A Prospective Observational Study to Evaluate the Safety of COVID-19 Vaccination in Children and Adolescents
Conditions: Pain, Injection Site Reaction, Adverse Drug Event
Sponsor: Duke University

Pediatric COVID-19 Vaccination (Lead)  
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A Prospective Observational Study to Evaluate the Safety of COVID-19 Vaccination in 
Children and Adolescents  
 
 
Short Title: Safety of Pediatric COVID-19 Vaccination (Lead)  
 
 
 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site (Duke University) Principal Investigator: Michael Smith, MD 
Lead Sub-principal Investigator: Emmanuel B. Walter, MD, MPH  
 
Contributing Site (Cincinnati Children’s Hospital Medical Center) Principal Investigator: 
Elizabeth Schlaudecker, MD, MPH 
Lead Sub-principal Investigator: Mary Allen Staat, MD, MPH 
  
Contributing Site (Columbia University) Investigator: Melissa Stockwell, MD, MPH 
 
Contributing Site (Kaiser Permanente) Investigator: Nicola Klein, MD, PhD  
 
Centers for Disease Control and Prevention (CDC) Principal Investigator:  
Karen R. Broder, MD  
CDC Sub-principal Investigator: Gloria Anyalechi, MD  
 
 
 
 
NCT05157191 
 
Version Number: 4.0 
 
April 3, 2023 
 
 
 

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STATEMENT OF COMPLIANCE 
• 
This trial will be conducted in compliance with the protocol, the International 
Conference on Harmonization (ICH) Guideline E6-Good Clinical Practice (GCP), 
and the applicable guidelines and regulatory requirements from the United States 
(US) Code of Federal Regulations (CFR), 45 CFR Part 46. 
• 
All study personnel with subject contact have completed Human Subjects 
Protection Training. 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY .............................................................................................................................................. 5 
1 
BACKGROUND .................................................................................................................................................. 8 
2 
STUDY OBJECTIVES ........................................................................................................................................ 9 
Primary Outcome Measures (POM): .......................................................................................................................... 10 
Secondary Outcome Measure (SOM): ....................................................................................................................... 10 
Exploratory Outcome Measures (EOM): .................................................................................................................. 10 
3 
STUDY DESIGN ............................................................................................................................................... 11 
3.1 
MAIN STUDY DESIGN ....................................................................................................................................................... 11 
3.2 
LABORATORY STUDIES.................................................................................................................................................... 11 
3.2.1 Serologic studies ..................................................................................................................................................... 11 
3.2.2 SARS-CoV-2 Antibody Assay ............................................................................................................................... 11 
3.2.3 Future studies .......................................................................................................................................................... 12 
4 
STUDY ENROLLMENT AND WITHDRAWAL......................................................................................... 12 
4.1 
SUBJECT INCLUSION CRITERIA ...................................................................................................................................... 12 
4.2 
SUBJECT EXCLUSION CRITERIA ..................................................................................................................................... 12 
4.3 
RECRUITMENT ................................................................................................................................................................. 12 
4.4 
REASONS FOR AND HANDLING OF WITHDRAWALS ................................................................................................... 13 
4.5 
TERMINATION OF STUDY ............................................................................................................................................... 13 
5 
STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ........................................................................ 13 
5.1 Schedule of Events ..................................................................................................................................................... 13 
5.2 Parent/LAR Permission Process (Informed Consent) ................................................................................. 19 
5.3 
Demographic Information, Medical History, Immunization History ............................................... 19 
5.3.1 Randomization........................................................................................................................................................ 19 
5.4 Data Collection ........................................................................................................................................................... 19 
5.4.1 Vaccine Supply, Storage, and Administration ............................................................................................ 20 
5.4.2 Biospecimen Collection & Handling ................................................................................................................ 20 
5.5 Reactogenicity & Safety Assessment .................................................................................................................. 21 
6 
LABORATORY ANALYSES .......................................................................................................................... 26 
6.1 COVID-19 IMMUNOGENICITY .......................................................................................................................................... 26 
7 
STATISTICAL CONSIDERATIONS ............................................................................................................. 27 
7.1 Sample Size and Power Estimation .................................................................................................................... 27 
7.2 
Analysis Plan ........................................................................................................................................................... 27 
7.2.1 Analysis Populations ............................................................................................................................................. 27 
7.2.2 
Primary Objective ........................................................................................................................................... 27 
7.2.3 
Secondary Objective ....................................................................................................................................... 28 
7.2.4 
Exploratory Objective .................................................................................................................................... 29 
7.2.5 Safety Monitoring Plan ........................................................................................................................................ 29 
7.3 
Data Management Plan...................................................................................................................................... 29 
7.3.1 Research Electronic Data Capture (REDCap) ............................................................................................. 29 
7.3.2 Role of the CDC Investigators in the Project ................................................................................................ 30 
8 
HUMAN SUBJECTS ........................................................................................................................................ 30 
8.1 Human Participants Involvement, Characteristics, and Design ............................................................. 30 
8.2 Sources of Material ................................................................................................................................................... 31 
8.3 Potential Risks and Benefits .................................................................................................................................. 31 

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8.4 Adequacy of Protection ........................................................................................................................................... 31 
8.4.1 ClinicalTrials.gov Requirements ...................................................................................................................... 31 
9.0 HUMAN SUBJECTS ............................................................................................................................................ 31 
9.1.1 Vulnerable Subjects ............................................................................................................................................... 31 
9.1.2 Vulnerable Subjects Research ........................................................................................................................... 32 
REFERENCES ............................................................................................................................................................. 33 
 
 

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PROTOCOL SUMMARY 
 
Title:  
A Prospective Observational Study to Evaluate the Safety of COVID-19 
Vaccination in Children and Adolescents 
Phase: 
Phase 4 
Population: 
Up to 320 male or female children and adolescents ≥ 5 years to < 16 years 
Clinical Sites: 
Four: Duke University (Lead); Cincinnati Children’s Hospital 
(Contributing); Kaiser Permanente (Contributing); Columbia University 
(Contributing) 
Study Duration: 
24 months  
 
Participant 
Duration: 
Approximately 7 months 
Description of 
Study Procedures: 
This is a prospective, observational study to evaluate the safety of 
COVID-19 vaccination in children and adolescents receiving vaccine as 
part of standard of care.  Children and adolescents who have not 
received any previous COVID-19 vaccines will be enrolled with their first 
dose.  Children and adolescents who have completed their primary 
vaccine series will enroll with their age-appropriate booster dose based 
on current FDA indications and CDC recommendations.  
  
Injection-site (local) and systemic reaction data and unsolicited adverse 
events will be assessed on vaccination day and daily during the 7 days 
following each COVID-19 vaccination dose using either identical web-
based or paper memory aids, depending on study participant preference. 
 
At 3 sites, serum samples will be collected for optional assessment of 
antibody titers to COVID-19.  Each participant who opts in will have 
baseline (within 3 days of vaccination) serologies obtained. Serum 
samples will also be collected for immunogenicity assessments at 28 
(+7) days after dose 2 or a booster dose. 
 
All participants will be followed for 181 days after the last study dose 2 or 
a booster dose for serious adverse events (SAEs) and adverse events of 
special interest (AESI). 
Objectives: 
Primary Objective (PO): 
PO: To characterize the safety of authorized and recommended COVID-
19 vaccines among children and adolescent participants   

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Secondary Objective (SO): 
SO: To assess the safety of simultaneous administration of COVID-19  
vaccine with other routinely recommended vaccines among children and 
adolescent participants 
Exploratory Objectives (EO): 
EO 1: To assess adolescent and parent perceptions of the COVID-19 
vaccine recommendations and experience with receipt of the vaccine 
 
EO 2: To assess the safety of COVID-19 vaccine stratified by baseline 
COVID-19 serostatus (positive versus negative) in a subset of child and 
adolescent participants 
 
EO 3: To assess adverse events of special interest through 6 months 
after dose 2 of COVID-19 vaccine or a booster dose 
 
EO 4: To assess serious adverse events through 6 months after dose 2 
of COVID-19 vaccine or a booster dose 
 
EO 5: To assess immune responses to SARS-CoV-2 antigens after 
COVID-19 vaccine 
Outcome Measures: Primary Outcome Measures (POM):  
POM 1: Proportion of participants with defined local or systemic 
reactogenicity events (stratified according to severity and in total) on 
days 1-7 after each dose of COVID-19 vaccine  
 
POM 2: Proportion of participants with at least one severe (Grade 3) 
solicited local or systemic reactogenicity event on days 1-7 after each 
dose of COVID-19 vaccine  
 
POM 3: Proportion of participants with at least one moderate-to-severe 
(Grade 2-3) solicited local or systemic reactogenicity event on days 1-7 
after each dose of COVID-19 vaccine  
 
POM 4: Proportion of participants with an unsolicited adverse event on 
days 1-7 after each dose of COVID-19 vaccine 
 
POM 5: Proportion of participants with an adverse event of special 
interest through 29 days after dose 2 of COVID-19 vaccine or a booster 
dose 
 
POM 6:  Proportion of participants with at least one serious adverse 
event through 29 days after dose 2 of COVID-19 vaccine or a booster 
dose and a description of the events 
 
 
Secondary Outcome Measure (SOM): 

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SOM 1: Assessment of primary outcome measures 1-6 in those 
receiving other routinely recommended vaccines with each dose of 
COVID-19 vaccine versus those receiving COVID-19 vaccine alone 
 
Exploratory Outcome Measures (EOM): 
EOM 1: Proportion of participants and legal guardians/parents with 
negative or positive perceptions of the vaccination experience based on 
participants responses to individual questions on the perceptions 
questionnaire 
 
EOM 2: Assessment of primary outcome measures 1-6 in those with 
positive baseline COVID-19 serostatus versus those with a negative 
baseline serostatus  
 
EOM 3: Proportion of participants with an adverse event of special 
interest through 6 months after dose 2 of COVID-19 vaccine or a booster 
dose 
 
EOM 4: Proportion of participants with a serious adverse event through 6 
months after dose 2 of COVID-19 vaccine or a booster dose 
 
EOM 5a:  
The proportion of participants seropositive to SARS-CoV-2 variants 
tested prior to and following mRNA COVID-19 vaccine in a subset of 
children and adolescents. 
 
EOM 5b: The geometric mean ID50 and ID80 titers of neutralizing 
antibodies for each SARS-CoV-2 variant tested pre- and post-mRNA 
COVID-19 vaccine in a subset of children and adolescent participants. 
Estimated Time to 
Complete 
Enrollment: 
12 months 

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1 BACKGROUND  
 
As of September 2022, there have been more than 95 million cases of COVID-19 
leading to more than one million deaths in the United States (1).  Although COVID-19 
infection is generally milder in children than adults, it does cause significant pediatric 
morbidity and mortality.  The American Academy of Pediatrics reports that 15 million 
children have been infected during the pandemic (2), leading to nearly 9000 cases of 
multisystem inflammatory syndrome in children (MIS-C) and 1500 deaths. From this 
perspective, safe and effective pediatric COVID-19 vaccines are needed to curb the 
pandemic.  
  
In May 2021, the FDA issued an Emergency Use Authorization (EUA) for the Pfizer-
BioNTech (Pfizer) mRNA COVID-19 vaccine in children aged 12-15.  In the Phase III 
trial leading to the EUA, 2,260 adolescents 12-15 years old were randomized 1:1 to 
receive 2 doses of 30 ug of the BNT162b2 vaccine or placebo administered 3 weeks 
apart (3) . Pain at the injection site was the most common local reaction, occurring in 
86% of vaccine recipients after dose 1, and was somewhat less common after dose 2 
(79%). Fatigue (60%), headache (55%), and chills (28%) were the most common 
systemic events after dose 1. These were slightly more common after dose 2 (fatigue 
(66%), headache (65%), and chills (42%).    
 
On October 29, 2021 the FDA issued an EUA for the Pfizer-BioNTech vaccine in 
children aged 5-11 years old, administered as 2 doses of 10 ug 3 weeks apart. The main 
safety study randomized children 2:1 to BNT162b2 (N=1518) vaccine or placebo 
(N=750); children were followed for at least 2 months after dose 2. In general, children 
had less severe systemic reactions than adolescents and young adults following the 
age-appropriate dose.  The most common systemic reactogenicity events in children 
aged 5-11 years after were fatigue (33.6-39.4%) and headache (22.4-28%).  In children 
aged 5-11 years fever was infrequent after dose 1 (2.5%) and dose 2 (6.5%).  There 
were no serious adverse events in the pediatric study that were considered related to the 
BNT162b2 study vaccine. No cases of myocarditis or anaphylaxis occurred in the study 
(4).   
 
In June 2022 the FDA issued an EUA for the Moderna mRNA-1273 vaccine in children 
and adolescents.  In the published phase III adolescent clinical trial 2,732 adolescents 
12-17 were randomized 2:1 to receive 2 doses of 100 ug of the mRNA-1273 vaccine or 
placebo, 4 weeks apart (5).  . Pain was the most common local reaction, occurring in 
94% of vaccine recipients after dose 1 and 93% after dose 2. The most common 
systemic reactions after dose 1 included fatigue (48%), headache (45%), myalgia and 
chills. Fatigue (68%) and headache (70%) were more common after dose 2.  
 
Although these randomized controlled trials demonstrate the safety and immunogenicity 
of mRNA vaccines in children, there are several gaps in our current knowledge.   
 
First, the initial clinical trials in adolescents excluded children with known history of 
COVID-19 infection.  Baseline antibody testing was ascertained in both trials.  
Approximately 4% of participants in the Pfizer trial and 6% in the Moderna trial were 
seropositive at baseline, suggesting a prior history of asymptomatic infection. There 
were no significant differences in reactogenicity between children who were seropositive 
and those who were not.  However, children with previous symptomatic infection may 

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have more robust reactogenicity, as has been seen in adults (6).  The Pfizer 5-11 year-
old trial did enroll children with prior COVID infections and found no significant 
differences in reactogenicity between children who did and did not have a prior history of 
infection (4). 
 
Secondly, the published pediatric trials did not include a diverse population. COVID-19 
infections, hospitalizations, and deaths disproportionately impact Black and Hispanic or 
Latinx populations (7). However, only 5% of participants in the Pfizer adolescent trial and 
3% in the Moderna adolescent trial were Black.  Similarly, only 12% of participants in 
each trial were of Hispanic or Latinx ethnicity. The Pfizer 5-11 year-old trial was slightly 
more diverse; 6.5% of participants were Black or African American and 21% were of 
Hispanic ethnicity (4). 
 
Finally, there are sparse data regarding reactogenicity of COVID-19 vaccine when co-
administered with other recommended vaccines.  In all of the pediatric Phase III clinical 
trials to date, receipt of any vaccine within 7 days of enrollment was an exclusion 
criterion (8). The current CDC clinical considerations for COVID-19 vaccine do allow for 
receipt of COVID-19 vaccines on the same day as other vaccines.  The guidance states 
that if multiple vaccines are administered at a single visit, each should be administered 
at a different injection site. (9). However, published data regarding the safety and 
reactogenicity of this approach are lacking. 
 
In September 2022, the FDA amended the use of the Pfizer-BioNTech vaccine to 
authorize bivalent vaccine for individuals ≥ 12 year-old (10).   However, there are no 
clinical data regarding the safety and immunogenicity of the BA.4 and BA.5 variant 
vaccines currently available in the United States. 
 
Herein, we propose a prospective observational safety study of children receiving 
COVID-19 vaccine per standard of care, including booster doses.  We hope to fill 
existing knowledge gaps concerning the safety of COVID-19 vaccines in the pediatric 
population by including children who were excluded from the trials, such as adolescents 
with a prior history of COVID-19 and those receiving concomitant vaccines. We also plan 
to make every effort to recruit a racially and ethnically diverse pediatric population.  
 
 
2 STUDY OBJECTIVES 
Primary Objective (PO): 
To characterize the safety of authorized and recommended COVID-19 vaccines among 
children and adolescent participants    
 
Secondary Objective (SO): 
To assess the safety of simultaneous administration of COVID-19 vaccine with other 
routinely recommended vaccines among children and adolescent participants  
 
Exploratory Objectives (EO): 
EO 1: To assess adolescent and parent perceptions of the COVID-19 vaccine 
recommendations and experience with receipt of the vaccine 

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EO 2: To assess the safety of COVID-19 vaccine stratified by baseline COVID-19 
serostatus (positive versus negative) in a subset of child and adolescent participants 
 
EO 3: To assess adverse events of special interest through 6 months after dose 2 of 
COVID-19 vaccine or a booster dose 
 
EO 4: To assess serious adverse events through 6 months after dose 2 of COVID-19 
vaccine or a booster dose 
 
EO 5: To assess immune responses to SARS-CoV-2 antigens after COVID-19 vaccine 
Primary Outcome Measures (POM):  
POM 1: Proportion of participants with defined local or systemic reactogenicity events 
(stratified according to severity and in total) on days 1-7 after each dose of COVID-19 
vaccine  
POM 2: Proportion of participants with at least one severe (Grade 3) solicited local or 
systemic reactogenicity event on days 1-7 after each dose of COVID-19 vaccine  
POM 3: Proportion of participants with at least one moderate-to-severe (Grade 2-3) 
solicited local or systemic reactogenicity event on days 1-7 after each dose of COVID-19 
vaccine  
POM 4: Proportion of participants with an unsolicited adverse event on days 1-7 after 
each dose of COVID-19 vaccine 
POM 5: Proportion of participants with an adverse event of special interest through 29 
days after dose 2 of COVID-19 vaccine or a booster dose  
POM 6: Proportion of participants with at least one serious adverse event occurring 
through 29 days after dose 2 of COVID-19 vaccine or a booster dose and a description 
of the serious adverse events  
 
Secondary Outcome Measure (SOM): 
 
SOM: Assessment of primary outcome measures 1-6 in those receiving other routinely 
recommended vaccines simultaneously with each dose COVID-19 vaccine versus those 
receiving COVID-19 vaccine alone 
 
Exploratory Outcome Measures (EOM): 
EOM 1: Proportion of participants and legal guardians/parents with negative or positive 
perceptions of the vaccination experience based on participants responses to individual 
questions on the perceptions questionnaire 
 
EOM 2: Assessment of primary outcome measures 1-6 in those with positive baseline 
COVID-19 serostatus versus those with a negative baseline serostatus  
 
EOM 3: Proportion of participants with an adverse event of special interest through 6 
months after dose 2 of COVID-19 vaccine or a booster dose 
 
EOM 4: Proportion of participants with a serious adverse event through 6 months after 
dose 2 of COVID-19 vaccine or a booster dose 
 

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EOM 5a:  The proportion of participants seropositive to SARS-CoV-2 variants tested 
prior to and following mRNA COVID-19 vaccine in a subset of children and adolescents 
 
EOM 5b: The geometric mean ID50 and ID80 titers of neutralizing antibodies for each 
SARS-CoV-2 variant tested pre- and post-mRNA COVID-19 vaccine in a subset of child 
and adolescent participants. 
 
3 STUDY DESIGN 
3.1 Main study design 
 
This study is a prospective, observational study to evaluate the safety of COVID-19 
vaccine in 320 children and adolescents 5 - < 16 years-old receiving the vaccine per 
standard of care. Children and adolescents who have not received any previous COVID-
19 vaccines will be enrolled with their first dose.  Children and adolescents who have 
completed their primary vaccine series will enroll with their age-appropriate booster dose 
based on current FDA indications and CDC recommendations.  With Day 1 serving as 
the day of vaccination, participants will be followed through Day 7 (total 7 days) after 
each dose of COVID-19 vaccine for symptoms of reactogenicity as described in Section 
5.1. Participants will also be followed for 7 days after each vaccination for unsolicited 
adverse events, through day 181 for SAEs, and through day 181 for adverse events of 
special interest. 
 
Demographic and medical history data will be collected and COVID-19 serostatus 
determined at baseline, and parent perceptions of COVID-19 vaccine will be assessed 
on Day 7 after each dose of vaccine.  Participant perceptions will also be collected on 
Day 7 in adolescents aged ≥ 12 years.  
 
3.2 Laboratory studies 
 
3.2.1 Serologic studies 
We will evaluate pre-serologic responses at three sites using an opt-in strategy.  
Prevaccination blood samples will be analyzed qualitatively for COVID-19 (SARS-CoV-
2) antibody status (positive or negative) at Cincinnati Children’s Hospital Medical Center 
in a CLIA-certified lab. Venous blood (approximately 5 mL of blood) will be collected 
from each participant in close proximity to the first vaccination (up to 3 days before or 
after vaccination).  Venous blood will also be collected approximately 28 days after the 
second dose of vaccine received and stored for COVID-19 vaccine immunogenicity 
studies. 
 
   
3.2.2 SARS-CoV-2 Antibody Assay 
For children and adolescents at participating sites, optional blood draws will occur on 
Day 1 (before vaccination) and 28 (+7) days after dose 2 or a booster dose to be stored 
for serum COVID-19 neutralization assays.  COVID-19 neutralizing antibody titers will be 
assessed for each variant tested.  Participants will not receive individual COVID-19 
antibody titer results; these are not routinely used in clinical practice. 
 

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3.2.3 Future studies 
In addition to the specified analyses described thus far, there might be other tests or 
assays that have yet to be identified that might be important for interpreting our study 
findings or of relevance to pediatric health outcomes. Additional laboratory assays may 
test for antibodies against other bacteria or viruses, markers of inflammation, or used in 
research on the health of children and adolescents. Specimens banked for use in other 
studies will be linked to information (including identifying information) that participants 
provided to the study.  Participants in the opt-in serology analyses must agree to 
potential future use of samples in order to be in the study.  Because it is unknown if 
future testing will be of any utility, results of future testing will not be provided.  
 
4 STUDY ENROLLMENT AND WITHDRAWAL  
Subject Inclusion and Exclusion Criteria will be reviewed at Visit 1 to assess eligibility for 
study participation. 
4.1  Subject Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in this 
observational study.   
1. Children ≥ 5 years to < 16 years 
2. Receiving first dose or a booster dose of a U.S. authorized or approved and 
recommended COVID-19 vaccine per standard of care. 
3. Parent/legal authorized representative (LAR) willing to provide written informed 
consent per local IRB requirements 
4. Participant willing to provide assent per local IRB requirements 
5. Intention of being available for entire study period and complete all relevant study 
procedures, including follow-up phone calls 
6. English or Spanish literate.   
4.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in 
this study: 
1. Current or planned participation in any clinical trial with an investigational product 
during the study period.* 
*Per protocol, co-enrollment in observational or behavioral intervention studies 
are permitted at any time. An investigational product may be permitted for 
therapy of an illness condition that occurs during the study period (e.g. COVID-19 
illness) 
2. Any condition, which, in the opinion of the investigators, may pose a health risk to    
the subject or interfere with the evaluation of the study objectives.   
3. Anyone who is a relative of any research study personnel or is an employee 
supervised by study staff 
4.3 Recruitment 
The 320 participants in this study will be male or female children receiving COVID-19 
vaccine per standard of care. Approximately 60 participants will be enrolled at Duke, 100 
will be enrolled at Cincinnati, 70 will be enrolled at Columbia, and 90 will be enrolled at 
Kaiser Permanente.   
 
Participants will be recruited from pediatric clinics and COVID-19 vaccination clinics 
affiliated with these sites. Medical records will be reviewed to identify, contact, and offer 

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study enrollment to potentially eligible children and adolescents. IRB-approved 
informational flyers/advertisements will be used to recruit children and adolescents 
receiving vaccination through public COVID-19 vaccination sites or clinics (primary care, 
or other clinic administering vaccine). Potential participants will be screened for eligibility 
and consented for study participation (if eligible) in-person (during routine care) or 
virtually (telephone or telehealth visit). Medical history, including vaccine history and 
COVID-19 disease history, will be obtained via participant and parent self-report with 
verification by chart review whenever feasible (including medical records, immunization 
registry records, and pharmacy records). 
4.4 Reasons for and Handling of Withdrawals 
The following may be reasons for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI). 
• 
Parent(s)/LAR(s) withdrawal of permission for their child to participate. 
• 
Subject withdrawal of assent (based on site IRB requirements)  
• 
Lost to follow-up. 
• 
Termination of the study by the sponsor. 
 
A parent/LAR may withdraw permission for their child to participate at any time and for 
any reason, without penalty.   Data collected prior to withdraw in the study will be 
included in the study.  
4.5 Termination of Study  
This study may be terminated for safety concerns of the principal investigators from the 
Lead or Contributing sites, CDC, or participating Institutional Review Boards (IRBs).   
 
5 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
5.1 Schedule of Events 
Children and adolescents meeting the proposed eligibility criteria (Section 4.0) will be 
recruited. Written informed consent will be obtained from study participants or their 
parent/guardian and assent from participants per local IRB requirements prior to 
conducting any study procedures. Table 1 describes the schedule of study visits for 
children enrolling with their first COVID dose.  
 

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a. Memory aid (solicited local and systemic reactogenicity events) to be completed by LAR/participant on Days 1-7 after vaccination. 
b. LAR/Participants completing paper diary only will be called 3 [+3] days after each dose of vaccine as a reminder and to prompt to 
bring paper diary to next visit 
c. May be clinic visit if COVID vaccine is administered at research site 
d. May be phone visit if not obtaining immunogenicity labs 
e. Blood draws are optional and will be only performed at participating sites 
f. Blood draw may be performed 3 days before or after vaccine 
g. Adolescent perceptions of COVID-19 vaccine will be collected for adolescents (ages 12 - < 16 only) 
 
Visit 1, Day of Vaccine or up to 3 Days Prior - Screening, Enrollment, and 
Vaccination (Clinic Visit) 
• Obtain parental permission by written informed consent and a release of medical 
record information, based on site IRB requirements 
• Obtain assent from child, based on site IRB requirements 
• Review and confirm study eligibility 
• Obtain information on preferred method of contact for follow-up (telephone or 
email, or text reminder reminder) 
• Obtain demographic data & COVID-19 vaccine history  
• Obtain history of vaccines within 2 weeks of enrollment  
• Obtain medical history, including COVID-19 disease history   
• Obtain concomitant medication and vaccine use 
• For children at participating sites, obtain optional blood sample within 3 days 
before or after vaccination for serologic analysis  
• Dispense thermometer, ruler (in order to standardize measurements) and memory 
aid. Review instructions for use of thermometer, ruler, and memory aid completion.  
Preference will be to complete the memory aid electronically, with paper as a back-
Table 1: Schedule of events: Primary Series (Dose 1 and 2) 
 
Procedure 
 
Visit 1 
 
 
Visit 1a 
 
 
Visit 2 
 
 
Visit 2a 
 
 
Visit 3 
 
 
Visit 4 
 
Type of contact 
Clinic 
Phone/Text
/Email/Data 
Review a, b 
Phone/Data 
Review c 
Phone/Text/Em
ail/Data 
Review a, b 
 
Clinic/  
Phone d 
Phone/Data 
Review 
Time Relative to 1st COVID-19 Vaccine 
1 (-3) 
1-7 (+3) 
 
 
 
 
Time Relative to 2nd COVID-19 Vaccine    
 
 
1 (+3) 
1-7 (+3) 
29 
(+ 7) 
 
181 
(+/- 7) 
Informed consent & Medical Release of Information 
X 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
 
 
 
 
Data Collection (Demographic information and Medical History) 
X 
 
 
 
 
 
COVID-19 Vaccination History 
X 
 
 
 
 
 
COVID-19 Disease History 
X 
X 
X 
X 
X 
X 
Concomitant Medications and Vaccines 
X 
X 
X 
X 
X 
X 
Standard of Care COVID-19 Vaccine    
X 
 
X 
 
 
 
Memory aid training + supplies (training on temperature) 
X 
 
X 
 
 
 
Blood draw e 
X f 
 
 
 
X 
 
Staff to review Memory aid form (REDCap or paper) 
 
X 
X 
X 
 
 
Obtain solicited adverse events 
 
X 
X 
X 
 
 
Obtain unsolicited adverse events 
 
X 
X 
X 
 
 
Obtain serious adverse event information and AESIs 
 
X 
X 
X 
X 
X 
Obtain parental and adolescent perceptions of COVID vaccine 
recommendations and receipt g 
 
X 
 
X 
 
 
Confirm date of next vaccine 
X 
X 
 
 
 
 
Confirm next study visit 
X 
X 
X 
X 
X 
 

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up.   
• Confirm anticipated date of COVID vaccine, if not already occurred 
• Confirm date of next scheduled study visit  
 
Visit 1a, Days 1-7 after dose 1 (Phone Visit) 
• Subjects/parent/LAR will complete their memory aid via paper or electronic entry 
at approximately the same time each day for days 1-7, study staff will review 
subject-entered data within the database or by phone contact  
• For participants using REDCap web-based system: 
o Study staff will send daily reminders to fill out the symptom diary 
o Record clinical data related to COVID diagnoses 
o Study staff will review REDCap system to confirm data capture and 
assess for any AE, AESIs, or SAEs on day 3 and 7 after vaccine 
o If any missing values, reported hives, or Grade 3 events occurred, 
the study staff will use phone contact to gather more information  
o The first parental and adolescent (if applicable) survey will be 
administered on day 7 after vaccine 
o Study staff will verify date of next COVID-19 vaccine and remind 
subjects to complete memory aid with next dose  
• For participants using paper diary: 
o Study staff will call participants on day 3 after vaccine as a reminder to fill 
out the symptom diary  
o The first parent and adolescent (if applicable) survey will be administered 
on day 7 
o Study staff will call participants on day 7 (+ 3 days) 
 
Record symptom diary 
 
Record COVID-19 diagnoses 
 
Record first parental and adolescent (if applicable) survey 
 
Verify date of next COVID-19 vaccine and remind subjects to 
complete memory aid with next dose 
 
 
Visit 2, COVID-19 Vaccine Dose 2 (+ 3 Days) (Clinic or Phone Visit) 
• Confirm receipt of second dose of COVID vaccine  
• Record any AEs, AESIs, SAEs, and concomitant medications and vaccinations as 
described in Section 5.5. 
• Record clinical data related to COVID-19 diagnoses 
• Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder) 
• Review instructions for use of thermometer, ruler, and memory aid completion. 
 
Visit 2a, Days 1 - 7 Days after dose 2 (Phone Visit) 
• 
Subjects/parent/LAR will complete their memory aid via paper or electronic 
entry at approximately the same time each day for days 1-7, study staff will 
review subject-entered data within the database or by phone contact  
• 
For participants using REDCap web-based system: 
o Study staff will send daily reminders to fill out the symptom diary 
o Record clinical data related to COVID diagnoses 
o Study staff will review REDCap system to confirm data capture and 
assess for any AE, AESIs, or SAEs on day 3 and 7 after vaccine 

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o If any missing values, reported hives, or Grade 3 or greater events 
occurred, the study staff will use phone contact to gather more 
information  
o The second parental and adolescent (if applicable) survey will be 
administered on day 7 after vaccine 
• 
For participants using paper diary: 
o Study staff will call participants on day 3 after vaccine as a reminder to fill 
out the symptom diary 
o The second parental and adolescent (if applicable) survey will be 
administered on day 7 after vaccine 
o Study staff will call participants on day 7 (+ 3 days) after vaccine 
 
Record symptom diary 
 
Record COVID-19 diagnoses 
 
Record second parental and adolescent (if applicable) survey 
 
Visit 3, 28 Days (window days 29-35) after COVID-19 Dose 2 (Clinic Visit or Phone 
Visit) 
• Clinic visit for optional post-vaccination blood draw for immunogenicity studies 
• If no blood draw, may be a phone visit 
• Review concomitant medications and vaccinations.   
• Solicit for the occurrence of any adverse events of special interest or serious adverse 
events. 
 
Visit 4, 180 days (window Days 174 - 188) after Dose 2 (Phone Visit) 
• Record any SAEs or adverse events of special interest as described in Section 5.5 
• Obtain concomitant medication and vaccine use 
 
Table 2 describes the schedule of study visits for children enrolling with their COVID-19 
booster dose. 
 

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a. Memory aid (solicited local and systemic reactogenicity events) to be completed by LAR/participant on Days 1-7 after vaccination. 
b. LAR/Participants completing paper diary only will be called 3 [+3] days after each dose of vaccine as a reminder and to prompt to 
bring paper diary to next visit 
c. May be phone visit if not obtaining immunogenicity labs 
d. Blood draws are optional and will be only performed at participating sites 
e. Blood draw may be performed 3 days before or after vaccine 
f. Adolescent perceptions of COVID-19 vaccine will be collected for adolescents (ages 12 - < 16 only) 
 
 
Table 2: Schedule of events: Booster Dose  
Procedure 
 
Visit 1 
 
 
Visit 1a 
 
 
Visit 2 
 
 
Visit 3 
 
Type of contact 
Clinic 
Phone/Text
/Email/Data 
Review a, b 
 
Clinic/ 
Phone c 
Phone/Data 
Review 
Time Relative to COVID-19 Vaccine Booster 
1 (-3) 
1-7 (+3) 
29 (+7) 
181 (+/- 7) 
Informed consent & Medical Release of Information 
X 
 
 
 
Review Eligibility Criteria 
X 
 
 
 
Data Collection (Demographic information and Medical History) 
X 
 
 
 
COVID-19 Vaccination History 
X 
 
 
 
COVID-19 Disease History 
X 
X 
X 
X 
Concomitant Medications and Vaccines 
X 
X 
X 
X 
Standard of Care COVID-19 Vaccine Booster 
X 
 
 
 
Memory aid training + supplies (training on temperature) 
X 
 
 
 
Blood drawd 
Xe 
 
X 
 
Staff to review Memory aid form (REDCap or paper) 
 
X 
 
 
Obtain solicited adverse events 
 
X 
 
 
Obtain unsolicited adverse events 
 
X 
 
 
Obtain serious adverse event information and AESIs 
 
X 
X 
X 
Obtain parental and adolescent perceptions of COVID vaccine 
recommendations and receipt f 
 
X 
 
 
Confirm next study visit 
X 
X 
X 
 

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Visit 1, Day of Vaccine or up to 3 Days Prior - Screening, Enrollment, and Vaccination 
(Clinic Visit) 
• Obtain parental permission by written informed consent and a release of medical 
record information, based on site IRB requirements 
• Obtain assent from child, based on site IRB requirements 
• Review and confirm study eligibility 
• Obtain information on preferred method of contact for follow-up (telephone or 
email, or text reminder reminder) 
• Obtain demographic data & COVID-19 vaccine history  
• Obtain history of vaccines within 2 weeks of enrollment  
• Obtain medical history, including COVID-19 disease history   
• Obtain concomitant medication and vaccine use 
• For children at participating sites, obtain optional blood sample within 3 days 
before or after vaccination for serologic analysis  
• Dispense thermometer, ruler (in order to standardize measurements) and memory 
aid. Review instructions for use of thermometer, ruler, and memory aid completion.  
Preference will be to complete the memory aid electronically, with paper as a back-
up.   
• Confirm date of next scheduled study visit  
 
Visit 1a, Days 1-7 after dose 1 (Phone Visit) 
• Subjects/parent/LAR will complete their memory aid via paper or electronic entry 
at approximately the same time each day for days 1-7, study staff will review 
subject-entered data within the database or by phone contact  
• For participants using REDCap web-based system: 
o Study staff will send daily reminders to fill out the symptom diary 
o Record clinical data related to COVID diagnoses 
o Study staff will review REDCap system to confirm data capture and 
assess for any AE, AESIs, or SAEs on day 3 and 7 after vaccine 
o If any missing values, reported hives, or Grade 3 events occurred, 
the study staff will use phone contact to gather more information  
o The parental and adolescent (if applicable) survey will be 
administered on day 7 after vaccine 
o Study staff will verify date of next study visit  
• For participants using paper diary: 
o Study staff will call participants on day 3 after vaccine as a reminder to fill 
out the symptom diary  
o The parent and adolescent survey (if applicable) will be administered on 
day 7 
o Study staff will call participants on day 7 (+ 3 days) 
 
Record symptom diary 
 
Record COVID-19 diagnoses 
 
Record parental and adolescent survey (if applicable) 
 
Visit 2, 28 Days (window days 29-35) after COVID-19 Booster (Clinic Visit or Phone 
Visit) 
• Clinic visit for optional post-vaccination blood draw for immunogenicity studies 
• If no blood draw, may be a phone visit 
• Review concomitant medications and vaccinations.   

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• Solicit for the occurrence of any adverse events of special interest or serious adverse 
events. 
 
Visit 3, 180 days (window Days 174 - 188) after COVID-19 Booster (Phone Visit) 
• Record any SAEs or adverse events of special interest as described in Section 5.5 
• Obtain concomitant medication and vaccine use 
 
 
5.2 Parent/LAR Permission Process (Informed Consent) 
The consent process will take place in research or clinic exam rooms behind closed 
doors to assure privacy of the prospective participant.  Study staff will be available to 
answer all parent/LAR and participant questions before and after permission is obtained.  
Parent(s)/LAR(s) will be given as much time as needed to decide whether or not to allow 
their child to participate.  We anticipate that the initial consent discussion, including 
presenting the information in the consent document and answering questions will take 
about 30 minutes.  Parent(s)/LAR(s) will have the opportunity to take the consent form 
home and discuss the document with other family members or friends.  During the 
consent process, it will be stressed that participation is voluntary and that parents/LARs 
can withdraw permission for their child to participate at any time.  Permission will not be 
obtained from parent(s)/LAR(s) who do not read, who are blind, or who do not 
read/understand English or Spanish. Parent(s)/LAR(s) will be given a copy of the signed 
informed consent to take home with them.  The original copy of the consent will be kept 
in the study records and a third copy will be included in the child’s medical record per 
local requirements. Eligibility will be assessed. Depending on site IRB requirements, 
assent may also be obtained from the child. 
 
5.3 Demographic Information, Medical History, Immunization History 
The participant’s age, race/ethnicity, and medical history will be obtained by 
parent/guardian report at the time of enrollment. The participant’s medical history, 
concomitant medications and vaccines taken within 2 weeks of enrollment will be 
obtained by review of the electronic health record (EHR) and will be reviewed and 
confirmed by the parent/guardian at the time of enrollment.   
 
Vaccines received during the study period will be documented by the clinic or research 
staff who administered the vaccines.  Documentation will include: product brand, lot 
number, site and date/time of vaccine administered during study participation.  
 
Throughout the study, the medical record will be reviewed to assess and record the 
occurrence of any serious adverse events or adverse events of special interest that 
occurred during the period of study enrollment. 
 
5.3.1 Randomization 
This is an observational study with no randomization.    
 
5.4 Data Collection  
Study staff will collect baseline participant data at study enrollment and reactogenicity 
data during follow-up phone calls visits. Table 3 describes the proposed variable 
domains and measures with further details below. 
 

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Table 3. Proposed Data Collection 
 
Domain 
Candidate Variables 
Clinic Study Visits 
Socio-demographic 
characteristics of participant 
Age (years), gender, race/ethnicity  
Medical history of participant 
Significant Medical Conditions  
Concomitant medications 
Over-the-counter and prescribed medications taken within 2 weeks of 
enrollment 
Vaccine history  
Collect vaccine history within 14 days prior to enrollment  
Vaccine administration 
 
Brand, lot number, site of vaccination, date/time of vaccination within 14 
days prior to enrollment and during study enrollment.   
Phone call and Clinic Visit Follow-up 
Solicited AEs 
Local (Refer to Table 4) Systemic (Refer to Table 5) 
COVID-19 Disease History 
COVID-19 diagnoses 
Adverse Events of Special 
Interest 
Myocarditis, pericarditis, multisystem inflammatory syndrome in 
children (MIS-C), allergic type reactions (as described in Section 5.5) 
 
Unsolicited AEs, SAEs and 
Clinically Significant Events 
Responses to open-ended inquiry on health status changes since 
enrollment 
Concomitant medications 
Over-the-counter and prescribed medications initiated since vaccination 
Concomitant vaccinations 
Vaccines administered within14 days of enrollment and since COVID-
19 vaccination 
Adolescent perceptions (ages 12 
to < 16 years old)  
Adolescent perspectives about COVID vaccination 
Parental perceptions 
Parental perspectives about COVID vaccination 
 
 
Vaccine Exposure Assessment  
Information on prior history of COVID-19 vaccination will be obtained at the time of study 
enrollment, based on self-report, to ensure that participants are COVID-19 vaccine 
naive.  
5.4.1 Vaccine Supply, Storage, and Administration  
Vaccination is not a study procedure. 
 
5.4.2 Biospecimen Collection & Handling  
At 3 participating sites (excluding Columbia), blood specimens will be collected from 
children in the optional serologic analyses during study Visits 1 and 3 as detailed in 
Table 1 for primary series as well as Visit 1 and Visit 2 for booster dose as detailed in 
Table 2. All blood samples will be collected into serum separator tubes, transported per 
site operational procedures and processed as follows: 
• Gently mix the tube by inverting 5 times.  Allow blood to clot at room temperature for 
at least 30 minutes. 
• Centrifuge tube within 8 hours of collection at 1100 to 1300 RCF(g) for 10 minutes. 
• Gently remove the vacutainer stopper avoiding serum contamination with red blood 
cells. Using a single-use pipette, transfer 0.5 mL aliquots of serum (top layer) into 
1.0mL or 1.8 mL cryovials.  

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• Attach the study-specific barcode labels to the cryovial aliquots.  Numbers should be 
placed lengthwise on the tube.  
• Freeze the cryovials at -20°C in the temperature-monitored research center freezer 
for future shipment.   
 
Serum aliquots will be stored at each of the participating site’s accessioning units until 
immunogenicity assessments are performed. 
 
5.5 Reactogenicity & Safety Assessment  
 
Frequency and occurrence of local and systemic reactogenicity events will be assessed 
through post-vaccination Day 7 using a standard memory aid. At the time of study 
enrollment, participants will be given a thermometer and instructed on using the memory 
aid to document oral temperatures and post-injection symptoms. Beginning on the 
evening following the first COVID-19 vaccination, LARs/participants will record the 
participants oral temperature using the study-supplied thermometer, the occurrence of 
solicited and unsolicited AEs, and concomitant medication use for the next 7 days (Day 
1 – 7). Similarly, following the second COVID-19 vaccination, LARs/participants will 
record the participant’s oral temperature using the study-supplied thermometer, the 
occurrence of solicited and unsolicited AEs, and concomitant medication use for the next 
7 days. Temperature will be recorded at roughly the same time each day. If a 
temperature > 100°F (37.8°C) is recorded, a second measurement will be taken. If more 
than one temperature is taken on the same day, the highest temperature should be 
recorded. Fever will be defined as a measured temperature ≥100.4°F (38°C). 
Participants will be queried during Visits 1a and 2a on solicited injection site adverse 
events, which will be classified as mild, moderate, or severe as described in Table 4. 
Participants will also be queried during Visits 1a and 2a on common post-injection 
systemic symptoms as described in Table 5.  
Unsolicited adverse events (AEs) will be collected and reported for the 7 days following 
each vaccine.  Any reports of new rash within 7 days after each dose will prompt a call 
from the study team to ascertain severity and the likelihood of an allergic reaction.  
Concomitant medication use, and concomitant vaccinations will be assessed through 29 
days after dose 2 or a booster dose. Serious adverse events (SAEs), adverse events of 
special interest (AESIs) and unscheduled medical care for COVID-19 illness will be 
assessed at 29 days after dose 2 of COVID-19 vaccine or a booster dose and through 
the end of the study (181 days after dose 2). 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. Participants (or their 
parents) will be encouraged to report any significant unsolicited adverse events in an 
open-ended question format, e.g. “How are you (or your child) doing? Are you (or your 
child) having any medical or clinical problems? If so, please tell me about them.”  
An adverse event of special interest (AESI) includes the following:  
• Allergic type reactions (including anaphylaxis, hives, or facial and limb swelling 
occurring within 7 days of a vaccination visit)  
• Myocarditis or pericarditis occurring during the study period 
• Multisystem inflammatory syndrome in children (MIS-C) during the study period 
 

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A serious adverse event (SAE) is defined as an AE that meets one of the following 
conditions: 
• Results in death during the period of protocol-defined surveillance  
• Is life-threatening (defined as immediate risk of death at the time of the event) 
• Requires inpatient hospitalization or prolonged hospitalization during the period of 
protocol-defined surveillance (other than routine hospital admission for an elective 
medical procedure or surgery)  
• Results in congenital anomaly or birth defect 
• Results in a persistent or significant disability/incapacity 
• Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Unsolicited adverse events, AESIs and SAEs will be graded as described in Table 6. 
Participants who report severe solicited adverse events or express any concern about 
symptoms/unsolicited events will be encouraged to follow up with their primary care 
provider. Study staff will assist with coordination of referral appointments as necessary. 
Parent/LAR will be asked to agree to the release of information to obtain and review 
medical records for any unscheduled medical appointments, including clinic visits and 
telehealth visits, through 29 days after the second dose.  Frequency and occurrence of 
serious AEs (SAEs), AESIs and unscheduled medical care for COVID-19 illness will be 
assessed through 181 days after dose 2 or a booster dose.  
 
 
Table 5: Systemic Reactogenicity  
Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever (°C)  
≥ 38.0 – 38.4 
≥ 100.4 - < 101.1° F 
>38.4 – 38.9 
≥ 101.1 - < 102° F 
> 38.9° C 
≥ 102° F 
Table 4: Injection-site Reactogenicity  
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain  
Does not interfere with 
activity  
Interferes with activity   
Prevents daily activity   
Tenderness  
Does not interfere with 
activity  
Interferes with activity  
Prevents daily activity  
Underarm or groin 
swelling on same side 
as vaccine  
Does not interfere with 
activity 
Interferes with activity  
Prevents daily activity 
Swelling 
 
5-11 years:  5-20 mm 
5-11 years: 21-70 mm 
5-11 years: >70 mm 
12 years >: 20-50 mm 
 
12 years >: 51 - 100 mm 
 
12 years: >100 mm 
 
Redness  
 
5-11 years:  5-20 mm 
5-11 years: 21-70 mm 
5-11 years: >70 mm 
12 years >: 20-50 mm 
 
12 years >: 51 - 100 mm 
 
12 years: >100 mm 
 
 

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Table 5: Systemic Reactogenicity  
Feverishness 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Chills 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Headache 
Does not interfere with 
activity  
Some interference with 
activity   
Prevents daily routine 
activity   
Fatigue 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Muscle Pain 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Joint Pain 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Vomiting 
Does not interfere with 
activity  
Some interference with 
activity  
Prevents daily routine 
activity  
Diarrhea 
Does not interfere with 
activity  
 
Some interference with 
activity  
Prevents daily routine 
activity  
Nausea  
Does not interfere with 
activity  
Some interference with 
activity   
Prevents daily routine  
activity  
Facial or lip 
swelling 
Does not interfere with 
activity 
Some interference with 
activity 
Prevents daily routine 
activity 
 
 
Table 6: Grading for Unsolicited Adverse Events, AESIs and SAEs 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Does not interfere with activity 
Some interference with activity 
Prevents daily routine activity 
 
 
In this study, COVID-19 vaccination is not a study procedure. COVID-19 vaccine 
administration will be given per standard of care to children and adolescents receiving 
vaccine under an EUA by the Food and Drug Administration. Published studies in 
children and adolescents found no vaccine-related serious adverse events in children or 
adolescents receiving BNT162b2 (3-5).  Lymphadenopathy was identified as an adverse 
event occurring more frequently in BNT162b2 vs. placebo groups during clinical trials 
(11). Post-authorization vaccine safety data have identified two safety concerns that 
rarely can occur after vaccination: severe allergic reactions, including anaphylaxis, and 
myocarditis and pericarditis (11). Therefore, we do not anticipate any significant issue 
with serious adverse events (SAEs).  Nevertheless, we will monitor study participants for 
SAEs during the protocol-defined surveillance period of 6 months after second dose or a 
booster dose. SAEs will be reported to the CDC and all participating IRBs according to 
institutional requirements. 
 
 

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Perceptions of COVID-19 vaccine 
At Day 7 (+3) following each of the vaccination visits we will assess adolescent (ages 12 
to < 16) and parent/LAR perceptions of the COVID-19 vaccine recommendations and 
experience with receipt of the vaccine. Questions are provided in Tables 7 and 8 below. 
We will use a Likert scale (strongly agree, agree, neither, disagree, strongly disagree) to 
assess response to the questions about concerns regarding COVID-19 vaccine safety.  
As noted, adolescent and parent perceptions regarding vaccine receipt will be assessed 
at the reactogenicity assessment visits after each vaccine. 
 
Table 7 Parental /LAR Perceptions of COVID-19 Vaccine Recommendations and Receipt 
Vaccine Recommendation: What is your primary source of information about the COVID-19 vaccine 
(Choose one or more options): 
o 
Television 
o 
Internet 
o 
Radio 
o 
Social media 
o 
Family and friends 
o 
Your child’s doctor or nurse 
o 
Another healthcare provider 
o 
Your child’s school 
o 
Another source (please explain): 
Vaccine Recommendation: COVID-19 vaccines have been adequately tested in adolescents and 
children 
Vaccine Recommendation: COVID-19 vaccine should be required for school entry 
Vaccine Receipt: Reactions at the vaccine site (pain, redness) were similar to other vaccines my 
child has received 
Vaccine Receipt: Other reactions (fever, tiredness, muscle aches) were similar to other vaccines my 
child has received 
Vaccine Receipt: I prefer that my child receives the COVID-19 vaccine on the same day as other 
vaccines 
 
 

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Causality (relatedness) Assessment   
Study site investigators will assess relatedness to COVID-19 vaccine or study 
procedures (related, possibly related, unlikely related, or not related) for SAEs and 
AESIs. Solicited symptoms in Tables 4 and 5 will all be considered to be related to 
COVID-19 vaccine and causality assessment will not be done for these events. The 
study investigators will use their clinical judgement to make causality assessments and 
may consult the Safety Review Panel or CISA Project for assistance with causality 
determinations. The final causality assessment decision is the responsibility of the site 
PI where the subject was enrolled.  
  
Reporting Adverse Events  
SAEs and unanticipated problems will be reported to the CDC and all participating IRBs 
according to institutional requirements. Vaccination is not a study procedure. 
 
Adverse events that occur in a recipient following COVID-19 vaccination should be 
reported to CDC’s Vaccine Adverse Event Reporting System (VAERS). Vaccination 
providers are required by the Food and Drug Administration to report the following that 
occur after COVID-19 vaccination under Emergency Use Authorization:  
• 
Vaccine administration errors  
• 
Serious adverse events  
• 
Cases of Multisystem Inflammatory Syndrome  
• 
Cases of COVID-19 that result in hospitalization or death  
Reporting is encouraged for any other clinically significant adverse event even if it is 
uncertain whether the vaccine caused the event. Information on how to submit a report 
to VAERS is available at https://vaers.hhs.gov  or by calling 1-800-822-7967.  
Table 8: Adolescent Perceptions (Ages 12 to < 16 years) of COVID-19 Vaccine 
Recommendations and Receipt 
Vaccine Recommendation: What is your primary source of information about the COVID vaccine 
(Choose one or more option): 
o 
Television 
o 
Internet 
o 
Radio 
o 
Social media 
o 
Family and friends 
o 
Your doctor or nurse 
o 
Another healthcare provider 
o 
Your school 
o 
Another source (please explain): 
Vaccine Recommendation: COVID-19 vaccines have been tested enough in adolescents 
Vaccine Recommendation: COVID-19 vaccine should be needed to go to school  
Vaccine Receipt: My reaction where I got the vaccine in the arm (pain, redness) were about the 
same to other vaccines I have received 
Vaccine Receipt: Other reactions (fever, tiredness, muscle aches) were about the same to other 
vaccines I have received 
Vaccine Receipt: I prefer to receive COVID-19 vaccine on the same day as other vaccines 

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6  LABORATORY ANALYSES  
Serum samples will be analyzed by the use of a qualitative enzyme-linked 
immunosorbent assay (ELISA) which measures IgG antibody to the SARS-CoV-2 Spike 
protein. Recombinant full length Spike protein is used to coat ELISA plates and serum 
samples that have an Optical Density (OD) value above the established cut off are 
considered positive for antibody. The assay was qualified for use in the Laboratory for 
Specialized Clinical Services at Cincinnati Children’s Hospital Medical Center (CCHMC), 
a laboratory that is certified by the Clinical Laboratory Improvement Amendments (CLIA) 
and College of American Pathologist (CAP) under US FDA Emergency Use 
Authorization. 
 
Qualitative serologic testing will be completed in periodic batches throughout the course 
of the study and will therefore not be available in real-time or for use in clinical decision-
making. CCHMC will share participant results with submitting study sites as permitted by 
CDC. Study sites may share results with participants as permitted by FDA, CDC, and 
local site regulations. 
 
6.1 COVID-19 Immunogenicity 
 
The Duke NAb Laboratory for HIV and SARS-CoV-2 Vaccine Research and 
Development (Duke NAb Lab, PI: David Montefiori) will assess the magnitude, kinetics 
and duration of neutralizing antibody responses against SARS-CoV-2 by using a 
validated assay in an environment that operates in compliance with Good Clinical 
Laboratory Practices (GCLP).  
 
Neutralization of SARS-CoV-2 Spike-pseudotyped viruses will be assessed in 
293T/ACE2 cells as described in SOP “CFAR02-A0026 Measuring Neutralizing 
Antibodies Against SARS-CoV-2 Using Pseudotyped Virus and 293T/ACE2 Cells.” This 
assay has been formally validated and is part of Drug Master File # 26862 with the US 
Federal Drug Administration. Assay validation was performed with human serum 
samples and monoclonal antibodies using the D614G form of the Wuhan-1 Spike, which 
is the dominant form of Spike protein in the global epidemic. This assay has also been 
validated using B.1.351(246R) and B.1.1.529 (BA1) and may be validated for other 
newly emerged variants as needed.  
 
Neutralization is measured by using lentiviral particles pseudotyped with SARS-CoV-2 
Spike and containing a firefly luciferase (Luc) reporter gene for quantitative 
measurements of infection by relative luminescence units (RLU). SARS-CoV-2 Spike-
pseudotyped viruses are prepared and titrated for infectivity by using mutated forms of 
an expression plasmid encoding codon-optimized full-length Spike of the Wuhan-1 strain 
(VRC7480) provided by Drs. Barney Graham and Kizzmekia Corbett at the Vaccine 
Research Center, National Institutes of Health (USA). Mutations were introduced into 
VRC7480 by site-directed mutagenesis using the QuikChange Lightning Site-Directed 
Mutagenesis Kit from Agilent Technologies. All mutations were confirmed by full-length 
Spike gene sequencing. Pseudovirions are produced in HEK 293T/17 cells by 
transfection using Fugene 6 Transfection Reagent and a combination of Spike plasmid, 
lentiviral backbone plasmid (pCMV ΔR8.2) and firefly Luc reporter gene plasmid (pHR' 
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for infectious dose (TCID50) by making serial 3-fold or 5-fold dilutions in quadruplicate 
for a total of 11 dilutions in 96-well flat-bottom plates. 
 
A pre-titrated dose of virus is incubated with 8 serial 5-fold dilutions of serum samples in 
duplicate in a total volume of 150 µl for 1 hr at 37°C in 96-well flat-bottom culture plates. 
Cells are detached using TrypLE Select Enzyme solution, suspended in growth medium 
(100,000 cells/ml) and immediately added to all wells (10,000 cells in 100 µL of growth 
medium per well). One set of 8 wells receives cells + virus (virus control) and another set 
of 8 wells receives cells only (background control). After 71-73 hrs of incubation, medium 
is removed by gentle aspiration and 30 µl of Promega 1X lysis buffer is added to all 
wells. After a 10 minute incubation at room temperature, 100 µl of Bright-Glo luciferase 
reagent is added to all wells. After 1-2 minutes, 110 µl of the cell lysate is transferred to 
a black/white plate. Luminescence is measured using a GloMax Navigator luminometer 
(Promega). Neutralization titers are the serum dilution at which RLUs are reduced by 
either 50% (ID50) or 80% (ID80) compared to virus control wells after subtraction of 
background RLUs. Serum samples are heat-inactivated for 30 minutes at 56°C prior to 
assay. 
 
For assay internal quality controls (IQC), a qualified positive control is tested on each 
assay plate (plate control). Assay run controls may consist of COVID-19 convalescent 
serum samples or SARS-CoV-2 vaccine recipients with high, medium and low ID50 and 
ID80 titers against the test virus, plus a normal human serum negative control. Levey-
Jennings plots will be generated during testing and checked for violations of standards 
that are based on the Westgard Rules. Violations of the Westgard Rules are investigated 
in real-time.  
7 STATISTICAL CONSIDERATIONS  
In collaboration with the Cincinnati, Columbia, and Kaiser teams, the research team at 
Duke will oversee the statistical analysis. Data will reside on a secure Duke server 
maintained by Duke Health Technology Solutions (DHTS). For the study, a database will 
be developed and a data set for the study without personal identifiers will be made 
available to the CDC upon request.  Duke statisticians will develop a comprehensive 
Statistical Analysis Plan.  The summary points of the analysis plan are presented below. 
 
7.1 Sample Size and Power Estimation  
Because this is an observational study with no randomization of subjects into treatment 
groups, there will be no formal statistical power or sample size calculation 
 
7.2 Analysis Plan  
 
7.2.1 Analysis Populations 
There will be one study population named the Study Cohort. The Study Cohort includes 
any participant that was enrolled and received at least one dose of a COVID-19 vaccine. 
 
7.2.2 Primary Objective     
Primary Objective – To characterize the safety of authorized and recommended COVID-
19 vaccines among children and adolescent participants    
 

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1) Tables will be produced that summarize each solicited local and systemic 
reactogenicity event by maximum classification (none, mild, moderate, and severe), as 
well as by moderate or severe through days 1-7 following COVID-19 vaccination for 
dose 1 and dose 2 or a booster dose. These tables will have the number and percentage 
for each classification and will be broken down by each site and across all sites. In 
addition, the number and percentage of participants with at least one moderate-to-
severe local or systemic reactogenicity event will be described, as well as the proportion 
of participants with at least one severe local or systemic reactogenicity event.  (POM 1, 
POM 2 and POM 3)  
 
2) Tables will be produced that summarize each unsolicited adverse event by maximum 
classification (none, mild, moderate, and severe), as well as by moderate or severe 
through days 1-7 following COVID-19 vaccination for dose 1 and dose 2 or a booster 
dose. These tables will have the number and percentage for each classification and will 
be broken down by each site and across all sites (POM4). 
 
3) Tables will be produced that summarize participants experiencing at least one serious 
adverse event or one AESI through the 29 days after dose 2 or a booster dose. This 
table will have the number and percentage for each outcome. Listings with the clinical 
narratives will also be provided. (POM5 and POM6)  
 
7.2.3 Secondary Objective  
  
Secondary Objective - To assess the safety of simultaneous administration of COVID-19 
vaccine with other routinely recommended vaccines among children and adolescent 
participants.  
 
1) Tables will be produced that summarize each solicited local and systemic 
reactogenicity event by maximum classification (none, mild, moderate, and severe), as 
well as by moderate or severe through days 1-7 following COVID-19 vaccination for 
dose 1 and dose 2 or a booster dose. These tables will have the number and percentage 
for each classification and will be broken down by concomitant childhood vaccine status 
(yes/no) by each site and across all sites. (SOM 1, SOM 2 and SOM 3) 
 
2) Tables will be produced that summarize each unsolicited adverse event by maximum 
classification (none, mild, moderate, and severe), as well as by moderate or severe 
through days 1-7 following COVID-19 vaccination for dose 1 and dose 2 or a booster 
dose. These tables will have the number and percentage for each classification and will 
be broken down by concomitant childhood vaccine status (yes/no) by each site and 
across all sites. (SOM 4) 
 
3) Tables will be produced that summarize participants experiencing at least one serious 
adverse event or one AESI through the 29 days after dose 2 or a booster dose. This 
table will have the number and percentage for each outcome and will be broken down by 
concomitant childhood vaccine status (yes/no). (SOM5 and SOM6) 
 
The proportions by concomitant vaccine status (yes/no) for secondary outcomes 1 to 6 
will be descriptively assessed using an exact Mantel-Haenszal statistic calculated using 
the Proc Logistic command in SAS at the two-sided alpha 0.05 level.  Further details will 

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be described in the statistical analysis plan.  The analysis for exploratory objectives will 
be described in the statistical analysis plan. 
 
7.2.4 Exploratory Objective 
 
Exploratory Objective- To assess immune responses to SARS-CoV-2 antigens after 
COVID-19 vaccine. 
 
The analysis for exploratory objectives will be detailed in the comprehensive Statistical 
Analysis Plan.  .    
 
7.2.5 Safety Monitoring Plan 
An interim safety data review of all SAEs will be performed with the goal of identifying 
unexpected safety concerns of clinical importance. The interim safety data review will be 
performed by a panel with relevant expertise who are not investigators on the study. The 
safety review panel will assess the clinical narratives of SAEs and AESIs for all 
participants who were vaccinated. Additional data reviews will be generated if the CDC 
and study investigators determine they are needed. There are no statistical analyses 
planned for this safety data review. 
 
7.3 Data Management Plan  
The novel Vanderbilt-designed resource developed specifically for online collection of 
research information, the Research Electronic Data Capture (REDCap) platform 
(https://projectredcap.org/), will be used to design study forms, including the reaction 
forms, and short customized questionnaires to collect information from study subjects. 
REDCap provides: 1) a streamlined process for rapidly building a database; 2) an 
intuitive interface for collecting data, with data validation and audit trail; 3) automated 
export procedures for seamless data downloads to common statistical packages; 4) 
branching logic, file uploading, and calculated fields; and 5) a quick and easy protocol 
set-up. This system will be used by Duke for data management.  All electronic linkages 
will fulfill regulations for protection of human subjects and requirements to minimize the 
risk of breach of confidentiality.  
 
All study-related documents containing protected health information, (e.g., enrollment 
logs, case report forms, memory aids, and perception surveys) completed by study 
participants, will be maintained in secure research offices at Duke, Cincinnati, Columbia 
and Kaiser, which are accessible to research staff only.  
 
The study team will utilize a secure, encrypted, file transfer method for sharing study 
documents and data with the CDC.  No personal identifiers will be included in any 
shared documents or datasets.   
 
7.3.1 Research Electronic Data Capture (REDCap)  
REDCap (http://project-redcap.org/) assists with the collection and management of data 
for diverse clinical and translational research studies. REDCap was designed around the 
concept of giving research teams an easy method to specify project needs and rapidly 
develop secure, web-based applications for collection, management and sharing of 
research data. REDCap accomplishes these key functions through use of a single study 

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metadata table referenced by presentation-level operational modules. Based on this 
abstracted programming model, databases are developed in an efficient manner with 
little resource investment beyond the creation of a single data dictionary. The concept of 
metadata-driven application development is well established, and the critical factor for 
successful data collection lies in creating a simple workflow methodology allowing 
research teams to autonomously develop study-related metadata in an efficient manner. 
Both products include secure institutional data hosting and include full audit-trails in 
compliance with Health Insurance Portability and Accountability Act (HIPAA) security 
requirements. The REDCap Consortium is comprised of 647 active institutions. The 
REDCap currently supports 68,000 projects with over 89,000 users spanning numerous 
research focus areas across the consortium.  The current project will use this software 
application for the design of electronic forms to collect information from study 
participants, to link the baseline data, sample collection date, and laboratory results in an 
automated database family, to perform data cleaning and data quality assurance 
efficiently, and to design an analytical dataset for the analysis of the project data.  
 
Data will be entered into the REDCap database by members of the study team from 
Duke, Cincinnati, Columbia, and Kaiser, using the paper case report forms utilized to 
record data collected as part of study procedures. Study investigators will be responsible 
for assuring that all paper records are securely stored according to the requirements of 
their IRBs. The study investigators will be responsible for assuring the accuracy of the 
data entered from the paper forms into REDCap.   
 
In order to perform data cleaning and data quality assurance efficiently, numerous built-
in filters and checks for consistency of the data including range and limit checks, 
branching logic and pull down menus to limit choices for categorical variables to a pre-
specified list will be implemented and performed automatically to minimize data entry 
error. The data will be randomly sampled and checked against source records on a 
regular basis. The data and related analytical datasets will also be stored at the lead and 
contributing sites with secured password-protected computers. 
 
7.3.2 Role of the CDC Investigators in the Project  
This study is funded by a CDC contract with Duke University, Cincinnati Children’s 
Hospital, Columbia University, and Kaiser Permanente as Task Orders in the CISA 
Project Contract.  The Duke University PI (will oversee the study in partnership with the 
Cincinnati Children’s Hospital PI, the Columbia University PI and the Kaiser Permanente 
PI).  CDC staff will collaborate with all sites to develop the protocol, conduct the study, 
ensure the study is aligned with US Department of Health and Human Services (CDC) 
public health priorities, and analyze the data and disseminate the results. CDC may 
receive access to coded data not containing any directly identifying information.  
 
8 
HUMAN SUBJECTS  
8.1 Human Participants Involvement, Characteristics, and Design   
Duke, Cincinnati, Columbia, and Kaiser investigators will be responsible for submitting 
the protocol, informed consent, memory aids, recruitment materials and any written or 
verbally conveyed materials specific to this project to their institutional review boards.  
The CDC, as the funding agency, supports an exception to the sIRB mandate for the 
participating sites under the provision at 114(b)(2)(ii). CDC staff will be responsible for 
submitting materials to the CDC for review and obtain reliance on Duke IRB.   

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To facilitate participant recruitment at the practices, we will request a waiver of consent 
and HIPAA authorization as per institutional requirements for ascertainment 
(identification, selection) and/or recruitment of potential participants while recording 
identifiable private health information (PHI) prior to obtaining the participant’s consent.  
This information will be obtained from review of the electronic scheduling and medical 
record systems in the clinics in order to determine eligibility for study enrollment. The 
PHI collected prior to consent will be used to recruit and screen only. Use of PHI in this 
manner involves no more than minimal risk to participants and no information will leave 
the study sites. Informed consent will be sought in accordance with 45 CFR 46.116, prior 
to enrollment. 
 
Continuing reviews will be submitted to the IRBs in accordance with the new Common 
Rule.  Protocol deviations or concerns about study integrity will be reported promptly to 
the overseeing IRB in accordance with institutional requirements. 
 
8.2 Sources of Material  
Medical history and immunization history will be obtained from the medical record and 
from parent and patient report.  Demographic information will be obtained from the 
medical record and parent/LAR and patient report.  Participants will record solicited 
adverse reactogenicity events and any medical intervention sought on the day of and 7 
days following both vaccinations on the memory aid. Memory aid captured information 
will be reported to the study team during a telephone call or in the web-based REDCap 
system. Information about SAEs and AESIs will be obtained through medical record 
review and visits.  
 
8.3 Potential Risks and Benefits  
Risks of blood drawing include pain, swelling, bleeding, or bruising at the site where the 
blood sample is collected. Subjects may also experience dizziness or fainting. 
 
8.4 Adequacy of Protection 
Every effort possible will be made to keep information about participants confidential. 
Computerized participant information will be kept in password protected files on secured 
servers.  Paper case report forms will be kept in locked files belonging to the study 
personnel.  Any publications resulting from this work will not contain any identifiable 
participant information. 
 
8.4.1 ClinicalTrials.gov Requirements  
This observational study is not required to be registered on ClinicalTrials.gov by 
regulation.  However, as requested by CDC, the study is registered on ClinicalTrials.gov 
(NCT NCT05157191). It is the responsibility of the lead site for creating, maintaining, 
and uploading pertinent information regarding the study to ClinicalTrials.gov.   
 
9.0 HUMAN SUBJECTS  
9.1.1 Vulnerable Subjects  
This study proposes to include children and adolescents. 
 

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9.1.2 Vulnerable Subjects Research  
Children are a vulnerable research population and require additional protections when 
they are potential research subjects.   Because this study is minimal risk with the 
potential for benefit, the permission of only one parent/LAR will be obtained.   Assent 
from participants 5 through <16 years of age will be obtained in a manner consistent with 
local IRB regulations.   
 
 

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Pediatrics AAo. Children and COVID-19 Vaccination Trends  
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Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, et al. 
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Ali K, Berman G, Zhou H, Deng W, Faughnan V, Coronado-Voges M, et al. 
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Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-
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Coadministration of COVID-19 Vaccines with other Vaccines [Internet]. 2021 
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FDA. Coronavirus (COVID-19) Update: FDA Authorizes Moderna, Pfizer-
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fda-authorizes-moderna-pfizer-biontech-bivalent-covid-19-vaccines-use. 
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