Phase I/II, Open-Label Dose-Finding Trial of High-Dose mRNA-1273 Booster for Lung Transplant Recipients
Phase: PHASE1
Conditions: Lung Transplant Recipient, SARS-CoV-2, Immunosuppression
Sponsor: University of California, Los Angeles

Phase I/II, Open-label Dose-finding Trial of High-Dose mRNA-1273 Booster for Lung Transplant 
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University of California, Los Angeles 
Clinical Research Protocol 
Phase I/II, Open-Label Dose-Finding Trial of High-Dose mRNA-1273 Booster for Lung Transplant 
Recipients 
 
Protocol Number: 
COVID-19  
NCT Number: 
NCT05280158 
Version Date: 
4/9/22 
Investigational Product: 
Moderna mRNA-1273 vaccine 
IND Number: 
28260 
Development Phase: 
Phase I/II 
Sponsor/Investigator: 
Yusaku Michael Shino, MD 
Funding Organizations: 
Pending 
Principal Investigator: 
Yusaku Michael Shino, MD 
Department of Medicine – Pulmonary Disease  
University of California, Los Angeles 
Box 951690, 43-229 CHS 
Los Angeles, CA 90095 
 
Medical Monitors: 
Yusaku Michael Shino, MD 
Department of Medicine – Pulmonary Disease  
University of California, Los Angeles 
Box 951690, 43-229 CHS 
Los Angeles, CA 90095 
 
Name: S. Sam Weigt, MD 
Department of Medicine – Pulmonary Disease  
University of California, Los Angeles 
Box 951690, 43-229 CHS 
Los Angeles, CA 90095 
 
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time.  The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure.  Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information.   
 

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Principal Investigator               Yusaku Michael Shino, MD 
 
Associate Professor, Division of Pulmonary and Critical Care 
Co- Investigator   
 
Otto Yang, MD  
Professor, Division of Infectious Disease 
Co- Investigator   
 
Stephen Samuel Weigt, MD 
 
Associate Professor, Division of Pulmonary and Critical Care  
Co- Investigator   
 
Jesse Lawton Clark, MD 
 
Associate Professor in Residence, Department of Infectious 
Diseases 
Co- Investigator   
 
Name: John A. Belperio, MD 
 
Professor, Division of Pulmonary and Critical Care 
Co- Investigator   
 
Name: David Elashoff, PhD 
Professor, Department of Biostatistics 
 
 
PROTOCOL AGREEMENT 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study participants enrolled under my supervision and providing complete and 
timely information, as outlined in the protocol.  It is understood that all information pertaining to the 
study will be held strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required 
to carry out the study in accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
 
Protocol Title:  Phase I/II, Open-label Dose-finding Trial of High-Dose mRNA-1273 Booster for Lung 
Transplant Recipients 
 
Protocol Date:  4/9/2022 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Table of contents ............................................................................................................................. 2 
1 
BACKGROUND .................................................................................................................. 15 
1.1 
Overview of Non-Clinical Studies ................................................................................. 16 
1.2 
Overview of Clinical Studies ......................................................................................... 16 
2 
STUDY RATIONALE ......................................................................................................... 16 
2.1 
Risk / Benefit Assessment .............................................................................................. 17 
3 
STUDY OBJECTIVES ......................................................................................................... 18 
3.1 
Primary Objective .......................................................................................................... 18 
3.2 
Secondary Objectives ..................................................................................................... 18 
4 
STUDY DESIGN.................................................................................................................. 19 
4.1 
Study Overview .............................................................................................................. 19 
5 
CRITERIA FOR EVALUATION ........................................................................................ 21 
5.1 
Primary Safety Endpoint ................................................................................................ 21 
5.2 
Secondary Immunogenicity Endpoints .......................................................................... 21 
5.3 
Safety Evaluations .......................................................................................................... 22 
6 
PARTICIPANT SELECTION .............................................................................................. 22 
6.1 
Study Population ............................................................................................................ 22 
6.2 
Inclusion Criteria ............................................................................................................ 22 
6.3 
Exclusion Criteria ........................................................................................................... 23 
7 
CONCURRENT MEDICATIONS ....................................................................................... 24 
7.1 
Allowed Medications and Treatments............................................................................ 24 
7.2 
Prohibited Medications and Treatments ......................................................................... 24 
8 
STUDY TREATMENTS ...................................................................................................... 25 
8.1 
Method of Assigning Participants to Treatment Groups ................................................ 25 
8.2 
Formulation .................................................................................................................... 25 
8.3 
Packaging and Labeling ................................................................................................. 26 
8.4 
Supply of Study Drug at the Site .................................................................................... 26 
8.4.1 
Dosage/Dosage Regimen ........................................................................................ 26 
8.4.2 
Dispensing............................................................................................................... 26 
8.4.3 
Administration Instructions .................................................................................... 26 

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8.5 
Supply of Study Drug at the Site .................................................................................... 26 
8.5.1 
Storage .................................................................................................................... 26 
8.6 
Measures of Treatment Compliance .............................................................................. 27 
9 
STUDY PROCEDURES AND GUIDELINES .................................................................... 27 
9.1 
Clinical Assessments ...................................................................................................... 27 
9.1.1 
Concomitant Medications ....................................................................................... 27 
9.1.2 
Demographics ......................................................................................................... 27 
9.1.3 
Medical History ...................................................................................................... 27 
9.1.4 
Physical Examination.............................................................................................. 27 
9.1.5 
Vital Signs ............................................................................................................... 27 
9.1.6 
Adverse Events ....................................................................................................... 28 
9.2 
Clinical Laboratory Measurements ................................................................................ 28 
 
Research Labs ......................................................................................................... 28 
9.2.1 
28 
9.2.2 
Clinical Labs ........................................................................................................... 28 
10 EVALUATIONS BY VISIT................................................................................................. 28 
10.1 Screening/Enrollment Day -30 to 0 (Phone) .................................................................. 28 
10.2 Visit 1 Day 1 (Clinic): Booster Day Vaccine #4 ............................................................ 28 
10.3 Visit 2 Day 3 +/-1 Day (Phone - 2 days post booster): .................................................. 29 
10.4 Visit 3 Day 7 +/-2 Days (Clinic Visit – 6 days post booster:) ....................................... 29 
10.5 Visit 4 Day 30 +/- 7 Days (Clinic – 29 days post booster): ........................................... 30 
10.6 Visit 5 Day 90 +/- 7 Days (Phone - 89 days post booster): ............................................ 30 
10.7 Visit 6 Day 180 +/- 7 Days (Phone – 179 days post booster): End of study ................. 30 
10.8 Unscheduled Additional Visit as needed ....................................................................... 30 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ............................. 30 
11.1 Adverse Events ............................................................................................................... 30 
11.2 Serious Adverse Experiences (SAE) .............................................................................. 35 
11.2.1 Serious Adverse Experience Reporting .................................................................. 35 
11.3 Adverse Events of Special Interest................................................................................. 35 
11.4 Medical Monitoring........................................................................................................ 38 
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS............................... 38 

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12.1 Screen Failures ............................................................................................................... 38 
12.2 Halting Criteria for Sentinel Group ................................................................................ 38 
12.3 Halting Criteria for Full Group ...................................................................................... 39 
12.4 Early Discontinuation of Study ...................................................................................... 39 
12.5 Withdrawal of Participants from the Study .................................................................... 40 
12.6 Lost to Follow-up ........................................................................................................... 40 
12.7 Replacement of Participants ........................................................................................... 41 
13 PROTOCOL VIOLATIONS ................................................................................................ 41 
14 STATISTICAL METHODS AND CONSIDERATIONS.................................................... 41 
14.1 General Considerations .................................................................................................. 41 
14.2 Demographic and Baseline Characteristics .................................................................... 42 
14.3 Analysis of Primary Endpoint ........................................................................................ 42 
14.4 Analysis of Secondary Endpoints .................................................................................. 42 
14.5 Analysis of Safety .......................................................................................................... 43 
14.6 Sample Size Justification ............................................................................................... 43 
14.7 Interim Analysis ............................................................................................................. 43 
15 DATA COLLECTION, RETENTION AND MONITORING ............................................ 44 
15.1 Data Collection Instruments ........................................................................................... 44 
15.2 Data Management Procedures ........................................................................................ 44 
15.3 Data Quality Control and Reporting .............................................................................. 44 
15.4 Archival of Data ............................................................................................................. 44 
15.5 Availability and Retention of Investigational Records .................................................. 44 
15.6 Monitoring ...................................................................................................................... 45 
15.7 Participant Confidentiality ............................................................................................. 45 
15.8 Protocol Amendments .................................................................................................... 45 
15.9 Institutional Review Boards and Independent Ethics Committees ................................ 45 
15.10 Informed Consent Form ................................................................................................. 46 
15.11 Publications .................................................................................................................... 46 
15.12 Investigator Responsibilities .......................................................................................... 46 
Appendix 1: Schedule of events ................................................................................................... 47 
Appendix 2: Adverse Events of Special Interest (AESI) Terms................................................... 49 

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Appendix 3: Table of Laboratory abnormalities ........................................................................... 52 
Appendix 4: Claim for Categorical Exclusion .............................................................................. 53 
REFERENCES ............................................................................................................................. 54 
 
 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
AESI 
adverse event of special interest 
AR 
adverse reaction 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
BNP 
aspartate aminotransferase 
brain naturetic peptide 
Bid 
twice a day 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
CK 
CKMB 
cm 
cMRI 
CONSORT 
Celsius  
creatinine kinase 
creatinine kinase myocardial band 
centimeter 
cardiac magnetic resonance imaging 
Consolidated Standard of Reporting Trials 
COVID-19 
Cr 
coronavirus disease 2019 
creatinine 
CrCL 
CRF 
creatinine clearance 
case report form 
CTSI 
Clinical & Translational Science Institute 
DHHS 
Department of Health and Human Services 
DMC 
Data Monitoring Committee 
DMF 
drug master file 
EC 
European Commission 
ECG 
electrocardiogram 
eCRF 
EKG 
EOS 
EU 
electronic case report form 
electrocardiogram 
end of study 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 

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GMC 
geometric mean concentrations 
GMT 
geometric mean titers 
HEENT 
head, ears, eyes, nose, throat 
Hg 
Mercury 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HTN 
Hypertension 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IM 
Intramuscular 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IU 
international unit 
IV 
Intravenous 
IVIG 
intravenous immune globulin 
Kg 
LLOQ 
LNP 
LOA 
Kilogram 
Lower limit of quantification 
lipid non-particle 
letter of authorization 
LTOS 
long term outcome study 
MAAE 
MD 
mg 
mL 
mm 
medically attended adverse event 
medical doctor 
milligram 
milliliter 
millimeter 
mRNA 
m2 
NaCl 
messenger RNA 
square meter 
sodium chloride 
Ng 
NOCM 
Nanogram 
new onset chronic medical condition 
NP 
nurse practitioner 
ORA 
Office of Regulatory Affairs 
PA 
Physician’s assistant 
PBMC 
peripheral blood mononuclear cell 
PI 
Principal Investigator 
Plt 
PP 
platelet 
per protocol 

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PT 
prothrombin time 
PTT 
partial prothrombin time 
RBD 
receptor binding domain 
RN 
registered nurse 
SAE 
serious adverse experience 
SARS-CoV-2 
SD 
severe acute respiratory syndrome coronavirus 2 
standard deviation 
S-2P 
T Bili 
UCLA 
spike protein 
total Bilirubin 
University of California, Los Angeles 
ug 
USP 
microgram 
United States Pharmacopeia 
WBC 
white blood cells 
 
 

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PROTOCOL SYNOPSIS 
TITLE 
Phase I/II, Open-label Dose-Finding Trial of High-Dose mRNA-1273 
Booster for Lung Transplant Recipients 
 
 
SPONSOR/INVESTIGAT
OR 
Yusaku Michael Shino, MD 
 
Department of Medicine – Pulmonary Disease  
University of California, Los Angeles 
Box 951690, 43-229 CHS 
Los Angeles, CA 90095 
Telephone:  310-866-6327 
Fax: 
 310-206-8622 
E-mail: MShino@mednet.ucla.edu 
 
 
FUNDING 
ORGANIZATIONS 
Departmental funding 
NUMBER OF SITES 
Single site  
 
 
RATIONALE 
Lung transplant recipients have poor outcomes after COVID-19 infection 
with case fatality rates ranging between 14-39% (1–4). In contrast to 
immunocompetent participants in vaccine trials, solid organ transplant 
recipients have had poor responses to SARS-CoV-2 vaccines with several 
studies reporting anti-SARS-CoV-2 antibody detection in only 34-54% after 
the second dose (5–7). Lung transplant recipients generally require higher 
levels of immunosuppression due to the allograft’s exposure to the external 
environment and active immune surveillance. Thus, vaccine responses have 
been even weaker for lung transplant recipients with several studies 
reporting antibody responses in less than 20% after the second dose (5, 8–
10). Booster vaccines (3rd dose) appear to improve immune responses for 
solid organ recipients (11–13), but has not been studied specifically for lung 
transplant recipients. 
 
 
STUDY DESIGN 
This is a Phase I/II open-label dose-finding trial among lung transplant 
recipients who received three or four mRNA vaccine doses (mRNA-1273 or 
BNT162b2) after lung transplantation to: standard-dose (50 ug), mid-dose 
(100 ug) or high-dose (200 ug) mRNA-1273 booster vaccine. Sixty 
participants will be enrolled into three dose groups: 1) Standard-dose – 20 
participants, 2) Mid-dose – 20 participants, 3) High-dose – 20 participants. 
The first 2 participants in both the mid-dose and high dose groups will be 
considered the ‘sentinel’ group. Participants in the sentinel group will 
receive the vaccine and undergo a 7-day observation period for safety and 
reactogenicity before additional participants are enrolled into that dose 
group.  

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Overall study enrollment will begin with the mid-dose sentinel group (n=2). 
During the observation period for the mid-dose sentinel group, we will 
enroll two participants into the standard-dose group. Once the mid-dose 
sentinel group completes their 7-day observation period without triggering 
halting rules and is approved to proceed by the DSMB, we will enroll the 
next 27 participants (Cohort 1) with a 2:1 randomization into the mid-dose 
(n=18) and standard-dose (n=9) groups.  
 
Once all 20 participants have received their mid-dose vaccine without 
triggering halting rules and is approved to proceed by the DSMB, we will 
enroll the high-dose sentinel group (n=2). Once the high-dose sentinel group 
completes their 7-day observation period without triggering halting rules 
and is approved to proceed by the DSMB, we will enroll the next 27 
participants (Cohort 2) with a 2:1 randomization into the high-dose (n=18) 
and standard-dose (n=9) groups. All 20 participants in the mid-dose group 
will be enrolled prior to the enrollment of the high-dose group.   
  
We will perform stratified randomization for the two cohorts based on: 1) 
the number of prior doses, and 2) prior receipt of any BNT162b2 vaccines. 
Randomization with be done by the UCLA Clinical and Translational 
Science Institute (CTSI) statistics team based on scheduled participants prior 
to the study visit. The 6 participants in the sentinel (n=4) and initial (n=2) 
groups (Table 1) will be assigned into the 3 groups based on their scheduled 
visit day. 
 
 
 
PRIMARY OBJECTIVE 
1. Evaluate safety of high-dose mRNA-1273 vaccine among lung 
transplant recipients measured by incidence of adverse events.  
2. Evaluate reactogenicity of high-dose mRNA-1273 vaccine among lung 
transplant recipients measured by FDA Toxicity Grading scale. 
 
 
SECONDARY 
OBJECTIVES 
1. Evaluate humoral immunogenicity measured by anti-RBD and anti-
spike (S-2P) IgG levels at Day 30.  
2. Evaluate humoral immunogenicity measured by neutralizing antibody 
titers from a pseudovirus neutralization assay at Day 30.   
3. Evaluate cellular immunogenicity measured by cellular response assays 
including flow cytometry with intracellular staining at Day 30.  
 
 

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NUMBER OF 
PARTICIPANTS 
60 Total: 
 
The following numbers of participants will be enrolled:  
1A) Standard-dose – Initial Group 
2 
50 ug 
1B) Standard-dose – Full Group 
18 
50 ug 
 
 
 
2A) Mid-dose – Sentinel Group 
2 
100 ug 
2B) Mid-dose – Full Group 
18 
100 ug 
 
 
 
3A) High-dose – Sentinel Group 
2 
200 ug 
3B) High-dose – Full Group 
18 
200 ug 
 
 
 
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. All adult lung transplant recipients (age ≥ 18 at the time of consent) 
who received all of their COVID-19 vaccines after lung 
transplantation. 
2. Received three or four doses of either the Moderna mRNA-1273 or 
Pfizer BNT162b2 vaccine with the last dose received at least 4 
months prior to study enrollment.  
3. Currently receiving standard regimen of three drug 
immunosuppression with prednisone, tacrolimus and mycophenolate 
mofetil (cellcept, minimum 250 mg bid) or mycophenolate sodium 
(myfortic, minimum 180 mg bid). 
4. Agrees not to receive other investigational agents for prophylaxis 
against COVID-19 including Evusheld monoclonal antibodies for at 
least 30 days after the study vaccine. 
5. Understands and agrees to comply with the study procedures and 
provides written informed consent. 
6. Is in stable health without any new or worsening medical conditions 
in the opinion of the Investigator. 
7. Female participants of childbearing potential (<1 year since start of 
menopause) may be enrolled in the study if the participant fulfills all 
the following criteria: 
a. Has a negative pregnancy test at Visit 1 Day 1. 
b. Has practiced adequate contraception or has abstained from 
all activities that could result in pregnancy for at least 28 
days prior to the first injection (Day 1). 
c. Has agreed to continue adequate contraception or practice 
abstinence through 3 months following the booster injection 
(Day 90). 

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d. Is not currently breastfeeding. 
e. Adequate female contraception is defined as consistent and 
correct use of a Food and Drug Administration (FDA) 
approved contraceptive method in accordance with the 
product label. For example: 
i. Barrier method (such as condoms, diaphragm, or 
cervical cap) used in conjunction with spermicide 
ii. Intrauterine device 
iii. Prescription hormonal contraceptive taken or 
administered via oral (pill), transdermal (patch), 
subdermal, or IM route 
iv. Sterilization of a female participant’s monogamous 
male partner prior to entry into the study 
v. Note: periodic abstinence (e.g., calendar, ovulation 
methods) and withdrawal are not acceptable 
methods of contraception. 
Exclusion Criteria: 
1. Previous documented COVID-19 infection. 
2. Use of investigational agents for prophylaxis against COVID-19 within 
90 days of the start of the study, including Evusheld monoclonal 
antibodies.  
3. Ongoing therapy for acute cellular or antibody mediated rejection. 
4. Intravenous immunoglobulins (IVIG) administration within the prior 3 
months or ongoing IVIG therapy.   
5. Anaphylaxis or allergic reaction to any prior vaccines. 
6. History of anaphylaxis or other significant adverse reaction requiring 
medical intervention after receipt of a vaccine. 
7. Is acutely ill or febrile 24 hours prior to or at the Day 1 visit. Fever is 
defined as a body temperature ≥ 38.0°C/100.4°F. Participants meeting 
this criterion may be rescheduled within the relevant window periods. 
Afebrile participants with minor illnesses can be enrolled at the 
discretion of the investigator. 
8. Pregnant or breastfeeding. 
9. Has a medical, psychiatric, or occupational condition that may pose 
additional risk as a result of participation, or that could interfere with 
safety assessments or interpretation of results according to the 
investigator’s judgment. 
10. Known history of hypertension (HTN) with systolic blood pressure (BP) 
> 180 mm Hg at the Day 1 visit.  

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11. Known history of hypotension with systolic blood pressure < 85 mm Hg 
at the Day 1 visit.  
12. Bleeding disorder considered a contraindication to IM injection or 
phlebotomy. 
13. Active malignancy diagnosed within previous 4 years (excluding non-
melanoma skin cancer). 
14. Received a major surgery including lung transplantation in the past 3 
months.  
 
 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
1.   mRNA-1273 is an LNP dispersion containing an mRNA that encodes for 
the pre-fusion stabilized spike protein 2019-nCoV. 
2.   mRNA-1273 will be received at a concentration of 0.2 mg/ml. The 
investigational pharmacy will prepare doses of 50 ug (0.25 ml) standard-
dose, 100 ug (0.5 ml) mid-dose and 200 ug (1 ml) high-dose.     
 
CONTROL PRODUCT, 
DOSE AND ROUTE OF 
ADMINISTRATION 
The mRNA-1273 vaccine, provided as a sterile liquid at a concentration of 
0.2 mg per milliliter, will be administered by injection into the deltoid 
muscle in a volume of 0.25 ml (50 ug), 0.5 ml (100 ug) or 1.0 ml (200 ug). 
Vaccine mRNA-1273 will be stored at 2° to 8°C (35.6° to 46.4°F) at clinical 
sites before preparation and vaccination. No dilution was required. Doses 
could be held in syringes for up to 8 hours at room temperature before 
administration. 
DURATION OF 
PARTICIPANT 
PARTICIPATION AND 
DURATION OF STUDY 
Treatment: Day 1 intramuscular injection  
Follow-up: 6 months 
Participants will be on study for up to 7 months. 
The total duration of the study for recruitment and completion of 
participants is expected to be up to 12 months. 
CONCOMMITANT 
MEDICATIONS 
Based on inclusion criteria, participants will be required to be on a regimen 
of triple immunosuppression including prednisone, mycophenolate mofetil 
(minimum 250 mg bid) or mycophenolate sodium (minimum 180 mg bid), 
and tacrolimus at the Day 1 study visit. Participants receiving IVIG or 
augmented immunosuppression for treatment of acute cellular rejection or 
antibody mediated rejection will be excluded from the study.  
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
1. Frequency and grade of each solicited local and systemic reactogenicity 
AE will be recorded on a daily diary using the FDA Toxicity Grading 
Scale and collected from Day 1 until Day 7.   
2. Frequency and grade of each unsolicited adverse events will be recorded 
on a daily diary and collected from Day 1 until Day 30. 

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3. Frequency of any serious adverse experiences (SAEs) and adverse 
events of special interests (AESIs) will be collected from Day 1 until 
Day 180.  
SECONDARY 
ENDPOINTS 
1. Humoral immunogenicity measured by anti-RBD and anti-spike (S-2P) 
IgG levels at Day 30.  
2. Humoral immunogenicity measured by neutralizing antibody titers from 
a pseudovirus neutralization assay at Day 30.   
3. Cellular immunogenicity measured by cellular response assays 
including flow cytometry with intracellular staining at Day 30. 
SAFETY 
EVALUATIONS 
The study will use a Data and Safety Monitoring Board (DSMB). DSMB 
reviews are required for study halting and restarting. Reporting to regulatory 
bodies (IRB, FDA) will only be required for serious adverse events judged 
by the treating physician and study investigators to be potentially related to 
the administration of the study drug. All other adverse events will be 
reviewed by the study investigators and reported per FDA and IRB 
regulations. The study will be overseen by CTSI Data and Safety monitoring 
Board. By allowing CTSI DSMB to oversee the study, the PI agrees to abide 
by the CTSI DSMB’s policies and procedures as outlined in the DSMB 
charter. 
PLANNED INTERIM 
ANALYSES  
Interim analysis of the secondary immunogenicity endpoints (humoral and 
cellular immunogenicity) may be conducted once all study participants have 
completed their Day 30 visit and blood draw.   
Statistical Analysis Plan 
Primary Objective Analysis:  
1. Safety: will be measured by the frequency and grade of AEs 
(solicited and unsolicited), SAEs, AESIs, MAAEs.  
2. Reactogenicity: will be measured by the occurrence of solicited 
injection site and systemic reactions.  Simple descriptive statistics 
will be used to summarize toxicities in terms of type, severity and 
minimum or maximum values for laboratory measures, time of 
onset, duration, and reversibility or outcome. Tables will be created 
to summarize these toxicities and side effects. Safety Analyses will 
be performed on Safety Analysis Set. 
 
Secondary Objective Analysis: 
1. Binding antibody: The anti-RBD and anti-spike (S-2P) IgG 
concentrations (log10 and geometric mean concentrations (GMC)) 
at Day 30 will be evaluated with comparisons between the standard-
dose versus high-dose groups. T-tests with two-sided p<0.05 
significance will be used (overall α level of 0.1). Changes in the 
anti-RBC and anti-spike IgG concentrations at Day 30 will be 
compared between the standard-dose versus high-dose groups using 
two sample T-tests with two-sided p<0.05 significance (overall α 
level of 0.1). The percent of participants with detectable antibody 

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levels (greater than the LLOQ) at Day 30 will also be evaluated 
using Fisher’s exact tests. Pairwise comparisons of binding 
antibodies will also be evaluated between the standard-dose versus 
mid-dose groups. 
 
2. Neutralizing antibody: Neutralizing antibody titers (geometric 
mean titers (GMT)) from a pseudovirus neutralization assay at Day 
30 will be compared between the standard-dose versus high-dose 
groups using T-tests with two-sided p<0.05 significance (overall α 
level of 0.1). Changes in the neutralizing antibody titers at Day 30 
will be compared between the standard-dose versus high-dose 
groups using two sample T-tests with two-sided p<0.05 significance 
(overall α level of 0.1). The percent of participants with detectable 
neutralizing antibody levels (greater than the LLOQ) at Day 30 will 
also be evaluated using Fisher’s exact tests. Pairwise comparisons of 
neutralizing antibodies will also be evaluated between the standard-
dose versus mid-dose groups. 
 
3. Cellular immunogenicity: The change in the frequency of target 
cytokine producing T-cells by flow cytometry with intracellular 
staining at Day 30 will be compared using the Kruskal-Wallis Test 
for the standard-dose versus high-dose groups. A comparison of T-
cell frequencies between the standard-dose versus high-dose groups 
will be evaluated using the Wilcoxon rank-sum test. Pairwise 
comparisons of cellular immunogenicity will also be evaluated 
between the standard-dose versus mid-dose groups. 
Rationale for Number of 
Participants 
The overall mean log10 IgG increase after the third (100 ug) vaccine dose 
was 0.46 with standard deviation (SD) 0.63. Assuming participants have a 
50% lower response to the 50 ug fourth-dose, the expected mean log10 IgG 
increase is 0.23. Assuming participants have a 100% higher response to the 
200 ug fourth-dose, their expected mean log10 IgG increase is 0.91. For 
80% power to detect this difference between high-dose and standard-dose 
groups with a SD of 0.63 for a two-sample t-test with two-sided α<0.05 
significance, the minimum required sample size is 15 per group. Thus, we 
will enroll 20 participants into each group. The first 2 participants in the mid 
and high-dose groups will be enrolled as the sentinel group to ensure an 
acceptable safety profile before the full group is enrolled.  
 
1 
BACKGROUND 
The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) emerged in December 2019 and has caused a 
global pandemic of unparalleled proportion with a respiratory illness named Coronavirus Disease 2019 
(Covid-19). The urgent need for interventions to reduce the high morbidity and mortality associated with 
Covid-19 has led to numerous vaccine candidates based on traditional and new platforms. mRNA-1273 is 

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a lipid-nanoparticle (LNP) encapsulated mRNA vaccine encoding a pre-fusion stabilized form of the 
SARS-CoV-2 spike protein (S-2P).  
1.1 
Overview of Non-Clinical Studies 
Non-clinical studies have demonstrated the immunogenicity, safety and vaccine efficacy of the mRNA-
1273 vaccine. Early studies in non-human primates showed robust SARS-CoV-2 neutralizing activity 
with rapid protection from high-dose SARS-CoV-2 challenge (1). Subsequent non-human primate studies 
showed a dose-response relationship between increasing mRNA-1273 doses and both serum anti-S-2P 
IgG levels as well as protection from viral challenge (2). No animals with anti-S-2P IgG > 645  
international units (IU)/mL had nasal swab positivity > 100,000 copies/swab. Furthermore, passive 
transfer of vaccine-induced IgG from non-human primates to naïve hamsters was protective against 
infection (2).  
1.2 
Overview of Clinical Studies 
Efficacy of the mRNA-1273 vaccine was demonstrated in a phase 3 randomized trial of 30,420 
participants in the COVE Study (3, 4). Vaccine efficacy in was 94.1% at preventing COVID-19 illness, 
including severe disease. Local and systemic reactions to the vaccine were common and included pain at 
injection site, headache, fatigue, myalgias and arthralgias. However, these reactions were transitory and 
there were no serious adverse events, episodes of thrombosis or myocarditis associated with the vaccine 
(3, 4). Hypersensitivity reactions were reported in 1.5% and 1.1% of participants in the vaccine and 
placebo groups, respectively.  
Several medical conditions have been reported in temporal association with COVID-19 vaccines. 
Thrombosis with thrombocytopenia syndrome (TTS) and Guillain-Barre syndrome (GBS) have been 
reported after the Johnson & Johnson Janssen vaccine (5), although these conditions have not been 
associated with the mRNA vaccines (Pfizer-BioNTech and Moderna). The mRNA vaccines have been 
associated with an increased risk of myocarditis and pericarditis, particularly among young males after 
the second dose (6–9). The incidence of myocarditis/pericarditis is low and estimated at 3.5 cases per 
million doses after second dose mRNA among all adults, and 24.3 cases per million among individuals 12 
to 29 years of age (10). Most reported cases of myocarditis/pericarditis occurred within the first 7 days of 
vaccination (7–9). Despite the potential for these rare but serious conditions, the benefit-risk assessment 
for Covid-19 vaccination remains strongly in favor of vaccination for those over age 5.     
The phase 1 mRNA-1273 clinical trial evaluated three doses: 25 ug, 100 ug and 250 ug. There was a 
dose-response relationship between increasing mRNA-1273 doses and serum anti-S-2P antibody levels. 
Systemic adverse reactions including fatigue, chills, headache, myalgia and injection site pain occurred in 
more than half the participants, and occurred more frequently with the 250 ug dose. Thus, the 100 ug dose 
was eventually chosen for the phase 3 clinical trial. 
 
 
2 
STUDY RATIONALE 
In contrast to immunocompetent participants in vaccine trials, solid organ transplant recipients have poor 
responses to SARS-CoV-2 vaccines with studies reporting anti-S-protein antibody detection in only 34-

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54% after the second dose (11–13). Lung transplant recipients in particular have weak responses to the 
vaccine with antibody responses observed in less than 20% after the second dose (11, 14–16). Due to the 
allograft’s exposure to the external environment and active immune surveillance, lung transplant 
recipients generally require higher levels of immunosuppression. Lung transplantation is also unique 
among the solid organ transplants in the direct infection and injury of the allograft by SARS-CoV-2.  
Thus, lung transplant recipients have had poor outcomes after COVID-19 infection with case fatality rates 
ranging between 14-39% (17–20). Third vaccine doses appear to improve immune responses for solid 
organ recipients (21–23), but has not been studied specifically for lung transplant recipients.  
The objectives of this study are to determine the safety, reactogenicity and immunogenicity of a mid-dose 
(100 ug) and high-dose (200 ug) booster mRNA-1273 vaccine among lung transplant recipients who 
previously received three or four mRNA-1273 vaccine doses.  
A single-center observational cohort study of 165 pts at UCLA found that only 35% of lung transplant 
recipients mounted an anti-RBD IgG antibody response after the second mRNA vaccine dose (Pfizer or 
Moderna), with an increase to 59% after the third dose. In contrast, lung transplant recipients who were 
either: 1) infected with COVID-19 or 2) received at least one vaccine dose before transplant, had higher 
antibody levels approaching those of healthy participants. This suggests that lung transplant recipients 
may be able to mount a stronger immune response to higher antigen exposure, and may be able to retain 
their antibody response afterwards. Importantly, we found that reactogenicity was significantly less for 
lung transplant recipients after both the second and third dose of the vaccine compared with healthy 
vaccine recipients. The frequency of any systemic adverse reaction (fever, fatigue, headache, myalgia, 
arthralgia, chills or nausea) was 46% after the third dose for lung transplant recipients compared with 
80% for healthy vaccine recipients.  
In summary, lung transplant recipients have weak antibody responses to the mRNA-1273 vaccine and 
remain at high risk for morbidity and mortality due to Covid-19. The 100 ug third dose was associated 
with significantly less systemic adverse reactions compared with healthy vaccine recipients. Thus, we 
hypothesize that we can safely improve the immunogenicity of the mRNA-1273 vaccine by administering 
a 100 ug or 200 ug booster dose to lung transplant recipients, instead of the currently recommended 50 ug 
booster dose. We will conduct the study as an open-label dose-finding trial comparing: standard-dose (50 
ug) booster, mid-dose (100 ug) and high-dose (200 ug) mRNA-1273 booster as described below.  
 
2.1 
Risk / Benefit Assessment 
Efficacy of the mRNA-1273 vaccine was demonstrated in a phase 3 randomized trial of 30,420 
participants in the COVD Study (3, 4). Vaccine efficacy in was 94.1% at preventing COVID-19 illness, 
including severe disease. Local and systemic reactions to the vaccine were common and included pain at 
injection site, headache, fatigue, myalgias and arthralgias. However, these reactions were transitory and 
there were no serious adverse events, episodes of thrombosis or myocarditis associated with the vaccine 
(3, 4). Hypersensitivity reactions were reported in 1.5% and 1.1% of participants in the vaccine and 
placebo groups, respectively.  
Rare episodes of myocarditis and pericarditis have been reported after the mRNA vaccines (Pfizer-
BioNTech and Moderna), particularly among young males after the second dose (9, 24, 25). The 
incidence of myocarditis/pericarditis is low and estimated at 3.5 cases per million doses after second dose 
mRNA among all adults, and 24.3 cases per million among individuals 12 to 29 years of age (10) . Most 

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reported cases of myocarditis/pericarditis occurred within the first 7 days of vaccination (7–9). Despite 
the potential for these rare but serious conditions, the benefit-risk assessment for Covid-19 vaccination 
remains strongly in favor of vaccination for those over age 5. Of note, myocarditis has also been 
associated with COVID-19 infection at a higher incidence than with the mRNA vaccines (6, 26). Analysis 
of a large national database found the risk ratio of myocarditis after vaccination to be 3.2 (95% CI 1.6-
12.4) compared with those who were unvaccinated (6). After COVID-19 infection, the risk ratio of 
myocarditis was 18.3 (95% CI 4.0-25.1) compared with those who were unvaccinated.   
The phase 1 mRNA-1273 clinical trial evaluated three doses: 25 ug, 100 ug and 250 ug. There was a 
dose-response relationship between increasing mRNA-1273 doses and serum anti-S-2P antibody levels. 
Systemic adverse reactions including fatigue, chills, headache, myalgia and injection site pain occurred in 
more than half the participants, and occurred more frequently with the 250 ug dose. Thus, the 100 ug dose 
was eventually chosen for the phase 3 clinical trial. 
Lung transplant recipients, due to their immune suppression medicines, have had weak responses to the 
COVID-19 vaccines with antibody responses noted in less than 20% after the second vaccine dose (16–
18). Lung transplantation is also unique among the solid organ transplants in the direct infection and 
injury of the allograft by SARS-CoV-2. Thus, lung transplant recipients have poor outcomes following 
COVID-19 infection with a high mortality rate. Third dose vaccines appear to improve immune responses 
for solid organ recipients, but has not been studied specifically for lung transplant recipients.  
The current CDC guidance is for moderately or severely immunocompromised patients to receive a 50 ug 
booster: 1) At least 3 months after 3rd dose (first booster), and 2) At least 4 months after 4th dose (2nd 
booster). We believe that this dosing will be insufficient for many lung transplant recipients, particularly 
in those who did not receive any vaccine doses prior to their lung transplant, and leave them at high risk 
of poor COVID-19 outcomes. Importantly, due to their immunosuppression, lung recipients appear to 
have decreased side effects and reactogenicity to the SARS-CoV-2 vaccine.  
We hypothesize that a 100 ug mid-dose and 200 ug high-dose mRNA-1273 booster dose can be safely 
administered to lung transplant recipients who previously received all of their vaccine doses after their 
lung transplant. We further hypothesize that the higher dose boosters will induce a stronger immune 
response to SARS-COV-2 as measured by humoral and cellular response assays. The objectives of this 
study are to test these two hypotheses.  
 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
1. Evaluate safety of high-dose mRNA-1273 booster vaccine among lung transplant recipients measured 
by incidence of adverse events.  
2. Evaluate reactogenicity of high-dose mRNA-1273 booster vaccine among lung transplant recipients 
measured by the FDA Toxicity Grading scale. 
3.2 
Secondary Objectives 
1. Evaluate humoral immunogenicity measured by anti-RBD and anti-spike (S-2P) IgG levels at Day 30. 

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2. Evaluate humoral immunogenicity measured by neutralizing antibody titers from a pseudovirus 
neutralization assay at Day 30.   
3. Evaluate cellular immunogenicity measured by cellular response assays including flow cytometry 
with intracellular staining at Day 30. 
 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a Phase I/II open-label dose-finding trial among lung transplant recipients who received three or 
four mRNA vaccine doses (mRNA-1273 or BNT162b2) after lung transplantation to: standard-dose (50 
ug), mid-dose (100 ug) or high-dose (200 ug) mRNA-1273 booster vaccine. Participants will be enrolled 
into three dose groups: 1) Standard-dose (50 ug) – 20 participants, 2) Mid-dose (100 ug) – 20 participants, 
3) High-dose (200 ug) – 20 participants. The first 2 participants in both the mid-dose and high dose 
groups will be considered the ‘sentinel’ group. Participants in the sentinel group will receive the vaccine 
and undergo a 7-day observation period for safety and reactogenicity before additional participants are 
enrolled into that dose group.  
Overall study enrollment will begin with the mid-dose sentinel group (n=2). During the observation 
period for the mid-dose sentinel group, we will enroll two participants into the standard-dose group. Once 
the mid-dose sentinel group completes their 7-day observation period without triggering halting rules and 
is approved to proceed by the DSMB, we will enroll the next 27 participants (Cohort 1) with a 2:1 
randomization into the mid-dose (n=18) and standard-dose (n=9) groups.  
Once all 20 participants have received their mid-dose vaccine without triggering halting rules and is 
approved to proceed by the DSMB, we will enroll the high-dose sentinel group (n=2). Once the high-dose 
sentinel group completes their 7-day observation period without triggering halting rules and is approved 
to proceed by the DSMB, we will enroll the next 27 participants (Cohort 2) with a 2:1 randomization into 
the high-dose (n=18) and standard-dose (n=9) groups. Thus, all 20 participants in the mid-dose group will 
be enrolled prior to enrollment of the high-dose group.  
We will perform stratified randomization for the two cohorts based on: 1) the number of prior doses, and 
2) prior receipt of any BNT162b2 vaccines. Randomization with be done by the UCLA Clinical and 
Translational Science Institute (CTSI) statistics team based on scheduled participants prior to the study 
visit. The 6 participants in the sentinel (n=4) and initial (n=2) groups (Table 1) will be assigned into the 3 
groups based on their scheduled visit day. 
This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of mid and high-
dose mRNA-1273 vaccine among lung transplant recipients who have received three or four prior mRNA 
vaccines. 
In-person visits will occur on Days 1 (booster vaccine), 7 and 30. Telephone visits will occur on Days 3, 
90 and 180.  Adverse events will be assessed in person (Days 1, 7 and 30) and by telephone calls (Days 3, 
90 and 180). All follow-up visits will include a detailed review for serious adverse experiences (SAEs), 
adverse events of special interest (AESIs) and medically attended adverse events (MAAEs).  
 

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Table 1: Treatment Arms: 
 
Groups will be enrolled as follows:           n                  Dose 
1) Mid-dose – Sentinel group 
2 
100 ug 
2) Standard-dose – Initial group 
2 
50 ug 
 
 
 
3) Cohort 1: 2:1 Randomization into 
 
 
           Mid-dose group 
18 
100 ug 
           Standard-dose group 
9 
50 ug 
 
 
 
4) High-dose – Sentinel group 
2 
200 ug 
     
 
 
5) Cohort 2: 2:1 Randomization into 
 
 
           High-dose group 
18 
200 ug 
           Standard-dose group 
9 
50 ug 
 
Cohorts 1 and 2 will be randomized to their dose and considered the full group.  
 
 
 
 
 
 
Mid-dose Sentinel Group (n=2)
Standard-dose Initial Group (n=2)
Cohort 1:    2:1 Randomization into  
Mid-dose (n=18) versus Standard-dose (n=9) Groups
High-dose Sentinel Group (n=2)
Once mid-dose sentinel group (n=2) clears 
7-day observation period
Once mid-dose full group (n=18) clears 
observation period
Cohort 2:     2:1 Randomization into: 
High-dose (n=18) versus Standard-dose (n=9)
Figure 1. Study enrollment flow diagram
Once high-dose sentinel group (n=2) clears 
7-day observation period

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5 
CRITERIA FOR EVALUATION 
5.1 
Primary Safety Endpoint 
Safety will be measured by the frequency and grade of solicited and unsolicited adverse events (AEs), 
SAEs, AESIs and MAAEs. Reactogenicity will be measured by the occurrence of solicited injection site 
and systemic reactions.   
1. Frequency and grade of each solicited local and systemic reactogenicity AE will be recorded on a 
daily diary using the FDA Toxicity Grading Scale and collected from Day 1 until Day 7.   
2. Frequency and grade of each unsolicited AEs will be recorded on a daily diary and collected from 
Day 1 until Day 30. 
3. Frequency of any SAEs, AESIs and MAAEs will be collected from Day 1 until Day 180.  
Simple descriptive statistics will be used to summarize toxicities in terms of type, severity and minimum 
or maximum values for laboratory measures, time of onset, duration, and reversibility or outcome. Tables 
will be created to summarize these toxicities and side effects. Safety Analyses will be performed on the 
Safety Analysis Set. 
5.2 
Secondary Immunogenicity Endpoints 
1. Binding antibody: The anti-RBD and anti-spike (S-2P) IgG concentrations (log10 and geometric 
mean concentrations (GMC)) at Day 30 will be evaluated with comparisons between the 
standard-dose versus high-dose groups. T-tests with two-sided p<0.05 significance will be used 
(overall α level of 0.1). Changes in the anti-RBC and anti-spike IgG concentrations at Day 30 will 
be compared pairwise between the standard-dose versus high-dose groups using two sample T-
tests with two-sided p<0.05 significance (overall α level of 0.1). The percent of participants with 
detectable antibody levels (greater than the LLOQ) at Day 30 will also be evaluated using 
Fisher’s exact tests. Pairwise comparisons of binding antibodies will also be evaluated between 
the standard-dose versus mid-dose groups.  
 
2. Neutralizing antibody: Neutralizing antibody titers (geometric mean titers (GMT)) from a 
pseudovirus neutralization assay at Day 30 will be compared between the standard-dose versus 
high-dose groups using T-tests with two-sided p<0.05 significance (overall α level of 0.1). 
Changes in the neutralizing antibody titers at Day 30 will be compared between the standard-dose 
versus high-dose groups using two sample T-tests with two-sided p<0.05 significance (overall α 
level of 0.1). The percent of participants with detectable neutralizing antibody levels (greater than 
the LLOQ) at Day 30 will also be evaluated using Fisher’s exact tests. Pairwise comparisons of 
neutralizing antibodies will also be evaluated between the standard-dose versus mid-dose groups. 
 
3. Cellular immunogenicity: The change in the frequency of target cytokine producing T-cells by 
flow cytometry with intracellular staining at Day 30 will be compared using the Kruskal-Wallis 
Test for standard-dose versus high-dose groups. A comparison of T-cell frequencies between the 
standard-dose versus high-dose groups will be evaluated using the Wilcoxon rank-sum test. 
Pairwise comparisons of cellular immunogenicity will also be evaluated between the standard-
dose versus mid-dose groups. 

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5.3 
Safety Evaluations 
The study will use a Data and Safety Monitoring Board (DSMB). DSMB reviews are required for study 
halting and restarting. Reporting to regulatory bodies (IRB, FDA) will only be required for serious 
adverse events judged by the treating physician and study investigators to be potentially related to the 
administration of the study drug, including suspected, unexpected, serious adverse reactions (SUSAR, 
Section 11). All other adverse events will be reviewed by the study investigators and reported per FDA 
and IRB regulations. The study will be overseen by CTSI Data and Safety monitoring Board. By allowing 
CTSI DSMB to oversee the study, the PI agrees to abide by the CTSI DSMB’s policies and procedures as 
outlined in the DSMB charter. 
 
Safety evaluations:  
1. Visit 1: Day 1 (booster day): informed consent, med history, inclusion criteria review, physical 
exam, blood draw, administration of booster, 30-minute observation.  
2. Telephone visit Day 3: Review for AEs, SAEs, AESIs and MAAEs.   
3. Visit 2: Day 7 - blood draw, physical exam and review for AEs, SAEs, AESIs and MAAEs.  
4. Visit 3: Day 30 - blood draw, physical exam and review for AEs, SAEs, AESIs and MAAEs. 
5. Telephone visit Day 90: Review for AEs, SAEs, AESIs and MAAEs.  
6. Telephone visit Day 180: Review for AEs, SAEs, AESIs and MAAEs. 
 
The following labs will be collected at baseline and clinic follow-up visits.  
1. Serum collected for antibody levels. 
2. PBMCs collected for cellular response assays including flow cytometry with intracellular 
staining. 
3. Whole blood collected for cellular response assays.  
4. Troponin, CK and cytokines banked from Day 0, 7 and 30. 
 
6 
PARTICIPANT SELECTION 
6.1 
Study Population 
Participants post lung transplant who previously received three or four mRNA-1273 or BNT162b2 
COVID-19 vaccines who meet the inclusion and exclusion criteria will be eligible for participation in this 
study.   
6.2 
Inclusion Criteria 
1. All adult lung transplant recipients (age ≥ 18 at the time of consent) who received all of their 
COVID-19 vaccines after lung transplantation. 
2. Received three or four doses of either the Moderna mRNA-1273 or Pfizer BNT162b2 vaccine 
with the last dose received at least 4 months prior to study enrollment.  
3. Currently receiving standard regimen of three drug immunosuppression with prednisone, 
tacrolimus and mycophenolate mofetil (minimum 250 mg bid) or mycophenolate sodium 
(minimum 180 mg bid). 

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4. Agrees not to receive other investigational agents for prophylaxis against COVID-19 including 
Evusheld monoclonal antibodies for at least 30 days after the study vaccine. 
5. Understands and agrees to comply with the study procedures and provides written informed 
consent. 
6. Is in stable health without any new or worsening medical conditions in the opinion of the 
Investigator. 
7. Female participants of childbearing potential (<1 year since start of menopause) may be enrolled 
in the study if the participant fulfills all the following criteria: 
a. Has a negative pregnancy test at Visit 1 Day 1. 
b. Has practiced adequate contraception or has abstained from all activities that could result 
in pregnancy for at least 28 days prior to the first injection (Day 1). 
c. Has agreed to continue adequate contraception or practice abstinence through 3 months 
following the booster injection (Day 90). 
d. Is not currently breastfeeding. 
e. Adequate female contraception is defined as consistent and correct use of a Food and 
Drug Administration (FDA) approved contraceptive method in accordance with the 
product label. For example: 
i. Barrier method (such as condoms, diaphragm, or cervical cap) used in 
conjunction with spermicide 
ii. Intrauterine device 
iii. Prescription hormonal contraceptive taken or administered via oral (pill), 
transdermal (patch), subdermal, or IM route 
iv. Sterilization of a female participant’s monogamous male partner prior to entry 
into the study 
v. Note: periodic abstinence (e.g., calendar, ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
6.3 
Exclusion Criteria 
1. Previous documented COVID-19 infection. 
2. Use of investigational agents for prophylaxis against COVID-19 within 90 days of the start of the 
study, including Evusheld monoclonal antibodies.  
3. Ongoing therapy for acute cellular or antibody mediated rejection. 
4. Intravenous immunoglobulins (IVIG) administration within the prior 3 months or ongoing IVIG 
therapy.   
5. Anaphylaxis or allergic reaction to any prior vaccines. 
6. History of anaphylaxis or other significant adverse reaction requiring medical intervention after 
receipt of a vaccine. 
7. Is acutely ill or febrile 24 hours prior to or at the Day 1 visit. Fever is defined as a body 
temperature ≥ 38.0°C/100.4°F. Participants meeting this criterion may be rescheduled within the 

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relevant window periods. Afebrile participants with minor illnesses can be enrolled at the 
discretion of the investigator. 
8. Pregnant or breastfeeding. 
9. Has a medical, psychiatric, or occupational condition that may pose additional risk as a result of 
participation, or that could interfere with safety assessments or interpretation of results according 
to the investigator’s judgment. 
10. Known history of hypertension (HTN) with systolic blood pressure (BP) > 180 mm Hg at the Day 
1 visit.  
11. Known history of hypotension with systolic blood pressure < 85 mm Hg at the Day 1 visit.  
12. Bleeding disorder considered a contraindication to IM injection or phlebotomy. 
13. Active malignancy diagnosed within previous 4 years (excluding non-melanoma skin cancer). 
14. Received a major surgery including lung transplantation in the past 3 months.  
 
Exclusion of Specific Populations:  
Because the effects on the fetus are not known, pregnant women will not be eligible for the trial. Women 
of childbearing potential (<1 year since start of menopause) must utilize a highly effective method of 
contraception and will be required to have a negative urine or serum pregnancy test within 24 hours prior 
to the vaccination. Children will not be included in this trial as presently there are no children receiving 
lung transplantation at UCLA.  Should the outcome of this trial be deemed acceptable, additional trials 
may be initiated, including those in other populations. 
 
 
 
7 
CONCURRENT MEDICATIONS 
This trial design allows for participants in all study arms to receive other investigational drugs for 
COVID-19 after Day 45 of the study.  
7.1 
Allowed Medications and Treatments 
Standard therapy for COVID-19 is allowed except for treatments noted in the exclusion criteria described 
above and as noted in the prohibited medications section below. Based on inclusion criteria, participants 
will be required to be on a regimen of triple immunosuppression including prednisone, mycophenolate 
mofetil (minimum 250 mg bid) or mycophenolate sodium (minimum 180 mg bid), and tacrolimus at the 
Day 1 study visit. Participants receiving IVIG or augmented immunosuppression for treatment of acute 
rejection or antibody mediated rejection will be excluded from the study. 
7.2 
Prohibited Medications and Treatments 
Use of investigational agents for prophylaxis against COVID-19 within 90 days of the start of the study, 
including Evusheld monoclonal antibodies. Use of investigational agents for prophylaxis including 
Evusheld against COVID-19 for at least 30 days after study vaccination, since this will affect the 
antibody-based secondary endpoints.  
 

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8 
STUDY TREATMENTS 
8.1 
Method of Assigning Participants to Treatment Groups 
This is a Phase I/II open-label dose-finding trial among lung transplant recipients who received three or 
four mRNA vaccine doses (mRNA-1273 or BNT162b2) after lung transplantation to: standard-dose (50 
ug), mid-dose (100 ug) or high-dose (200 ug) mRNA-1273 booster vaccine. Participants will be enrolled 
into three dose groups: 1) Standard-dose – 20 participants, 2) Mid-dose – 20 participants, 3) High-dose – 
20 participants. The first 2 participants in both the mid-dose and high dose groups will be considered the 
‘sentinel’ group. Participants in the sentinel group will receive the vaccine and undergo a 7-day 
observation period for safety and reactogenicity before additional participants are enrolled into that dose 
group.  
Overall study enrollment will begin with the mid-dose sentinel group (n=2). During the observation 
period for the mid-dose sentinel group, we will enroll two participants into the standard-dose group. Once 
the mid-dose sentinel group completes their 7-day observation period without triggering halting rules and 
is approved to proceed by the DSMB, we will enroll the next 27 participants (Cohort 1) with a 2:1 
randomization into the mid-dose (n=18) and standard-dose (n=9) groups.  
Once all 20 participants have received their mid-dose vaccine without triggering halting rules and is 
approved to proceed by the DSMB, we will enroll the high-dose sentinel group (n=2). Once the high-dose 
sentinel group completes their 7-day observation period without triggering halting rules and is approved 
to proceed by the DSMB, we will enroll the next 27 participants (Cohort 2) with a 2:1 randomization into 
the high-dose (n=18) and standard-dose (n=9) groups. All 20 participants in the mid-dose group will be 
enrolled prior to enrollment of the high-dose group.  
We will perform stratified randomization for the two cohorts based on: 1) the number of prior doses, and 
2) prior receipt of any BNT162b2 vaccines. Randomization with be done by the UCLA Clinical and 
Translational Science Institute (CTSI) statistics team based on scheduled participants prior to the study 
visit. The 6 participants in the sentinel (n=4) and initial (n=2) groups (Table 1) will be assigned into the 3 
groups based on their scheduled visit day. 
If the halting criteria is triggered for the high-dose group and further enrollment of this group is not 
recommended by the study investigators, DSMB or IRB, the study will continue randomized enrollment 
into the mid-dose and standard-dose groups with a 1:2 ratio to complete the enrollment of 60 participants 
total. Since the expected immunogenicity difference between the mid-dose and standard-dose group is 
smaller, we will require more participants to detect a difference between these two groups. The 1:2 
enrollment ratio into the mid-dose and standard-dose groups will even the distribution of participants into 
these two groups. The primary endpoint analysis for safety and reactogencity will not be affected by a 
restriction of participants into the mid-dose and standard-dose groups. 
 
8.2 
Formulation   
mRNA-1273 is provided as a sterile liquid for injection, white to off white dispersion in appearance, at a 
concentration of 0.2 mg/ml. Please refer to letter of authorization (LOA) from to cross-reference the drug 
master file (DMF).  

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8.3 
 Packaging and Labeling 
Each of the study products will be labeled according to manufacturer specifications and include the 
statement “Caution: New Drug Limited by Federal Law to Investigational Use.” Sterile empty vials will 
be provided with latex-free stoppers. 
8.4 
Supply of Study Drug at the Site 
mRNA-1273 will be stored as per manufacturer guidelines, dispensed, and accounted for by the 
investigational pharmacy.  
8.4.1 
Dosage/Dosage Regimen 
Investigational product mRNA-1273 will be administered via intramuscular injection (IM) at three doses: 
standard-dose (50 ug), mid-dose (100 ug) or high-dose (200 ug).  
 
Table 2: Dosing and Administration 
 
Group 
Sample Size 
Dose 
Route 
Frequency 
1 Standard 
20 
50 ug 
IM 
Day 1 
2 Mid-dose 
20 
100 ug 
IM 
Day 1 
3 High-dose 
20 
200 ug 
IM 
Day 1 
8.4.2 
Dispensing 
Investigational product mRNA-1273 will be received at 0.2 mg/ml concentration and dispensed by the 
investigational pharmacy undiluted at three dosages: 50 ug (0.25 ml), 100 ug (0.5 ml) and 200 ug (1 ml).  
8.4.3 
Administration Instructions  
 Each dose will be administered via IM injection into the deltoid muscle on Day 1.  
8.5 
Supply of Study Drug at the Site 
Study drug will be supplied by Moderna and stored at the UCLA investigational pharmacy as per 
manufacturer guidelines, dispensed, and accounted for by the investigational pharmacy.  
8.5.1 
Storage 
Vaccine mRNA-1273 will be stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and 
vaccination. No dilution will be required. Doses could be held in syringes for up to 8 hours at room 
temperature before administration.  
The number of study drug dispensed will be recorded on the Investigational Drug Accountability Record.  
The UCLA Clinical & Translational Science Institute - Office of Regulatory Affairs (CTSI ORA) will 
verify these documents throughout the course of the study. 

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8.6 
Measures of Treatment Compliance 
Not applicable  
 
 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration of the 
study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the participant or 
participant’s legal representative.  If appropriate, assent must also be obtained prior to conducting any 
study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
Based on inclusion criteria, participants will be required to be on a regimen of triple immunosuppression 
including prednisone, mycophenolate mofetil (minimum 250 mg bid) or mycophenolate sodium 
(minimum 180 mg bid), and tacrolimus at the Day 1 study visit. Participants receiving IVIG or 
augmented immunosuppression for treatment of acute rejection, antibody mediated rejection or chronic 
rejection will be excluded from the study.  
9.1.2 
Demographics 
Demographic information will be recorded at enrollment including race, ethnicity, sex, age, BMI, 
medication history, co-morbidities including cardiovascular disease, risk factors for cardiovascular 
disease, and immunosuppressive agents. 
9.1.3 
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, and 
information regarding underlying risk factors will be recorded at screening. 
9.1.4 
Physical Examination  
A complete physical examination will be performed by either the investigator or a sub-investigator who is 
a physician or a qualified member (NP) of the study team at Day 1. Qualified members of the study team 
(MD, NP, RN and PA) will perform a symptom directed physical exam on Days 7 and 30. New abnormal 
physical exam findings will be documented and will be followed by a physician or other qualified staff at 
the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse oximetry, and respiratory rate will be performed and recorded. 

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9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. Duration (start 
and stop dates and times), severity/grade, outcome, treatment and relation to study drug will be recorded 
on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 
Research Labs 
Blood will be obtained and sent to the research lab for:   
1. Total immunoglobulins: IgG, IgA, IgM. 
2. Anti-RBD, anti-spike binding and neutralizing antibody levels  
3. PBMCs collected for cellular response assays including flow cytometry with intracellular 
staining. 
4. Whole blood collected for cellular response assays. 
5. Troponin / CK and cytokines for storage on Days 0, 7 and 30.  
9.2.2 
Clinical Labs 
The following may be checked for any unscheduled visits: Complete blood count with differential, 
comprehensive metabolic panel, tacrolimus / sirolimus level, C-reactive protein, erythrocyte 
sedimentation rate (ESR), total immunoglobulins (IgG, IgA, IgM), anti-RBD, anti-spike and neutralizing 
antibody levels, PBMCs collected for cellular response assays including flow cytometry with intracellular 
staining, whole blood collected for cellular response assays, troponin / CK, cytokines, PT, PTT, INR (16 
mL of venous blood).    
 
10 
EVALUATIONS BY VISIT 
10.1 Screening/Enrollment Day -30 to 0 (Phone) 
1. Pre-screen participants via chart review using HIPAA waiver. 
2. Invite eligible participants by phone to participate in study. 
3. A qualified member of the study team will review study and provide ICF form. Participants will 
be asked to sign consent at Visit 1 prior to initiating any study-related procedures. 
4. Assign the participant a unique screening number. 
10.2 Visit 1 Day 1 (Clinic): Booster Vaccine Day 
1. For participants who meet inclusion/exclusion criteria, the investigator team will again review the 
study with the participant (or participant’s legal representative) in person and obtain written 
informed consent and HIPAA authorization. 
2. Record demographic data. 
3. Record medical history. 
4. Review of birth control history with female participants of childbearing potential (<1 year since 
start of menopause). 

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5. For women of childbearing potential, counsel participants to use adequate birth control methods 
required during the trial to avoid pregnancy. 
6. For women of childbearing potential, urine pregnancy test will be checked prior to study drug 
administration on Visit 1 (Day 1).  
7. Confirmation participants meet all inclusion criteria and no exclusion criteria review. 
8. Review pre-study concomitant medications and therapies and record on the appropriate CRF.  
9. Review of influenza and any all 2019-CoV vaccinations or other experimental coronavirus 
vaccines. 
10. Vital signs (HR, BP, temperature, oximetry), and height and weight for determination of BMI. 
11. Full physical exam will include assessments of the following organs and organ systems: skin, 
head, ears, eyes, nose, and throat (HEENT), neck, lungs, heart, liver, spleen, abdomen, 
extremities, lymph nodes (axillary and cervical), and nervous system. 
12. Obtain blood samples for baseline: Total immunoglobulins (IgG, IgA, IgM), anti-RBD, anti-spike 
binding and neutralizing antibody levels, PBMCs collected for cellular response assays including 
flow cytometry with intracellular staining, whole blood collected for cellular response assays, 
troponin / CK and cytokines for storage.  
13. Confirm group assignment: standard-dose, mid-dose or high-dose group.   
14. Inform participants of their designated dose. 
15. Administration of booster vaccine. 
16. Participants will be observed for 30-minutes post injection administration.  
17. Dispense daily diary of symptoms for first 7 days after injection dispensed to participant 
measuring FDA Toxicity Grading Scale and adverse events.  
10.3 Visit 2 Day 3 +/-1 Day (Phone – 2 days post booster): 
1. All participants will complete a daily diary of solicited and unsolicited AEs from the vaccination 
until 7 days post-vaccination. Reactogenicity will be measured by the occurrence of solicited 
injection site and systemic reactions for the first 7 days post-vaccination utilizing the FDA 
Toxicity Grading Scale. 
2. Participants will be contacted by telephone to query for safety events and review daily diaries. 
Based on the information collected, participants may be asked to return to the clinic for 
evaluation for an unscheduled visit. 
3. Review daily diaries, AEs (solicited and unsolicited), SAEs, AESIs and MAAEs.  
4. Participants will contact their primary care doctor, lung transplant pulmonologist or study 
principal investigator with any SAEs, AESIs or MAAEs.  
10.4 Visit 3 Day 7 +/-2 Days (Clinic Visit – 6 days post booster): 
1. Vital signs (HR, BP, temperature, oximetry), and height and weight for determination of BMI. 
2. Symptom-directed (targeted) physical exam. Targeted physical examinations should also include 
an assessment for signs suggestive of AEs and AESIs. Interim or unscheduled physical 
examinations will be performed at the discretion of the PI or appropriate sub-investigator, if 
necessary, to evaluate AEs or abnormal clinical laboratory test results. 
3. Obtain blood samples for follow-up: Total immunoglobulins (IgG, IgA, IgM), anti-RBD, anti-
spike binding and neutralizing antibody levels, PBMCs collected for cellular response assays 
including flow cytometry with intracellular staining, whole blood collected for cellular response 
assays, troponin / CK and cytokines for storage. 

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5. Review daily diaries, AEs (solicited and unsolicited), SAEs, AESIs and MAAEs.  
10.5 Visit 4 Day 30 +/- 7 Days (Clinic – 29 days post booster): 
1. Vital signs (HR, BP, temperature, oximetry), and height and weight for determination of BMI. 
2. Symptom-directed (targeted) physical exam. Targeted physical examinations should also include 
an assessment for signs suggestive of AEs and AESIs. Interim or unscheduled physical 
examinations will be performed at the discretion of the PI or appropriate sub-investigator, if 
necessary, to evaluate AEs or abnormal clinical laboratory test results. 
3. Obtain blood samples for follow-up:  Total immunoglobulins (IgG, IgA, IgM), anti-RBD, anti-
spike binding and neutralizing antibody levels, PBMCs collected for cellular response assays 
including flow cytometry with intracellular staining, whole blood collected for cellular response 
assays, troponin / CK and cytokines for storage. 
4. Review daily diaries, AEs (solicited and unsolicited), SAEs, AESIs and MAAEs.  
10.6 Visit 5 Day 90 +/- 7 Days (Phone – 89 days post booster): 
1. Participants will be contacted by telephone to query for safety events. AEs (solicited and 
unsolicited), SAEs, AESIs and MAAEs will be reviewed. Based on the information collected, 
participants may be asked to return to the clinic for evaluation. 
10.7 Visit 6 Day 180 +/- 7 Days (Phone – 179 days post booster): End of study 
1. Participants will be contacted by telephone to query for safety events. AEs (solicited and 
unsolicited), SAEs, AESIs and MAAEs will be reviewed. Based on the information collected, 
participants may be asked to return to the clinic for evaluation. 
10.8 Unscheduled Additional Visit as needed 
1. Clinical evaluation for symptoms to include physical exam and ECG as needed.  
2. Obtain blood samples for evaluation: Complete blood count with differential, comprehensive 
metabolic panel, tacrolimus / sirolimus level, C-reactive protein, erythrocyte sedimentation rate 
(ESR), total immunoglobulins (IgG, IgA, IgM), anti-RBD, anti-spike and neutralizing antibody 
levels, PBMCs collected for cellular response assays including flow cytometry with intracellular 
staining, whole blood collected for cellular response assays, troponin / CK, cytokines, PT, PTT, 
INR (16 mL of venous blood).    
3. AEs (solicited and unsolicited), SAEs, AESIs and MAAEs will be reviewed. Based on the 
information collected, participants may be asked to return to the clinic for evaluation. 
 
 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship with the 
treatment.  An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory 

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finding), symptom or disease temporally associated with the administration of an investigational product, 
whether or not related to that investigational product.  Any medical condition that is present at the time 
that the subject is screened will be considered as baseline and not reported as an AE. However, if the 
severity of any pre-existing medical condition increases, it will be recorded as an AE. 
AEs can be further divided into solicited AEs and unsolicited AEs. Solicited AEs are those for which the 
study team will specifically query the subject whether they occurred. Unsolicited AEs are those events 
that the subject report occurring without being queried about the specific event.  
A suspected adverse event is one for which there is a ‘reasonable possibility’ that the drug caused the 
adverse event. A ‘reasonable possibility’ means there is evidence to suggest a causal relationship between 
the drug and the adverse event, but implies a lesser degree of certainty about causality compared with an 
adverse event. An unexpected AE is one of a type not identified in nature, severity, or frequency in the 
current Investigator’s Brochure or of greater severity or frequency than expected based on the information 
in the Investigator’s Brochure. All AEs will be assessed for severity and relationship to study intervention 
(Tables 3 and 4). Suspected, Unexpected, Serious Adverse Reactions (SUSAR) is an adverse event where 
a causal relationship with the study drug is at least possible but not listed in the Investigator Brochure 
(IB), Package Insert, and/or Summary of Product Characteristics and includes any of the following: 
suspected AE, unexpected AE and serious adverse experience (SAE). Episodes of myocarditis or 
pericarditis occurring in temporal association with vaccination will be reported as a SUSAR. Medically 
attended adverse event (MAAE) is defined as hospitalization, an emergency room visit or an otherwise 
unscheduled visit to or from medical personnel for any reason.  
Frequency and grade of each solicited AE (local and systemic reactogenicity) will be collected until Day 
7 using the FDA Toxicity Grading Scale to be recorded on a daily diary. Frequency and grade of each 
unsolicited AEs will be collected until Day 30. Frequency of any SAEs, AESIs and MAAEs will be 
collected until Day 180. After Day 30 through the end of study on Day 180, only SAEs, AESIs and 
MAAEs will be reported as AEs. All AEs, solicited and unsolicited, will be captured on the appropriate 
CRF. Information to be collected for AEs includes event description, date of onset, assessment of 
severity, relationship to study product and alternate possible etiology, date of resolution, seriousness, and 
outcome. AEs occurring during the study-collection and reporting period will be documented 
appropriately regardless of relationship. AEs will be followed to resolution or stabilization. 
 
Solicited Adverse Events: 
Solicited AEs are anticipated local and systemic AEs for which consistent collection of 
information is desired. Study clinicians will follow and collect resolution information for any 
reactogenicity symptoms that are not resolved within 7 days. Solicited AEs (i.e., reactogenicity) will be 
collected using a daily diary and recorded on the appropriate CRF from the time of the vaccination until 7 
days post vaccination (Days 1-7). For this study, solicited AEs will be defined and graded as follows 
(Tables 3): 
 
 
Table 3: Solicited Adverse Reactions and Grading 
 

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Reaction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Injection site pain 
None 
Does not 
interfere with 
activity  
Repeated use of over-
the-counter pain reliever 
> (greater than) 24 hours 
or interferes with activity  
Any use of 
prescription pain 
reliever or prevents 
daily activity 
Requires emergency 
room visit or 
hospitalization 
Injection site 
erythema 
(redness) 
< (less than) 
25 mm or 
 < 2.5 cm 
25 - 50 mm or 
2.5 - 5 cm 
51 - 100 mm or 
5.1 - 10 cm 
> 100 mm or 
> 10 cm 
Necrosis or exfoliative 
dermatitis (severe skin 
rash causing skin 
discoloration or 
peeling) 
Injection site 
swelling/induration 
(hardness) 
< 25 mm or 
< 2.5 cm 
25 - 50 mm or 
2.5 - 5 cm 
51 - 100 mm or 
5.1 - 10 cm  
> 100 mm or 
> 10 cm 
Necrosis (severe 
swelling with skin 
discoloration, 
blistering, or peeling) 
Axillary 
(underarm) 
swelling or 
tenderness 
ipsilateral to the 
side of injection 
None 
No interference 
with activity 
Repeated use of over-
the-counter (non-
narcotic) pain reliever > 
24 hours or some 
interference with activity 
Any use of 
prescription (narcotic) 
pain reliever or 
prevents daily activity 
Requires emergency 
room visit or 
hospitalization 
Headache 
None 
No interference 
with activity 
Repeated use of over-
the-counter pain reliever 
> 24 hours or some 
interference with activity 
Significant; any use of 
prescription pain 
reliever or prevents 
daily activity 
Requires emergency 
room visit or 
hospitalization 
Fatigue 
None 
No interference 
with activity  
Some interference with 
activity 
Significant; prevents 
daily activity  
Requires emergency 
room visit or 

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Reaction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
hospitalization 
Myalgia (muscle 
aches all over 
body) 
None 
No interference 
with activity  
Some interference with 
activity 
Significant; prevents 
daily activity  
Requires emergency 
room visit or 
hospitalization 
Arthralgia (joint 
aches in several 
joints) 
None 
No interference 
with activity  
Some interference with 
activity 
Significant; prevents 
daily activity  
Requires emergency 
room visit or 
hospitalization 
Nausea/vomiting 
None 
No interference 
with activity or 1-
2 episodes/ 
24 hours 
Some interference with 
activity or 
> 2 episodes/24 hours 
Prevents daily activity, 
requires outpatient 
intravenous hydration 
(fluids given through 
blood veins) 
Requires emergency 
room visit or 
hospitalization for low 
blood pressure 
Chills 
None 
No interference 
with activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
Requires emergency 
room visit or 
hospitalization 
Fever  
< 38.0°C 
< 100.4°F 
38.0 – 38.4°C 
100.4 – 101.1°F 
38.5 – 38.9°C 
101.2 – 102.0°F 
39.0 – 40.0°C 
102.1 – 104.0°F 
> 40.0°C 
> 104.0°F 
Rash 
No rash 
Localized rash, 
without 
associated 
symptoms 
Maculopapular rash 
(bumpy and red rash) 
covering < 50% body 
surface area 
Generalized urticarial 
rash (hives or itchy 
rash) covering > 50% 
body surface area 
Generalized 
exfoliative, ulcerative 
or bullous dermatitis 
(severe skin rash 
causing skin 
discoloration, peeling 
or blistering) 

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Reaction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
If you experience any grade 4 symptom from your daily diary, or any other severe symptoms that prevents your daily 
activity AND requires you to see a doctor, please call Dr. Michael Shino immediately at 310-206-6766. The operator 
will answer the call, please tell them that you would like to "page Dr Shino". Dr Shino or another covering Dr will call 
you back.  
Source: Guidance for industry – Toxicity Grading Scale for Heathy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials; tables for clinical abnormalities (DHHS 2007).  
 
Unsolicited Adverse Events 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
staff or revealed by observation, physical examination or other diagnostic procedures must be 
recorded on the appropriate CRF. Unsolicited AEs of all severities will be reported from the time of study 
product administration through Day 30. After Day 30, only SAEs and AESIs will be reported through the 
end of the study (Day 180).  
 
AE Severity 
”Table 3: Solicited Adverse Reactions and Grading” will be used to assess and grade solicited AE 
severity. “Appendix 3: Table of Laboratory Abnormalities” will be used to grade any laboratory 
abnormalities observed. If the adverse event is not covered in Table 3 and Appendix 3, the guidelines 
shown in Table 4 below should be used to grade severity. It should be pointed out that the term “severe” 
is a measure of intensity and that a severe AE is not necessarily serious. 
Table 4.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
These events do not interfere with the participant’s daily activities. 
Moderate (2) 
These events cause some interference with the participant’s daily activities 
and require limited or no medical intervention. 
Severe (3) 
These events prevent the participant’s daily activity and require intensive 
therapeutic intervention.  
 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following guidelines in Table 5. 
Table 5.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 

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Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage 
of the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the participant’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
11.2 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
1. death 
2. a life-threatening adverse experience 
3. inpatient hospitalization or prolongation of existing hospitalization 
4. a persistent or significant disability/incapacity 
5. a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the participant or require intervention to prevent one of the outcomes listed.  
Participants will be instructed to call a study team line (attended 24-hours per day) if they experience any 
grade 4 symptom from the “Solicited Adverse Reactions and Grading” table (Table 3), any severe 
unsolicited AE (Table 4), or any SAE. The study team member will interview, document and triage the 
participant for further evaluation.  
11.2.1 
Serious Adverse Experience Reporting 
All SAEs that occur (whether or not related to study drug) will be reported per UCLA OHRPP IRB 
guidelines and policy. The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional Review Board 
(IRB), the site investigator will report SAEs to the IRB and FDA.   
11.3 
Adverse Events of Special Interest 
An AESI is an AE (serious or nonserious) of scientific and medical topic of interest, for which ongoing 
monitoring and immediate notification by the investigator is required and documentation is in the form of 
a case narrative. Such events may require further investigation to characterize and understand them. Refer 
to Appendix 2 for a list of AESIs pertinent to this study. All AESIs will be collected through the entire 

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study period and must be reported immediately and in all circumstances within 7 days of becoming aware 
of the event. AESIs were identified as immunologically driven sequelae of COVID-19 and thus topics of 
interest/AESIs for all COVID vaccines. 
 
Anaphylaxis 
All suspected cases of anaphylaxis should be recorded and reported as an SAE and AESI, based on 
criteria for a medically important event, unless the event meets other serious criteria. For reporting 
purposes, a participant who displays signs/symptoms consistent with anaphylaxis as shown below should 
be reported as a potential case of anaphylaxis. This is provided as general guidance for investigators and 
is based on the Brighton Collaboration case definition (27). 
Anaphylaxis is an acute hypersensitivity reaction with multi-organ-system involvement that can 
present as, or rapidly progress to, a severe life-threatening reaction. It may occur following 
exposure to allergens from a variety of sources. Anaphylaxis is a clinical syndrome characterized 
by: 
1. Sudden onset AND 
2. Rapid progression of signs and symptoms AND 
3. Involving 2 or more organ systems, as follows: 
a. Skin/mucosal: urticaria (hives), generalized erythema, angioedema, generalized pruritus 
with skin rash, generalized prickle sensation, red and itchy eyes 
b. Cardiovascular: measured hypotension, clinical diagnosis of uncompensated shock, loss 
of consciousness or decreased level of consciousness, evidence of reduced peripheral 
circulation 
c. Respiratory: bilateral wheeze (bronchospasm), difficulty breathing, stridor, upper airway 
swelling (lip, tongue, throat, uvula, or larynx), respiratory distress, persistent dry cough, 
hoarse voice, sensation of throat closure, sneezing, rhinorrhea 
d. Gastrointestinal: diarrhea, abdominal pain, nausea, vomiting 
 
Acute Myocarditis and/or Pericarditis 
All suspected cases of probable or confirmed myocarditis, pericarditis, or myopericarditis should be 
recorded as an AESI, and reported as an SAE, if the event meets seriousness criteria. As an SAE, the 
event should be reported immediately and in all circumstances within 72 hours. The investigator will 
submit any updated myocarditis, pericarditis, or myopericarditis case data within 72 hours of it being 
available. For reporting purposes, a participant who displays signs/symptoms consistent with the CDC 
case definitions as described below (27), should be reported as a potential case of confirmed or probable 
myocarditis, pericarditis, or myopericarditis. 
The CDC case definitions are intended to serve as a guide to help in the diagnosis and reporting 
of suspected cases of myocarditis and/or pericarditis; however, the diagnosis of suspected cases is left to 
the investigator’s clinical judgement. 
 
Acute Myocarditis Case Definition 
Presence of ≥ 1 new or worsening of the following clinical symptoms (persons who lack the listed 
symptoms but who meet other criteria may be classified as subclinical myocarditis [probable or 
confirmed]): 
1. Chest pain/pressure/discomfort 

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2. Dyspnea/shortness of breath/pain with breathing 
3. Palpitations 
4. Syncope 
AND 
For PROBABLE CASE: 
Presence of ≥ 1 new finding of the following: 
1. Troponin level above upper limit of normal (any type of troponin) 
2. Abnormal electrocardiogram (ECG or EKG) or rhythm monitoring findings consistent 
with myocarditis 
To meet the ECG or rhythm monitoring criterion, a probable case must include at least one of the 
following: 
a. ST segment or T-wave abnormalities 
b. Paroxysmal or sustained atrial, supraventricular, or ventricular arrhythmias 
c. AV nodal conduction delays or intraventricular conduction defects 
 
       3. Abnormal cardiac function or wall motion abnormalities on echocardiogram 
4. Cardiac magnetic resonance imaging (cMRI) finding consistent with myocarditis (28). 
AND  
1. No other identifiable cause of the symptoms and findings 
 
For CONFIRMED CASE: 
1. Histopathologic confirmation of myocarditis (using Dallas criteria (29)) 
OR 
2. cMRI findings consistent with myocarditis in the presence of troponin level above 
upper limit of normal (any type of troponin). 
AND 
1. No other identifiable cause of the symptoms and findings 
 
Acute Pericarditis Case Definition 
Presence of ≥ 2 new or worsening of the following clinical features (30): 
1. Acute chest pain (Typically described as pain made worse by lying down, deep 
inspiration, or cough; and relieved by sitting up or leaning forward, although other 
types of chest pain may occur) 
2. Pericardial rub on examination 
3. New ST-elevation or PR-depression on EKG 
4. New or worsening pericardial effusion on echocardiogram or magnetic resonance 
imaging 
 
Myopericarditis Case Definition 
Participants who meet criteria for both myocarditis and pericarditis may be described under 
myopericarditis. 

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11.4 
Medical Monitoring 
Michael Shino, MD or S. Sam Weigt, MD should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 
Yusaku Michael Shino, MD 
Telephone:  310-866-6327 
Pager: 310-206-6766 Pgr#24405 
 
S. Sam Weigt, MD 
Telephone: 310-825-8599 
Pager: 310-206-6766 Pgr#20928 
 
 
12 
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
12.1 
Screen Failures 
Screen failures are defined as participants who consent to participate in the study but are not subsequently 
assigned to study intervention. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
 
After the screening assessments have been completed, the PI or qualified designee is to review the 
inclusion and exclusion criteria and determine the participant’s eligibility for the study. Only the 
following information will be collected on screen failures: demographics (age, screen number, sex, 
ethnicity, and race, BMI, medication history, co-morbidities including cardiovascular disease, risk factors 
for cardiovascular disease, and immunosuppressive agents) and reason for ineligibility. Participants who 
are found to be ineligible will be told the reason for ineligibility. 
 
12.2 
Halting Criteria for Sentinel Group 
The study will be paused if any of the following events occur in the mid-dose (n=2) or high-dose (n=2) 
sentinel groups and enrollment may resume only after the DSMB reviews the events and permits the 
study to continue.  
1. Any grade 4 (Table 3) solicited local or systemic reaction considered to be at least possibly 
related to vaccination within 7 days after administration of the vaccine. 
2. Two or more grade 3 (Table 3) solicited local or systemic reaction in the same dose group 
considered to be at least possibly related to vaccination that lasted at least 48 hours within 7 days 
after administration of the vaccine.  
3. Any severe allergic reaction that is at least possibly related to vaccination within 24 hours after 
administration of the vaccine.  

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4. Any SAE within 28 days after administration of the vaccine considered to be at least possibly 
related to vaccination.  
5. Any episode of myocarditis / pericarditis within 28 days after administration of the vaccine.  
6. Any new episodes of elevated troponin, ECG and physical exam findings concerning for 
myocarditis / pericarditis within 28 days after administration of the vaccine.  
7. Any death unless determined to be definitely not related to vaccination within 90 days after 
administration of the vaccine.  
12.3 
Halting Criteria for Full Group (Cohorts 1 and 2) 
The study will be paused if any of the following events occur in the full group (standard (n=18), mid 
(n=18) and high dose (n=18) groups) and enrollment may resume only after the DSMB reviews the events 
and permits the study to continue.  
1. Any grade 4 (Table 3) solicited local or systemic reaction in the mid or high-dose groups 
considered to be at least possibly related to vaccination within 7 days after administration of the 
vaccine. 
2. Three or more grade 3 (Table 3) solicited local or systemic reaction in the same dose group 
considered to be at least possibly related to vaccination that lasted at least 48 hours within 7 days 
after administration of the vaccine. 
3. Any three participants with severe allergic reaction that is at least possibly related to vaccination 
within 24 hours after administration of the vaccine.  
4. Any SAE within 28 days after administration of the vaccine considered to be at least possibly 
related to vaccination.  
5. Any episode of myocarditis / pericarditis within 28 days after administration of the vaccine.  
6. Any new episodes of elevated troponin, ECG and physical exam findings concerning for 
myocarditis / pericarditis within 28 days after administration of the vaccine.  
7. Any death unless determined to be definitely not related to vaccination within 90 days after 
administration of the vaccine. 
If the halting criteria is triggered for the high-dose group and further enrollment of this group is not 
recommended by the study investigators, DSMB or IRB, the study will continue randomized enrollment 
into the mid-dose and standard-dose groups with a 1:2 ratio to complete the enrollment of 60 participants 
total. Since the expected immunogencity difference between these two groups will be smaller, we will 
require more participants to detect a difference between these two groups. The 1:2 enrollment ratio into 
the mid-dose and standard-dose groups will even the distribution of participants into these two groups. 
The primary endpoint analysis for safety and reactogencity will not be affected by a restriction of 
participants into the mid-dose and standard-dose groups. 
 
12.4 
Early Discontinuation of Study  
A participant may be discontinued from study treatment at any time if the participant or study team 
determines that it is not in the participant’s best interest to continue.  The following is a list of possible 
reasons for study treatment discontinuation:  

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1. Participant withdrawal of consent  
2. Participant is not adherent with study procedures 
3. Adverse event that in the opinion of the investigator would be in the best interest of the 
participant to discontinue study treatment 
4. Protocol violation requiring discontinuation of study treatment 
5. Loss to follow-up 
If a participant is withdrawn from treatment due to an adverse event, the participant will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for participant withdrawals.  
The reason for the participant’s withdrawal from the study will be recorded in the study. 
12.5 
Withdrawal of Participants from the Study 
A participant may be withdrawn from the study at any time if the participant, the sponsor/investigator, or 
the study team determines that it is not in the participant’s best interest to continue.   
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals.  The reason for the participant’s withdrawal from the study will be specified in the 
participant’s source documents.  As noted above, participants who discontinue study early (i.e., they 
withdraw prior to the last visit) should have an early discontinuation visit if they have been discharged 
from the hospital. Participants who withdraw should be encouraged to come in for a final laboratory visit. 
When a participant withdraws or is withdrawn from the study, the reason(s) for withdrawal will be 
recorded by the investigator on the relevant page of the eCRF. These participants will be requested to 
complete the EOS assessments scheduled for end of participation. 
12.6 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
without stating an intention to withdraw consent and is unable to be contacted by the study site. The 
following actions must be taken if a participant fails to return to the study site for a required study visit: 
1. The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule, and 
ascertain whether the participant wishes to and/or should continue in the study. 
2. Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts (e.g., dates of telephone calls and registered letters) should be documented in the 
participant’s study source document. 

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3. Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
4. A participant should not be considered lost to follow-up until due diligence has been completed. 
Date of withdrawal/lost to follow-up should be the date of last contact with the participant where 
safety status of the participant was assessed (e.g., study site visit, telephone call). 
12.7 
Replacement of Participants 
Any participant who is withdrawn or who is lost to follow-up from the study may be replaced at the 
principal investigator’s discretion. 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the participant, investigator, or Sponsor fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, participant safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 
1. Failure to meet inclusion/exclusion criteria 
2. Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. 
The Investigator will determine if a protocol violation will result in withdrawal of a participant. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form 
detailing the violation will be generated. This form will be signed by the Investigator. The form will be 
sent to the IRB and a copy will be filed in the site’s regulatory binder.  
 
 
14 STATISTICAL METHODS AND CONSIDERATIONS 
14.1 
General Considerations 
Data collected in this study will be presented using summary tables and participant data listings. 
Continuous variables will be summarized using descriptive statistics, specifically the mean, median, 
standard deviation, minimum, and maximum. Categorical variables will be summarized by frequencies 
and percentages. Data Sets Analyzed: 
• 
Intent-to-Treat (ITT) Analysis Set 
The ITT analysis set includes all participants who are enrolled into a treatment (dose) group regardless of 
whether participants receive any study drug(s), or receive a different regimen from the regimen they were 
randomized to. Participants will be assigned into a dose group as described above.  
• 
Safety Analysis Set 
A safety analysis set will include data from participants who receive at least one dose of study treatment, 
with treatment assignments designated according to the actual treatment received. This analysis set will 
be used in the analyses of safety variables (primary endpoint) as well as study treatment administration. 
• 
Per-Protocol (PP) Analysis Set 

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The PP analysis set includes data from participants in the ITT analysis set who meet the general criteria 
defining the target population for this study, are adherent to the protocol, are compliant with study drug 
treatment, and are evaluable for relevant efficacy endpoints. Treatment assignment will be designated 
according to the actual treatment received. The PP analysis set will be used in the analyses of the 
secondary endpoints. The PP analysis set will only include participants randomized to the dose-group 
(Cohorts 1 and 2, Figure 1). The PP analysis set will exclude participants in the sentinel mid-dose (n=2), 
sentinel high-dose (n=2) and initial standard-dose groups (n=2) who were not randomized to their dose-
group. Participants who are found to have detectable anti-N-protein IgG antibody levels (representing 
prior infection) at their Day 1 (baseline) visit will be excluded from the PP analysis set.  
14.2 
Demographic and Baseline Characteristics 
The following demographic variables at screening will be included: race, ethnicity, sex, age, BMI, 
medication history, co-morbidities including cardiovascular disease, risk factors for cardiovascular 
disease, and immunosuppressive agents.   
14.3 
Analysis of Primary Endpoint 
Safety will be measured by the frequency and grade of AEs (solicited and unsolicited), SAEs, AESIs, 
MAAEs. Reactogenicity will be measured by the occurrence and severity of solicited injection site and 
systemic reactions. Simple descriptive statistics will be used to summarize toxicities in terms of type, 
severity and minimum or maximum values for laboratory measures, time of onset, duration, and 
reversibility or outcome. Tables will be created to summarize these toxicities and side effects. Safety 
Analyses will be performed on Safety Analysis Set. 
14.4 
Analysis of Secondary Endpoints 
1. Binding antibody: The anti-RBD and anti-spike (S-2P) IgG concentrations (log10 and geometric 
mean concentrations (GMC)) at Day 30 will be evaluated with comparisons between the standard-
dose versus high-dose groups. T-tests with two-sided p<0.05 significance will be used (overall α level 
of 0.1). Changes in the anti-RBC and anti-spike IgG concentrations at Day 30 will be compared 
between the standard-dose versus high-dose groups using two sample T-tests with two-sided p<0.05 
significance (overall α level of 0.1). The percent of participants with detectable antibody levels 
(greater than the LLOQ) at Day 30 will also be evaluated using Fisher’s exact tests. Pairwise 
comparisons of binding antibodies will also be evaluated between the standard-dose versus mid-dose 
groups. 
 
2. Neutralizing antibody: Neutralizing antibody titers (geometric mean titers (GMT)) from a 
pseudovirus neutralization assay at Day 30 will be compared between the standard-dose versus high-
dose groups using T-tests with two-sided p<0.05 significance (overall α level of 0.1). Changes in the 
neutralizing antibody titers at Day 30 will be compared between the standard-dose versus high-dose 
using two sample T-tests with two-sided p<0.05 significance (overall α level of 0.1). The percent of 
participants with detectable neutralizing antibody levels (greater than the LLOQ) at Day 30 will also 
be evaluated using Fisher’s exact tests. Pairwise comparisons of neutralizing antibodies will also be 
evaluated between the standard-dose versus mid-dose groups. 
 

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3. Cellular immunogenicity: The change in the frequency of target cytokine producing T-cells by flow 
cytometry with intracellular staining at Day 30 will be compared using the Kruskal-Wallis Test for 
the standard-dose versus high-dose groups. A comparison of T-cell frequencies between the standard-
dose versus high-dose groups will be evaluated using the Wilcoxon rank-sum test. Pairwise 
comparisons of cellular immunogenicity will also be evaluated between the standard-dose versus 
mid-dose groups. 
14.5 
Analysis of Safety 
Safety is the primary endpoint and described above. Simple descriptive statistics will be used to 
summarize frequency and grade of AEs (solicited and unsolicited), SAEs, AESIs and MAAEs. Safety 
Analyses will be performed on Safety Analysis Set. 
14.6 
Sample Size Justification 
The overall mean log10 IgG increase after the third (100 ug) vaccine dose was 0.46 with standard 
deviation (SD) 0.63. Assuming participants have a 50% lower response to the 50 ug fourth-dose, the 
expected mean log10 IgG increase is 0.23. Assuming participants have a 100% higher response to the 200 
ug fourth-dose, their expected mean log10 IgG increase is 0.91. For 80% power to detect this difference 
between high-dose and standard-dose groups with a SD of 0.63 for a two-sample t-test with two-sided 
α<0.05 significance, the minimum required sample size is 15 per group. Thus, we will enroll 20 
participants in each group. The first 2 participants in the mid and high-dose groups will be enrolled as the 
sentinel group to ensure an acceptable safety profile before the full group is enrolled.  
If the halting criteria is triggered for the high-dose group and further enrollment of this group is not 
recommended by the study investigators, DSMB or IRB, the study will continue randomized enrollment 
into the mid-dose and standard-dose groups with a 1:2 ratio to complete the enrollment of 60 participants 
total. Since the expected immunogenicity difference between the mid-dose and standard-dose group is 
smaller, we will require more participants to detect a difference between these two groups. The 1:2 
enrollment ratio into the mid-dose and standard-dose groups will even the distribution of participants into 
these two groups. The primary endpoint analysis for safety and reactogencity will not be affected by a 
restriction of participants into the mid-dose and standard-dose groups. 
 
14.7 
Interim Analysis 
Interim analysis of the secondary immunogenicity endpoints (humoral and cellular immunogenicity) may 
be conducted once all study participants have completed their Day 30 visit and blood draw.   
 
 
 

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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 
Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each participant treated with the study drug.   
Study personnel will enter data from source documents corresponding to each participant into the 
protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the information 
corresponding to that visit is available.  Participants will not be identified by name in the study database 
or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
participant number. 
The Investigator is responsible for all information collected on participants enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the completion 
of the study. 
15.2 
Data Management Procedures 
The data will be entered into a secure, de-identified, database.  The study coordinators will be responsible 
for data processing, in accordance with procedural documentation.  Database lock will occur once quality 
assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
15.3 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks 
will be implemented and applied to the database on a regular basis. The study database will be updated in 
accordance with the resolved queries.  All changes to the study database will be documented. 
15.4 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; appropriate 
backup copies of the database and related software files will be maintained.  Databases are backed up by 
the database administrator in conjunction with any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for analysis 
is locked and cleaned per established procedures. 
15.5 
Availability and Retention of Investigational Records 
The Sponsor/Investigator must make study data accessible to the monitor, IRB/ and Regulatory Agency 
(e.g., FDA) inspectors upon request.  A file for each participant must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source documentation 
related to that participant.  The Investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 

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All study documents (participant files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the investigational 
product or for two years after centers have been notified that the IND has been discontinued.  There may 
be other circumstances for which the Sponsor/Investigator is required to maintain study records. 
15.6 
Monitoring 
This study will be monitored by the UCLA Clinical & Translational Science Institute – Office of 
Regulatory Affairs (CTSI ORA). Monitoring visits will be conducted according to the U.S. CFR Title 21 
Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the 
Sponsor/Investigator grants permission to the appropriate regulatory authorities to conduct on-site 
monitoring and/or auditing of all appropriate study documentation.  
15.7 
Participant Confidentiality 
In order to maintain participant confidentiality, only a participant number will identify all study 
participants on CRFs and other documentation.  
 
 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers 
(21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 
CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be 
identified by a coded number and initials only.  All study records will be kept in a locked file cabinet and 
code sheets linking a participant’s name to a participant identification number will be stored separately in 
another locked file cabinet.  Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU 
Data Protection Directive 95/46/EC). 
15.8 
Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor/Investigator. Protocol amendments cannot 
be implemented without prior written IRB approval except as necessary to eliminate immediate safety 
hazards to participants. A protocol amendment intended to eliminate an apparent immediate hazard to 
participants may be implemented immediately, provided the IRBs are notified within five working days. 
15.9 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB.  Serious adverse experiences 
regardless of causality will be reported to the IRB in accordance with the standard operating procedures 
and policies of the IRB, and the Investigator will keep the IRB informed as to the progress of the study.  
The Investigator will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning participant recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB. The 

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IRB unconditional approval of the study protocol and the informed consent form will be in the possession 
of the Investigator before the study is initiated. This approval must refer to the study by exact protocol 
title and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB 
approval except when necessary to eliminate immediate hazards to the participants or when the change(s) 
involves only logistical or administrative aspects of the study.  Such modifications will be submitted to 
the IRB and written verification that the modification was submitted and subsequently approved should 
be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; serious and/or 
unexpected adverse experiences occurring during the study in accordance with the standard operating 
procedures and policies of the IRB; new information that may affect adversely the safety of the 
participants of the conduct of the study; an annual update and/or request for re-approval; and when the 
study has been completed. 
15.10 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local 
regulations. 
The Investigator will prepare the informed consent form, and HIPAA authorization and provide the 
documents to the IRB/.  The consent form generated by the Investigator must be approved by the IRB.  
The written consent document will embody the elements of informed consent as described in the 
International Conference on Harmonisation and will also comply with local regulations. The Investigator 
will include the IRB/ -approved copy of the Informed Consent Form in the study file. 
A properly executed, written, informed consent will be obtained from each participant prior to entering 
the participant into the trial.  Information should be given in both oral and written form and participants 
(or their legal representatives) must be given ample opportunity to inquire about details of the study.  If a 
participant is unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal 
representative may sign for the participant.   A copy of the signed consent form) will be given to the 
participant or legal representative of the participant and the original will be maintained with the 
participant’s records. 
15.11 Publications  
The publication or presentation of any study results shall comply with all applicable privacy laws, 
including, but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
15.12 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of participants. 
2. 
Personally, conduct or supervise the study (or investigation). 

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3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and approval 
meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance with 
§21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for 
initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity and all 
unanticipated problems involving risks to participants or others (to include amendments and IND 
safety reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when necessary to 
eliminate hazards to the participants. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312. 
 
APPENDIX 1.  SCHEDULE OF EVENTS 
 
Screening 
Day -30 to 
Day 0 
Visit 1 
Day 1 
Clinic 
Visit 2 
Day 3 
Phone 
+/-1 
day 
Visit 3 
Day 7 
Clinic 
+/-2 
days 
Visit 4 
Day 30 
Clinic 
+/-7 
days 
Visit 5 
Day 90 
Phone 
+/-7 
days 
Visit 6 
Day 180 
Phone 
+/-7 
days 
Unscheduled 
visit as 
needed 
Informed 
Consent 
 
X 
 
 
 
 
 
 
Demographic 
data 
 
X 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
Eligibility 
review 
X 
X 
 
 
 
 
 
 
Con meds 
 
X 
 
 
 
 
 
 
Pre-study meds 
 
X 
 
 
 
 
 
 
Review CoV 
vaccinations 
 
X 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
 
 
 
Vital Signs (HR, 
BP, temperature, 
oximetry) 
 
X 
 
X 
X 
 
 
 
Full physical 
exam 
 
X 
 
 
 
 
 
X 

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Targeted 
physical exam 
 
 
 
X 
X 
 
 
 
Blood draw* 
 
X 
 
X 
X 
 
 
X 
Group 
assignment 
 
X 
 
 
 
 
 
 
IP administration 
 
X 
 
 
 
 
 
 
30-minute post-
dose observation 
 
X 
 
 
 
 
 
 
Review AEs, 
SAEs, AESIs, 
MAAEs 
 
 
X 
X 
X 
X 
X 
X 
Review 
myocarditis and 
pericarditis 
symptoms 
 
 
X 
X 
X 
X 
X 
X 
Dispense daily 
diary 
 
X 
 
 
 
 
 
 
Diary review 
 
 
X 
X 
 
 
 
 
Pregnancy test 
(women of child-
bearing 
potential) 
 
X 
 
 
 
 
 
 
Birth control 
history (women 
of child-bearing 
potential) 
 
X 
 
 
 
 
 
 
Review 
participants’ use 
of  appropriate 
birth control (if 
applicable) 
 
X 
 
 
 
 
 
 
 
*Baseline labs must be drawn before vaccine dose. Day 7 must be drawn +/- 2 days. All other 
labs can be drawn +/- 7 days.   
 
 
 
 

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APPENDIX 2: ADVERSE EVENTS OF SPECIAL INTEREST (AESI) TERMS 
The Investigator’s medical judgement must be applied to assess an event as an AESI, as most 
AESIs are based on medical concepts. The table below does not provide a comprehensive list of 
terms.  
 
The following table describes events/medical concepts that are of interest in COVID-19 vaccine safety 
surveillance. Some are specific to vaccines; however, some are of interest due to their occurrence in the 
context of concurrent or recent COVID-19. Events falling into the descriptions below should be reported 
as AESIs, per protocol, even when they occur during/following COVID infection.  
 
Please note: COVID-19 itself is not an AESI. 
 
Medical Concept 
Medical Concept Descriptions/Guidance 
0. Not an AESI 
 
1. Anosmia, Ageusia 
 
• New onset of anosmia or ageusia associated with COVID-19 or idiopathic 
etiology  
• DOES NOT INCLUDE anosmia or ageusia associated with sinus/nasal 
congestion, congenital, or traumatic etiologies  
2. Subacute thyroiditis 
 
• Acute inflammatory disease of the thyroid (immune-mediated or 
idiopathic) 
• DOES NOT INCLUDE new onset of chronic thyroiditis 
3. Acute pancreatitis 
 
• New onset of pancreatitis in the absence of a clear, alternate etiology, 
such as alcohol, gallstones, trauma, recent invasive procedure, etc. 
4. Appendicitis  
• Any event of appendicitis  
5. Rhabdomyolysis 
 
• New onset of rhabdomyolysis in the absence of a clear, alternate etiology, 
such as drug/alcohol abuse, excessive exercise, trauma, etc. 
6. Acute respiratory 
distress syndrome 
(ARDS) 
• New onset of ARDS/respiratory failure due to acute inflammatory lung 
injury 
• DOES NOT INCLUDE non-specific symptoms of shortness of breath or 
dyspnea, nor events with underlying etiologies of heart failure or fluid 
overload 
7. Coagulation disorders 
• New onset of thrombosis, thromboembolic event, or non-traumatic 
hemorrhage/bleeding disorder (ex. stroke, DVT, pulmonary embolism, 
disseminated intravascular coagulation (DIC), etc.) 
8. Acute cardiovascular 
injury 
• New onset of clinically confirmed, acute cardiovascular injury, such as 
myocarditis, pericarditis, arrhythmia confirmed by ECG (ex. atrial 
fibrillation, atrial flutter, supraventricular tachycardia), stress 
cardiomyopathy, heart failure, acute coronary syndrome, myocardial 
infarction, etc. 
• DOES NOT INCLUDE transient sinus tachycardia/bradycardia, non-specific 
symptoms such as palpitations, racing heart, heart fluttering or pounding, 
irregular heartbeats, shortness of breath, chest pain/discomfort, etc. 

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Medical Concept 
Medical Concept Descriptions/Guidance 
9. Acute kidney injury 
• New onset of acute kidney injury or acute renal failure in the absence of a 
clear, alternate etiology, such as urinary tract infection/urosepsis, trauma, 
tumor, nephrotoxic medications/substances, etc.; 
• Increase in serum creatinine by ≥ 0.3 mg/dl (or ≥26.5 µmol/l) within 48 
hours; OR 
• Increase in serum creatinine to ≥ 1.5 times baseline, known or presumed 
to have occurred within prior 7 days 
10. Acute liver injury 
• New onset in the absence of a clear, alternate etiology, such as trauma, 
tumor, hepatotoxic medications/substances, etc.: 
• >3-fold elevation above the upper normal limit for ALT or AST; OR 
• >2-fold elevation above the upper normal limit for total serum bilirubin or 
GGT or ALP 
11. Dermatologic 
findings  
• Chilblain-like lesions 
• Single organ cutaneous vasculitis 
• Erythema multiforme 
• Bullous rash 
• Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Drug reaction with eosinophilia and systemic 
symptoms (DRESS), fixed drug eruptions, and necrotic or exfoliative 
reactions 
12 Systemic 
inflammatory syndromes  
• Multisystem inflammatory syndrome in adults (MIS-A) or children (MIS-C) 
• Kawasaki’s disease 
• Hemophagocytic lymphohistiocytosis (HLH) 
13. Thrombocytopenia 
• Platelet count < 150 x10^9/L (thrombocytopenia) 
• New clinical diagnosis, or worsening, of thrombocytopenic condition, such 
as immune thrombocytopenia, thrombocytopenic purpura, or HELLP 
syndrome 
14. Acute aseptic 
arthritis  
 
Clinical syndrome characterized by acute onset of signs and symptoms of 
joint inflammation without recent trauma for a period of no longer than 
6 weeks, synovial increased leukocyte count and the absence of 
microorganisms on Gram stain, routine culture and/or PCR. 
• DOES NOT INCLUDE new onset of chronic arthritic conditions 
15. New onset, or 
worsening, of 
neurological disease 
• Immune-mediated neurological disorders 
• Guillain-Barre Syndrome 
• Acute disseminated encephalomyelitis (ADEM) 
• Peripheral facial nerve palsy (Bell’s palsy)  
• Transverse myelitis 
• Encephalitis/Encephalomyelitis 
• Aseptic meningitis 
• Seizures/convulsions/epilepsy 
• Narcolepsy/hypersomnia 
16. Anaphylaxis  
• Anaphylaxis associated with study drug administration 

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Medical Concept 
Medical Concept Descriptions/Guidance 
17. Other syndromes 
 
• Fibromyalgia  
• Postural Orthostatic Tachycardia Syndrome  
• Chronic Fatigue Syndrome  
• Myalgic encephalomyelitis  
• Post viral fatigue syndrome 
• Myasthenia gravis 
 
 
 
 
 

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APPENDIX 3: TABLE OF LABORATORY ABNORMALITIES 
 
Test
Mild             
(Grade 1)
Moderate        
(Grade 2)
Severe           
(Grade 3)
Potentially Life 
Threatening      
(Grade 4)
Sodium (Hyponatremia) mEq/L
132 - 134
130 - 131
125 - 129
< 125
Sodium (Hypernatremia) mEq/L
144 - 145
146 - 147
148 - 150 
> 150
Potassium (Hyperkalemia) mEq/L
5.4 - 5.6
5.6 - 5.8
5.8 - 6.0
> 6.0
Potassium (Hypokalemia) mEq/L
3.2 - 3.5
3.0 - 3.1
2.8 - 2.9
< 2.8
Glucose (Hypoglycemia) mg/dL
65 - 69
55 - 64
45 - 54
< 45
Glucose (Hyperglycemia) mg/dL
        Fasting
110 - 110
111 - 125
> 125
Requires insulin
        Random
110 - 125
126 - 200
> 200
Requires insulin
Blood Urea Nitrogen (BUN) mg/dL
30 - 35
35 - 40
> 40
Requires dialysis
Creatinine (Cr) mg/dL
1.8 - 2.3
2.4 - 2.8
2.9 - 3.2
> 3.2 or Requires 
dialysis
Calcium (Hypocalcemia) mg/dL
8.0 - 8.4
7.5 - 7.9
7.0 - 7.4
< 7.0
Calcium (Hypercalcemia) mg/dL
10.5 - 11.0
11.1 - 11.5
11.6 - 12.0
> 12.0
Magnesium (Hypomagnesemia) mg/dL
1.3 - 1.5
1.0 - 1.2
0.7 - 0.9
< 0.7
Phosporus (Hypophosphatemia) mg/dL
2.3 - 2.5
2.0 - 2.2
1.6 - 1.9
< 1.6
CPK
1.25 - 1.5 ULN
1.6 - 3.0 x ULN
3.1 - 10 x ULN
> 10 x ULN
Albumin (Hypoalbuminemia) mg/dL
2.5 - 2.8
2.1 - 2.4
< 2.1
---
Protein (Hypoproteinnemia) mg/dL
5.0 - 5.5
4.4 - 4.9
< 4.4
---
Alkaline Phosphatate - Increase by Factor
1.1 - 2.0 x ULN
1.6 - 3.0  x ULN
3.1 - 10 x ULN
> 10 x ULN
Liver function Tests (ALT, AST) - Increase by 
Factor
1.1 - 2.5 x ULN
2.6 - 5.0 ULN
5.1 - 10 x ULN
> 10 x ULN
Bilirubin - when accompanied by any increase 
in LFTs - Increase by Factor
1.1 - 1.25 x ULN
1.26 - 1.5 x ULN
1.51 - 1.75 x ULN
>1.75 x ULN
Bilirubin - when LFTs are normal - Increase by 
Factor
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.0 - 3.0 x ULN
>3.0 x ULN
Pancreatic enzymes (Amylase, lipase)
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.0 - 5.0 x ULN
>5.0 x ULN
Hemoglobin (Female)
8.6 - 9.1
8.1 - 8.5
7.0 - 8.0
< 7.0
Hemoglobin (Female) change from baseline 
value gm/dL
1.2 - 1.5
1.6 - 2.0
2.1 - 5.0
> 5.0
Hemoglobin (Male)
9.1 - 9.5
8.6 - 9.0
7.5 - 8.5
< 7.5
Hemoglobin (Male) change from baseline 
value gm/dL
1.2 - 1.5
1.6 - 2.0
2.1 - 5.0
> 5.0
WBC (High) cell/mm3 
15,000  - 20,000
20,001 - 25,000
25,001 - 30,000
> 30,000
WBC (Low) cell/mm3
1,501 - 2,000
1,001 - 1,500
500 - 1,000
< 500
Lymphocyte (Low) cell/mm3
601 - 800
401 - 600
200 - 400
< 200
Neutrophil (Low)  cell/mm3
701 - 1,000
501 - 700
401 - 500
< 400
Eosinophils (High)  cell/mm3
650 - 1,500
1,501 - 5,000
> 5,000
Hypereosiniphilic
Platelets (Low)  cell/mm3
60,001 - 80,000
40,001 - 60,000
> 25,000 - 40,000
< 25,000
Prothrombin time (PT) - Increase by Factor
1.11 - 1.2
1.21 - 1.3
1.31 - 1.4 x ULN
>1.4 ULN
Partial thrombinplastin time (PTT) - Increase 
by Factor
1.31 - 1.4
1.41 - 1.5
1.51 - 1.6 x ULN
>1.6 ULN
Fibrinogen (High) mg/dL
400 - 500
501 - 600
> 600
---
Fibrinogen (Low) mg/dL
150 - 200
125 - 149
100 - 124
< 100 or associated with 
gross bleeding or 
disseminated intravascular 
coagulation
[1] ULN - Upper limit of normal. 
[2] Values highlighted in yellow are adjusted from "Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers
 Enrolled in Preventitive Vaccine Clinical Trials" to reflect immunosuppressed lung transplant population.

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APPENDIX 4: CLAIM FOR CATEGORICAL EXCLUSION 
 
Per 21 CFR 25.15(d) that, to our knowledge, no extraordinary circumstances exist that would warrant the 
preparation of an environmental assessment (EA). 
 
 
 

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