Safety of Simultaneous Versus Sequential Administration of mRNA COVID-19 Vaccines and Quadrivalent Inactivated Influenza (IIV4) in Adults, Adolescents and Children: A Randomized Observer Blinded Study
Phase: PHASE4
Conditions: Quality of Life, Injection Site Reaction, Adverse Drug Event, Systemic Reaction
Sponsor: Duke University

 
 
 
 
Safety of Simultaneous versus Sequential Administration of mRNA COVID-19 Vaccines and 
Quadrivalent Inactivated Influenza (IIV4) in Adults, Adolescents and Children: A Randomized 
Observer Blinded Study 
 
Short Title: Simultaneous mRNA COVID-19 and IIV4 Vaccination Study 
 
 
Centers for Disease Control & Prevention 
Clinical Immunization Safety Assessment (CISA) Project 
 
 
Lead Site (Duke University) Principal Investigator: Emmanuel B. Walter, MD, MPH 
Lead Site Sub-principal Investigator: Ken Schmader, MD 
 
Contributing Site (Johns Hopkins University) Principal Investigator: Kawsar Talaat, MD 
 
Contributing Site (Cincinnati Children’s Hospital Medical Center) Principal Investigator: 
Elizabeth Schlaudecker, MD, MPH 
Contributing Site Sub-principal Investigator: Mary Staat, MD, MPH 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Karen R. Broder, MD 
CDC Sub-principal Investigator: Jonathan Duffy, MD, MPH 
 
 
 
NCT #: NCT05028361 
 
Version Number: 7.0 
15 March 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 
1 
BACKGROUND ................................................................................................................ 10 
1.1 
Background ................................................................................................................ 10 
1.2 
Summary and Rationale ............................................................................................. 18 
2 
STUDY OBJECTIVES AND OUTCOME MEASURES....................................................... 19 
Primary .................................................................................................................................. 19 
Secondary ............................................................................................................................. 19 
Exploratory ............................................................................................................................ 21 
3 
STUDY DESIGN ................................................................................................................ 23 
3.1 
Main study design ...................................................................................................... 23 
3.2 
Laboratory Studies ..................................................................................................... 23 
4 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................... 25 
4.1 
Subject Inclusion Criteria ........................................................................................... 25 
4.2 
Subject Exclusion Criteria .......................................................................................... 25 
4.3 
Temporary Delay Criteria (Visit 1, 2 and 3 (for primary COVID-19 vaccine series)) .... 26 
4.4 
Recruitment ............................................................................................................... 26 
4.5 
Reasons for and Handling of Withdrawals .................................................................. 28 
4.6 
Termination of Study .................................................................................................. 28 
5 
STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ................................................. 28 
5.1 
Schedule of events and data collection ...................................................................... 28 
5.2 
Treatment Assignment Procedures ............................................................................ 41 
5.2.1 Randomization ....................................................................................................... 41 
5.3 
Data Collection ........................................................................................................... 41 
5.3.1 Study Product Supply, Storage, and Administration ................................................ 41 
5.3.2 Blinding .................................................................................................................. 42 
5.4 
Reactogenicity and Safety Assessment ...................................................................... 43 
5.4.1 Causality (relatedness) Assessment ....................................................................... 47 
5.4.2 Reporting of Adverse Events .................................................................................. 47 
5.4.3 Safety Monitoring Plan ........................................................................................... 47 
5.5 
Health-Related Quality of Life (HRQOL) ..................................................................... 48 
5.5.1 Generic Measures of HRQOL ................................................................................ 48 
5.6 
Biospecimens Collection & Handling .......................................................................... 49 
5.6.1 Serum .................................................................................................................... 49 
6 
LABORATORY ANALYSES ............................................................................................. 49 
6.1 
Baseline SARS-CoV-2 antibody ................................................................................. 49 
6.2 
Influenza Hemagglutination Inhibition (HAI) Assay ..................................................... 49 
6.3 COVID-19 Immunogenicity .............................................................................................. 50 
6.4 Future Studies ................................................................................................................. 51 
7 
STATISTICAL CONSIDERATIONS ................................................................................... 51 

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7.1 
Analysis Plan ............................................................................................................. 51 
7.1.1 Sample Size ........................................................................................................... 51 
7.1.2 Analysis Populations .............................................................................................. 52 
7.1.3 Primary Objective 1 ................................................................................................ 52 
7.1.4 Secondary Objective 1 ........................................................................................... 53 
7.1.5 Secondary Objective 2 ........................................................................................... 53 
7.1.6 Secondary Objective 3 ........................................................................................... 53 
7.1.7 Secondary Objective 4 ........................................................................................... 54 
7.1.8 Exploratory Objectives ........................................................................................... 54 
7.2 
Data Management ..................................................................................................... 54 
7.2.1 Research Electronic Data Capture (REDCap) ........................................................ 54 
7.3 
Role of the CDC Investigators in the Project ............................................................... 55 
8 
HUMAN SUBJECTS ......................................................................................................... 55 
8.1 
Human Subjects Involvement, Characteristics, and Design ........................................ 55 
8.2 
Sources of Material .................................................................................................... 56 
8.3 
Potential Risks and Benefits ....................................................................................... 56 
8.4 
Adequacy of Protection Against Risks ........................................................................ 57 
8.4.1 Protections against Risk ......................................................................................... 58 
8.4.2 ClinicalTrials.gov Requirements ................................................................................. 58 
8.5 
Human Subjects ......................................................................................................... 59 
8.5.1 Vulnerable Subjects Research ............................................................................... 59 
REFERENCES .......................................................................................................................... 60 
APPENDIX ................................................................................................................................ 64 
Appendix A: EQ-5D-5L and VAS ........................................................................................... 65 
Appendix B: Corticosteroid Dose Charts ................................................................................ 66 

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Protocol Summary 
 
Title: 
Safety of Simultaneous versus Sequential Administration of 
mRNA COVID-19 Vaccines and Quadrivalent Inactivated 
Influenza (IIV4) in Adults, Adolescents and Children: A 
Randomized Observer Blinded Study 
Phase: 
Phase IV 
Population: 
450 persons ≥5 years of age for whom both COVID-19 and 
influenza vaccines are indicated and for whom COVID-19 
vaccine is recommended by the ACIP. 
Clinical Sites: 
Three: Duke University (Lead); Johns Hopkins University 
(Contributing); Cincinnati Children’s Hospital (Contributing) 
Study Duration: 
36 months total 
• 
12 months to recruit/enroll, 6 months during each of two 
influenza seasons 
5 months to perform analysis and laboratory assays after the 
end of follow-up period 
Participant Duration and 
Number of Participants: 
• 
120 days for 450 total participants at 3 sites 
Description of Study 
Procedures: 
This study is a prospective, randomized clinical trial. During 
this study, participants will be randomly assigned to receive 
quadrivalent inactivated influenza vaccine (IIV4) and mRNA 
COVID-19 vaccine either simultaneously or sequentially, 7-14 
days apart. For participants receiving their primary dose series, 
a second dose of mRNA COVID-19 vaccine will be 
administered either 3 to 8 weeks or 4 to 8 weeks following the 
first dose, depending upon the mRNA COVID-19 vaccine 
provided. Participants receiving a booster dose of mRNA 
COVID-19 vaccine will receive a single COVID-19 dose within 
the study per current CDC guidelines. 
Solicited symptoms of reactogenicity will be assessed on 
vaccination day and daily during the 7 days following each 
Vaccination Visit using either electronic or paper symptoms 
diaries, depending on study participant preference. Quality of 
life data will be collected using electronic or paper diaries on 
day of Vaccination Visit 1 and daily during the 7 days following 
the visit. Serious adverse events and adverse events of special 
interest will be collected throughout the duration of the study. 

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Serum samples from participants will be collected for 
determination of COVID-19 serostatus at baseline. Serum 
samples will be taken throughout the study to determine IIV4 
immunogenicity and for potential future studies. 
Objectives: 
Primary Objective: 
- 
To compare the proportion of participants with 
moderate or more severe fever, chills, myalgia, or 
arthralgia in the group receiving IIV4 simultaneously 
with mRNA COVID-19 vaccine at Vaccination Visit 1 
(Simultaneous group) with the group receiving IIV4 
alone one to two weeks later at Vaccination Visit 2 
(Sequential group) following both Vaccination Visit 1 
and 2 
Secondary Objective: 
- 
To compare the proportion of participants with 
moderate or more severe fever, chills, myalgia, or 
arthralgia in the Simultaneous versus the Sequential 
Group following the first vaccination visit 
- 
To compare the proportion of participants with 
moderate or more severe fever, chills, myalgia, or 
arthralgia in the Simultaneous versus Sequential Group 
following the second vaccination visit 
- 
To describe the proportions of participants in the 
Simultaneous and Sequential vaccination groups with 
solicited local and systemic reactogenicity events 
according to severity grade after the first and second 
vaccination visit and third vaccination visit for those 
receiving two doses of mRNA COVID-19 vaccine 
- 
To describe the proportions of participants in the 
Simultaneous and Sequential vaccination groups 
experiencing at least one serious adverse event and a 
description of these events 
Exploratory Objective: 
- 
To compare the proportion of participants with 
moderate or more severe fever, chills, myalgia, or 
arthralgia in the Simultaneous versus Sequential Group 
following the third vaccination visit for those receiving 
two doses of mRNA COVID-19 vaccine 
- 
To further characterize and describe the proportion of 
participants in the Simultaneous and Sequential groups 
with local or systemic reactogenicity events of greater 
severity following each vaccination visit and 
cumulatively 
- 
To describe the proportion of participants in 
Simultaneous and Sequential groups experiencing at 

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least one unsolicited adverse event and one adverse 
event of special interest and to characterize these 
events 
- 
To compare the change of health related quality of life 
(HRQOL) from baseline in the Simultaneous versus 
Sequential groups following the Vaccination Visit 1 
- 
To assess the safety profiles in the simultaneous and 
sequential group participants by COVID-19 serostatus 
at baseline 
- 
To assess the safety profiles in the simultaneous and 
sequential group participants by vaccine product (Pfizer 
or Moderna). 
- 
To assess the effect of simultaneous administration of 
IIV4 and COVID-19 vaccine on IIV4 immunogenicity as 
assessed by hemagglutination inhibition assay (HAI) 
- 
To assess serum antibody levels to SARS-CoV-2 
antigens 
Outcome Measures: 
Primary Outcome Measure: 
- 
Comparison of the proportion of participants reporting 
at least one solicited reactogenicity event to include 
fever, chills, myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group with the 
Sequential group within 1-7 days following both 
Vaccination Visit 1 and Vaccination Visit 2 
Secondary Outcome Measure: 
- 
Comparison of the proportion of participants reporting 
at least one solicited reactogenicity event to include 
fever, chills, myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group with the 
Sequential group within 1-7 days following Vaccination 
Visit 1 visit during which participants receive either IIV4 
or placebo with an mRNA COVID-19 vaccine 
- 
Comparison of the proportion of participants reporting 
at least one solicited reactogenicity event to include 
fever, chills, myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group with the 
Sequential group within 1-7 days following Vaccination 
Visit 2 during which participants receive either IIV4 or 
placebo without an mRNA COVID-19 vaccine 
- 
The proportion of participants in each vaccination group 
reporting specified solicited local and systemic 
reactogenicity events of any severity and by severity 
grade within 1-7 days following the first vaccination visit 
during which participants receive either IIV4 or placebo 
with an mRNA COVID-19 vaccine 
- 
The proportion of participants in each vaccination group 
reporting specified solicited local and systemic 

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reactogenicity events of any severity and by severity 
grade within 1-7 days following the second vaccination 
visit during which participants receive either IIV4 or 
placebo 
- 
The proportion of participants in each vaccination group 
reporting specified solicited local and systemic 
reactogenicity events of any severity and by severity 
grade within 1-7 days following the third vaccination 
visit during which all participants receive an mRNA 
COVID-19 vaccine alone for those receiving two doses 
of mRNA COVID-19 vaccine 
- 
The proportion of participants in Simultaneous and 
Sequential Groups with at least one serious adverse 
event occurring during the study period and a 
description of each event 
Exploratory Outcome Measure: 
- 
Comparison of the proportion of participants reporting 
at least one solicited reactogenicity event to include 
fever, chills, myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group with the 
Sequential group within 1-7 days following Vaccination 
Visit 3 during which all participants receive an mRNA 
COVID-19 vaccine alone for those receiving two doses 
of mRNA COVID-19 vaccine 
- 
The proportion of participants reporting at least one 
moderate or greater or at least one severe or greater 
solicited local or systemic reactogenicity event in each 
vaccination group within 1-7 days following the first 
vaccination during which participants receive either IIV4 
or placebo with an mRNA COVID-19 vaccine 
- 
The proportion of participants reporting at least one 
moderate or greater or at least one severe or greater 
solicited local or systemic reactogenicity event in each 
vaccination group within 1-7 days following the second 
vaccination visit which participants receive either IIV4 
or placebo 
- 
The proportion of participants reporting at least one 
moderate or greater or at least one severe or greater 
solicited local or systemic reactogenicity event in each 
vaccination group within 1-7 days following the third 
vaccination visit during which all participants receive an 
mRNA COVID-19 vaccine alone for those receiving two 
doses of mRNA COVID-19 vaccine 
- 
The proportion of participants reporting at least one 
moderate or greater or at least one severe or greater 
solicited local or systemic reactogenicity event in each 

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vaccination group within 1-7 days following all 
vaccination visits combined 
- 
The proportion of participants in each vaccination group 
with an unsolicited adverse event occurring during the 7 
days post each vaccination visit according to severity 
and system organ classification 
- 
The proportion of participants in each vaccination group 
with an adverse event of special interest occurring 
during the study period according to event type 
- 
Comparison between vaccination groups of the mean 
maximal change in score from baseline on the 
EuroQOL 5 dimensions-5 level (EQ-5D-5L) and 
EuroQOL visual analogue scale (EQ VAS) within 1-7 
days following the first vaccination visit 
- 
To compare secondary outcomes 3a, 3b, 3c, and 4a 
according to baseline COVID-19 serostatus 
- 
To compare secondary outcomes 3a, 3b, 3c, and 4a 
according to vaccine product (Pfizer or Moderna). 
- 
The proportion of participants in each vaccination group 
with a seroprotective HAI titer (≥ 1:40) pre- and post- 
IIV4 immunization for each IIV4 antigen 
- 
The proportion of participants in each vaccination group 
achieving seroconversion following IIV4 (an HAI titer > 
1:40 following IIV4 if the baseline titer is < 1:10 or a 
four-fold rise in HAI titer if the baseline titer is > 1:10) 
for each IIV4 antigen 
- 
The geometric mean HAI titer (GMT) for each IIV4 
antigen pre- and post-IIV4 in each vaccination group 
- 
The geometric mean fold rise (GMFR) in HAI titer for 
each vaccination group 
- 
The proportion of participants in each vaccination group 
seropositive to SARS-CoV-2 variants tested prior to 
and following mRNA COVID-19 vaccine 
- 
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 each vaccination 
group 
Estimated Time to Complete 
Enrollment: 
Approximately 6 months for enrollment for the 2021-2022 
influenza season and 6 months for enrollment during the 2022- 
2023 influenza season 

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1 BACKGROUND 
1.1 Background 
 
COVID-19 
Coronavirus disease 2019 (COVID-19) is caused by a coronavirus called Severe Acute 
Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). COVID-19 was first noted in late 2019 
among clusters of pneumonia cases occurring in Wuhan China. The virus spread globally, in a 
rapid manner, with the first case among a US resident reported in January 20201. On March 11, 
the World Health Organization declared COVID-19 a pandemic2. During the course of 2020 and 
2021, the pandemic occurred in multiple distinct waves in the US, with the most recent wave 
starting in late 2021 and persisting into early 2022. As of April 3rd, 2022, over 79 million COVID- 
19 cases and over 950,000 deaths have been reported in the United States3, making this the 
worst pandemic to occur in this country since the 1918 Spanish flu. With the emergence of 
numerous viral variants including the B1.1.529 Omicron variant and B.1.617.2 Delta variant in 
addition to other variants being monitored, the current trajectory of the pandemic remains 
uncertain 4. 
 
Typical symptoms of COVID-19 include fever, chills, cough, shortness of breath, difficulty 
breathing, fatigue, myalgia, body aches, headache, new loss of taste or smell, sore throat, 
congestion, runny nose, nausea, vomiting, and diarrhea. Complications of COVID-19 are varied 
and include pneumonia, acute respiratory failure, acute respiratory distress syndrome, acute 
liver, kidney and/or cardiac injury, secondary infections, septic shock, disseminated 
intravascular coagulation, blood clots, multisystem inflammatory syndrome in children and 
adults, rhabdomyolysis and neurologic symptoms. Among known risk factors for severe illness 
are advanced age, cancer, chronic kidney disease, chronic obstructive pulmonary disease, 
Down syndrome, obesity, serious heart conditions (heart failure, coronary artery disease or 
cardiomyopathies), immunocompromised state from solid organ transplant, sickle cell disease 
and type 2 diabetes mellitus, smoking and pregnancy 5. 
 
 
Influenza 
Epidemic influenza is a highly infectious disease that occurs annually throughout the temperate 
regions in both hemispheres in their respective winter months 6. Influenza infection occurs in all 
age groups and is a major public health threat, as it has the ability to spread rapidly through 
populations and affect a large number of people. While infection rates are generally highest 
among school age children, the highest rates of serious morbidity and mortality occur among 
individuals over 65 years of age and in children less than 1 year of age 7. Underlying medical 
conditions such as chronic cardiac, pulmonary, kidney and metabolic disorders, and various 
types of immunosuppression increase the likelihood of potential complications8. 
 
Uncomplicated influenza illness is characterized by the abrupt onset of constitutional symptoms 
including: fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis. 
Influenza virus infection can also lead to more serious illness such as primary viral pneumonia 
and exacerbation of underlying medical conditions. Common complications include bacterial 
pneumonia, sinusitis, and otitis media. The estimated annual number of influenza-associated 
hospitalizations in the United States is 226,000 and the estimated annual number of deaths is 

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34,470 9,10. Hospitalizations due to influenza are typically more prevalent in seasons during 
which A(H3N2) subtype predominates. 
 
COVID-19 and Influenza 
 
In the spring of 2020 COVID-19 emerged late in the course of the 2019-2020 seasonal influenza 
epidemic, with co-infection being reported in some individuals11. Of potential concern, was the 
possibility of a simultaneous surge in both COVID-19 cases and influenza cases during the 
2020-2021 season. However, influenza activity in the United States during the 2020-2021 
season remained relatively low and to date has remained relatively low during the 2021-22 
season. If both COVID-19 and influenza infections peaked simultaneously during subsequent 
seasons, there could be a significant future impact on utilization of health care resources 
potentially overburdening the health care system. 
 
 
COVID-19 Vaccines 
 
The Pfizer-BioNTech COVID-19 vaccine (BNT162b2) (marketed as Comirnaty) received FDA- 
licensure for individuals 16 years and older on August 23rd, 2021 for primary dose series. The 
Moderna COVID-19 vaccine (marketed as Spikevax) received FDA approval on January 31st, 
2022 for individuals 18 years and older for primary dose series. Numerous other COVID-19 
vaccines are currently in different phases of preclinical and clinical development. Six vaccines 
have recently completed or are currently undergoing late stage Phase 3 clinical testing in the 
United States including the two mRNA vaccines, two viral vectored vaccines, and two 
adjuvanted recombinant protein-based vaccines12. Prior to approval, the Moderna mRNA 
vaccine (mRNA-1273) received US Food and Drug Administration (FDA) Emergency Use 
Authorization (EUA) for persons 18 years of age and older13, and the Pfizer-BioNTech COVID- 
19 vaccine received an initial EUA in December 2020 for persons 16 years of age and older and 
expanded its EUA to include individuals 12 -15 years of age on May 10, 2021 and individuals 5 - 
11 years of age on October 29, 202114. Both Pfizer-BioNTech and Moderna vaccines are based 
on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA and formulated in lipid 
nanoparticles (LNPs). Among study participants without evidence of SARS-CoV-2 infection, the 
Pfizer/BioNTech vaccine (BNT162b2) was 95.0% (95% CI 90.3%, 97.6%) effective at 
preventing confirmed COVID-19 occurring at least 7 days after the second dose of vaccine 15. 
The Moderna vaccine (mRNA-1273) demonstrated a vaccine efficacy of 94.1% (95% CI 89.3%, 
96.8%) for the prevention of symptomatic SARS-COV-2 infection with onset at least 14 days 
after the second injection, with 11 COVID-19 cases in the vaccine group and 185 COVID-19 
cases in the placebo group 16. The Janssen adenovirus 26 vectored COVID-19 vaccine (Ad26 
COV2.S) received EUA from the FDA on February 27, 2021 but due to being a viral vector 
vaccine it will not be further addressed by this study evaluating the simultaneous administration 
of influenza and mRNA COVID-19 vaccines. 
 
BNT162b2 is currently authorized under the FDA EUA for persons 5 – 15 years of age and 
approved for persons 16 years of age and older, while the mRNA-1273 is approved for persons 
18 years of age and older. CDC’s Advisory Committee on Immunization Practices (ACIP) has 
recommended use of these vaccines, according to the specifications in the EUAs; CDC has also 
published interim clinical considerations for use of COVID-19 vaccines17,18. Both vaccines are 
administered intramuscularly with the Pfizer-BioNTech vaccine (30 µg, 0.3mL each for persons 

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≥ 12 years of age and 10 µg, 0.2mL each for persons 5-11 years of age) being administered 21 
days apart and the Moderna vaccine (100 µg, 0.5mL each) being administered 28 days apart as 
a primary series in particular, for populations that include moderately or severely 
immunocompromised, adults over 65 years of age and those who need rapid protection against 
COVID-19. Doses should not be administered earlier than recommended but if given within a 4- 
day period prior to the scheduled time may be considered valid. The second dose can be 
administered between 3 and 8 weeks after the first dose for the Pfizer- BioNTech vaccine and 
between 4 and 8 weeks after the first dose for the Moderna vaccine. The vaccines are not 
considered to be interchangeable, however under extenuating circumstances such as when the 
brand of the first dose of vaccine is unknown, any mRNA COVID-19 vaccine may be 
administered 28 days following the first dose17. 
 
On August 12, 2021, the FDA amended the Pfizer-BioNTech and Moderna mRNA COVID-19 
vaccine EUAs to include the use of a third dose of vaccine in specific immunocompromised 
populations for persons 12 years of age and older and persons 18 years of age or older for the 
respective vaccines.19 Additionally, the CDC also recommended that moderate or severely 
immune compromised populations receive an additional third dose of the mRNA COVID-19 
vaccines to enhance the immune response20. Subsequent to these actions, the U.S. 
government has expanded authorizations and recommendations for a third dose of COVID-19 
vaccine as infections rose from the coronavirus Delta variant and then the Omicron variant, 
citing data indicating diminishing protection from the vaccines over time. The FDA initially 
authorized a booster dose for both Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines 
for all persons 18 years of age and older on November 19, 2021. Subsequent to this action, the 
EUA was extended for the Pfizer-BioNTech mRNA COVID-19 vaccine to include 16-17 year 
olds on December 9, 2021 and 12-15 year olds on January 3, 2022. The CDC has made 
comparable recommendations to follow the EUAs21-24. Both the EUA and recommendations for 
the interval between the primary series and booster dose have also been shorted to 5 months. 
On March 29, 2022 FDA authorized a second booster dose for persons aged 50 and older and 
certain immunocompromised individuals; CDC updated guidance for second booster doses, 
with a 4-month interval between a first and second booster dose13,17. 
 
Local and systemic side effects occurring within the week after vaccination as reported from the 
BNT162b2 Phase2/3 reactogenicity subset are noted in Table 1. In general, both local and 
systemic side effects were reported more frequently in those who were younger and following 
the second dose of vaccine. 
 
Table 1. BNT162b2 Reactogenicity (Phase 2/3) 25 
Dose 1 
Dose 2 
16-55 years 
>55 years 
16-55 years 
>55 years 
Local 
Pain 
83.1% 
71.1% 
77.8% 
66.1% 
Redness 
4.5% 
4.7% 
5.9% 
7.2% 
Swelling 
5.8% 
6.5% 
6.3% 
7.5% 
Systemic 
Fever 
3.7% 
1.4% 
15.8% 
10.9% 
Fatigue 
47.4% 
34.1% 
59.4% 
50.5% 
Headache 
41.9% 
25.2% 
51.7% 
39.0% 

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Chills 
14.0% 
6.3% 
35.1% 
22.7% 
Vomiting 
1.2% 
0.5% 
1.9% 
0.7% 
Diarrhea 
11.1% 
8.2% 
10.4% 
8.3% 
Muscle pain 
21.3% 
13.9% 
37.3% 
28.7% 
Joint pain 
11.0% 
8.6% 
21.9% 
18.9% 
 
Overall, the frequency of any severe systemic event after Dose 1 was ≤0.9% or less. After Dose 
2, severe systemic events had frequencies of <2% with the exception after Dose 2 of fatigue 
(3.8%) and headache (2.0%). Severe fever (>38.9°C to 40.0°C) was reported in the BNT162b2 
group after Dose 1 for 0.2% and after Dose 2 for 0.8% 15. 
 
A higher frequency of unsolicited, non-serious adverse events was reported in the vaccine 
group compared to placebo group and was primarily attributed to local reactions and systemic 
adverse events in subjects not in the reactogenicity subset and are consistent with solicited 
reactions/events reported by reactogenicity subset participants during the first 7 days following 
vaccination. In the all-enrolled population of (total N=43,448), the proportions of participants 
who reported at least 1 serious adverse event (SAE) during the time period from Dose 1 to the 
data cutoff date (November 14, 2020) were 0.6% in the BNT162b2 vaccine group and 0.5% in 
the placebo group. Three SAEs reported in the BNT162 group were considered by the 
investigator as related to vaccine or vaccine administration: shoulder injury, ventricular 
arrhythmia, and lymphadenopathy. 
 
Local and systemic side effects as reported from the mRNA-1273 Phase 3 reactogenicity subset 
are noted in Table 2. Similar to the Pfizer-BioNTech vaccine, in general, both local and 
systemic side effects were reported more frequently in those who were younger and following 
the second dose of vaccine. 
 
 
Table 2. mRNA-1273 Reactogenicity (Phase 3) 16 
Dose 1 
Dose 2 
18-<64 years 
≥65 years 
18-<64 years 
≥65 years 
Local 
Any 
87.4% 
74.6% 
90.3% 
83.8% 
Pain 
86.9% 
74.0% 
89.9% 
83.2% 
Redness 
3.0% 
2.3% 
8.9% 
7.5% 
Swelling 
6.7% 
4.4% 
12.6% 
10.8% 
Axillary swelling 
and tenderness 
of the vaccination 
arm 
11.6% 
6.1% 
16.2% 
8.6% 
Systemic 
Any 
57.0% 
48.3% 
81.9% 
71.9% 
Fever 
0.9% 
0.3% 
17.4% 
10.0% 
Headache 
35.3% 
24.5% 
62.8% 
46.2% 
Fatigue 
38.4% 
33.3% 
67.6% 
58.3% 
Myalgia 
23.7% 
19.7% 
61.6% 
47.1% 

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Table 2. mRNA-1273 Reactogenicity (Phase 3) 16 
Dose 1 
Dose 2 
18-<64 years 
≥65 years 
18-<64 years 
≥65 years 
Arthralgia 
16.6% 
16.4% 
45.5% 
35.0% 
Nausea and 
Vomiting 
9.4% 
5.2% 
21.4% 
11.8% 
Chills 
9.2% 
5.4% 
48.6% 
30.9% 
 
Overall, the frequency of any Grade 3 systemic event after Dose 1 ranged from 2.0 to 2.9% 
depending upon age. After Dose 2, Grade 3 systemic events were reported by 15.7% in the younger 
group and 2.0% in the older group26 . 
 
The proportion of participants who reported severe unsolicited AEs was 1.4% following any vaccine 
dose (275 participants) and 1.3% following any placebo dose (225 participants). The most frequently 
reported severe AEs that occurred in greater numbers of vaccine than placebo recipients were 
headache, myalgia, arthralgia, injection site erythema, and injection site pain. The frequency of non- 
fatal serious adverse events was low and without meaningful imbalances between study arms (1% in 
the mRNA-1273 group and 1% in the placebo group). 
 
A more detailed comparison of selected systemic reactogenicity events and their grading following 
Dose 1 of mRNA-1273 and BNT162b2 is included below (Table 3): 
 
Table 3. Selected Systemic Reactogenicity Events and Grading following BNT162b2 
and mRNA-1273 
Systemic 
Symptom 
Grade 
BNT162b2 15 25 
Grade 
mRNA-127316 
18 to 55 years of 
age 
18-<65 years 
Fever 
> 38.0°C 
3.7% 
≥ 38.0°C 
0.9% 
> 38.0°C to 
38.4°C 
2.8% 
38.0°C to 
38.4°C 
0.6% 
> 38.4°C to 
38.9°C 
0.7% 
38.5°C to 
38.9°C 
0.2% 
> 38.9°C to 
40.0°C 
0.3% 
> 39.0°C to 
40.0°C 
<0.1% 
> 40.0°C 
0.0% 
> 40.0°C 
<0.1% 
> 38.4°C 
1.0% 
≥ 38.5°C 
≈0.4% 
Chills 
Any 
14.0% 
Any 
9.2% 
Mild 
10.0% 
Grade 1 
6.8% 
Moderate 
3.6% 
Grade 2 
2.2% 
Severe 
0.4% 
Grade 3 
0.1% 
Moderate or 
Severe 
4.0% 
Grade 2 or 3 
2.3% 
+* 

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Table 3. Selected Systemic Reactogenicity Events and Grading following BNT162b2 
and mRNA-1273 
Systemic 
Symptom 
Grade 
BNT162b2 15 25 
Grade 
mRNA-127316 
18 to 55 years of 
age 
18-<65 years 
Muscle pain 
Any 
21.3% 
Any 
23.7% 
Mild 
11.2% 
Grade 1 
16.5% 
Moderate 
9.5%. 
Grade 2 
6.6% 
Severe 
0.6% 
Grade 3 
0.6% 
Moderate or 
Severe 
10.1% 
Grade 2 or 3 
7.2% 
Joint pain 
Any 
11.0% 
Any 
16.6% 
Mild 
6.4% 
Grade 1 
12.0% 
Moderate 
4.3% 
Grade 2 
4.2% 
Severe 
0.2% 
Grade 3 
0.4% 
Grade 4 
<0.1% 
Moderate or 
Severe 
4.5% 
Grades 2,3 or 
4 
≈4.7% 
 
In a study comparing the safety and immunogenicity of BNT162b2 vaccine in adolescents to 
that in adults local and systemic events were generally mild to moderate in severity and were 
reported at similar frequencies in both age cohorts. As with adults, systemic events were 
reported more often after BNT162b2 dose 2 than after dose 1. The vaccine produced a greater 
immune response in adolescents than adults and was highly effective27. 
 
A study assessing two 10 µg doses of BNT162b2 in children 5 to 11 years of age each 
administered 3 weeks apart, showed the vaccine to be safe, immunogenic and efficacious in 
this age group as well. Solicited injection site and systemic reactions were generally mild to 
moderate and lasted 1 to 2 days. In general, systemic events were reported more commonly 
after the second dose than the first dose. Fever occurred in 8.3% of recipients after the first 
and second dose.28 
 
Hypersensitivity Reactions and mRNA COVID-19 Vaccines 
In the Pfizer mRNA phase III trial, more participants reporting hypersensitivity-related adverse 
events in the vaccine group (137 [0.63%]) compared with the placebo group (111 [0.51%]). 
There were no anaphylactic or severe hypersensitivity reactions reported (FDA EUA). 
 
In the Moderna mRNA COVID vaccine phase III trial, more participants reported 
hypersensitivity-related adverse events in the vaccine group 1.5% of vaccine recipients (258 
events in 233 participants) compared with the placebo group 1.1% of placebo recipients (185 
events in 166 participants). There were no anaphylactic or severe hypersensitivity reactions 
with close temporal relation to the vaccine. There was one anaphylactic reaction occurring 63 
days after the second dose of the vaccine that did not meet the Brighton Collaboration 
Anaphylaxis Case Definition (FDA EUA). 

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There have been numerous reports of anaphylactic reactions after the Pfizer and Moderna 
vaccine after the start of vaccination campaigns (MMWR January 22, 2021, Vol. 70; MMWR 
January 15, 2021, Vol. 70). The update on anaphylaxis reports to VAERS following mRNA 
COVID Vaccines through January 18, 2021 (January ACIP meeting), showed following results: 
Table 4. Anaphylaxis reports to VAERS following COVID-19 vaccines. 
 
Table 4. BNT162b2 and Moderna Anaphylactic Reactions 
Characteristic 
Pfizer-BioNTech 
(N = 50) 
Moderna 
(N = 21) 
Median age, years (range) 
38.5 (26-63) 
39 (24-63) 
Female (%) 
47 (94) 
21 (100) 
Minutes to symptom onset, 
median 
10 
10 
Symptom onset ≤15 minutes 
(%) 
37 (74) 
18 (86) 
Symptom onset ≤30 minutes 
(%) 
45 (90) 
19 (90) 
Documented h/o of allergies 
40 (80) 
18 (86) 
Documented h/o of prior 
anaphylaxis 
12 (24) 
5 (24) 
Dose number (1st 2nd, unk) 
42, 3, 5 
19, 1, 1 
 
The anaphylaxis reporting rate (analytic period Dec 14 – Jan 18) for the Pfizer mRNA vaccine is 
4.7 per million doses and for Moderna mRNA vaccine, 2.5 per million doses29. Both mRNA 
vaccines include a warning that anaphylaxis may occur after mRNA vaccines and that 
appropriate medical treatment for management must be immediately available30,31. 
 
Myocarditis and Pericarditis and mRNA COVID-19 Vaccines 
 
Since April 2021, increased cases of myocarditis and pericarditis have been reported in the 
United States after mRNA COVID-19 vaccination (Pfizer-BioNTech and Moderna), particularly in 
adolescents and young adults after the second dose32. In June 2021, the FDA updated the 
EUAs for both mRNA COVID-19 vaccines to describe the risk for myocarditis and pericarditis 
after mRNA COVID-19 vaccines30,31. 
 
While absolute risk remains small, evidence suggests the risk might be reduced by extending 
the interval between the first and second dose. Studies in adolescents (ages 12-17 years) and 
adults have shown the small risk of myocarditis associated with mRNA COVID-19 vaccines 
might be reduced and peak antibody responses and vaccine effectiveness may be increased 
with an interval up to 8 weeks following the initial dose. There are currently no data available for 
children ages 11 years and younger. A 3- or 4-week interval continues to be the recommended 
interval for people who are moderately to severely immunocompromised, adults ages 65 years 
and older, and others who need rapid protection due to increased concern about community 
transmission or risk of severe disease33. 

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Booster Doses 
 
The safety of a booster dose (dose 3) of the Pfizer COVID-19 vaccine was assessed in about 
300 adults aged 18-55 years. The reactogenicity and safety profile observed after the booster 
dose was generally similar to that observed after Dose 2 of the initial two-dose vaccination 
series. Lymphadenopathy was more frequent after dose 3 (5.2%), compared with 0.4% in 
persons aged ≥16 years after dose 1 or 2. Most cases had axillary lymphadenopathy that 
resolved within 5 days after onset.13,34 The safety of a booster (dose 3) of the Moderna COVID- 
19 vaccine at half the dose (50ug) was assessed in 168 persons over 18 years of age. The 
reactogenicity and safety profile observed after the booster dose was generally similar to that 
observed after Dose 2 of the initial two-dose vaccination series35. FDA identified no new safety 
concerns following second booster dose of Pfizer COVID-19 vaccine administered to older 
adults13,36. 
 
Influenza and Influenza Vaccine 
 
Inactivated influenza virus vaccines (IIVs) have been available in the United States for over 50 
years and influenza vaccination remains the most effective strategy for reducing the burden of 
disease caused by influenza. In the United States, vaccination of all persons aged 6 months and 
older is recommended on an annual basis37. In the 2021-22 influenza season all influenza 
vaccine formulations are quadrivalent (IIV4) and contain hemagglutinin (HA) from four prototypic 
influenza types/subtypes that commonly circulate including: influenza A (H1N1pdm09), 
influenza A (H3N2), and 2 different influenza B lineages (B Yamagata and B Victoria) 37. For 
adults 65 years of age and older, who may not develop as robust an immune response as 
younger individuals, both high dose and adjuvanted formulations of IIV4 have been developed. 
High dose and adjuvanted formulations have been shown to be more immunogenic when 
compared to standard dose formulations in older adults8. High-dose influenza vaccine has also 
been shown to be more effective than standard dose influenza vaccine in a randomized clinical 
trial. 
 
 
On the basis of review of the evidence concerning high-dose inactivated influenza vaccine (HD- 
IIV), recombinant influenza vaccine (RIV), and MF59-adjuvanted inactivated influenza vaccine 
(aIIV), the CDC’s Advisory Committee on Immunization Practices (ACIP) recently modified 
recommendations for influenza vaccination of persons aged ≥65 years38. ACIP now 
recommends that adults aged ≥65 years preferentially receive any one of the following higher 
dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine 
(HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted 
inactivated influenza vaccine (aIIV4). If none of these three vaccines is available at an 
opportunity for vaccine administration, then any other age-appropriate influenza vaccine should 
be used. Higher dose vaccines include HD-IIV4 and RIV4, both of which contain a higher dose 
of HA antigen per virus than standard-dose vaccines (60 µg for HD-IIV4 and 45 µg for RIV4, 
compared with 15 µg for standard-dose inactivated vaccines). Adjuvanted inactivated influenza 
vaccine (aIIV4) contains MF59 adjuvant. 

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Side effects after an inactivated influenza vaccine may include soreness, redness and swelling 
at the injection site, fever, muscle aches, and headache. There also may be a very small 
increased risk of Guillain- Barré Syndrome (GBS) or anaphylaxis after an inactivated influenza 
vaccine39. 
 
1.2 Summary and Rationale 
In clinical practice, the FDA approved the Pfizer-BioNTech and Moderna COVID-19 vaccines 
and granted an Emergency Use Authorization for Janssen COVID-19 vaccine in February 2021. 
Hence, vaccines for both COVID-19 and influenza prevention have the potential for being 
administered at the same time seasonal influenza vaccine is available. In the pre-licensure 
efficacy studies, neither the Pfizer-BioNTech or Moderna mRNA vaccines were evaluated for 
either safety or immunogenicity when co-administered with a non-COVID-19 vaccine. The 
Phase 3 trial of the AstraZeneca chimpanzee adenovirus-vectored COVID-19 vaccine did not 
prohibit influenza vaccination but simultaneous administration was not systematically evaluated. 
Initial guidance from the CDC stated that COVID-19 vaccines should be given alone with at 
least 14 days either before or after receipt of any other vaccines, including an influenza vaccine, 
because of limited information on the safety and effectiveness of co-administration. Current 
guidance now states that COVID-19 vaccines can be administered on the same day as other 
vaccines but mentions that it is unknown if simultaneous administration will affect 
reactogenicity17,37,40. A single study has assessed the safety and immunogenicity of a 3rd dose 
of Moderna’s mRNA COVID-19 vaccine and High-Dose quadrivalent influenza vaccine when 
administered simultaneously to adults 65 years and older. No safety concerns or immune 
interference were observed.41 
 
Due to the potential for severe influenza complications and resulting morbidity and mortality, it 
remains particularly important that influenza vaccine is encouraged for all persons 6 months of 
age and older without any contraindications. Likewise, as the pandemic continues and COVID- 
19 vaccines become available it is critically important that their use be encouraged in those 
populations for whom there is an authorization and an ACIP recommendation. To date, we are 
unaware of any studies evaluating the safety and immune responses following concomitant 
administration of both mRNA COVID-19 and influenza vaccines in a more general population. 
Hence, we aim to study the safety of simultaneous versus sequential administration of mRNA 
COVID-19 vaccine and IIV4. Participants receiving mRNA COVID-19 vaccines as either 
standard of care or a study procedure will be randomized to receive either IIV4 or placebo within 
8 hours of their initial dose of mRNA COVID-19 vaccine. Those receiving IIV4 will receive 
placebo 14 days later and those receiving placebo will receive IIV4 14 days later. 
 
We have elected to evaluate the mRNA COVID-19 vaccines for evaluations for three reasons: 
1) there is greater accumulated experience with using mRNA COVID-19 vaccines in the 
population; 2) the different reactogenicity profiles for the mRNA COVID-19 vaccines as 
compared to the Janssen adenoviral vector COVID-19 vaccine decreases the ability of a single 
small study to address the question of co-administration safety13 and 3) the preferential 
recommendation for the use of mRNA COVID-19 vaccines over the Janssen vaccine for both 
primary and booster vaccination due to concerns related to thrombosis with thrombocytopenia 
syndrome following Janssen COVID-19 vaccine42. In addition, we hope to assess the effects of 

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pre-existing COVID-19 antibody before vaccination on the occurrence of vaccine side effects 
and to assess the effects of COVID-19 vaccine administration on IIV4 immunogenicity. 
 
The current protocol allows for inclusion of persons receiving a booster dose of mRNA COVID- 
19 vaccine. Administration of booster dose mRNA COVID-19 vaccines to participants who are 
enrolled in this protocol, will adhere to current FDA prescribing recommendations for licensed or 
EUA mRNA COVID-19 vaccines and to ACIP recommendations for their use as the approvals 
and recommendations are made. Inclusion of persons receiving a booster dose of COVID-19 
vaccine will allow for enhanced recruitment during the influenza vaccination season in which it is 
expected that most adults and many children receiving an mRNA COVID-19 vaccine in this 
study will be receiving a booster dose rather than an initial vaccine two-dose series. 
 
 
2 STUDY OBJECTIVES AND OUTCOME MEASURES 
 
OBJECTIVE 
OUTCOME 
Primary 
1. To compare the proportion of 
participants with moderate or more 
severe fever, chills, myalgia, or 
arthralgia in the group receiving IIV4 
simultaneously with mRNA COVID- 
19 vaccine at Vaccination Visit 1 
(Simultaneous group) with the group 
receiving IIV4 alone one to two 
weeks later at Vaccination Visit 2 
(Sequential group) following both 
Vaccination Visit 1 and 2 
Hypothesis: The proportion 
of participants with moderate 
or more severe fever, chills, 
myalgia or arthralgia will be 
noninferior (not higher) in the 
Simultaneous group versus 
the Sequential group. 
1a. Comparison of the proportion of 
participants reporting at least one solicited 
reactogenicity event to include fever, chills, 
myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group 
with the Sequential group within 1-7 days 
following both Vaccination Visit 1 and 
Vaccination Visit 2 
Secondary 
1. To compare the proportion of 
participants with moderate or more 
severe fever, chills, myalgia, or 
arthralgia in the Simultaneous 
versus the Sequential Group 
following the first vaccination visit 
1a. Comparison of the proportion of 
participants reporting at least one solicited 
reactogenicity event to include fever, chills, 
myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group 
with the Sequential group within 1-7 days 
following Vaccination Visit 1 visit during 
which participants receive either IIV4 or 
placebo with an mRNA COVID-19 vaccine 

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2. To compare the proportion of 
participants with moderate or more 
severe fever, chills, myalgia, or 
arthralgia in the Simultaneous 
versus Sequential Group following 
the second vaccination visit 
2a. Comparison of the proportion of 
participants reporting at least one solicited 
reactogenicity event to include fever, chills, 
myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group 
with the Sequential group within 1-7 days 
following Vaccination Visit 2 during which 
participants receive either IIV4 or placebo 
without an mRNA COVID-19 vaccine 
3. To describe the proportions of 
participants in the Simultaneous and 
Sequential vaccination groups with 
solicited local and systemic 
reactogenicity events according to 
severity grade after the first and 
second vaccination visit and third 
vaccination visit for those receiving 
two doses of mRNA COVID-19 
vaccine 
3a. The proportion of participants in each 
vaccination group reporting specified 
solicited local and systemic reactogenicity 
events of any severity and by severity 
grade within 1-7 days following the first 
vaccination visit during which participants 
receive either IIV4 or placebo with an 
mRNA COVID-19 vaccine 
3b. The proportion of participants in each 
vaccination group reporting specified 
solicited local and systemic reactogenicity 
events of any severity and by severity 
grade within 1-7 days following the second 
vaccination visit during which participants 
receive either IIV4 or placebo 
3c. The proportion of participants in each 
vaccination group reporting specified 
solicited local and systemic reactogenicity 
events of any severity and by severity 
grade within 1-7 days following the third 
vaccination visit during which all 
participants receive an mRNA COVID-19 
vaccine alone for those receiving two 
doses of mRNA COVID-19 vaccine 
4. To describe the proportions of 
participants in the Simultaneous and 
Sequential vaccination groups 
experiencing at least one serious 
adverse event and a description of 
these events 
4a. The proportion of participants in 
Simultaneous and Sequential Groups with 
at least one serious adverse event 
occurring during the study period and a 
description of each event 

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Exploratory 
1. To compare the proportion of 
participants with moderate or more 
severe fever, chills, myalgia, or 
arthralgia in the Simultaneous 
versus Sequential Group following 
the third vaccination visit for those 
receiving two doses of mRNA 
COVID-19 vaccine 
1a. Comparison of the proportion of 
participants reporting at least one solicited 
reactogenicity event to include fever, chills, 
myalgia, or arthralgia of moderate or 
greater severity in the Simultaneous group 
with the Sequential group within 1-7 days 
following Vaccination Visit 3 during which 
all participants receive an mRNA COVID- 
19 vaccine alone for those receiving two 
doses of mRNA COVID-19 vaccine 
2. To further characterize and describe 
the proportion of participants in the 
Simultaneous and Sequential groups 
with local or systemic reactogenicity 
events of greater severity following 
each vaccination visit and 
cumulatively 
2a. The proportion of participants reporting 
at least one moderate or greater or at least 
one severe or greater solicited local or 
systemic reactogenicity event in each 
vaccination group within 1-7 days following 
the first vaccination during which 
participants receive either IIV4 or placebo 
with an mRNA COVID-19 vaccine 
2b. The proportion of participants reporting 
at least one moderate or greater or at least 
one severe or greater solicited local or 
systemic reactogenicity event in each 
vaccination group within 1-7 days following 
the second vaccination visit which 
participants receive either IIV4 or placebo 
2c. The proportion of participants reporting 
at least one moderate or greater or at least 
one severe or greater solicited local or 
systemic reactogenicity event in each 
vaccination group within 1-7 days following 
the third vaccination visit during which all 
participants receive an mRNA COVID-19 
vaccine alone for those receiving two 
doses of mRNA COVID-19 vaccine 
2d. The proportion of participants reporting 
at least one moderate or greater or at least 
one severe or greater solicited local or 
systemic reactogenicity event in each 
vaccination group within 1-7 days following 
all vaccination visits combined 

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3. To describe the proportion of 
participants in Simultaneous and 
Sequential groups experiencing at 
least one unsolicited adverse event 
and one adverse event of special 
interest and to characterize these 
events 
3a. The proportion of participants in each 
vaccination group with an unsolicited 
adverse event occurring during the 7 days 
post each vaccination visit according to 
severity and system organ classification 
3b. The proportion of participants in each 
vaccination group with an adverse event of 
special interest occurring during the study 
period according to event type 
4. To compare the change of health- 
related quality of life (HRQOL) from 
baseline in the Simultaneous versus 
Sequential groups following the 
Vaccination Visit 1 
4a. Comparison between vaccination 
groups of the mean maximal change in 
score from baseline on the EuroQOL 5 
dimensions-5 level (EQ-5D-5L) and 
EuroQOL visual analogue scale (EQ VAS) 
within 1-7 days following the first 
vaccination visit 
5. To assess the safety profiles in the 
simultaneous and sequential group 
participants by baseline COVID-19 
serostatus 
5a. To compare secondary outcomes 3a, 
3b, 3c, and 4a according to baseline 
COVID-19 serostatus 
6. To assess the safety profiles in the 
simultaneous and sequential group 
participants by vaccine product 
(Pfizer or Moderna). 
6a. To compare secondary outcomes 3a, 
3b, 3c, and 4a according to vaccine 
product (Pfizer or Moderna). 
7. To assess the effect of simultaneous 
administration of IIV4 and COVID-19 
vaccine on IIV4 immunogenicity as 
assessed by hemagglutination 
inhibition assay (HAI) 
7a. The proportion of participants in each 
vaccination group with a seroprotective HAI 
titer (≥ 1:40) pre- and post-IIV4 
immunization for each IIV4 antigen 
7b. The proportion of participants in each 
vaccination group achieving 
seroconversion following IIV4 (an HAI titer 
> 1:40 following IIV4 if the baseline titer is < 
1:10 or a four-fold rise in HAI titer if the 
baseline titer is > 1:10) for each IIV4 
antigen 
7c. The geometric mean HAI titer (GMT) 
for each IIV4 antigen pre- and post-IIV4 in 
each vaccination group 
7d. The geometric mean fold rise (GMFR) 
in HAI titer for each vaccination group 
8. To assess serum antibody levels to 
SARS-CoV-2 antigens 
8a. The proportion of participants in each 
vaccination group seropositive to SARS- 
CoV-2 variants tested prior to and following 
mRNA COVID-19 vaccine 

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8b. 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 each vaccination 
group 
 
 
3 STUDY DESIGN 
3.1 Main study design 
This study is a prospective, randomized, clinical trial to assess the safety of simultaneous 
versus sequential administration of mRNA COVID-19 and IIV4 vaccines in 450 persons age ≥5 
years enrolled at Duke University Medical Center (Lead Contractor), Johns Hopkins University 
(Contributing Contractor), and Cincinnati Children’s Hospital Medical Center (Contributing 
Contractor). Participants will be enrolled in the 2021-2022 and 2022-2023 influenza seasons. 
Individuals will be enrolled who have not received their influenza vaccine during the influenza 
season during which they are recruited and are either receiving a booster dose of mRNA 
COVID-19 vaccine (for ages booster is authorized and recommended) or are receiving a 
primary two-dose mRNA COVID-19 vaccine series (5 years of age or older). Future mRNA 
COVID vaccines may include SARS-CoV-2 viral variants which may be included in this study if 
authorized or approved by the FDA and recommended by the CDC. Health, demographic and 
health-related quality of life (HRQOL) data will be collected from study participants 12 years of 
age or older at baseline. All participants receiving an mRNA COVID-19 vaccine on Day 1 (Visit 
1) will be randomized to receive quadrivalent inactivated influenza vaccine (IIV4) or placebo. 
Persons aged <65 years will receive standard dose IIV4 (SD-IIV4) or saline placebo injection. 
To qualify for the study, children < 9 years of age must only need to receive a single dose of 
IIV4 per ACIP recommendations for the 2022-2023 season. Persons aged ≥65 years will 
receive high-dose IIV4 (HD-IIV4) or saline placebo injection. Participants will receive the 
vaccines in an observer-blinded manner on the same day as they receive mRNA COVID-19 
vaccine. Seven to fourteen days later (Visit 2) those who received IIV4 at Visit 1 will receive 
placebo and those who received placebo on at Visit 1 will receive IIV4 (SD-IIV4 or HD-IIV4, 
depending upon age). Participants will then receive a second mRNA COVID-19 vaccine (Visit 
3), if applicable, and according to the recommended schedule for vaccination for the respective 
mRNA COVID-19 vaccine product used. 
 
With Day 1 serving as the initial day of vaccination, participants will be followed through Day 7 
(total 7 days) for solicited symptoms of reactogenicity as described in Section 5.4. HRQOL data 
will be collected during this time period for persons aged ≥ 12 years. Solicited reactogenicity 
events will also be monitored through Day 7 (total 7 days) following Visit 2 (all participants) and 
Visit 3 (only those participants receiving primary 2-dose COVID-19 vaccine series). Participants 
will also be followed for 7 days after each vaccination visit for unsolicited adverse events, 
through Day 120 for serious adverse events (SAEs) and through Day 120 for adverse events of 
special interest (AESI), as described in Section 5.4. 
 
3.2 Laboratory Studies 
 
3.2.1 Influenza Hemagglutination Inhibition Assay 

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mRNA COVID-19 vaccine naïve participants will have blood draws on Day 1 (before 
vaccination) and Day 21 (2021-2022 season) or Day 29 (2022-2023 season) (Pfizer/BioNTech 
mRNA vaccine) or Day 29 (Moderna mRNA post-IIV4 vaccination to be stored for serum 
hemagglutination inhibition (HAI) antibody titers. Those receiving a booster dose of mRNA 
COVID-19 vaccine will have blood draws on Day 1 (before vaccination) and Day 29. HAI 
antibody titers will be compared between groups receiving COVID-19 and IIV4 simultaneously 
or sequentially for each of the four influenza vaccine strains contained in the respective 
vaccines for that season. Participants will not receive individual HAI antibody titer results; these 
are not routinely used in clinical practice. 
 
3.2.2 SARS-CoV-2 Antibody Assay 
3.2.2.1 Qualitative baseline assessment 
Participants will have blood draws on day 1 (before vaccination) as noted in 3.2.1 
Serum will be assayed for the presence of SARS-CoV-2 antibody using the AdviseDx SARS- 
CoV-2 IgG II assay and the Alinity I SARS-CoV-2 IgG assay. The assays are intended for use 
as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2 indicating 
recent or prior infection. 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. The current tests described above are allowed under the FDA’s Emergency Use 
Authorization during the COVID-19 pandemic. Duke will share participant results with each 
study site as permitted by FDA and CDC. Study sites may share results with participant as 
permitted by FDA, CDC, and local site regulations. 
 
3.2.2.2 Quantitative SARS-CoV-2 assessments 
Participants will have blood draws on Day 1 (before vaccination) and following each vaccination 
according to schedules outlined in Section 5.1 to be stored for serum COVID-19 neutralization 
assays. COVID-19 neutralizing antibody titers will be compared between groups receiving 
COVID-19 and IIV4 simultaneously or sequentially for each variant tested. Participants will not 
receive individual COVID-19 antibody titer results; these are not routinely used in clinical 
practice. 
 
3.2.3 Future studies 
In addition to the specified analyses described thus far, there may be other tests or assays that 
have yet to be identified that may be important for interpreting our study findings or of relevance 
to vaccine outcomes. Additional laboratory assays may test for antibodies against other bacteria 
or viruses, markers of inflammation, or used in research on the health of the participants. 
Specimens banked for use in other studies will be linked to information (including identifying 
information) that participants provided to the study. Subjects/subject’s legally authorized 
representative (LAR) 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. 

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4 STUDY ENROLLMENT AND WITHDRAWAL 
4.1 Subject Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in this 
interventional study. 
1. Persons aged ≥5 years if receiving primary two-dose mRNA COVID-19 vaccine series or 
persons aged ≥12 years if receiving a booster mRNA COVID-19 vaccine dose according 
to FDA authorization or approval and ACIP recommendation. Note: receipt of an mRNA 
COVID-19 vaccine within 8 hours of enrollment is permitted 
* Individuals age 5-11 receiving a booster may be enrolled in the event a booster for 
individuals age 5-11 is authorized or approved and recommended by the ACIP. 
2. English or Spanish literate 
3. Intention of receiving influenza vaccine and mRNA COVID-19 vaccine based on ACIP- 
CDC guidelines 
4. Willing to provide written informed consent 
5. Intention of being available for entire study period and complete all relevant study 
procedures, including follow-up phone calls and clinic visits 
4.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in this 
study: 
1. Currently pregnant, planning to become pregnant within the first three months of the 
study per participant self-report or likely to be pregnant per screening criteria as defined 
in Section 5.1 at Visit 1 
2. Prior receipt of IIV4 during the respective influenza season in which they are being 
enrolled 
3. < 9 years of age and recommended to receive two doses of IIV4 during the respective 
influenza season in which they are being enrolled 
4. Prior receipt of non-mRNA COVID-19 vaccine 
5. Documented COVID-19 infection within 6 weeks prior to enrollment confirmed by either 
medical history or lab testing 
6. History of severe allergic reaction after a previous dose of any influenza vaccine; or to 
an influenza vaccine component, including egg protein 
7. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (e.g. anaphylaxis) to any component of an mRNA vaccine 
8. Receipt of any licensed inactivated vaccine within 2 weeks prior to enrollment in this 
study, receipt of any licensed live vaccine within 4 weeks prior to enrollment in this 
study, or receipt of Shingrix (Zoster Vaccine Recombinant, Adjuvanted) or HEPLISAV-B 
(Hepatitis B Vaccine (Recombinant), Adjuvanted) vaccine within 6 weeks prior to 
enrollment in this study or planning receipt of any vaccines following enrollment until 6 
weeks after receipt of the second dose of mRNA COVID-19 vaccine 
9. Has an active neoplastic disease (excluding non-melanoma skin cancer or prostate 
cancer that is stable in the absence of therapy) or a history of any hematologic 
malignancy* 
*Participants with a history of malignancy may be included if, after previous treatment by 
surgical excision, chemotherapy or radiation therapy, the participant has been observed 
for a period that in the investigator’s estimation provides a reasonable assurance of 
sustained cure 

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10. Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating 
intramuscular injection (a daily aspirin may be acceptable). 
11. Has immunosuppression as a result of an underlying illness or medications, such as 
antirejection/transplant regimens or immunomodulatory agents. Stable HIV disease is 
permitted per the following parameters: 
a. Confirmed stable HIV disease defined as document viral load <50 copies/mL and 
CD4 count >200 within 6 months before enrollment, and on stable antiretroviral 
therapy for at least 6 months 
12. Has known hepatitis B (HBV) or hepatitis C (HBC). Stable HBV or HBC are permitted 
per the following parameters: 
a. If known HBV: confirmed inactive chronic HBV infection: HBsAg present for ≥6 
months and HBeAg negative, anti-HBe positive; serum HBV DNA <2000 IU/mL; 
persistently normal ALT or AST levels; in those who had liver biopsy, findings 
that confirm absence of significant necroinflammation 
b. If known HCV: evidence of sustained virological response for ≥12 weeks after 
treatment or without evidence of HCV RNA viremia (undetectable HCV RNA) 
13. Use of oral, parenteral, or high-dose inhaled glucocorticoids* 
*For definition of high-dose inhaled glucocorticoids, reference Appendix B. 
14. History of Guillain-Barré syndrome 
15. Prior enrollment in this study during the 2021-22 flu season 
16. Anyone who is already enrolled or plans to enroll in another 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. 
17. Hearing loss determined by the investigators to prevent successful communication over 
the phone 
18. History of myocarditis or pericarditis 
19. History of multisystem inflammatory syndrome in children (MIS-C) or adults (MIS-A). 
20. Has injury or other reason why deltoid site on both arms cannot be used for 
vaccinations. 
21. 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. 
22. Anyone who is a relative of any research study personnel. 
23. Anyone who is an employee of any research study personnel. 
4.3 Temporary Delay Criteria (Visit 1, 2 and 3 (for primary COVID-19 vaccine series)) 
1. History of febrile illness (> 100.0°F or 37.8°C) within the past 72 hours prior to vaccine 
administration 
4.4 Recruitment 
Potential participants ≥5 years of age will be recruited from several sources at Duke University 
Medical Center (DUMC), Johns Hopkins University (JHU), and Cincinnati using varying 
techniques. Study investigators will enroll at least 450 persons over two influenza seasons 
(2021-2022 and 2022-2023). Approximately 160 will be enrolled at Duke, 160 will be enrolled at 
Johns Hopkins, and 130 at Cincinnati Children’s Hospital. 

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The general techniques for how subjects will be recruited include the following: Study staff, 
including PIs and clinical research coordinators will approach patients/patient’s LAR(s) seen 
during clinic visits about the study; notify other health care professionals in their health system 
about the study via letters and flyers for potential referrals; notify potential subjects/ subject’s 
LAR(s) about the study via study registries and recruitment service programs. More specific 
mechanisms to DUMC, JHU, and Cincinnati are described below. In addition, research staff will 
work with local COVID-19 vaccination clinics to recruit study participants. 
 
At DUMC, we will plan to enroll persons for whom the COVID-19 vaccine is recommended by 
the ACIP. Duke will plan to work with Duke Employee Health and Wellness (OEHW) to identify 
employees that have not yet been vaccinated or may require a COVID-19 vaccine booster dose. 
Duke will then use that list of healthcare workers in an effort to assist with recruitment. In 
addition, Duke will partner with local COVID-19 vaccination clinics and other Duke clinics for 
potential participant referrals. For the proposed study, we will not enroll long-term care facility 
residents. These sources are likely to be sufficient, but if not, we will utilize other past 
successful strategies such as a letter campaign to households of older adults and advertising in 
senior citizen newspapers and general local newspapers. 
 
At JHU, we will also enroll people for whom the COVID-19 vaccine is recommended by the 
ACIP. For community outreach, we partner with local broadcast, cable television, and OTT 
(over-the-top) providers to run 15 and 30 second commercials that are IRB-approved under our 
general screening protocol. In addition, the Center for Immunization Research (CIR) has its own 
website (https://centerforimmunizationresearch.org/) which includes a “Join A Study” page 
dedicated to recruitment for upcoming studies. The CIR has also partnered with local 
community organizations to increase awareness of and community involvement in clinical trials 
of coronavirus vaccines. This includes community organizations in the African American 
community as well as the LatinX community. We have Spanish-speaking staff who can enroll 
and consent subjects in Spanish. 
 
The CIR maintains a recruitment tracking system that securely stores contact information for 
previous study participants and others who have previously contacted the Center. CIR staff may 
contact those people who have expressed permission to be contacted for future studies as an 
additional recruitment method. In addition to our dedicated recruitment phone line, people can 
contact us directly via our CIR Facebook, Twitter, and website to learn about our studies. 
 
In order to recruit health care workers and other frontline workers, specifically targeted 
advertisements will be used in health care settings to recruit those workers. For the 2021-2022 
season, in order to recruit healthcare workers, we may partner with Occupational health so that 
workers are informed of the study at the time of the annual influenza vaccination. 
 
At Cincinnati Children’s Hospital Medical Center (CCHMC), we will also enroll persons for whom 
the COVID-19 vaccine is recommended by the ACIP. We have been very successful in 
recruiting adults through email advertisements to our employee population. We have over 
16,000 employees, and we have recruited successfully from this population and their friends 
and family members for many trials. We will also reach out to the public vaccination clinic at 
CCHMC, which is now vaccinating individuals ages 5 and over with COVID-19 vaccine. We may 
recruit pediatric participants with direct outreach to patients scheduled to receive a COVID-19 
vaccine at our Pediatric Primary Care Clinic. In regard to older adults, we will continue to 

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collaborate with our local retirement communities to recruit and enroll older adults. We will not 
enroll long-term care facility residents for this study. We have successfully enrolled older adults 
for previous vaccine trials from our collaborating retirement community, Maple Knoll Village. We 
believe that these resources will be sufficient, but if not, we will utilize other past successful 
strategies like our vaccine trial participant database and advertisements in local medical offices, 
hospitals, and retirement communities. 
 
At all sites, existing patients or their parent(s)/LAR(s) may be approached by phone call. The 
study will be reviewed with the patient or their parent(s)/LAR(s), and if the patient is interested, 
then initial eligibility screening will take place on the phone following an IRB-approved script. A 
waiver of documentation of consent will be approved from the reviewing IRB in order to carry out 
these screening activities. 
 
4.5 Reasons for and Handling of Withdrawals 
The following may be reason for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI). 
• 
Subject or parent(s)/LAR(s) withdrawal of consent. 
• 
Loss to follow-up. 
• 
Subject unable to return for study appointments 
• 
Termination of the study by the sponsor 
 
Subjects or their parent(s)/LAR(s) may withdraw their consent for study participation at any time 
and for any reason, without penalty. Subjects who withdraw from the study prior to 
randomization will be replaced. Subjects who withdraw from the study after randomization will 
not be replaced. Data collected before withdrawal will still be used for analysis. 
 
4.6 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 and data collection 
Persons meeting the proposed eligibility criteria (Section 4) will be recruited. Written informed 
consent will be obtained from study participants/participant’s LAR(s) prior to conducting any 
study procedures. Prescreening may take place over the phone prior to Visit 1. Tables 5-7 
describe the schedule of study visits with further details below for the BNT162b2 and mRNA- 
1273 COVID-19 vaccines, respectively. 

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5.1.1 Primary Two-Dose COVID-19 Series Schedule of Events 
 
Table 5: BNT162b2 (Pfizer-BioNTech) Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 31 
Visit 3a 
Visit 3b 
Visit 42 
Visit 5 
Visit 6 
Un- 
Scheduled 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Phone/ 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-15(+6) 
29 
22-57 
22-57(+6) 
36-43 
50-85 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
21-56 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Time Following Visit 3a 
(Days) [Window] 
0-6 
28 [+/-4] 
Informed consent & 
Medical Release of 
Information 
X 
Review Eligibility Criteria 
X 
Review Temporary Delay 
Criteria 
X 
X 
X6 
Demographic and Health 
History 
X 
Influenza and COVID-19 
Vaccination History 
X 
Obtain unsolicited adverse 
events 
X 
X 
X 
X 
Obtain SAE and AESI 
information 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Additional COVID-19 
vaccinations 
X 
HRQOL measure7 
X 
X 
Measure temperature 
X 
X 
X6 
X 
Venipuncture 
X 
X 
X 
X 
Randomization 
X 
Vaccination with COVID- 
19 vaccine 
X8 
X9,10 

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Table 5: BNT162b2 (Pfizer-BioNTech) Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 31 
Visit 3a 
Visit 3b 
Visit 42 
Visit 5 
Visit 6 
Un- 
Scheduled 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Phone/ 
Clinic 
Phone/Text 
/Email/Data 
Review3.4.5 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-15(+6) 
29 
22-57 
22-57(+6) 
36-43 
50-85 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
21-56 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Time Following Visit 3a 
(Days) [Window] 
0-6 
28 [+/-4] 
Vaccination with IIV4 or 
Placebo 
X 
X 
Memory Aid, Link to 
electronic symptom diary 
given to participant 
X 
X 
X 
Assess for any immediate 
reactogenicity symptoms 
X 
X 
X 
Electronic Diary Review3 
X 
X 
X 
Complete electronic or 
paper symptom diary1 
X 
X 
X 
X 
X 
X 
 
1. 
Note that Visit 3 is timed relative to Visit 1 but may be conducted on the same day as Visit 3a if Visit 3a occurs 24-28 days after Visit 1. Visit 3 and Visit 4 should 
not occur on the same day. 
2. 
Note that Visit 4 is timed relative to Visit 2 and may be conducted on the same day as Visit 3a if Visit 3a occurs 24-28 days after Visit 2. Visit 3 and Visit 4 should 
not occur on the same day. 
3. 
Symptom diary (solicited local and systemic reactogenicity events) to be completed by participant on Days 1-7 after vaccination. 
4. 
Participants completing paper diary only will be called 2-4 days following Visits 1, 2, and 3 as a reminder and to prompt to bring paper diary to next visit 
5. 
Electronic diary records will be reviewed by study staff at days 2-4 days and 8-10 days following Visit 1, 2 and 3. 
6. 
If Visit 3a is conducted by telephone as standard of care these procedures do not need to be performed 
7. 
HRQOL will only be collected for participants 12 years of age and older. 
8. 
Receipt of BNT162b2 within 8 hours of enrollment is permitted 
9. 
Receipt of BNT162b2 within 36 hours prior to study visit is permitted 
10. Extended interval beyond 25 days not recommended for persons < 12 years of age 

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Table 6: mRNA-1273 (Moderna) Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 31 
Visit 3a 
Visit 3b 
Visit 42 
Visit 5 
Visit 6 
Un- 
Scheduled 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5 
Clinic 
Phone/ 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5l 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-15(+6) 
29 
29-57 
29-57(+6) 
36-43 
57-85 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
28-56 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Time Following Visit 3a 
(Days) [Window] 
0-6 
28 [+/-4] 
Informed consent & 
Medical Release of 
Information 
X 
Review Eligibility Criteria 
X 
Review Temporary Delay 
Criteria 
X 
X 
X6 
Demographic and Health 
History 
X 
Influenza and COVID-19 
Vaccination History 
X 
Obtain unsolicited adverse 
events 
X 
X 
X 
X 
Obtain SAE and AESI 
information 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Additional COVID-19 
vaccinations 
X 
HRQOL measure7 
X 
X 
Measure temperature 
X 
X 
X6 
X 
Venipuncture 
X 
X4 
X4 
X 
Randomization 
X 
Vaccination with COVID- 
19 vaccine 
X8 
X9,10 
Vaccination with IIV4 or 
Placebo 
X 
X 

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Table 6: mRNA-1273 (Moderna) Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 31 
Visit 3a 
Visit 3b 
Visit 42 
Visit 5 
Visit 6 
Un- 
Scheduled 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5 
Clinic 
Phone/ 
Clinic 
Phone/Text 
/Email/Data 
Review3,4,5l 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-15(+6) 
29 
29-57 
29-57(+6) 
36-43 
57-85 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
28-56 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Time Following Visit 3a 
(Days) [Window] 
0-6 
28 [+/-4] 
Memory Aid, Link to 
electronic symptom diary 
given to participant 
X 
X 
X 
Assess for any immediate 
reactogenicity symptoms 
X 
X 
X 
Electronic Diary Review2 
X 
X 
X 
Complete electronic 
symptom diary1 
X 
X 
X 
X 
X 
X 
1. 
Note that Visit 3 is timed relative to Visit 1 but may be conducted on the same day as Visit 3a if Visit 3a occurs 24-32 days after Visit 1. Visit 3 and Visit 4 should 
not occur on the same day. 
2. 
Note that Visit 4 is timed relative to Visit 2 and may be conducted on the same day as Visit 3a if Visit 3a occurs 24-32 days after Visit 2. Visit 3 and Visit 4 should 
not occur on the same day. 
3. 
Symptom diary (solicited local and systemic reactogenicity events) to be completed by participant on Days 1-7 after vaccination. 
4. 
Participants completing paper diary only will be called 2-4 days following Visits 1, 2, and 3 as a reminder and to prompt to bring paper diary to next visit 
5. 
Electronic diary records will be reviewed by study staff at days 2-4 days and 8-10 days following Visit 1, 2 and 3. 
6. 
If Visit 3a is conducted by telephone as standard of care these procedures do not need to be performed 
7. 
HRQOL will only be collected for participants 12 years of age and older. 
8. 
Receipt of BNT162b2 within 8 hours of enrollment is permitted 
9. 
Receipt of BNT162b2 within 36 hours prior to study visit is permitted 
10. Extended interval beyond 32 days not recommended for persons < 12 years of age 

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Visit 1, Study Day 1 - Screening, Enrollment, and Vaccination (Clinic Visit) 
• 
Obtain written informed consent and release of medical record information 
• 
Obtain information on preferred method of contact for follow-up (telephone, text or 
email) 
• 
Review and confirm study eligibility and temporary delay criteria including pregnancy 
status and pregnancy intention for women of childbearing potential. 
For women of childbearing potential only, the study team can assess likelihood of 
pregnancy based upon the following criteria if there are concerns regarding pregnancy. 
If yes to any, can be reasonably certain not pregnant if no symptoms or signs of 
pregnancy. 
o Is ≤ 7 days after the start of menses 
o Has not had sexual intercourse since the start of last menses 
o Has been consistently using a reliable method of contraception 
o Is ≤ 7 days after spontaneous or induced abortion 
o Is within 4 weeks postpartum 
o Is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast 
majority [≥ 85%] of feeds are breastfeeds), amenorrheic and < 6 months 
postpartum 
• 
Obtain demographic and medical history including history of influenza and COVID-19 
vaccination and reported PCR test positive COVID-19 infection 
• 
Obtain concomitant medication use in preceding 30 days 
• 
Obtain baseline HRQOL assessment (for participants 12 years of age and older) 
• 
Obtain oral temperature 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5- 
11 years of age prior to vaccination for serologic analysis (Section 5.6.1) 
• 
Randomize study participant to observer-blinded IIV4 or placebo (Section 5.6.1) 
• 
Participant will either receive or have just received (within 8 hours) mRNA COVID-19 
vaccine per local standard of care or mRNA COVID-19 vaccine will be administered in 
the deltoid muscle by trained, licensed research staff. 
• 
Trained, licensed unblinded staff will administer study product (IIV4 or placebo) in the 
opposite deltoid muscle in which mRNA COVID-19 vaccine was administered 
• 
 Ensure participants/participant’s LAR(s) receive the IIV4 Vaccine Information Sheet 
(VIS)39 and/or the respective fact sheet for recipients and caregivers for mRNA 
COVID-19 vaccine during visit13,43. 
• 
Dispense paper memory aid (if subject selects paper), thermometer, and ruler (in order 
to standardize measurements). Review instructions for use of thermometer, ruler, and 
electronic memory aid completion. 
• 
Observe participant for a minimum of 30 minutes and assess for any immediate 
reactogenicity symptoms 
• 
Confirm date of next appointment 
 
Visit 1a, Study Days 1 – 7 Post Visit 1 
• 
Participants/participant’s LAR(s) complete electronic or paper solicited symptom diary 
and HRQOL assessment at approximately the same time each day for days 1-7 
• 
Participants/participant’s LAR(s) using paper diary: 

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o Study staff will call participants/participant’s LAR(s) on 2-4 days following Visit 1 
as a reminder to fill out the symptom diary and HRQOL assessments on day 1-7 
post Visit 1 regarding reactogenicity events and to bring the diary card to the next 
visit. 
o Participants/participant’s LAR(s) will be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
• 
Participants/participant’s LAR(s) using REDCap web-based system: 
o Study staff will send daily reminders to fill out the symptom diary and HRQOL 
o Study staff will review REDCap system to confirm data capture and assess for 
any AE or SAEs 2-4 days and 8-10 days following Visit 1. 
o The study team will contact participants/participant’s LAR(s) if they have any 
missing information. The study team may also contact participants if more 
information is needed to better describe AEs [including SAEs and severe (Grade 
3) events] reported in the REDCap web-based system. 
o All participants/participant’s LAR(s) using the REDCAP web-based system will 
be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
 
Visit 2, Study Day 8-15 Clinic Visit 
• 
Review any temporary delay criteria 
• 
Record any unsolicited AEs within the first 7 days post-vaccination, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain oral temperature 
• 
Trained, licensed unblinded staff will administer IIV4 or placebo in the deltoid muscle 
as described in Section 5.3.1. 
• 
Ensure participants/participant’s LAR(s) receive the IIV4 Vaccine Information Sheet 
(VIS) 
• 
Ensure participants/participant’s LAR(s) receive IIV4 Vaccine Verification 
• 
Dispense paper memory aid, thermometer if needed, and ruler if needed (in order to 
standardize measurements). Review instructions for use of thermometer, ruler, and 
electronic memory aid completion. 
• 
Observe participant for a minimum of 30 minutes and assess for any immediate 
reactogenicity symptoms 
• 
Confirm date of next appointment 
 
Visit 2a, Study Days 1 – 7 Post Visit 2 
• 
Participants/participant’s LAR(s) complete electronic or paper solicited symptom diary 
each day at approximately the same time each day for days 1-7 
• 
Participants/participant’s LAR(s) using paper diary: 
o Study staff will call participants/participant’s LAR(s) on days 2-4 following Visit 

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2 as a reminder to fill out the symptom diary on day 1-7 post Visit 2 regarding 
reactogenicity events and to bring the diary card to the next visit. 
o Participants/participant’s LAR(s) will be: 
 
 Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare if they have symptoms 
they find concerning 
• 
Participants/participant’s LAR(s) using REDCap web-based system: 
o Study staff will send reminders to fill out the symptom diary on day 1-7 post Visit 
2 regarding reactogenicity events. 
o Study staff will review REDCap system to confirm data capture and assess for 
any AE or SAEs 2-4 days and 8-10 days following Visit 2 
o The study team will contact participants/participant’s LAR(s) if they have any 
missing information. The study team may also contact participants/participant’s 
LAR(s) if more information is needed to better describe AEs [including SAEs 
and severe (Grade 3) events] reported in the REDCap web-based system. 
o All participants/participant’s LAR(s) using the REDCAP web-based system will 
be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
 
Visit 3 Study Day 29 (BNT162b2 or mRNA-1273) Clinic Visit 
• 
Record any unsolicited AEs within the first 7 days post-vaccination, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5- 
11 years of age prior to vaccination for serologic analysis (Section 5.6.1) 
• 
Confirm date of next appointment 
 
Visit 3a, Study Day 22-57 (BNT162b2) or 29-57 (mRNA-1273) Phone/Clinic Visit 
• 
Review and confirm study eligibility and temporary delay criteria 
• 
Record any unsolicited AEs within the first 7 days post-vaccination, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain oral temperature 
• 
Participant will either receive or have just received (within 36 hours) mRNA COVID-19 
vaccine per local standard of care or mRNA COVID-19 vaccine will be administered in 
the deltoid muscle by trained, licensed research staff.as described in Section 5.3.1. 
• 
Ensure participants/participant’s LAR(s) receive the respective fact sheet for mRNA 
COVID-19 vaccine during visit. 
• 
Dispense paper memory aid, thermometer if needed, and ruler if needed (in order to 
standardize measurements). Review instructions for use of thermometer, ruler, and 
electronic memory aid completion. 
• 
Observe participant for a minimum of 30 minutes (if mRNA COVID-19 vaccine is given 
at the study visit) and assess for any immediate reactogenicity symptoms 
• 
Confirm date of next appointment 

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Visit 3b, Study Days 1 – 7 Post Visit 3 
• 
Participants/participant’s LAR(s) complete electronic or paper solicited symptom diary 
each day at approximately the same time each day for days 1-7 
• 
Participants/participant’s LAR(s) using paper diary: 
o Study staff will call participants/participant’s LAR(s) on days 2-4 following Visit 
3 as a reminder to fill out the symptom diary on day 1-7 post Visit 3 regarding 
reactogenicity events and to bring the diary card to the next visit 
o Participants/participant’s LAR(s) will be: 
 
 Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
• 
Participants/participant’s LAR(s) using REDCap web-based system: 
o Study staff will send reminders to fill out the symptom diary on day 1-7 post Visit 
3 regarding reactogenicity events. 
o Study staff will review REDCap system to confirm data capture and assess for 
any AE or SAEs on 2-4 days and 8-10 days following Visit 3 
o The study team will contact participants/participant’s LAR(s) if they have any 
missing information. The study team may also contact participants/participant’s 
LAR(s) if more information is needed to better describe AEs [including SAEs 
and severe (Grade 3) events] reported in the REDCap web-based system. 
o All participants/participant’s LAR(s) using the REDCAP web-based system will 
be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
 
Visit 4, Study Day 36-43 (BNT162b2 or mRNA-1273 vaccine) Clinic Visit 
• 
Record any unsolicited AEs within the first 7 days post-vaccination, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5- 
11 years of age prior to vaccination for serologic analysis (Section 5.6.1) 
• 
Confirm date of next appointment 
 
Visit 5, Study Day 50-85 (BNT162b2) or 57-85 (MRNA-1273) Clinic Visit 
• 
Record any SAEs and AESI 
• 
Obtain concomitant medication use 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5- 
11 years of age prior to vaccination for serologic analysis (Section 5.6.1) 
 
Visit 6, Study Day 121 Phone Visit 
• 
Record any additional COVID-19 vaccinations since Visit 3a 
• 
Record any SAEs and AESI 
• 
Obtain concomitant medication use 

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Unscheduled Visits 
• 
Obtain vital signs including oral temperature 
• 
Review any solicited (≤ day 7) AEs submitted electronically, unsolicited AEs, SAEs, 
AESI, and concomitant medications (throughout period of enrollment) 
 
5.1.2 Booster Dose mRNA COVID-19 Vaccine Schedule of Events 
 
Table 7: Booster Dose Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 3 
Visit 4 
Visit 5 
Un- 
Scheduled 
Clinic 
Phone/Text 
Email/Data 
Review1,2,3 
Clinic 
Phone/Text 
Email/Data 
Review1,2,3 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-21 
29 
36-43 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Informed consent & 
Medical Release of 
Information 
X 
Review Eligibility Criteria 
X 
Review Temporary Delay 
Criteria 
X 
X 
Demographic and Health 
History 
X 
Influenza and COVID-19 
Vaccination History 
X 
Obtain unsolicited adverse 
events 
X 
X 
X 
Obtain SAE and AESI 
information 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Additional COVID-19 
vaccinations 
X 
HRQOL measure4 
X 
X 
Measure temperature 
X 
X 
X 
Venipuncture 
X 
X 
X 
Randomization 
X 
Vaccination with COVID- 
19 vaccine 
X5 
Vaccination with IIV4 or 
Placebo 
X 
X 
Memory Aid, Link to 
electronic symptom diary 
given to participant 
X 
X 
Assess for any immediate 
reactogenicity symptoms 
X 
X 
Electronic Diary Review2 
X 
X 

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Table 7: Booster Dose Schedule of Events 
Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 2a 
Visit 3 
Visit 4 
Visit 5 
Un- 
Scheduled 
Clinic 
Phone/Text 
Email/Data 
Review1,2,3 
Clinic 
Phone/Text 
Email/Data 
Review1,2,3 
Clinic 
Clinic 
Phone 
Clinic 
Estimated 
Study Day 
(Relative to Visit 1) 
1 
1-7 
8-15 
8-21 
29 
36-43 
121 
Time Following Visit 1 
(Days) [Window] 
0 
0-6 
7-14 [+2] 
28 [+/-4] 
120 (+/-14) 
Time Following Visit 2 
(Days) [Window] 
0-6 
28 [+/-4] 
Complete electronic 
symptom diary1 
X 
X 
X 
X 
1 Symptom diary (solicited local and systemic reactogenicity events) to be completed by participant on Days 1-7 after 
vaccination. 
2 Participants completing paper diary only will be called at days 3 [+2] and 17[+2] as a reminder and to prompt to 
bring paper diary to next visit 
3 Electronic diary records will be reviewed by study staff at day 3[+2], 8[+2], 17[+2], and 22[+2] for completion or 
issues. 
4 HRQOL will only be collected for participant 12 years of age and older. 
5 Receipt of mRNA-1273 or BNT162b2 within 8 hours of enrollment is permitted 
 
Visit 1, Study Day 1 - Screening, Enrollment, and Vaccination (Clinic Visit) 
• 
Obtain written informed consent and release of medical record information 
• 
Obtain information on preferred method of contact for follow-up (telephone or email) 
• 
Review and confirm study eligibility and temporary delay criteria including pregnancy status 
and pregnancy intention for women of childbearing potential. 
For women of childbearing potential only, the study team can assess likelihood of 
pregnancy based upon the following criteria if there are concerns regarding pregnancy. 
If yes to any, can be reasonably certain not pregnant if no symptoms or signs of 
pregnancy. 
o Is ≤ 7 days after the start of menses 
o Has not had sexual intercourse since the start of last menses 
o Has been consistently using a reliable method of contraception 
o Is ≤ 7 days after spontaneous or induced abortion 
o Is within 4 weeks postpartum 
o Is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast 
majority [≥ 85%] of feeds are breastfeeds), amenorrheic and < 6 months 
postpartum 
• 
Obtain demographic and medical history including history of influenza and COVID-19 vaccination 
and reported PCR test positive COVID-19 infection 
• 
Obtain concomitant medication use in preceding 30 days 
• 
Obtain baseline HRQOL assessment (for participants 12 years of age and older) 
• 
Obtain oral temperature 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5-11 
years of age prior to vaccination for serologic analysis (Section 5.6.1) 
• 
Randomize study participant to observer-blinded IIV4 or placebo (Section 5.6.1) 
• 
Participant will either receive or have just received (within 8 hours) mRNA COVID-19 
vaccine per local standard of care or mRNA COVID-19 vaccine will be administered in 

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the deltoid muscle by trained, licensed research staff. 
• 
Trained, licensed unblinded staff will administer study product (IIV4 or placebo) in the 
opposite deltoid muscle in which mRNA COVID-19 vaccine was administered 
• 
Ensure participants/participant’s LAR(s) receive the IIV4 Vaccine Information Sheet 
(VIS)39 and/or the respective fact sheet for recipients and caregivers for mRNA COVID-19 
vaccine during visit13,43. 
• 
Dispense paper memory aid (if subject selects paper), thermometer, and ruler (in order to 
standardize measurements). Review instructions for use of thermometer, ruler, and 
electronic memory aid completion. 
• 
Observe participant for a minimum of 30 minutes and assess for any immediate 
reactogenicity symptoms 
• 
Confirm date of next appointment 
 
Visit 1a, Study Days 1 – 7 Post Visit 1 
• 
Participants/participant’s LAR(s) complete electronic or paper solicited symptom diary 
and HRQOL assessment at approximately the same time each day for days 1-7 
• 
Participants/participant’s LAR(s) using paper diary: 
o Study staff will call participants/participant’s LAR(s) on days 2-4 following Visit 1 
as a reminder to fill out the symptom diary and HRQOL assessments on day 1-7 
post Visit 1 regarding reactogenicity events and to bring the diary card to the next 
visit. 
o Participants/participant’s LAR(s) will be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
• 
Participants/participant’s LAR(s) using REDCap web-based system: 
o Study staff will send daily reminders to fill out the symptom diary and HRQOL 
o Study staff will review REDCap system to confirm data capture and assess for 
any AE or SAEs on 2-4 days and 8-10 days following Visit 1. 
o The study team will contact participants/participant’s LAR(s) if they have any 
missing information. The study team may also contact participants/participant’s 
LAR(s) if more information is needed to better describe AEs [including SAEs and 
severe (Grade 3) events] reported in the REDCap web-based system. 
o All participants/participant’s LAR(s) using the REDCAP web-based system will 
be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
 
Visit 2, Study Day 8 - 15 Clinic Visit 
• 
Review any temporary delay criteria 
• 
Record any unsolicited AEs within the first 7 days post-vaccination, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain oral temperature 

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• 
Trained, licensed unblinded staff will administer IIV4 or placebo in the deltoid muscle as 
described in Section 5.3.1. 
• 
Ensure participants/participant’s LAR(s) receive the IIV4 Vaccine Information Sheet (VIS) 
• 
Ensure participants/participant’s LAR(s) receive IIV4 Vaccine Verification 
• 
Dispense paper memory aid, thermometer if needed, and ruler if needed (in order to 
standardize measurements). Review instructions for use of thermometer, ruler, and 
electronic memory aid completion. 
• 
Observe participant for a minimum of 30 minutes and assess for any immediate 
reactogenicity symptoms 
• 
Confirm date of next appointment 
 
Visit 2a, Study Days 1 – 7 Post Visit 2 
• 
Participants/participant’s LAR(s) complete electronic or paper solicited symptom diary 
each day at approximately the same time each day for days 1-7 post Visit 2 
• 
Participants/participant’s LAR(s) using paper diary: 
o Study staff will call participants/participant’s LAR(s) on day 3 post Visit 2 as a 
reminder to fill out the symptom diary on day 1-7 post Visit 2 regarding 
reactogenicity events and to bring the diary card to the next visit. 
o Participants/participant’s LAR(s) will be: 
 
 Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare if they have symptoms 
they find concerning 
• 
Participants/participant’s LAR(s) using REDCap web-based system: 
o Study staff will send reminders to fill out the symptom diary on day 1-7 post Visit 
2 regarding reactogenicity events. 
o Study staff will review REDCap system to confirm data capture and assess for 
any AE or SAEs on 2-4 days and 8-10 days following Visit 2. 
o The study team will contact participants/participant’s LAR(s) if they have any 
missing information. The study team may also contact participants/participant’s 
LAR(s) if more information is needed to better describe AEs [including SAEs 
and severe (Grade 3) events] reported in the REDCap web-based system. 
o All participants/participant’s LAR(s) using the REDCAP web-based system will 
be: 
 
Asked to notify the study staff if they or their child is hospitalized or 
have a severe adverse event 
 
Follow up with their or their child’s healthcare provider if they have 
symptoms they find concerning 
 
Visit 3, Study Day 29 Clinic Visit 
• 
Record any unsolicited AEs, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5-11 
years of age prior to vaccination for serologic analysis (Section 5.6.1) 
• 
Confirm date of next appointment 

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Visit 4, Study Day 36 - 43 Clinic Visit 
• 
Record any unsolicited AEs, SAEs, AESI 
• 
Obtain concomitant medication use 
• 
Obtain 10mL blood sample for those ≥ 12 year of age and 5mL blood sample for those 5-11 
years of age prior to vaccination for serologic analysis (Section 5.6.1) 
 
Visit 5, Study Day 121 Phone Visit 
• 
Record any additional COVID-19 vaccinations since Visit 1 
• 
Record any SAEs and AESI 
• 
Obtain concomitant medication use 
 
Unscheduled Visits 
• 
Obtain vital signs including oral temperature 
• 
Review any solicited (≤ day 7) AEs submitted electronically, unsolicited AEs, SAEs, AESI, 
and concomitant medications (throughout period of enrollment) 
 
5.2 Treatment Assignment Procedures 
This study is a prospective, randomized, observer-blinded, clinical trial involving subjects aged 
≥5 years of age who are to receive COVID-19 and IIV4 vaccines. 
 
5.2.1 Randomization 
Participants will be randomized (1:1) to receive either IIV4 or saline by an unblinded vaccinator 
at Visit 1. Those receiving IIV4 at visit 1 will receive saline placebo at Visit 2 and those 
receiving saline placebo at Visit 1 will receive IIV4 at Visit 2. Randomization will be stratified by 
age (5 to < 12 years of age, 12 to < 18 years of age, 18 to <65 years of age, and ≥ 65 years of 
age) and receipt of either a primary two-dose series or any booster dose of mRNA COVID-19 
vaccine (for ages booster is authorized and recommended) using a permuted block 
randomization scheme stratified by Lead and Contributing Sites. The project statistician will 
generate permuted block randomization schemes which will be uploaded to REDCap. The 
randomization schedule will not be available to the study staff, so the next randomization 
allocation will not be known before randomization occurs. Following confirmation of study 
eligibility criteria during Visit 1, participant randomization will be through REDCap with treatment 
allocation recorded on the unblinded vaccinator CRF. In the event that REDCap is unavailable, 
manual randomization will occur through the use of envelopes. The project statistician will 
prepare 10 envelopes per age group and vaccine series per site (total of 60 per site) that will 
use the same randomization strategy as the primary scheme embedded in REDCap. When an 
unblinded team member is informed of the age group, he/she will pull the next envelope in 
order. In order to capture the allocation per subject, a separate form in REDCap will be used by 
the unblinded personnel to add the assignment. A log will need to be kept at the site capturing 
these instances. 
5.3 Data Collection 
5.3.1 Study Product Supply, Storage, and Administration 
In order to ensure adherence to study randomization assignment, age-appropriate, licensed IIV4 
or saline placebo will be administered as a study procedure. EUA or approved mRNA COVID- 
19 vaccine will be administered either per standard of care or as a study procedure depending 

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on the study site and location. Licensed SD-IIV4 and HD-IIV4 vaccine (prefilled syringes) will be 
purchased for study administration and maintained at the study sites and stored at 2°C to 8°C in 
a research-specific medication refrigerator. Licensed or EUA COVID-19 vaccine will be stored 
per manufacturer specifications. While research staff maintain daily temperature logs for the 
medication storage, it is also monitored 24/7 with alarm activation if out of range. Research staff 
are notified of any alarm activations and have an on-call system in place to report to the 
research center for further investigation. Any potentially compromised vaccine will be 
quarantined for further disposition based on site-specific SOPs and investigator assessment. 
A licensed unadjuvanted standard dose egg-based IIV4 will be the designated study product for 
influenza vaccination of persons less than 65 years of age44. Study sites will work to coordinate 
the brand of IIV4 administered. A single administration of IIV4 comprises intramuscular delivery 
of 0.5mL total volume of the vaccine for persons 5 through 64 years of age. 
Fluzone High-Dose (Sanofi) will be the designated study products for influenza vaccination of 
persons 65 years of age and older. A single administration of HD-IIV4 comprises intramuscular 
delivery of 0.7mL total volume of the vaccine for adults 65 years of age and older. 
Sterile normal saline supplied by each site’s respective pharmacy will be used as placebo. A 
single administration of placebo comprises intramuscular deliver of 0.5 mL total volume of 
normal saline for persons 5 through 64 years of age and 0.7 mL total volume for those 65 years 
of age and older. 
mRNA COVID-19 vaccine will be administered per FDA and ACIP recommendations for 
administration. The primary two-doses mRNA COVID-19 vaccine series will be administered in 
two doses, approximately 21 to 56 days or 28 to 56 days apart depending upon the FDA or 
CDC recommendations. The booster dose of mRNA COVID-19 vaccine will be administered 
according to FDA authorization or EUA and ACIP recommendation. 
Vaccine lot numbers, dose, and site of vaccine administration will be recorded by research staff. 
After administration, used study syringes will be disposed of according to standard operating 
procedure. 
Emergency management supplies including epinephrine (1:1000) and trained staff will be 
available for initial treatment of an allergic reaction, if needed. 
5.3.2 Blinding 
SD-IIV4, HD-IIV4, and/or placebo will be administered to blinded participants in the opposite 
deltoid muscle, to which the mRNA COVID-19 vaccine was administered at Visit 1. SD-IIV4 or 
HD-IIV4 will be administered by unblinded licensed staff. In order to keep the participant 
blinded, the vaccine administrator will keep the prefilled syringes out of view of the participant at 
all times and will instruct the participant to turn their head in the opposite direction of the arm in 
which the vaccine is being administered. Similar instructions will be given to any persons 
accompanying the patient in the room. After administration, used study syringes will be 
disposed of according to site-specific SOPs. A licensed provider (MD, DO, NP, PA, RN, LPN), 
who will be trained on treating adverse reactions, will be immediately available at the time of 
vaccine administration along with emergency management supplies available for initial 
treatment of an allergic reaction if needed. Additionally, clinical members of the blinded data 
collection team will be present to assist study subjects. 

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5.3.3 Unblinding 
A copy of participant treatment assignments will be retained at the site in a REDCap database 
file accessible only to the unblinded site staff. In the event of an occurrence when knowledge of 
the treatment assignment will influence subject’s care, the Principal Investigator may be 
provided with the treatment assignment. The Principal Investigator must contact the Lead Site, 
Duke and document the event with information regarding the reasons for unblinding. After 
discussion with the Lead site, the Principal Investigator may receive the treatment assignment 
from the Lead site or if necessary, from the on-site secure file by the unblinded staff. Unblinding 
events should be reported to the CDC. 
All subjects will be unblinded at the end of study and informed of whether they received the 
influenza and COVID vaccines either sequentially or simultaneously. 
 
5.3.4 Incorrect Dose Administration 
In the event that a participant who is ≥ 65 years of age inadvertently receives standard-dose 
influenza vaccine rather than high-dose influenza vaccine, using shared decision making, they 
will be offered the opportunity to receive the preferred high-dose influenza vaccine a minimum 
of 28 days following the receipt of the standard-dose vaccine. Although there is no current 
recommendation to follow receipt of a standard-dose vaccine by a high-dose vaccine, 
participants will be offered high-dose vaccine to assure they achieve optimal protection from 
infection. A minimum interval of 28 days was chosen based on the routine practice of 
administering two separate standard-doses influenza vaccine 28 days apart in children who are 
influenza vaccine naïve. Participants choosing to receive a subsequent high-dose influenza 
vaccine will be called on Days 3 and 8 following receipt of their vaccine to review for the 
occurrence of any unsolicited adverse events. They will continue to be followed for the 
occurrence of AESIs and SAES as outlined in Section 5.4 below. 
5.4 Reactogenicity and Safety Assessment 
Participants will be assessed for any immediate reactogenicity in a period at least 30 minutes 
after vaccine administration while at the study site. They will be assessed for the following 
potential systemic reactions such as anaphylaxis related symptoms (e.g., dyspnea, chest 
tightness, wheezing, cough, stridor, urticarial, flushing, nasal congestion, dizziness, syncope, 
diaphoresis, emesis) or other medical symptoms (e.g., feverishness, chills/shivering, fatigue, 
myalgia, arthralgia, headache, nausea/vomiting, diarrhea). They will be assessed for any 
potential injection site reactions including pain, tenderness, erythema or induration. 
 
Frequency and occurrence of solicited local and systemic reactogenicity will be assessed daily 
through post-vaccination Day 7 following Visits 1, 2 and 3 (if primary two-dose COVID-19 
vaccine series) using a standard memory aid. Participants/participant’s LAR(s) will submit this 
information electronically on a daily basis. For participants unable to submit electronically, paper 
memory aid completion and collection will be acceptable but not preferred. Injection site and 
systemic solicited events will be graded as noted in Tables 8 and 9 45. Participants/participant’s 
LAR(s) will be further queried upon presence of symptoms. Unsolicited adverse events (AEs) 
will be assessed during the first 7 days following each vaccination visit and concomitant 
medications will be assessed from 30 days prior to Visit 1 through the study period. Serious AEs 
(SAEs) and new onset of adverse events special interest (AESI) will be assessed through the 
entire period of a subject’s participation (see below). Unsolicited AEs and SAEs will also be 
graded as to whether they are noticeable but do not interfere with activity (Grade 1), interfere 

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with some activity but did not need a medical visit or absenteeism (Grade 2), or prevent daily 
activity and/or resulted in medical visit and/or absenteeism (grade 3) or require an emergency 
room visit or hospitalization (Grade 4). 
At the time of study enrollment, participants/participant’s LAR(s) will be given a thermometer 
and instructed on using the symptom diary to document oral temperatures and post-injection 
symptoms. Beginning on the evening of Study Visits 1, 2 and 3 (if primary two-dose COVID-19 
vaccine series) (Day 1) following vaccination, participants/participant’s LAR(s) will record their or 
their child’s oral temperature using the study-supplied thermometer, the occurrence of solicited 
AEs, for the next 7 days (Day 1 – 7). Temperature will be recorded at roughly the same time 
each day. If a temperature ≥ 100.0°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 (38.0°C). 
Participants/participant’s LAR(s) will be queried during Visits 2, 3, and 4 on any solicited 
adverse events following vaccination. Injection site reactogenicity will be assessed separately 
for COVID-19 vaccine and IIV4 or placebo as described in Table 8. 
 
 
Table 8. Injection-site Reactogenicity Grading 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Pain 
Noticeable but 
does not 
interfere with 
activity 
Interferes with 
activity but did not 
need a medical 
visit or 
absenteeism [i.e. 
missing work or 
school] 
Significant; 
prevents daily 
activity and/or 
resulted in medical 
visit and/or 
absenteeism [i.e. 
missing work or 
school] 
Requires an emergency 
room (ER) visit or 
hospitalization 
Induration/Swelling 
(≥ 12 years of age) 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Requires an emergency 
room (ER) visit or 
hospitalization 
Induration/Swelling 
(< 12 years of age) 
0.5 – 2 cm 
2.0 -7.0 cm 
> 7 cm 
Requires an emergency 
room (ER) visit or 
hospitalization 
Erythema/Redness 
(≥ 12 years of age) 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Requires an emergency 
room (ER) visit or 
hospitalization 
Erythema/Redness 
(< 12 years of age) 
0.5 – 2 cm 
2.0 -7.0 cm 
> 7 cm 
Requires an emergency 
room (ER) visit or 
hospitalization 
Axillary (underarm) 
swelling or 
tenderness 
ipsilateral to side 
of injection 
Noticeable but 
does not 
interfere with 
activity 
Interferes with 
activity but did not 
need a medical 
visit or 
absenteeism [i.e. 
missing work or 
school] 
Significant; 
prevents daily 
activity and/or 
resulted in medical 
visit and/or 
absenteeism [i.e. 
Requires an emergency 
room (ER) visit or 
hospitalization 

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Table 8. Injection-site Reactogenicity Grading 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
missing work or 
school] 
 
Participants/participant’s LAR(s) will also be queried during Visits 2, 3, and 4 on common post- 
injection systemic symptoms as described in Table 9. 
 
Table 9. Systemic Reactogenicity Grading (FDA modified) 
Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) 
(°F) 
38.0 - 38.4 
100.4 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
39.0 – 40.0 
102.1-104.0 
> 40.0 
>104.0 
Nausea/vomiting 
Noticeable but does 
not interfere with 
activity or 1 – 2 
episodes/24 hours 
Some interference with 
activity or > 2 episodes/24 
hours 
Significant; prevents daily activity 
and/or resulted in medical visit 
and/or absenteeism [i.e. missing 
work or school] 
Requires an ER 
visit or 
hospitalization 
Diarrhea 
Noticeable but does 
not interfere with 
activity or 2 – 3 loose 
stools/24 hours 
Some interference with 
activity or 4-5 loose 
stools/24 hours 
Significant; prevents daily activity 
and/or resulted in medical visit 
and/or absenteeism [i.e. missing 
work or school] or 6 or more 
watery stools or > 24 hours 
Requires an ER 
visit or 
hospitalization 
Headache 
Noticeable but does 
not interfere with 
activity 
Some interference with 
activity but did not need a 
medical visit or 
absenteeism [i.e. missing 
work or school] 
Significant; prevents daily routine 
activity and/or resulted in 
medical visit and/or absenteeism 
[i.e. missing work or school] 
Requires an ER 
visit or 
hospitalization 
Fatigue 
Noticeable but does 
not interfere with 
activity 
Some interference with 
activity but did not need a 
medical visit or 
absenteeism [i.e. missing 
work or school] 
Significant; prevents daily routine 
activity and/or resulted in 
medical visit and/or absenteeism 
[i.e. missing work or school] 
Requires an ER 
visit or 
hospitalization 
Myalgia 
Noticeable but does 
not interfere with 
activity 
Some interference with 
activity but did not need a 
medical visit or 
absenteeism [i.e. missing 
work or school] 
Significant; prevents daily routine 
activity and/or resulted in 
medical visit and/or absenteeism 
[i.e. missing work or school] 
Requires an ER 
visit or 
hospitalization 
Arthralgia 
Noticeable but does 
not interfere with 
activity 
Some interference with 
activity but did not need a 
medical visit or 
absenteeism [i.e. missing 
work or school] 
Significant; prevents daily routine 
activity and/or resulted in 
medical visit and/or absenteeism 
[i.e. missing work or school] 
Requires an ER 
visit or 
hospitalization 
Chills 
Noticeable but does 
not interfere with 
activity 
Some interference with 
activity but did not need a 
medical visit or 
absenteeism [i.e. missing 
work or school] 
Significant; prevents daily routine 
activity and/or resulted in 
medical visit and/or absenteeism 
[i.e. missing work or school] 
Requires an ER 
visit or 
hospitalization 

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During Visits 2, 3, 4 participants/participant’s LAR(s) will be encouraged to report any significant 
adverse events occurring within 7 days of the vaccination visits and during Visits 2, 3, 4, 5, and 
6 any serious 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.” Participants/participant’s LAR(s) who report severe solicited or unsolicited adverse 
events or express any concern about symptoms/unsolicited events will be encouraged to follow 
up with their or their child’s primary care provider. Study staff will assist with coordination of 
referral appointments as necessary. Medical records will be obtained and reviewed for the 
occurrence of any adverse events, serious adverse events or adverse events of special interest 
throughout the study period. 
Unsolicited adverse events (AEs) will be collected and reported for the 7 days following each 
vaccine visit. Serious adverse events (SAEs) and adverse events of special interest (AESI) will 
be collected and reported during the entire study period [i.e. from enrollment through 120 days 
following enrollment]. Unsolicited AEs, SAEs, and AESIs will be graded as follows. 
 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Noticeable but does 
not interfere with 
activity or 
measurement 
Interferes with activity 
but did not need a 
medical visit or 
absenteeism [i.e. 
missing work or school] 
Significant; prevents 
daily activity and/or 
resulted in medical visit 
and/or absenteeism [i.e. 
missing work or school] 
Requires an ER visit or 
hospitalization 
 
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. 
 
An 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 
• 
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 participant 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. 
An adverse event of special interest (AESI) includes the following: 
• 
COVID-19 illness 
• 
Multisystem inflammatory syndrome 
• 
Guillain-Barre syndrome 

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• 
Allergic type reactions (including anaphylaxis, hives, or facial and limb swelling occurring 
within 7 days of a vaccination visit) 
• 
Myocarditis or pericarditis 
 
5.4.1 Causality (relatedness) Assessment 
Study site investigators will assess relatedness to vaccine or study procedures (related, possibly 
related, unlikely related, or not related) for unsolicited AEs, SAEs and AEs of special interest. 
Relatedness determinations of these events will inform IRB reporting and safety monitoring 
(Section 5.4.3). Solicited symptoms in Tables 8 and 9 will all be considered to be related to 
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 Expert Safety 
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. 
 
5.4.2 Reporting of Adverse Events 
COVID-19 vaccine administration will follow site-specific vaccine campaign administration 
guidelines in accordance with current recommendations from the US Food and Drug 
Administration and the Advisory Committee on Immunization Practices (ACIP). There are no 
previously published COVID-19 trials evaluating the concomitant administration of influenza 
vaccine; however, we do not foresee having a significant issue with serious adverse events 
(SAEs). 
 
SAEs and unanticipated problems will be reported to the CDC and all participating IRBs 
according to institutional requirements. 
 
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 external icon or by calling 1-800-822-7967. 
5.4.3 Safety Monitoring Plan 
As a lead site, Duke will coordinate an interim safety review. This review will be performed by a 
panel of vaccine safety experts. Duke will provide one subject matter expert to serve on the 
safety panel. CDC will appoint two subject matter experts from other CISA sites that are not 
participating in this study. The safety experts will review SAEs and AESI and create an interim 
report. This review will occur once approximately 100 subjects are enrolled or at the end of the 
influenza season, whichever occurs first. As the Lead Site, Duke will prepare narratives of the 
SAEs and AESI for the safety panel. This plan is designed to monitor safety while minimizing 
introduction of bias into the study and minimizing burden to study investigators. 

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5.5 Health-Related Quality of Life (HRQOL) 
 
5.5.1 Generic Measures of HRQOL 
HRQOL assessments will be performed for persons aged ≥12 years at baseline and daily for 7 
days following receipt of either COVID-19 vaccine plus placebo or following COVID-19 vaccine 
plus influenza vaccine. Assessments will include the EQ-5D-5L and the EQ-VAS. 
 
EQ-5D-5L 
The EQ-5D is a standardized, generic measure of health status that provides information on 
HRQOL and activities of daily living: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression (http://www.euroqol.org/) 46. In addition, the instrument contains the EQ 
Visual Analogue Scale (EQ-VAS) which measures the respondent’s self-rated health. 
 
The EQ-5D-5L is the new version of the EQ-5D that increases the levels of severity from three 
to five to significantly increase reliability and sensitivity while maintaining feasibility and reducing 
ceiling effects (Appendix A) 47,48. The descriptive system comprises 5 dimensions of mobility, 
self-care, usual activities, pain/discomfort, anxiety /depression. For each of these dimensions, 
there are 5 response levels: no problems, slight problems, moderate problems, severe 
problems, and extreme problems. The respondent is asked to indicate his/her health state by 
ticking in the box against the most appropriate statement in each of the 5 dimensions. This 
decision results in a 1-digit number expressing the level selected for that dimension. The digits 
for 5 dimensions can be combined in a 5-digit number describing the respondent’s health state 
from 11111 as best health and 55555 as worst health These numbers are converted to a Utility 
Index that ranges from -0.109 (worst health) to 1.000 (best health) for US specific values. The 
minimum clinically important difference ranges from 0.05 to 0.1 depending on health conditions 
being studied. The EQ-5D-5L will be used for participants 12 years of age and older. HRQOL 
will not be collected for participants 5-11 years of age. 
 
EQ-VAS 
The EQ-VAS records the respondent’s self-rated health on a 20 cm vertical, visual analogue 
scale with endpoints labelled ‘the best health you can imagine’ (100) and ‘the worst health you 
can imagine’ (0). The respondent marks an ‘X’ on the scale number to indicate how their health 
is ‘today.’ The minimum clinically important difference on the VAS is 8. 
 
The EQ-5D-5L and EQ-VAS have several advantages for use in this study. The measure is 
applicable to a wide range of health conditions and treatments and provide a simple descriptive 
profile and a single index value for health status. It has been validated in US and international 
populations and in adolescents and adults of all ages46,49,50. The measure is useful for 
monitoring the health status of patient groups at different moments in time and assessing the 
seriousness of conditions at different moments in time. The measure is designed for self- 
completion by respondents. It is simple, straightforward, take only a few minutes to complete 
and can easily be completed by adolescents and older adults. The instrument was designed to 
reduce respondent burden while achieving standards of precision for purposes of group 
comparisons involving multiple health dimensions. It has been widely used throughout the 
world in many different studies, including randomized controlled clinical trials, vaccine studies, 
and HRQOL studies. HRQOL will not be collected for participants aged 5-11 years of age. 

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5.6 Biospecimens Collection & Handling 
 
5.6.1 Serum 
Blood specimens will be collected during study visits as described in Tables 5 and 6. 
All blood samples (≈ 5 or 10 mL, depending upon age of the participant) will be collected into 
serum separator tubes and processed as follows: 
• Allow blood to clot at room temperature for at least 30 minutes while standing upright in a 
rack. 
• 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 1.0 mL aliquots of serum (top layer) into 1.0mL or 1.8 mL 
cryovials, up to 5 cryovials are expected for those 12 years of age and older and up to 2 
cryovials are expected for those 5-11 years of age. If less than 1 mL of processed serum is 
collected, it is a protocol deviation 
• All cryovial aliquots will be barcode labelled and contain a unique identifier via REDCap. 
Numbers should be placed lengthwise on the tube. 
• Freeze the cryovials at -80°C in the temperature-monitored research center freezer for 
future shipment. 
• Serum aliquots will be stored in the Duke Human Vaccine Institute Accessioning Lab, the 
Johns Hopkins Center for Immunization Research laboratory, and at CCHMC Schubert 
Research Clinic Laboratory until planned HAI analyses at which point the samples stored at 
JHU and Cincinnati will be shipped to Duke for planned laboratory analysis 
 
6 LABORATORY ANALYSES 
6.1 Baseline SARS-CoV-2 antibody 
Serum samples obtained at the Visit 1 (prior to vaccination) will be assayed for the presence of 
pre-existing SARS-CoV-2 antibody using the AdviseDx SARS-CoV-2 IgG II assay and the 
Alinitiy I SARS-CoV-2 IgG assay. The AdviseDx SARS-CoV-2 IgG II assay is a 
chemiluminescent microparticle immunoassay intended for the qualitative and semi-quantitative 
detection of IgG spike antibodies to SARS-CoV-2 in human serum. The Alinity I SARS-CoV-2 
IgG assay is a chemiluminescent microparticle immunoassay intended for the qualitative 
detection of nucleocapsid IgG antibodies to SARS-CoV-2 in human serum. All results will be 
interpreted as either positive or negative. A positive result on any assay will be interpreted as a 
positive antibody test result. The assays are intended for use as an aid in identifying individuals 
with an adaptive immune response to SARS-CoV-2 indicating recent or prior infection. Both 
assays are currently only for use under the FDA’s Emergency Use Authorization. 
SARS-CoV-2 antibody assays will be performed in the Immunology Virology Quality 
Assessment Center (IVQAC) at the DHVI. The IVQAC is a GCLP laboratory which is also 
accredited by CAP, CLIA and ISO-17043. 
6.2 Influenza Hemagglutination Inhibition (HAI) Assay 
Influenza Hemagglutination Inhibition (HAI) Assays will be performed on sera collected, 
contingent on additional funding. Briefly, reference wild-type, reassortant, or vaccine virus 
strains representative of the specific viral antigens included in the 2021-22 influenza vaccine will 
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participant serum samples collected pre- and 21 or 28 days post-vaccination from all study 
participants. To accomplish these activities, all participant samples will be interrogated for 
influenza antibodies against the strains of interest using the influenza hemagglutination 
inhibition assay (HI). This assay is considered the “gold-standard” measure by which to 
evaluate seroconversion/seroprotection in response to seasonal influenza vaccination. This 
assay will be performed in accordance with the Duke Regional Biocontainment Laboratory 
Virology Unit’s fully optimized and approved SOP (RVUSOP004 Influenza HI of Serum 
Samples). Briefly, test samples will be assayed by HAI as duplicate 2-fold dilution series 
starting at 1:10. Serum dilutions are then incubated with a concentration of virus verified to 
possess a known potential for red blood cell (RBC) agglutination. The presence of virus-specific 
antibodies is visualized via incubation of the virus-serum mixture with a RBC solution; the 
endpoint titer for a given dilution series is then expressed as the reciprocal of the final dilution in 
which complete HAI is observed. By convention, seronegative samples are defined as having 
an endpoint HAI titer < 40 and seropositive samples as having an endpoint titer of ≥1:40; and 
seroconversion as a 4-fold change in endpoint titer relative to pre-immunization baseline or a 
change from <10 to ≥1:4051. 
 
6.3 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' CMV 
Luc) in a 1:17:17 ratio in Opti-MEM (Life Technologies). Pseudovirions are titrated 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. 

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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. 6.4 Future Studies 
 
In addition to the specified analyses described thus far, there may be other tests or assays that 
have yet to be identified that may be important for interpreting our study findings or of relevance 
to co-administration of mRNA COVID-19 vaccines and IIV4 simultaneously. Additional 
laboratory assays may test for antibodies against other bacteria or viruses, markers of 
inflammation, or used in research assessing vaccine co-administration or health outcomes. 
Specimens banked for use in other studies will be linked to information (including identifying 
information) that participants provided to the study. Because it is unknown if future testing will 
be of any utility, results of future testing will not be provided. 
 
7 STATISTICAL CONSIDERATIONS 
In collaboration with Johns Hopkins University and Cincinnati Children’s Hospital sites, 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 Analysis Plan 
 
Should an interim safety analysis be required, the alpha level will be adjusted to assure the 
overall type I error is maintained at the one-sided alpha 0.025 level for the primary outcome of 
non-inferiority. 
7.1.1 Sample Size 

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Safety: Four reactogenicity events were included in the primary statistical endpoint: fever, 
chills, myalgia, or arthralgia of moderate or greater severity. These were considered clinically 
meaningful and were solicited in both mRNA COVID-19 vaccine trials. Headache and fatigue 
were also solicited reactogencity in both trials, but each occurred at the moderate-severe grade 
in >10% of participants after dose 1 placebo (in the Pfizer- Pfizer-BioNTech trial) and were 
thought to be less specific13. Based on data from prelicensure studies10,52,53, we assume that 
15% of participants will have at least one reaction of moderate severity or greater to include 
fever, chills, myalgia, or arthralgia reactogenicity event in the Sequential group. We have 
selected a clinically meaningful noninferiority margin of 10%. We plan to recruit a total of 450 
participants and assume a 5% drop out rate, leaving N=428 or N=214 per study group. 
Statistical calculations show that with a one-side alpha level of 0.025, and 214 subjects in each 
group across all study sites, there is 82.6% power to be able to demonstrate that the proportion 
of participants with at least one severe solicited local or systemic reactogenicity event in the 
Simultaneous group is noninferior to the Sequential group. Enrollment in this study shall occur 
during two influenza season (2021-22, 2022-23). 
7.1.2 Analysis Populations 
Full Analysis Population 1: 
• 
This population is defined as all subjects who are randomized, vaccinated, and provide 
at least one day of complete data on the symptom diary. 
Full Analysis Population 2: 
• 
This population is defined as all subjects who are randomized and vaccinated. 
Immunogenicity Population: 
• 
This population defined as subjects who received vaccine, provide baseline and Visit 3 
and Visit 4 blood draws of acceptable volume and quality within the protocol-defined 
time frame with no protocol violations affecting immunogenicity. Protocol violations 
affecting the immunogenicity analyses will be defined in the Statistical Analysis Plan 
(SAP). The acceptable visit window for sample analysis will be -7/+14 days from the 
target date. Any subject with sufficient data for either or both of the influenza and SARS- 
CoV-2 analysis will be included in this population. Should 10% or more of the total study 
population be excluded from the Immunogenicity Population due to missing the visit 
window, then an additional analysis will be performed including these subjects with the 
missing visit window exclusion. 
The Full Analysis Population 1 is the primary population for analysis unless otherwise stated. 
 
7.1.3 Primary Objective 1 
• 
To compare the proportion of participants with moderate or more severe fever, chills, 
myalgia, or arthralgia in the group receiving IIV4 simultaneously with mRNA COVID-19 
vaccine at Vaccination Visit 1 (Simultaneous group) with the group receiving IIV4 alone 
one to two weeks later at Vaccination Visit 2 (Sequential group) following both 
Vaccination Visit 1 and 2 
o Hypothesis: The proportion of participants with moderate or more severe fever, 
chills, myalgia or arthralgia will be noninferior (not higher) in the Simultaneous 
group versus the Sequential group. 

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This objective will be assessed for visits 1 and 2 using a one-sided noninferiority test with the 
alpha level set at 0.025 and noninferiority margin of 10%. The null hypothesis is the 
Simultaneous group is inferior (i.e., Simultaneous group will have a higher proportion) to the 
Sequential group in regards to the proportion of participants with at least one moderate or 
severe fever, chills, myalgia, or arthralgia event after visits 1 and 2. 
 
Ho: Simultaneous group - Sequential group ≥ 0.10 (10%) 
 
The alternative hypothesis is the Simultaneous group is noninferior to the Sequential group in 
regards to the proportion of participants with at least one moderate or severe fever, chills, 
myalgia, or arthralgia event after visits 1 and 2. 
 
Ha: Simultaneous group - Sequential group < 0.10 (10%) 
 
The upper bound of a site-stratified Newcombe binomial confidence interval (Yan and Su 2010) 
with Cochran-Mantel-Haenszel (CMH) weighting of the difference will be used to make these 
assessments with no adjustment to the alpha level for multiple comparisons. 
 
7.1.4 Secondary Objective 1 
• 
To compare the proportion of participants with moderate or more severe fever, chills, 
myalgia, or arthralgia in the Simultaneous versus the Sequential Group following the first 
vaccination visit 
 
7.1.5 Secondary Objective 2 
• 
To compare the proportion of participants with moderate or more severe fever, chills, 
myalgia, or arthralgia in the Simultaneous versus Sequential Group following the second 
vaccination visit 
 
Secondary objectives 1 and 2 will be evaluated using a Mantel-Haenszal statistic in a stratified 
analysis by site at the alpha 0.05 level. No adjustments will be made to the alpha level for these 
evaluations. 
 
7.1.6 Secondary Objective 3 
• 
To describe the proportions of participants in the Simultaneous and Sequential 
vaccination groups with solicited local and systemic reactogenicity events according to 
severity grade after the first and second vaccination visit and third vaccination visit for 
those receiving two doses of mRNA COVID-19 vaccine 
 
Tables (one for each visit 1, 2, and 3) will be produced that summarize each solicited local and 
systemic reactogenicity event by classification (none, mild, moderate, and severe), as well as by 
moderate or severe for each study group. These tables will have the number and percentage for 
each classification by study group and the confidence interval of the difference between the 
study groups. 

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7.1.7 Secondary Objective 4 
• 
To describe the proportions of participants in the Simultaneous and Sequential 
vaccination groups experiencing at least one serious adverse event and a description of 
these events 
A table will be produced that summarize participants experiencing at least one serious adverse 
event during the study period by group. This table will have the number and percentage for each 
outcome by study group and the confidence interval of the difference between the study groups. 
Listings with the clinical narratives will also be provided. The primary analysis population will be 
the Full Analysis Population 2. 
 
7.1.8 Exploratory Objectives 
The analysis for the exploratory objectives will be detailed in the comprehensive 
Statistical Analysis Plan. The Immunogenicity Population will be the primary analysis 
population for exploratory HAI and COVID immunogenicity objectives. 
7.2 Data Management 
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, diaries completed by study participants, will be maintained in secure research 
offices at Duke, John Hopkins CIR, and Cincinnati Children’s Hospital, 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. 
 
7.2.1 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 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 

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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, 
Johns Hopkins CIR, and Cincinnati Children’s Hospital 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. Assigned identifiers will be 
used in 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 Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Duke University, Johns Hopkins University and 
Cincinnati Children’s Hospital as Task Orders in the CISA Project Contract. 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 Subjects Involvement, Characteristics, and Design 
Duke, Johns Hopkins University, and Cincinnati Children’s Hospital investigators will be 
responsible for submitting the protocol, informed consent, diaries, recruitment letters, flyers, and 
any written or verbally conveyed materials specific to this project to their institutional review 
boards. CDC staff will be responsible for submitting materials to the CDC Human Subjects 
Review for determination to rely on Duke IRB. 
 
To facilitate subject recruitment at the practices, we will request a waiver of consent and HIPAA 
authorization for ascertainment (identification, selection) and/or recruitment of potential subjects 

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while recording identifiable private health information (PHI) prior to obtaining the subject’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 where 
available. We will review only the minimum amount of information necessary to determine 
eligibility, i.e. date of birth, medical and surgical history, and recent laboratory test results. 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 subjects and no information will leave the study sites. 
 
Requests for continuing review, when required, will be submitted at each engaged institution in 
accordance with institutional procedures. Protocol deviations or concerns about study integrity 
will be reported promptly to the overseeing IRB or CDC in accordance with institutional 
requirements. 
8.2 Sources of Material 
Medical history and immunization history will be obtained from the medical record when 
available and from patient report. Demographic information will be obtained from the medical 
record and patient report. Subjects will record solicited adverse reactogenicity events and any 
medical intervention sought on study days 1-7 following each vaccination visit on the symptom 
diary. Diary information will either be reported electronically or on paper which will be given to 
the study team during a study visit. Diary information reported electronically will be preferred but 
paper reporting will be allowed. The research staff will assess oral temperature. 
 
8.3 Potential Risks and Benefits 
 
mRNA COVID-19 vaccines 
Two COVID-19 vaccine received Emergency Use Authorization (EUA) by the FDA in December 
2020. BNT162b2 received FDA approval for individuals ≥ 16 years of age and mRNA-1273 
received authorization for those ≥18 years of age. The Pfizer/BioNTech mRNA COVID-19 
vaccine received additional EUA for adolescents 12 to 15 years in May 2021 and children 5 to 
11 years in October 2021. These vaccines have been recommended at these ages by the ACIP. 
Participants will be provided with the respective fact sheets for the mRNA COVID-19 vaccine 
they receive including the BNT162b2 https://www.fda.gov/media/144414/download and the 
MRNA-1273 https://www.fda.gov/media/144638/download 
Side effects that have been reported with mRNA COVID-19 vaccines include both injections site 
reactions as well as general side effects. Injection site reactions include: pain, tenderness and 
swelling of the lymph nodes in the same arm of the injection, swelling (hardness), and redness 
at the injection site. General side effects include: fatigue, headache, muscle pain, joint pain, 
chills, nausea and vomiting, fever and feeling unwell. There is a remote chance that an mRNA 
COVID-19 vaccine could cause a severe allergic reaction, usually occurring within a few 
minutes to hours after getting a dose of vaccine. Signs of a severe allergic reaction can include: 
difficulty breathing, facial and throat swelling, tachycardia, total body rash, dizziness and 
weakness. There have been rare reports of cases of inflammation of the heart—called 
myocarditis and pericarditis—happening after mRNA COVID-19 vaccination30-32. The events 
have mainly occurred in adolescents and young adults and more often after the second dose of 
vaccine. Available data from short-term follow-up suggest that most individuals have had 
resolution of symptoms, but information is not yet available about potential long-term 
sequelae30,31. These may not be all the possible side effects of the mRNA COVID-19 vaccines. 

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Serious and unexpected side effects may also occur. mRNA COVID-19 vaccines are still being 
studied in clinical trials. Available data support the safety of dose 3 mRNA COVID-19 vaccine 
in immunocompromised individuals13. Available data support the safety of booster doses of 
mRNA COVID-19 vaccine13. 
 
SD-IIV4 and HD-4 
SD-IIV4 and HD-IIV4 are FDA-licensed vaccines approved for use in persons ≥ 6 months of age 
and those ≥65 years old, respectively. Both vaccines are standard clinical practice and 
recommended by the CDC. Participants will be provided with the CDC Vaccine Information 
Statement (VIS) for IIV4 (https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.pdf). 
 
IIV4 risks include minor problems such as soreness, redness, swelling, or pain where the shot 
was given, hoarseness, sore, red or itchy eyes, cough, fever, aches, headache, itching, fatigue, 
all of which usually occur within 1-2 days of vaccination and are self-limiting. More serious 
problems including a small increased risk of Guillain-Barré Syndrome estimated at 1 or 2 
additional cases per million people vaccinated can occur. This is much lower than the risk of 
severe complications from influenza infection, which can be prevented by IIV454. In addition, 
any medication can cause a severe allergic reaction, or anaphylaxis, which is estimated at ~ 1 
in one million doses of IIV4 administered55. 
 
General Vaccine Risks 
Some people get severe pain in the shoulder and have difficulty moving the arm where a shot 
was given. This happens very rarely. Syncope (fainting) can occur in association with 
administration of injectable vaccines. Sitting or lying down when space is available for about 15 
minutes can help prevent fainting, and injuries caused by a fall, as recommended in the ACIP 
General Recommendations on Immunization 8. Subjects should inform their doctor if they feel 
dizzy or have vision changes or ringing in the ears. 
 
As with any licensed or authorized vaccine, protection may not occur in 100% of vaccinated 
persons for either COVID-19 or influenza vaccines. 
 
Blood Drawing 
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. There is a small risk of 
infection around the vein where the blood was collected. Each study subject will be asked to 
have up to 4 blood samplings with the total volume not to exceed 60mL over an approximately 4 
month period of time. 
 
Delay of Influenza Protection 
There is a potential risk of a short delay in influenza protection by delaying the receipt of 
influenza vaccine 2 weeks. 
 
Confidentiality 
An additional risk of study participation is the potential for loss of confidentiality. 
 
8.4 Adequacy of Protection Against Risks 

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8.4.1 Protections against Risk 
To decrease the possibility of infection at the site of blood drawing, the area on the arm above 
the vein where blood will be taken will be prepped with 70% isopropyl alcohol antiseptic prior to 
venipuncture. 
Subjects/subject’s LAR(s) will be counseled on possible side effects following vaccination and 
followed closely in the immediate post-vaccination period and during the following week for 
assessment of moderate to severe local or systemic reactogenicity. In the immediate post- 
vaccination period, all subjects will be monitored in a sitting or lying position for 30 minutes 
following vaccinations to help prevent fainting, and injuries caused by a fall. Subjects with a prior 
history of severe allergic reaction after a previous dose of any influenza vaccine or COVID-19 
vaccine, or to a vaccine component, including egg protein, will be excluded from study 
enrollment. Epinephrine and equipment for managing an airway will be available for immediate 
use if needed to treat a severe allergic reaction or anaphylaxis. Subjects will be evaluated and 
cared for as described in the Unscheduled Visit section above 
Data Safety monitoring, as described above (Section 5.4.3), shall also be done. 
The study team will provide documentation to the participant and primary care provider 
regarding receipt of COVID-19 vaccine and influenza vaccine. Documentation of COVID-19 
vaccine receipt will be provided on the date received. Documentation of influenza vaccine 
receipt will be provided at Visit 2 when it can be assured that all participants will have received 
an influenza vaccine. 
Participants will be counseled that if they are concerned that they have an influenza-like illness 
(characterized by fever and irritability, cough, sore throat, or vomiting) or symptoms of COVID- 
19 which may overlap with influenza, they should seek care for with their health care provider. If 
the provider suspects or determines that the participant has influenza, there are medications to 
treat influenza illness and the provider may opt to treat the participant with one of these 
medications. If a participant’s care requires the identity of the date of receipt of influenza 
vaccine, blinding will be broken for that patient. At the end of the study, the 
participants/participant’s LAR(s) and providers will receive documentation about the timing of 
influenza vaccination for each participant. If influenza activity become widespread, study 
enrollment may be paused. The National Institutes of Health (NIH) provides treatment and 
management recommendations for COVID-19 patients 
https://www.covid19treatmentguidelines.nih.gov/. 
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. 
The CDC provides a Certificate of Confidentiality to protect the privacy of research participants. 
This certificate limits the disclosure of subject identifiable information. The investigators cannot 
disclose identifiable information except for if required by law, if participant consented to 
disclosure or if the information is used for other scientific research. Information may be 
disclosed to the CDC or the FDA. 
8.4.2 ClinicalTrials.gov Requirements 
The project is registered on ClinicalTrials.gov (NCT05028361). 

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8.5 Human Subjects 
In obtaining and documenting informed consent, the Investigator and study team will comply 
with the applicable regulatory requirements, Good Clinical Practices, and ethical principles. The 
written informed consent form must be signed and dated by the study participant prior to 
initiation of any study activities. 
 
8.5.1 Vulnerable Subjects Research 
Children are a vulnerable research population and require additional protections when they are 
potential research subjects. Children will receive approved or authorized vaccines consistent 
with ACIP recommendations. All children will receive an influenza vaccine at one time point and 
will receive a placebo at one time point. Thus, all children enrolled in the study will be 
immunized against seasonal influenza. 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 17 years of age will be obtained in a manner consistent with local IRB regulations. For 
participants turning 18 years of age during the course of the study, parental consent will be 
obtained at enrollment and written informed consent will be obtained from the participant after 
their 18th birthday. 

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APPENDIX 
Appendix A: EQ-5D-5L and VAS 
Appendix B: Corticosteroid Dose Charts 

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Appendix A: EQ-5D-5L and VAS 

USA (Spanish) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cuestionario de Salud 
 
 
Versión en español para los EE. UU. 
 
(Spanish version for the USA) 

2 
USA (Spanish) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
Debajo de cada encabezamiento, marque UNA casilla, la que mejor describe su salud 
HOY. 
MOVILIDAD 
No tengo problemas para caminar 
 
Tengo problemas leves para caminar 
 
Tengo problemas moderados para caminar 
 
Tengo problemas graves para caminar 
 
No puedo caminar 
 
CUIDADO PERSONAL 
No tengo problemas para lavarme o vestirme solo/a 
 
Tengo problemas leves para lavarme o vestirme solo/a 
 
Tengo problemas moderados para lavarme o vestirme solo/a 
 
Tengo problemas graves para lavarme o vestirme solo/a 
 
No puedo lavarme o vestirme solo/a 
 
ACTIVIDADES DE TODOS LOS DÍAS (Ej.: trabajar, estudiar, hacer las tareas 
domésticas, actividades familiares o actividades de ocio) 
No tengo problemas para realizar mis actividades de todos los días 
 
Tengo problemas leves para realizar mis actividades de todos los días 
 
Tengo problemas moderados para realizar mis actividades de todos los días   
Tengo problemas graves para realizar mis actividades de todos los días 
 
No puedo realizar mis actividades de todos los días 
 
DOLOR / MALESTAR 
No tengo dolor ni malestar 
 
Tengo dolor o malestar leve 
 
Tengo dolor o malestar moderado 
 
Tengo dolor o malestar intenso 
 
Tengo dolor o malestar extremo 
 
ANSIEDAD / DEPRESIÓN 
No estoy ansioso/a ni deprimido/a 
 
Estoy levemente ansioso/a o deprimido/a 
 
Estoy moderadamente ansioso/a o deprimido/a 
 
Estoy muy ansioso/a o deprimido/a 
 
Estoy extremadamente ansioso/a o deprimido/a 
 

3 
USA (Spanish) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
La mejor salud 
que se pueda 
imaginar 
 
• Nos gustaría saber lo buena o mala que es su salud HOY. 
• La escala está numerada de 0 a 100. 
• 100 representa la mejor salud que se pueda imaginar. 
0 representa la peor salud que se pueda imaginar. 
• Por favor haga una X en la escala para indicar cuál es su 
estado de salud HOY. 
• Ahora, por favor escriba en la casilla que encontrará a 
continuación el número que ha marcado en la escala. 
 
 
 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
SU SALUD HOY = 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
La peor salud 
que se pueda 
imaginar 

© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. USA (English) v1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
English version for the USA 

Subject ID:  
 
2 
© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. USA (English) v1.1 
 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
 
MOBILITY 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 

Subject ID:  
 
3 
© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. USA (English) v1.1 
 
 
 
 
 
The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
YOUR HEALTH TODAY = 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health 
you can imagine 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 

 
Simultaneous mRNA COVID-19 and IIV4 Vaccination Study 
 
Version 7.0 
15 March 2023 
 
 
Appendix B: Corticosteroid Dose Charts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
66 

 
 
 
0-4 years of age 
5-11 years of age 
:.12 years of age 
Daily Dose 
Low 
Medium• 
High• 
Low 
Medium• 
High• 
Low 
Medium• 
High• 
MEDICATION 
BeclomethasoneMDI' 
N/A 
N/A 
N/A 
80-160 mcg 
>160-320 mcg 
>320 mcg 
80-240 mcg 
>240-480 mcg 
>480 mcg 
40 mcg/puff 
80 mcg/puff 
1-2 puffs 
2x/day 
1puff 2x/day 
3-4 puffs 
2x/day 
2 puffs 2x/day 
:.3 puffs 2x/day 
1-3 puffs 
2x/day 
1 puff am, 
4-6 puffs 
2x/day 
2-3 puffs 
:.4 puffs 
 
 
 
 
 
inhalation 
2 inhs' pm 
Budesonlde Nebules 
0.25-0.5 mg 
>0.5-1.0 mg 
>l.0mg 
0.5mg 
1.0 mg 
2.0mg 
N/A 
N/A 
N/A 
0.25 mg 
1-2 nebs'/day 
1 neb' 2x/day 
0.5 mg 
1 neb'/day 
2 nebs'/day 
3 nebs'/day 
1neb'/day 
1neb' 2x/day 
1.0mg 
1neb'/day 
2 nebs'/day 
1neb'/day 
1neb' 2x/day 
Clclesonlde MOit 
N/A 
N/A 
N/A 
80-160 mcg 
>160-320 mcg 
>320 mcg 
160-320 mcg 
>320--640 mcg 
>640 mcg 
1puff am, 
80 mcg/puff 
1-2puffs/day 
2 puffs pm- 
2 puffs 2x/day 
:.3 puffs 2x/day 
1-2 puffs 2x/day 
3-4 puffs 2x/day 
160 mcg/puff 
1puff/day 
1puff 2x/day 
:.2 puffs 2x/day 
2 puffs 2x/day 
:.3 puffs 2x/day 
Flunlsollde MOit 
N/A 
N/A 
N/A 
160 mcg 
320-480 mcg 
:.480 mcg 
320 mcg 
>320--640 mcg 
>640 mcg 
80 mcg/puff 
1puff 2x/day 
2-3 puffs 2x/day 
:.4 puffs 2x/day 
2 puffs 2x/day 
3-4 puffs 2x/day 
:.5 puffs 2x/day 
2 puffs pm 
2x/day 
2x/day 
Budesonlde op1t 
N/A 
N/A 
N/A 
180-360 mcg 
>360-720 mcg 
>720 mcg 
180-540 mcg 
>540-1,080 mcg 
>1,080 mcg 
90 mcg/inhalation 
180 mcg/ 
1-2 inhs' 2x/day 
3-4 inhs' 2x/day 
2 inhs' 2x/day 
:.3 inhs' 2x/day 
1-3 inhs' 2x/day 
1inh' am, 
2-3 inhs' 2x/day 
 
 
:.4 inhs' 2x/day

 
 
 
Adapted from NAEPP Expert Report 3 and https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf