistician and statistical analyst, no study 
personnel will see this report. 
 
Patient data from in-person visits will also be recorded in the electronic medical records.  Any 
original subject files and protocol paperwork will be kept in the secured Office of Clinical Trials.  
We will keep these files within the Office of Clinical Trials until 2 years after the study completion 
at that time they will be archived to the State Record Center. 
 
Transfer of data: LabCorp will perform quantitative COVID-19 antibody levels, they will transfer 
final data to UW for final analysis in files that will be password protect by LabCorp IT service.  
 
Specimens at UW will be labeled with the subject’s study ID number and date of collection so that 
the data collected for this protocol can be linked to the sample. Samples will be stored in 
Rennebohm Hall at the University of Wisconsin. Only investigators and key personnel assigned 
to the laboratory have access to the lab. Samples will be coded (labeled with subject ID and date 
of collection) before they arrive at the laboratory. All computers used for data storage and analysis 
are password protected and used exclusively by key personnel. 
 
Any future studies that will use these specimens will be conducted by UW researchers and 
submitted for separate IRB approval. Only coded samples and data will be released for future 
research. Information linking the samples and data to individual participants will not be released. 
 
All data will be labeled with the subject’s study ID number and stored at the University of 
Wisconsin. Data will be stored in an Excel spreadsheet on secured servers and will only be 
accessible to those with a valid UW username and password with the right to see those files. The 
link connecting the subject ID number and study data will be stored separately from the study 
data. The servers are housed in locked cabinets inside locked, climate-controlled rooms. Access 
to UW servers is restricted by UW firewalls. Any connections to UW servers from outside the UW 
network must travel over UW Madison’s virtual private network (VPN). This ensures that all 
communications between the UW and remote user are encrypted. 
 
The samples shipped to LabCorp will be destroyed by them. Cell-mediated immunity will be 
analyzed, and the samples will be banked. Banked data may be used in future research to study 
the clinical outcomes of the COVID-19 vaccination and the sustained protection provided by the 
vaccine. These data may also be utilized to study the safety of vaccination and its long-term 
protection against COVID-19.  
 
 
 

12.0 
STUDY ANALYSIS 
12.1 
Number of Subjects (Statistical Justification)  
 
We used results from our previous COVID-19 vaccine study to calculate our sample size 
needed for this study.We anticipate that antibody concentrations wane but with infection and 
multiple doses of vaccine, we estimated that the trough antibody concentration will be 
somewhat higher than it was after two doses of vaccine. The sample size 20 patients for this 
study was chosen based on feasibility and practicality of enrolling such patient populations. 
Therefore, a formal sample size estimation was not calculated, as the results would be deem 
descriptive and exploratory in nature. However, this sample size is sufficient to provide accuracy 
in estimating adverse event rates. 
 
 
12.2. Statistical Analysis  
In general, simple descriptive statistics will be provided to summarize demographics and 
baseline characteristics parameters.  Categorical data will be summarized as frequency and its 
corresponding percentage.  For continuous data, frequency (n), mean, standard deviation, 
median (as appropriate), minimum, and maximum will be provided for each of the parameters. A 
formal statistical analysis plan (SAP) will be developed before the database lock. It will include a 
detailed description of summaries and mock-ups of tables, listings, and figures to be included in 
the clinical study report. 
 
In analyzing the primary endpoint, frequencies and percentages of antibody concentrations will 
be summarized in table formats. For exploratory purposes, a paired t-test will be utilized to test 
whether, on average, there is a change of at least 15% antibody blood concentration between 
the first and second blood draws. A test statistics and degrees of freedom, including the 95% 
confidence intervals will be reported 
 
For the secondary endpoints, we will use descriptive statistics and formal tests (for exploratory 
purposes) to analyze the data, as described above, when appropriate and informative.  
 
 
 
 

13.0 
SAFETY REPORTING 
13.1 
Definitions:  
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a medicinal product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.  
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse reactions 
which arise from: use of a medicinal product within the terms of the marketing authorization; use 
outside the terms of the marketing authorization, including overdose, misuse, abuse and 
medication errors; and occupational exposure*. 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
 
Adverse Events will be reported in accordance with all 21 CFR 312.32 requirements” 
(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32) 
 
Medically attended AEs  
 
MAEs will be collected during the 6 months after vaccination. Medically attended AEs are defined 
as AEs leading to a visit to or from medical personnel for any reason. A phone call with a 
healthcare professional was not considered medically attended. 
Participants will be asked about any AE at FU1, V2, and V3.  Research coordinators will interview 
all participants at these visits and ask them about any AE since immunization.   
 
 
Serious adverse Event.  
An adverse event is considered "serious" if, in the view of either the investigator or sponsor, meets 
any of the following criteria:  
• 
Results in death  
• 
Are life-threatening (Refers to an AE in which the subject was at risk of death at the time 
of the event. It does not refer to an event, which hypothetically, might have caused death 
if it were more severe.)  
• 
Requires an inpatient hospitalization or prolongation of an existing hospitalization   

• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.)  
• 
Results in a congenital anomaly/birth defect, constitute, based upon appropriate medical 
judgment, an event that may jeopardize the subject’s health and may require medical or 
surgical intervention to prevent one of the other outcomes listed above.  
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization and that 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”)  
 
 
13.11 Relationship of Adverse Event to Study Vaccine 
 
The relationship or association of the study vaccine in causing or contributing to the AE will be 
characterized by the investigator as “Related” or “Not Related”.    All AE, SAE, Adverse of 
Special interest will be presented in a summary table.   If the relationship information is missing, 
the AE will be considered “Related” in the summary but will be presented as missing in the data 
listings. 
 
We will use a binary scale related versus not related.  We will use the following definitions: 
 
• 
Not related: There is not a reasonable possibility of relationship to study vaccine. The 
AE does not follow a reasonable temporal sequence from administration of study 
vaccine or can be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
• 
Related: There is a reasonable possibility of relationship to study vaccine. The AE 
follows a reasonable temporal sequence from administration of study vaccine and 
cannot be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, or concomitant medications), represents a 
known reaction to study vaccine or other vaccines in its class, is consistent with the 
known pharmacological properties of the study vaccine, and/or resolves with 
discontinuation of the study vaccine(and/or recurs with re-challenge, if applicable). 
 
 
13.2 
Severity of Event 
All AEs will be assessed by the principal investigator using the Table below.  
 
The intensity of the following solicited AEs will be assessed as described: 
 

 
 
 
 
Table Intensity scales for AEs 
Event 
Intensity grade 
Parameter 
Pain at 
administration 
site 
0 
None 
1 
Mild: Any pain neither interfering with nor 
preventing normal everyday activities. 
 
2 
Moderate: Painful when limb is moved and 
interferes with everyday activities. 
 
3 
Severe: Significant pain at rest. Prevents normal 
everyday activities. 
 
4 
Potentially life threating: Emergency room (ER) 
visit or hospitalization  
Redness at administration site 
Greatest surface diameter in mm (see below) 
Swelling at administration site 
Greatest surface diameter in mm (see below) 
Temperature* 
Temperature in °F (see below) 
Pruritis at 
administration 
site  
0 
None 
1 
Mild: Itchy sensation that neither interferes with 
nor prevents normal everyday activities. 
2 
Moderate: Itchy sensation that interferes with 
normal everyday activities. 
 
3 
Severe: Itchy sensation that prevents normal 
everyday activities. 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Headache 
0 
None 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal 
activity 
 
3 
Severe: Headache that prevents normal activity 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Fatigue 
0 
None 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal 
activity 
 
3 
Severe: Fatigue that prevents normal activity 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Myalgia 
0 
None 
 
1 
Mild: Myalgia present but does not interfere with 
activity 
 
2 
Moderate: Myalgia that interferes with normal 
activity 
 
3 
Severe: Myalgia that prevents normal activity 
 

Event 
Intensity grade 
Parameter 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Arthralgia 
0 
None 
 
1 
Mild: Arthralgia present but does not interfere 
with activity 
 
2 
Moderate: Arthralgia that interferes with normal 
activity 
 
3 
Severe: Arthralgia that prevents normal activity 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Gastrointestinal 
symptoms 
0 
None 
 
1 
Mild: Gastrointestinal symptoms that are easily 
tolerated 
 
2 
Moderate: Gastrointestinal symptoms that 
interfere with normal activity 
 
3 
Severe: Gastrointestinal symptoms that prevent 
normal activity 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Shivering/chills 
0 
None 
 
1 
Mild: Shivering that is easily tolerated 
 
2 
Moderate: Shivering that interferes with normal 
activity 
 
3 
Severe: Shivering that prevents normal activity 
 
4 
Potentially life threating: ER visit or 
hospitalization 
Acute 
allergic 
event 
0 
none 
1 
Transient flushing or rash; drug fever <38°C (<100.4°F) 
 
2 
Rash; flushing; urticaria; dyspnea; drug fever 
≥38°C (≥100.4°F) 
 
3 
Symptomatic bronchospasm, with or without 
urticaria; parenteral medication(s) indicated; 
allergy-related edema/angioedema; hypotension 
 
4 
Anaphylaxis/Death 
Syncope 
0 
None 
1 
Pre-syncopal symptoms light headness. 
 
2 
Symptoms without loss of consciousness 
 
3 
Symptoms with loss of consciousness 
 
4 
Life threatening consequences 
Paresthesia 
0 
None 

Event 
Intensity grade 
Parameter 
1 
Asymptomatic; loss of deep tendon reflexes or 
paresthesia (including tingling) but not interfering 
with function 
 
2 
Sensory alteration or paresthesia (including 
tingling), interfering with function, but not 
interfering with ADL 
 
3 
Sensory alteration or paresthesia interfering with 
ADL 
 
4 
Disabling 
Hypoesthesia 
0 
None 
1 
Asymptomatic; altered sensory response  (e.g 
touch, virbtation or cold temperature) but not 
interfering with function 
 
2 
Sensory alteration, interfering with function, but 
not interfering with ADL 
 
3 
Sensory alteration interfering with ADL 
 
4 
 
Disabling 
*Fever is defined as temperature ≥ 38.0°C (100.4°F) by any route. The preferred location 
for measuring temperature will be the oral route. 
 
The maximum intensity of injection administration site redness/swelling and fever will be 
graded as follows: 
 
Redness/swelling 
Fever 
0: 
≤20 mm 
<38.0°C (100.4°F) 
1: 
>20 - ≤50 mm 
≥38.0°C (100.4°F) - ≤38.5°C (101.3°F) 
2: 
>50 - ≤100 mm 
>38.5°C (101.3°F) - ≤39.0°C (102.2°F) 
3: 
>100 mm 
>39.0°C (102.2°F) 
4 
Necrosis or exfoliative 
dermatitis 
Fever resulting in hospitalization  
 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The 
assessment will be based on the investigator’s clinical judgement. 
 
The intensity should be assigned to 1 of the following categories: 
 
Grade  
 
1 (mild) 
An AE which is easily tolerated by the 
participant, causing minimal discomfort and 
not interfering with everyday activities. 
 
2 (moderate) 
An AE which is sufficiently discomforting to 
interfere with normal everyday activities. 

 
 
3 (severe) 
An AE which prevents normal, everyday 
activities. Such an AE would, for example, 
prevent attendance at work/school and would 
cause the participant to seek medical advice. 
 
 
 
 
4 (potentially life 
threating) 
An AE which results in an emergency room 
visit or hospitalization  
 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets 1 of the pre-defined 
outcomes as described in the section above. 
 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4) because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; however, 
the event itself may be of relatively minor medical significance (such as a Grade 3 headache). 
This is different from serious, which is based on the patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function. Severe AE (grade 3 or 4) do not necessarily need to be considered as serious. 
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
 
13.21 Adverse Events of Special Interest 
Myocarditis and pericarditis will be adverse events of special interest.   All patients will be 
counseled on the potential risk of myocarditis or pericarditis from COVID-19 vaccination.  
 
1) Potential myocarditis and pericarditis events  
a. 
Participants reporting acute chest pain, shortness of breath, palpitations, or other signs 
or symptoms of myocarditis or pericarditis within 4 to 6 weeks after vaccination must be referred 
to a cardiologist for evaluation and management. 
b. 
Cases of myocarditis and pericarditis will be followed until resolution of symptoms and 
abnormal test findings. 
 
Myocarditis and pericarditis cases will be defined by based on the Centers for Disease Control 
and Prevention (CDC) care definition. 23 (Appendix 5) 
 

2) IBD flares will be evaluated based on SCAI, PDAI, and SCCAI based on follow-up at V1, V2, 
& V3,. 
 
3) Solid organ transplant rejection will be reviewed based on follow-up at V1, V2, & V3. 
Episodes of acute rejection will be documented by chart review.    
 
 
13.22 Expectedness to Study Intervention 
The PI will be responsible for determining whether an AE is expected or unexpected in relation 
to the study procedures and intervention(s) (as applicable).  
 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described in the clinical protocol, device manual, 
investigator’s brochure, the package insert(s), the IRB application, or the informed consent 
document. Expectedness is recorded for both study procedures and interventions. 
13.23 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study subject presenting for medical care, or upon review by a study 
monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
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 study subject’s condition deteriorates at 
any time during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after the 
administration of the study drug through the 6 month follow-up visit. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution, stabilization, or completion of study 
participation. 
13.24 Reporting AEs and SAEs 
Institution/Investigator is solely responsible for reporting all Adverse Events and Serious Adverse 
Events to regulatory authorities, investigators, IRBs or IECs, and Novavax, as applicable, in 
accordance with national regulations in the countries where the study is conducted.  

13.24.1 
Reporting AEs 
• 
AEs will be recorded from the initiation of study treatment until the 6 month follow-up visit. 
• 
AEs will be recorded regardless of whether they are considered related to the study drug(s). 
• 
All AEs will be recorded on the appropriate study specific eCRF form within <the clinical trial 
management system>. 
• 
All AEs considered related to the vaccine will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or study completion.  
13.24.2 
Reporting of SAEs 
The sponsor-investigator will immediately review all SAEs, whether or not considered study 
intervention-related, including those listed in the protocol or package insert and will provide an 
assessment of whether there is a reasonable possibility that the study intervention caused the 
event.  
 
All SAEs will be followed until satisfactory resolution or until the sponsor-investigator deems the 
event to be chronic or the subject is stable. Other supporting documentation of the event may 
be requested by the Data Coordinating Center (DCC) should be provided as soon as possible. 
 
The sponsor-investigator will be responsible for notifying the FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the sponsor's initial receipt of the information. In addition, the sponsor-
investigator must notify FDA and all participating investigators in an Investigational New Drug 
(IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting. 
13.24.3 
Additional Reporting Requirements 
Regardless of expectedness or causality, all must also be reported in English by a facsimile to 
Novavax or a designee: 
 
Adverse Event Reporting. Investigator shall report all Adverse Events (“AEs”), 
including follow-up information, as defined below, concerning a Novavax Product 
directly to Novavax by emailing PostmarketingPVOps@Novavax.com in the form of 
a CIOMS I Form or electronic AE Data Capture Form:   
o   within one (1) Business Day of receipt/awareness of a Serious Adverse 
Event (SAE), as defined below;  
o   within three (3) Business Days of receipt/awareness of an AEs.  
  
On a monthly basis, Investigator will provide a listing of all AEs sent to Novavax 
PostmarketingPVOps@Novavax.com for the previous month. The reconciliation list 
should be provided no later than the 15th of the month for the previous month. Any 
discrepancy identified during reconciliation shall be investigated, clarified, and agreed 
upon by both parties.  

Novavax shall be solely responsible for reporting of Adverse Event information to 
regulatory authorities, which shall include reporting of individual Adverse Events and 
periodic safety reports.  
“Adverse Event” means any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product. This includes other safety information such as:  
o   Overdose, abuse, or misuse of the product;  
o   An adverse event occurring from the withdrawal of the product;  
o   Lack of product effect/efficacy;  
o   Accidental exposure;  
o   Medication error (i.e., administration of expired product)  
o   Pregnancy or exposure during breast feeding;  
o   Suspected transmission of infectious agents;  
o   An unexpected therapeutic or clinical benefit;  
o   Off label use.  
  
“Serious Adverse Event” means any untoward medical occurrence that, at any dose,   
o   results in death;  
o   is life-threatening;  
o   requires inpatient hospitalization or prolongation of an existing 
hospitalization;   
o   results in persistent or significant disability or incapacity;  
o   is a congenital anomaly/birth defect; or  
o   is a medically important event or reaction.  
  
 
 

Fatal and Life-Threatening SAEs within 1 business day of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non-life threatening) events within 3 business  days of the 
sponsor-investigator’s observation or awareness of the event 
 
All reported adverse drug reactions and safety issues related to Novavax will be included in the 
final study report. 
13.25 Unanticipated Problems 
An unanticipated problem (UP), as defined by the DHHS Office for Human Research Protection 
(OHRP), is any incident, experience, or outcome that meets all of the following criteria:  
• 
The incidence, experience, or outcome is unexpected given the research procedures 
described in protocol-related documents (e.g., the study protocol, the informed consent 
documents, the Investigator’s Drug Brochure) and the characteristics of the subject 
population being studied. An event may be considered unexpected if it exceeds the 
nature, severity, or frequency described in the study-related documents, Investigator’s 
Drug Brochure, product labeling, or package insert. 
• 
The incidence, experience, or outcome is related or probably related to participation in 
the research study. “Probably related” means the incidence, experience, or outcome is 
more likely than not to be caused by the research study procedures. 
• 
The occurrence of the incidence, experience, or outcome suggests that the research 
places subjects or others at a greater risk of harm (physical, psychological, economic, or 
social) than was previously known or recognized. 
 
The investigator will report UPs to the reviewing IRB and to the Data Coordinating Center 
(DCC). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol, informed consent documents, or other 
corrective actions that have been taken or are proposed in response to the UP. 
 
Report UPs within the timeframe specified by the IRB of record. 
13.26 Safety Oversight and Stopping Rules 
To evaluate whether the vaccine results in SAE, IBD flares, transplant rejection, or 
myocarditis/pericarditis these will be monitored with the following DSMP. For every 40 patients 
enrolled in the study, the rate of SAE and IBD flares or episodes of acute rejection will be 
reviewed. SAE will be reviewed based on follow-up at V1, V2, V3, and vaccine diaries. IBD flares 
will be evaluated based on SCAI, PDAI, and SCCAI, and episodes of acute rejection will be 
documented by chart review.  Episodes of potential myocarditis or pericarditis will be reviewed 
after evaluation by a cardiologist and defined based on CDC case definition (appendix 5).A The 
Principal Investigator (PI) will be responsible for reviewing these data will be reviewed 
continuously and pause the study if any stopping rules are met.  He will have the SMC review the 
AE and determine if study should be stopped.    
 

The study will be halted if any of the following criteria are met: 
 
• 
Any serious AE occurs, including death, that is assessed as  related to the product and 
occurring within the entire length of the study. 
• 
Three or more participants experience the same or similar grade 3 or greater AEs, 
including laboratory abnormalities, that are assessed as related to the product, and 
occurring within the entire length of the study. 
• 
More than 5 participants have an IBD flare of at least moderate activity (defined by the 
Short Crohn’s Disease Activity Index [sCDAI], Simplified Pouchitis Disease Activity Index 
[PDAI], or the Simple Clinical Colitis Activity Index [SCCAI]) without a known cause.  
• 
More than 4 participants have allograft rejection that requires treatment without a known 
cause. 24 
• 
More than 2 participants have an episode of myocarditis or pericarditis. 
 
 
In the event that study stopping rules are met, enrollment and vaccine administration in the study 
will be paused while an assessment by the Sponsor-Investigator takes place. 
 
 
 
Progress reports and notifications of unanticipated problems, adverse events, protocol deviations, 
and protocol violations will be reported to the IRB per the posted guidance. 
13.27 Study Monitoring 
  
We will use an internal safety monitoring committee (SMC) comprised of experienced clinical 
researchers representing a diversity of backgrounds, skills and knowledge. The SMC helps 
investigators ensure subject safety, research integrity, and compliance with federal regulations 
and local policies. The SMC also makes recommendations to the PI that could include actions 
of continuation, modification, suspension, or termination. 
 
The SMC will be able to meet on an adhoc basis to review any number of AE, SAE, or AE of 
special interest that may have met the stopping rules.  They will determine if these events have 
met the criteria for halting the study.  Recruiting will halt until the SMC has determine whether 
the stopping rules have been met.  If the SMC determines the stopping rules have not been met 
then resumption of enrollment will continue.  
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirements. 
• Monitoring for this study will be performed by the University of Wisconsin – Madison’s 
Central Monitoring Service. 
• On site monitoring will be conducted for this study which will include a site initiation visit, 
interim monitoring visits, and close out visit as outlined in the clinical monitoring plan. 
Monitoring will include review of regulatory files, investigational product, and up to 20% of 
subject records and data. Additional records may be reviewed, as needed, to ensure 
compliance with applicable regulatory requirements. 

• The sponsor-investigator will be provided copies of monitoring reports within 30 days of 
visit. 
 

14.0 
RISK-BENEFIT  
14.1 
Risks of Study 
The risks to subjects in this trial will be minimized by compliance with the eligibility criteria, clinical 
monitoring, adherence to protocol requirements, and investigator guidance regarding specific 
safety areas. 
 
Appropriate medical treatment will be available to manage immediate allergic reactions in the event 
an acute anaphylactic reaction occurs following administration of the Novavax COVID-19 Vaccine, 
Adjuvanted. 
 
Adverse reactions reported in clinical trials following administration of the Novavax COVID-19 
Vaccine, Adjuvanted include injection site pain/tenderness, fatigue/malaise, muscle pain, 
headache, joint pain, nausea/vomiting, injection site redness, injection site swelling, fever, chills, 
injection site pruritus, hypersensitivity reactions, lymphadenopathy-related reactions, myocarditis, 
and pericarditis. 
 
Myocarditis, pericarditis, anaphylaxis, paresthesia, and hypoesthesia have been reported following 
administration of the Novavax COVID-19 Vaccine, Adjuvanted outside of clinical trials.   
 
The rate of IBD flares or solid organ transplant rejections will be evaluated in the study populations 
following the administration of the Novavax COVID-19 vaccine.  
 
To ensure subject privacy, the study procedures will be performed in a private room. The study 
team members will be in a private space when conducting study phone/video calls with potential 
participants. 
 
The specific safety areas that will be closely monitored in this subject population are the risk of 
flares post-immunization and the rates of transplant rejection.  
 
Loss of confidentiality: There is a risk that the subject information could become known to someone 
not involved in this study. 
 
Phlebotomy: Blood draws can cause bruising in the skin at the injection site and, rarely, infection 
in the skin. Rarely, dizziness or fainting occurs after blood is drawn. 
14.2 
Potential Benefits of Study  
Beyond any protection from COVID-19 infection conferred by this vaccine booster dose, this study 
may benefit other people in the future by helping us learn more about immune responses to the 
recombinant COVID-19 vaccine in immunosuppressed populations, especially a mix and match 
strategy. This study will help determine whether patients with IBD on certain immunosuppressive 
regimens will require booster doses of COVID-19 vaccines.  
 

15.0 
STUDY FEASBILITY 
 
Currently greater than 1500 patients are seen at UW health for the treatment of their inflammatory 
bowel disease and at least 800 transplants are performed annually. The majority of patients with 
IBD and solid organ transplant recipients who are seen at UW health facilities will be eligible to 
participate in our study. We have 6 providers that focus exclusively seen patients with IBD and 
the transplant surgery group consist of 13 faculty. We anticipate that we will be able to recruit 35 
patients per month to participate in our study.  
 
The primary outcome will be 1 month post-immunization, so we anticipate that we could submit 
this information as a late-breaking abstract to Digestive Disease Week 2025 in February 2025.  
 
The study duration will be approximately 2 years. Each subject will be involved in the study for 
approximately 6 months. 
 
The strengths of conducting studies at the University of Wisconsin include a collaborative team 
with research expertise, and access to the Wisconsin Immunization Registry (WIR), a state-wide 
computerized internet database that was developed to record and track immunization records of 
Wisconsin residents. The WIR captures 97% of vaccines administered in the state,25 including 
data from both public and private providers, and 98.5% of Wisconsin residents have an active 
WIR record.26 We recently used the WIR to show high COVID-19 vaccine uptake among patients 
with IBD. 27 
 
 

16.0 
APPENDICES 
16.1 
Appendix 1: Short Crohn’s Disease Activity Index (sCDAI)  
The sCDAI uses the same scale as the full CDAI, such that scores <150 define remission, 150–
219 mild activity, 220–450 moderate activity, and >450 severe activity. Computation is 
straightforward: 19 
 
 
Where L is the number of liquid stools, A is the rating of abdominal pain (0–3, none to severe), W 
is the rating of general wellbeing (0–4, generally well to terrible), and n is the day of follow-up. In 
study 1, we estimated sCDAI scores from only 1 day of data by multiplying the individual 
component scores by 7.  
16.2 
Appendix 2: Simple Clinical Colitis Activity Index 
 
Simple Clinical Colitis Activity Index (SCCAI)  
 
Sub score Category 
Scores 
 
0 
1 
2 
3 
4 
Bowel Frequency (day) 
1-3 
4-6 
7-9 
>9 
 
Bowel Frequency (night) 
0 
1-3 
4-6 
 
 
Urgency of defecation 
None 
Hurry 
Immediately 
Incontinence 
 
Blood in stool 
None 
Trace 
Occasionally 
frank 
Usually frank 
 
General well-being 
Very 
Well 
Slightly 
below par 
Poor 
Very poor 
Terrible 
Extra-intestinal 
manifestations 
(arthritis, 
pyoderma gangrenosum, 
erythema 
nodosum, 
uveitis) 
 
1 
per 
manifestation 
 
 
 
 
 
A maximum score of 19 points: 
1) Remission = Score of 0 to 4 points 
2) Mild Activity = Score of 5 to 7 points 
3) Moderate Activity = Score of 8 to 16 points 
4) Severe Activity = Score of > 16 points 
 
 
 
 
 
 
 

 
Appendix 2b: Pouchitis Disease Activity Index (PDAI) 
 
Criteria 
Score 
Clinical 
Stool frequency 
Usual post-operative stool frequency 
0 
1-2 stools/day > post-operative usual 
1 
3 or more stools/day > post-operative 
usual 
2 
Rectal bleeding 
None or rare 
0 
Present daily 
1 
Fecal urgency or abdominal cramps 
None 
0 
Occasional 
1 
Usual 
2 
Fever (body temperature >37.8°C) 
Absent 
0 
Present 
1 
Score >6 pouchitis. 
 
Score < 6 remission  
 
 
16.3 
Appendix 3: List of potential Immune-mediated Diseases (pIMDs)  
 
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) 
 

Medical Concept 
Additional Notes 
Thrombotic 
thrombocytopenic purpura 
• 
Also 
known 
as 
“Moschcowitz-syndrome” 
or 
“microangiopathic hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 
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 
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 
 

Medical Concept 
Additional Notes 
Celiac disease 
 
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 
• 
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-
encephalitis, 
 
or 
acute 
necrotizing 
hemorrhagic 
encephalomyelitis)  

Medical Concept 
Additional Notes 
• 
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 
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 

Medical Concept 
Additional Notes 
 
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 
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  

Medical Concept 
Additional Notes 
Other (including multisystemic) 
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 
 
 
 
 
 
 
Appendix 4. Centers for Disease Control and Prevention:  
Case definitions of probable and confirmed myocarditis, pericarditis, and myopericarditis 
 
Condition 
Definition 
Acute myocarditis 
PROBABLE 
Presence of ≥1 new or worsening of the following clinical symptoms:* 
• chest pain, pressure, or discomfort 
• dyspnea, shortness of breath, or pain with breathing 
• palpitations 
• syncope 
OR, infants and children aged 
<12 years might instead have ≥2 of the following symptoms: 
• irritability 
• vomiting 
• poor feeding • tachypnea 
• lethargy 
AND 
≥1 new finding of 

• troponin level above upper 
limit of normal (any type of 
troponin) 
• abnormal electrocardiogram 
(ECG or EKG) or rhythm monitoring findings consistent with myocarditis§ 
• abnormal cardiac function or wall motion abnormalities on echocardiogram 
• cMRI findings consistent with myocarditis¶ 
AND 
• No other identifiable cause of 
the symptoms and findings 
CONFIRMED  
Presence of ≥1 new or worsening of the following clinical symptoms:* 
• chest pain, pressure, or discomfort 
• dyspnea, shortness of breath, or pain with breathing 
• palpitations 
• syncope 
OR, infants and children 
aged <12 years might instead have ≥2 of the following symptoms: 
• irritability 
• vomiting 
• poor feeding • tachypnea 
• lethargy 
AND 
≥1 new finding of • Histopathologic 
confirmation of 
myocarditis† 
• 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 
Acute pericarditis** 
Presence of ≥2 new or worsening of the following clinical features: 
• acute chest pain†† 
• pericardial rub on exam 
• new ST-elevation or PR-depression on EKG • new or worsening pericardial 
effusion on 
echocardiogram or MRI 
 
Myopericarditis 
This term may be used for patients who meet criteria for both myocarditis 
and pericarditis. 
Abbreviations: AV = atrioventricular; cMRI = cardiac magnetic resonance imaging; ECG or EKG 
= electrocardiogram. 
* Persons who lack the listed symptoms but who meet other criteria may be classified as 
subclinical myocarditis (probable or confirmed). 
† UsingtheDallascriteria(AretzHT,BillinghamME,EdwardsWD,etal.Myocarditis. A histopathologic 
definition and classification. Am J Cardiovasc Pathol 1987; 1:3–14). Autopsy cases may be 
classified as confirmed clinical myocarditis on the basis of meeting histopathologic criteria if no 
other identifiable cause. 

§ To meet the ECG or rhythm monitoring criterion, a probable case must include at least one of 
1) ST-segment or T-wave abnormalities; 2) Paroxysmal or sustained atrial, supraventricular, or 
ventricular arrhythmias; or 3) AV nodal 
¶ conduction delays or intraventricular conduction defects. 
Using 
either 
the 
original 
or 
the 
revised 
Lake 
Louise 
criteria. 
https://www. 
sciencedirect.com/science/article/pii/S0735109718388430?via%3Dihub 
** https://academic.oup.com/eurheartj/article/36/42/2921/2293375 
†† 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 
might occur. 
 

17.0 
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