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Safety of Simultaneous versus Sequential
Administration of mRNA COVID -19 and
Quadrivalent Inactivated Influenza (IIV4)
Vaccines: A Randomized Placebo Controlled Trial
(ClinicalTrials.gov ID: NCT05028361)
Emmanuel “Chip” Walter MD, MPH
ACIP October 25, 2023
Disclaimer
•The findings and conclusions in this presentation are
those of the presenter and do not necessarily represent the official position of the Centers for Disease Control and Prevention
•Mention of a product or company name is for identification purposes only and does not constitute endorsement by CDC
•This study was supported by the CDC Clinical Immunization Safety Assessment (CISA) Project
2
Study Rationale
•Influenza and COVID -19 vaccines are recommended
for persons 6 months of age and older to prevent
illness and complications resulting from these infections.
*
•Available data support the simultaneous administration of these vaccines as currently ACIP recommended.
•However, there are limited data from placebo-controlled studies (none from the US) evaluating the safety of simultaneous administration of influenza and mRNA COVID -19 vaccines.
3*Clinical Guidance for COVID- 19 Vaccination | CDC and Prevention and Control of Seasonal Influenza with Vaccines: Recommendations
of the Advisory Committee on Immunization Practices —United States, 2023– 24 Influenza Season | MMWR (cdc.gov)
Design, Population, Recruitment
•Design : prospective, randomized,
placebo -controlled, observer -blind
study
•Population : non- pregnant 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
and intending to receive a quadrivalent
inactivated influenza vaccine (IIV4)*
•Recruitment : 3 CISA sites –Duke
University, Cincinnati Children’s Hospital Medical Center (CCHMC), and John Hopkins University (JHU) during
the 2021- 2022 and 2022- 2023
influenza seasons
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SimultaneousSequentiala
*Persons ≥65 years received High -Dose IIV4 (Fluzone High -Dose Quadrivalent); those <65 years received standard dose IIV4 (FluLaval or Fluzone Quadrivalent)
Study Aims and Objectives:
Primary objective : To compare the proportion of participants with
moderate or more severe fever, chills, myalgia, or arthralgia (RE)*
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
–Primary outcome: considered present if participant has at least one of
the RE symptoms on at least one day during days 1 to 7 following Visit 1 and/or Visit 2
Hypothesis : The proportion of participants with moderate or more
severe fever, chills, myalgia or arthralgia will be non -inferior (not
higher) in the Simultaneous group versus the Sequential group
5*RE: reactogenicity event
Secondary Objectives
•To compare the proportion of participants with RE in the
Simultaneous group versus the Sequential group following Vaccination Visit 1 and 2 separately
•To describe the proportions of participants in each group with solicited local and systemic reactogenicity events according to
severity grade after vaccination visits
•To describe the proportions of participants in each group experiencing at least one serious adverse event and a description of these events
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Study Aims and Objectives:
Exploratory Objectives
•To further characterize and describe the proportion of participants
in each group with local or systemic reactogenicity events of
greater severity
•To describe the proportion of participants each group experiencing at 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 both groups following the Vaccination Visit 1
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Study Procedures Summary
•After randomization (1:1) to either the simultaneous or
sequential group and a baseline blood draw, participants
received study influenza vaccine or placebo according to
assignment
•Solicited Reactogenicity: Days 1 -7* after V1, V2, V3a
•Unsolicited Adverse Events: Days 1 -7 after V1, V2, V3a
•Health -Related Quality of Life (HRQOL): Days 1 -7 after V1
only
•Adverse Events of Special Interest (AESIs): Days 1 -121
•Serious Adverse Events (SAEs): Days 1 -121
•Blood draws for immunogenicity: baseline and post -
vaccination (data not yet available)
8 *Day 1 is the vaccination day
Statistical Methods
•Full Analysis Population 2
–All randomized and vaccinated participants
–Participant characteristics and adverse event outcomes
•Full Analysis Population 1
–All participants who are randomized, vaccinated, and provide at least one day of complete data on the
symptom diary
–Reactogenicity outcomes
•Statistical Testing
–Primary outcome was conducted at the one -sided alpha 0.025 level using the upper bound of a stratified by site
Newcombe binomial confidence interval with Cochran -Mantel -Haenszel (CMH) weighting of the difference with
a noninferiority margin of 10%.
–Comparisons of proportions between the simultaneous and sequential groups used an exact Mantel -Haenszel
statistic in a stratified analysis by site to control for the randomization blocks at the two- sided alpha 0.05 level.
Study site adjusted odds ratios and corresponding 95% confidence intervals for proportions were also calculated.
–The changes in HRQOL after Visit 1 were evaluated using Mann -Whitney U tests. For the HRQOL comparisons
we used a two- sided alpha at the 0.05 level.
–Summary statistics were used to describe REs, AEs, SAEs and AESIs. 95% confidence intervals of the difference between vaccination groups were calculated.
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Study Consort Diagram
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Demographics / Enrollment Site
Characteristic Simultaneous (n=169) Sequential (n=166) Total (N=335)
Sex: Female 96 (56.8%) 115 (69.3%) 211 (63.0%)
Male 73 (43.2%) 51 (30.7%) 124 (37.0%)
Race: White Only 123 (72.8%) 113 (68.1%) 236 (70.4%)
Black Only 31 (18.3%) 33(19.9%) 64 (19.1%)
Other 15 (8.9%) 20 (12.0%) 35 (10.4%)
Ethnicity: Hispanic 12 (7.1%) 9 (5.4%) 21 (6.3%)
Age (yrs): 5 to <12 4 (2.4%) 2 (1.2%) 6 (1.8%)
12 to <18 11 (6.5%) 13 (7.8%) 24 (7.2%)
18to <65 146 (86.4%) 143 (86.1%) 289 (86.3%)
>=65 8 (4.7%) 8 (4.8%) 16 (4.8%)
Site: CCHMC 67 (39.6%) 63 (38.0%) 130 (38.8%)
Duke 79 (46.7%) 81 (48.8%) 160 (47.8%)
JHU 23 (13.6%) 22 (13.3%) 45 (13.4%)
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Season, COVID -19 Vaccine Received,
Vaccination and COVID -19 History
Characteristic Simultaneous (n=169) Sequential (n=166) Total (N=335)
Season: 2021- 2022 37 (21.9%) 36 (21.7%) 73 (21.8%)
2022- 2023 132 (78.1%) 130 (78.3%) 262 (78.2%)
COVID -19 Vaccine Brand:
Pfizer -BioNTech Monovalent 34 (20.1%) 35(21.1%) 69(20.6%)
Pfizer -BioNTech Bivalent 130 (76.9%) 125 (75.3%) 255 (76.1%)
Moderna Monovalent 4 (2.4%) 4 (2.4%) 8 (2.4%)
Moderna Bivalent 1 (0.6%) 2 (1.2%) 3 (0.9%)
Prior COVID -19 Vaccine
Yes 165 (97.6%) 166 (100.0%) 331 (98.8%)
Prior COVID -19 and/or
+ nucleocapsid ab
Yes 96 (56.8%) 95 (57.2%) 191 (57.0%)
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Primary Outcome
Proportions with moderate or more severe fever, chills, myalgia, or arthralgia
(RE) in participants in sequential versus simultaneous group
13Moderate or more severe fever, chills, myalgia, or arthralgia following Visit 1 and/or Visit 2
No Yes Non -inferiority Test 10% Margin*
Group N % N % Diff Lower
95% CIUpper
95% CIp-value
Simultaneous 125 74.40 43 25.60
Sequential 114 68.67 52 31.33 -0.0563 -0.1517 0.0404 0.0007
Ho: Sim-Seq≥ 0.10 (10%)
Conclusion: The rate of moderate or more server fever, chills, myalgia, or
arthralgia in simultaneous group is considered not worse/not higher than
the rate in sequential group and the noninferiority criteria was met. The
upper limit of the 95% confidence interval (CI) of the difference for Sim
minus Seq was 4.0% and the noninferiority margin was 10%; therefore, the
null hypothesis of inferiority was rejected . *Site -stratified Newcombe binomial confidence interval with Cochran -Mantel -Haenszel (CMH) weighting of the difference
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 visitSecondary Objective
14Moderate or more severe fever, chills, myalgia, or arthralgia following Visit 1
No Yes
Group N % N % Odds Ratio (95%CI) p-value*
Simultaneous 128 76.19 40 23.81
Sequential 119 71.69 47 28.31 0.80 (0.49, 1.30) 0.3851
*Exact Mantel -Haenszel statistic in a stratified analysis by site
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 second
vaccination visitSecondary Objective
15Moderate or more severe fever, chills, myalgia, or arthralgia following Visit 2
No Yes
Group N % N % Odds Ratio (95%CI) p-value*
Simultaneous 163 97.02 5 2.98
Sequential 157 94.58 9 5.42 0.54 (0.18, 1.63) 0.2886
*Exact Mantel -Haenszel statistic in a stratified analysis by site
Percent With Injection Site Reaction
Visit 1
16More ≥ moderate pain in simultaneous group* More ≥ moderate pain and swelling in sequential group*
*95% CI of difference in proportions between does not contain zero020406080100
Sim Seq Sim Seq Sim Seq Sim Seq
Pain Swelling Erythema Axillary Swelling
and TendernessPercent
Solicited Event and GroupInjection Site Reactions Visit 1
COVID -19 Vaccine
Mild Moderate Severe Life Threatening020406080100
Sim Seq Sim Seq Sim Seq Sim Seq
Pain* Swelling Erythema Axillary Swelling
and Tenderness*Percent
Solicited Event and GroupInjection Site Reactions Visit 1
Influenza Vaccine or Placebo
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
*95% CI of difference in proportions between does not contain zero
17Percent With Injection Site Reaction
Visit 2
More ≥ moderate pain and axillary swelling/ tenderness in sequential group*
*95% CI of difference in proportions between does not contain zero020406080100
Sim Seq Sim Seq Sim Seq Sim Seq
Pain* Swelling* Erythema Axillary Swelling and
Tenderness*Percent
Solicited Event and GroupInjection Site Reactions Visit 2
Influenza Vaccine or Placebo
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
18Percent With Systemic Reaction
Visit 1
No differences in ≥ moderate systemic symptoms020406080100
Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq
Fever Chills Fatigue Myalgia Headache Arthralgia Nausea &
VomitingDiarrheaPercent
Solicited Event and GroupSystemic Reactions Visit 1
Mild Moderate Severe Life Threatening
19Percent With Systemic Reaction
Visit 2
No differences in ≥ moderate systemic symptoms020406080100
Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq
Fever Chills* Fatigue* Myalgia* Headache Arthralgia Nausea &
VomitingDiarrhea*Percent
Solicited Event and GroupSystemic Reactions Visit 2
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
Objective : 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
eventsSecondary Objective
20At Least One Serious Adverse Event
No Yes
Group N % N % Difference (Sim -Seq)(95%CI)
Simultaneous 168 99.41 1 0.59
Sequential 165 99.40 1 0.60 -0.01 ( -1.66, 1.64)
SAE Descriptions
21Group Vaccine Onset
since Visit
1 Sex Age groupCategory Relatedness Description
Sequential Pfizer -BioNTech
Bivalent14 days Female 50-64 Hospitalization/
prolongation of
existing hospitalizationUnlikely related Small bowl obstruction with
incarcerated ventral herniaPast medical history (PMH): abdominal surgeries and cancer
Simultaneous Pfizer -BioNTech
Monovalent19 Weeks Female 18-49
years Other importantmedical eventNot related Spontaneous abortion occurring at
16 weeks gestation PMH: COVID -19 illness (mild) 9
weeks after visit 1; (Note: Participant did not report being pregnant or intention of becoming pregnant at enrollment)
•Objective : 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 eventsExploratory Objective
22At Least One Unsolicited Adverse Event within 7 Days of a Vaccination Visit (Preliminary)
No Yes Percent Yes
Group N % N % 95% CI Difference (Sim -Seq)
(95%CI)
Simultaneous 148 87.57 21 12.43 (7.86, 18.37)
Sequential 150 90.36 16 9.64 (5.61, 15.18) 2.79 ( -3.91, 9.49)
•AEs within 7 days of vaccine (n=45)
–29 simultaneous group in 21 participants (3 possibly related)
–16 sequential group in 16 participants (1 related, 2 possibly related)
•Objective : 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 eventsExploratory Objective
23At Least One Adverse Event of Special Interest
No Yes Percent Yes
Group N % N % 95% CI Difference (Sim -Seq)
(95%CI)
Simultaneous 150 88.76 19 11.24 (6.91, 17.00)
Sequential 157 94.58 9 5.42 (2.51, 10.04) 5.82 ( -0.06, 11.70)
•AESIs (n=28)
–29 COVID -19 illnesses (unrelated): Sim Group* (n=18) SeqGroup* (n=9)
–1 allergic type reaction (possibly related): Sim Group (n=1)
*One person in each group reported 2 COVID -19 illness events
Exploratory Objective
•Objective : To compare the change of health -related quality of life (HRQOL) from
baseline in the Simultaneous versus Sequential groups following the Vaccination
Visit 1
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Limitations
•Most data come from use of bivalent Pfizer -BioNTech
mRNA COVID -19 vaccine during one season
–Very little use of Moderna mRNA vaccine
•Very few children ages 5- 11 years and older adults
≥65 years enrolled
•Enrollment limited by COVID -19 pandemic; enrolled
~70% of target
•Study too small to detect rare adverse events
•People known to be pregnant not included; a future
CISA study assessing safety of simultaneous influenza and COVID -19 vaccines during pregnancy is planned
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Summary
•Simultaneous administration of influenza and mRNA COVID -19 vaccines is well tolerated
when compared to sequential administration
–Occurrence of moderate or more severe fever, chills, myalgia, or arthralgia was not
higher in the simultaneous (25.6%) vs. sequential (31.3%) group
–No significant differences in occurrence of adverse events within 7 days, adverse events of special interest, serious adverse events, and HRQOL
•As previously observed in other studies injection site and systemic reactions were associated with mRNA COVID -19 vaccine and influenza vaccine; most reactions were mild
or moderate
–Most frequent injection site reactions after either vaccine were pain and axillary swelling/tenderness
–Most frequent systemic reactions after COVID -19 vaccine, with or without influenza vaccine, were fatigue,
myalgia, headache, chills and arthralgia
–Receipt of influenza vaccine alone was associated chills, fatigue, myalgia and diarrhea
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Acknowledgements
•Duke University (Duke)
–Principal Investigator: Emmanuel B. Walter, MD, MPH
–Investigators: Ken Schmader MD, Wes Rountree , MPH , Marek S. Poniewierski MD, MS ,
Rachel L. Spreng PhD
•John Hopkins University (JHU)
–Principal Investigator: Kawsar Talaat, MD
•Cincinnati Children’s Hospital Medical Center (CCHMC)
–Principal Investigator: Elizabeth Schlaudecker, MD, MPH
–Investigator: Mary Staat, MD, MPH
•CDC
–Principal Investigator: Karen Broder, MD
–Investigators: Jonathan Duffy, MD, MPH, Oidda Museru MSN, MPH, Lisa A. Grohskopf
MD, MPH, Anju Goel MD, MPH (contractor)
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Extra Slides
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Serious Adverse Event (SAE) Definition
•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.
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Adverse Event of Special Interest (AESI)
Definition
•An AESI includes the following:
–COVID -19 illness
–Multisystem inflammatory syndrome
–Guillain -Barre syndrome
–Allergic type reactions (including anaphylaxis, hives, or facial
and limb swelling occurring within 7 days of a vaccination visit)
–Myocarditis or pericarditis
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Injection Site Reactions Grading
31Table 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
activityInterferes 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 cmRequires an emergency room (ER)
visit or hospitalization
Induration/Swelling(< 12 years of age)0.5 –2 cm 2.0 -7.0 cm > 7 cmRequires an emergency room (ER)
visit or hospitalization
Erythema/Redness(≥ 12 years of age)2.5 –5 cm 5.1 –10 cm > 10 cmRequires an emergency room (ER)
visit or hospitalization
Erythema/Redness(< 12 years of age) 0.5 –2 cm 2.0 -7.0 cm > 7 cmRequires an emergency room (ER)
visit or hospitalization
Axillary (underarm)
swelling or tenderness ipsilateral to side of injection Noticeable but does
not interfere with
activityInterferes 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
Systemic Reactions Grading
32Table 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/vomitingNoticeable but does not interfere
with activity or 1 –2 episodes/24
hoursSome interference with activity or
> 2 episodes/24 hoursSignificant; prevents daily activity and/or resulted in medical visit
and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
DiarrheaNoticeable but does not interfere
with activity or 2 –3 loose stools/24
hoursSome interference with activity or
4-5 loose stools/24 hoursSignificant; 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 hoursRequires an ER visit or
hospitalization
HeadacheNoticeable but does not interfere
with activitySome 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
FatigueNoticeable but does not interfere
with activit ySome 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 activitySome 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
ArthralgiaNoticeable but does not interfere
with activitySome 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 activitySome 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
EQ-5D-5L and VAS
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Subject Inclusion Criteria
•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.
•English or Spanish literate
•Intention of receiving influenza vaccine and mRNA COVID -19 vaccine
based on ACIP -CDC guidelines
•Willing to provide written informed consent
•Intention of being available for entire study period and complete all relevant study procedures, including follow -up phone calls and clinic visits
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Subject Exclusion Criteria
•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 protocol at Visit 1
•Prior receipt of IIV4 during the respective influenza season in which they are being enrolled
•< 9 years of age and recommended to receive two doses of IIV4 during the respective influenza season in which they are being enrolled
•Prior receipt of non -mRNA COVID -19 vaccine
•Documented COVID -19 infection within 6 weeks prior to enrollment confirmed by either medical
history or lab testing
•History of severe allergic reaction after a previous dose of any influenza vaccine; or to an influenza vaccine component, including egg protein
•History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of an mRNA vaccine
•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
35
Subject Exclusion Criteria
•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
•Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating intramuscular injection (a
daily aspirin may be acceptable).
•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:
–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
•Has known hepatitis B (HBV) or hepatitis C (HBC). Stable HBV or HBC are permitted per the following
parameters:
–If known HBV: confirmed inactive chronic HBV infection: HBsAg present for ≥6 months and
HBeAg negative, anti- HBepositive; 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
–If known HCV: evidence of sustained virological response for ≥12 weeks after treatment or
without evidence of HCV RNA viremia (undetectable HCV RNA)
36
Subject Exclusion Criteria
•Use of oral, parenteral, or high -dose inhaled glucocorticoids*
*For definition of high -dose inhaled glucocorticoids, reference Appendix B.
•History of Guillain -Barré syndrome
•Prior enrollment in this study during the 2021 -22 flu season
•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.
•Hearing loss determined by the investigators to prevent successful communication over
the phone
•History of myocarditis or pericarditis
•History of multisystem inflammatory syndrome in children (MIS -C) or adults (MIS -A).
•Has injury or other reason why deltoid site on both arms cannot be used for vaccinations.
•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.
•Anyone who is a relative of any research study personnel.
•Anyone who is an employee of any research study personnel.
37