Document text
Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 1of 60VERSION 8.0; 23MAR2021
TABLE OF CONTENTS
INVESTIGATORS ................................ ................................ ................................ .................... 4
ABBREVIAT IONS ................................ ................................ ................................ ................... 5
1. BACKGROUND ................................ ................................ ................................ ................... 7
1.1. RSV I N OLDER ADULTS AND PREGNANT WOMEN (ROAPS) ...................... 7
1.2. COVID -19 Amendment for COVID VE / Sub -study 6 ................................ .......... 11
2. STUDY OBJECTIVES ................................ ................................ ................................ ........ 13
2.1. ROAPS RSV AND SUB -STUDIES 1 – 5 OBJECTI VES ................................ .....13
2.1.1. Primary Objective ................................ ................................ ....................... 13
2.1.2. S econdary Objectives ................................ ................................ ................. 13
2.1.3. Exploratory Objectives ................................ ................................ ............... 13
2.2. COVID VE / SUB -STUDY 6 OBJECTI VES ................................ ......................... 15
3. METHODS ................................ ................................ ................................ .......................... 17
3.1. ROAPS RSV Sub -Studies #1 –5 and All Non -COVID VE Methods.................... 17
3.2. COVID VE Sub -Study #6 Methods ................................ ................................ ........ 21
3.2.1. Definition of Test- Negative Controls ................................ ......................... 21
3.2.2. Vaccination................................ ................................ ................................ .21
3.2.3. Patient Sociodemographic Characteristics, Clinical History , and
Health Behaviors and Lifesty le................................ ................................ ........ 24
3.2.4. Sensitivity Analy ses................................ ................................ .................... 25
4. STUDY POPUL ATION ................................ ................................ ................................ ......26
4.1. ROAPS RSV and COVID VE ARI ................................ ................................ ......... 26
4.1.1. ROAPS SUB -STUDY 5 Study Population ................................ ................ 27
4.1.2. ROAPS RSV Sample Size ................................ ................................ .......... 27
4.2. ROAPS I nclusion / Exclusion Criteria ................................ ................................ ....28
4.2.1. ROAPS RSV Inclusion / Exclusion Criteria for the Acutely Ill Cases ......28
4.2.2. Sub- Study #5 Inclusion and Exclusion Criteria for the Secondary
Objectives #4 (pregnant women)................................ ................................ .....29
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 2of 604.2.2.1. I nclusion and Exclusion Criteria for the Healthy Controls
(Exploratory Objective #2 -3) ................................ ............................ 29
4.2.3. ROAPS RSV I nclusion and Exclusion Criteria for the 18 -49 year
olds with COPD or CHF Exacerbations (Exploratory Objective #11) ............ 30
4.3. COVID VE Inclusion / Exclusion Criteria................................ .............................. 31
5. ROAPS RSV CASE FI NDING, ENROLLMENT, A ND PROCEDURES
INCLUDING SPECI MEN C OLLECT ION................................ ................................ ........ 32
5.1. Convalescent Serology ................................ ................................ ............................ 32
5.2. ROAPS RSV L aboratory Procedures ................................ ................................ ......33
5.3. ROAPS RSV Ethical Considerations and Sub- Studies #1 – 5................................ 33
6. COVID VE / SUB -STUDY #6 DATA ANALYSI SAND REPORTING OF
RESUL TS................................ ................................ ................................ ........................... 35
6.1. COVID VE Analy sis Populations ................................ ................................ ........... 35
6.1.1. Per- Protocol Population ................................ ................................ .............. 35
6.2. Statistical Analy sis................................ ................................ ................................ ..35
6.2.1. Estimated Crude (Unadjusted) VE ................................ ............................. 35
6.2.2. Estimating Adjusted VE ................................ ................................ ............. 35
6.2.3. Handling Missing Data................................ ................................ ............... 36
6.2.4. Analy sis Timings ................................ ................................ ........................ 36
6.2.5. Hy pothesis Testing ................................ ................................ ..................... 36
6.2.6. Sample Size Determination ................................ ................................ ........ 37
7. ROAPS AND SUB -STU DIES 1 -5 DATA ANALYS IS AND REPORTING OF
RESUL TS................................ ................................ ................................ ........................... 38
7.1. Justification ................................ ................................ ................................ ............. 38
7.2. Data Entry and Management ................................ ................................ ................... 39
8.COMPLIANCE WITH GOO D CLINI CAL PRACTI CE................................ .................... 39
8.1. Ethical Conduct of the Study ................................ ................................ .................. 39
8.2. I nstitutional Review Board (IRB)/Independent Ethics Committee (IEC) .............. 39
8.3. Participant Information and Consent................................ ................................ .......39
8.4. Participant Recruitment ................................ ................................ ........................... 40
9. SAFETY ................................ ................................ ................................ .............................. 40
10. REFERENCES ................................ ................................ ................................ .................. 42
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 3of 6011. APPENDICES ................................ ................................ ................................ ................... 47
11.1. Appendix A: Schedule of Events –ROAPS Acutel y Ill Cases ............................. 47
11.2. Appendix B: Schedule of Events –Sub-Study #4................................ ................ 49
11.3. Appendix C: Schedule of Events –Healthy Controls* ................................ ........ 50
11.4. Appendix D: Schedule of Events –Sub-Study #5 ................................ ............... 51
11.5. Appendix E: Schedule of Events – COVID VE Sub -Study #6............................ 52
11.6. Appendix F: Study Patient Flow – Acutel y Ill Cases ROAPS RSV and
COVID VE* ................................ ................................ ................................ .............. 53
11.7. Appendix G: Patient Flow – Health y Controls* ................................ ................... 54
11.8. Appendix H: Proposed Definitions for Chest Radiograph y Confirmed
Pneumonia ................................ ................................ ................................ ................. 56
11.9. Appendix I : Screening Log ................................ ................................ ................... 57
11.10. Appendix J: COVID VE Sample Size................................ ................................ .59
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 4of 60INVESTIGATORS
Evan J. Anderson, MD, Principal I nvestigator (Overall) and Emory University Hospital Site
Lead Investigator
Nadine Rouphael, MD, Co-Investigator and Emory Universit y Hospital Midtown Site Lead
Investigator
Larry Anderson, MD, Co-Investigator
Colleen Kraft, MD MSCI, Co-Investigator
Christina Rostad, MD, Co-Investigator
Kathy Stephens, RN, MSN, Research Nurse Manager, Lead Nurse
Ben Lopman, PhD, Co-Investigator, statistics lead
Ashley Tippett, MPH, MLS(ASCP)CM, Database architect
Laila Hussaini MPH, Lead Study Coordinator
Anne Piantadosi, MD, PhD , Co-Investigator
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Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 5of 60ABBREVIATIONS
Abbreviation Stands for
ACIP Advisory Committee on Immunization Practices
ADL activities of daily life
AE Adverse Event
AIDS acquired immunodeficiency syndrome
ARI acute respiratory illness
BAL bronchoalveolar lavage
BMI body mass index
CCI Charlson comorbidity index
cCCI classic Charlson comorbidity index
CHF congestive heart failure
CHOA Children’s Healthcare of Atlanta
CI confidence interval
COPD chronic obstructive pulmonary disease
COVID -19 coronavirus disease 2019
DSU Drug Safety Unit
ED emergency department
EDB Exposure during breastfeeding
EDP Exposure during pregnancy
EUA emergency use authorization
EUH Emory University Hospital
EUHM Emory University Hospital Midtown
HIV human immunodeficiency virus
ICD9 International Classification of Diseases
LAR legally -authorized representative
LOE Lack of efficacy
MOP Manual of procedures
mRNA messenger RNA
NAAT Nucleic acid amplification test
NP nasopharyngeal
OP oropharyngeal
OR odds ratio
PCR polymerase chain reaction
PBMC peripheral blood mononuclear cells
PPE personal protective equipment
QOL quality of life
RRI Research Reportable Injury
RSV respiratory syncytial virus
RVP respiratory viral panel
SAE Serious Adverse Event
SARS -CoV -2 severe acute respiratory syndrome coronavirus –2
SAP statistical analysis plan
SOC standard of care
TND test-negative design
uCCI updated Charlson comorbidity index
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 6of 60VE vaccine effectiveness
wGA weeks gestational age
WHO World Health Organization
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 7of 601.BACKGROUND
1.1.RSV IN OLDER ADULTS AND PREGNANT WOMEN (ROAPS)
Respiratory syncytial virus (RSV) is the single most important cause of serious lower
respiratory tract infections in U.S. children. RSV is estimated to cause 50,000 – 125,000
hospitalizations/y ear in U.S. children <5 years of ag e.1,2After an initial infection, subsequent
infections tend to be less severe and often manifest as mild upper respiratory tract infections.
RSV is also an important pathogen later in life with severe disease also occurring among those
with compromised cardiac, pulmonary or immune systems and in the elderly.3-5It is uncertain
the extent to which severe disease in the elderl y is due to lack of immunological control due to
complications from age-associated co-morbidities. Estimates of the RSV disease burden
requiring hospit alization in adults are limited but suggest that up to 10% of adults presenting
with acute respiratory illness (ARI) during the winter have RSV.3,5-8Data regarding RSV in
pregnant women, a candidate population for vaccine implementation, are particularl y limited.
The RSV season frequently overlaps with the influenza season which confounds the ability to
define RSV’s clinical and epidemiological features. The l imited available data show that age,
chronic medical conditions (e.g., COPD, cardiac disease, immunodeficiency ) are significant
risk factors and that fever is less commonly observed with RSV than with influenza infection,
while cough, dyspnea, and wheezing may be more common.9-11 These limited data primaril y
come from a single center in Rochester, New York.5,10-24
The exact timing of the adult RSV season relative to the pediatric season is not known. We
know that the RSV season in children extends beyond the influenza season (See Figure above
Influenza and RSV Identified at 2 Children’s Healthcare of Atlanta (CHOA )Hospitals
2012 -2015). In Atlanta, RSV in children extends from the beginning of October through
early -mid March. Available data suggests that most cases of RSV in adults occur during the
winter season, similar to cases inchildren.3,5,12,14 ,15,24,25Cases detected by standard of care
(SOC) testing from several large adult hospitals in Atlanta are outlined in the Figure below
(Influenza and RSV Identified at EUH and EUHM 2012 – 2015 ). 050100150
8.12.12
9.30.12
11.18.12
1.13.13
3.3.13
4.28.136.16.13
8.4.13
9.22.13
11.10.13
12.29.13
2.16.14
4.6.14
5.25.14
7.13.14
8.31.14
10.19.14
12.7.141.25.15Total Number of RSV
and Influenza IsolatesInfluenza and RSV Identified at 2 CHOA Hospitals 2012 -2015
Total Influenza
Total RSV
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 8of 60Despite nearly 50 years of effort, neither a vaccine nor highly effective antiviral therap y has
been licensed; however, promising RSV vaccines are in development. Phase 2 and 3 clinical
trials in pregnant women have begun (NCT04032093 and NCT04424316 ).26,27Establishing
the current population -based RSV burden of disease , clinical and epidemiological features in
hospitalized adults is crucial for understanding the potential for an RSV vaccine impact . By
expanding our understanding of RSV in pregna nt women and older adults ,we will be better
positioned to assess potential impact and cost benefit of a vaccination program in pregnant
women and older adults.
Substantial RSV -related disease and hospitalizations occurs in infants with highest risk in those
<2 months of age (1970/100,000) followed by those 3 – 5 months of age (897/100,000).28Risk
among those that are preterm is even higher due to underly ing chronic lung disease, smaller
airway s, and decreases in maternal antibody transfer across the placenta to preterm infants.29-
31The current leading approaches towards prevention of disease among infants are maternal
RSV vaccination and potentially monoclonal antibodies and clinical trials are ongoing.
Maternal vaccination is likely to be utilized for prevention of RSV in neonates and infants. In
addition to directly protecting the mother, maternal antibodies are likely to be transferred
across the placenta beginning at 32 weeks gestational age (wGA) to the unborn fetus. Data
about the timing (wGA) and quantity of antibodies transferred across the placenta are fairly
limited for RSV.32-35Additional data about antibody transfer across the placenta of RSV
antibodies could be determined by collecting maternal serology and cord blood specimens at
the time of delivery .
SARS -CoV -2, the cause of COVID -19, emerged as a pathogen in humans in December 2019
and spread worldwide to become a pandemic over the next several months.36,37The rapid
emergence of COVID -19 in Atlanta resulted in the need to halt enrollment into ROAPS in mid-
March 2020 (end of season 2 of surveillance). Early data from the Southern Hemisphere
indicates that COVI D-19 and the social interventions that have been impleme nted (e.g., face
masks, social distancing) and potential changes in the willingness to seek healthcare have had
substantial impact upon the burden of influenza and the influenza season.38It is unknown
whether such interventions might impact the influenza and RSV seasons in the US. Such data
are critical for understanding the lower bound of influenza and RSV disease that occur in the 0.010.020.030.040.050.0Influenza %, RSV Actual
ValuesInfluenza and RSV Identified at EUH and EUHM 2012 -2015
%
Influenza
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 9of 60setting of substantial social interventions and changes in healthcare seeking behavior. After
discussion with the study funder (Pfizer), we will continue to perform prospective RSV and
viral surve illance (e.g., SARS -CoV -2) among pregnant women , adults with CHF or COPD,
and older adults requiring hospitalization during the pre -planned Season 3 (2020 – 2021). The
approach to respiratory virus surveillance during ROAPS needed to change due to the uniq ue
impact that COVID -19 hashad upon healthcare. This includes, but is not limited to, risk of
transmission to healthcare providers, potential shortages of personal protective equipment
(PPE), and shortages of respiratory swabs.
Beginning the summer of 2020, all admitted patients to EUH and EUHM are receiving standard
of care (SOC) testing for SARS -CoV -2 upon hospital admission. Note that beginning in Season
3 (2020 –21), we will modify the approach to salvage SOC specimens sent from admitted
patients me eting enrollment criteria. These salvaged SOC specimens will then be tested with
study -specific BioFire RVP testing retrospectively and potentially with future Pfizer assay s
(e.g., dedicated PCR). Substudies #1, 2, and 4 will continue during Season 3 with
modifications as detailed below. Additionally , patient interviews and onsite follow -ups will
be limited to those enrolled in certain substudies, cough specimens will not be obtained, and a
control population of healthy outpatients will not be enrolled. This will simplify Season 3 and
the efforts involved, while minimizing risks for study staff and patients.
To clarify where procedures will differ beginning in Season 3, we have offset changes
throughout the protocol with Modifications Beginning in Season 3: with the modification in
italics.
In addition to modifications to Season 3 due to SARS -CoV -2, Pfizer and Emory identified an
opportunity for ROAPS to further evaluate both RSV and SARS -CoV -2 illness and antibody
transfer among pregnant women . SARS -CoV -2 can cause severe disease in pregnant women
(including fetal loss) and in infants and young children.39,40Vaccines for COVID -19 are
rapidly being developed with a number of candidates alread y in Phase 3 clinical trials.41-46
Although expansion of vaccine clinical trials into children has occurred down to age 12,47,48it
is unlikely that vaccines will be available for children <6 months of age in the near future.
Maternal vaccination, in addition to providing benefit to the mother, could provide benefit to
the infant through decreasing maternal disease and through the passive transfer of maternal
antibody to the infant. In addition to directly protecting the mother, maternal antibodies are
likely to be transferred across the placenta beginning at 32 weeks gestational age (wGA) to the
unbo rn fetus. Data about the timing (wGA) and quantity of antibodies transferred across the
placenta are limited for COVID -19. Additional data about antibody transfer across the placenta
of COVID -19 antibodies could be determined by collecting maternal serolo gy and cord blood
specimens at delivery. The Advisory Committee on Immunization Practices (ACI P) noted that
“potential risks of mRNA vaccines to the pregnant person and the fetus are unknown because
these vaccines have not been studied in pregnant people.” They advised that “If pregnant
people are part of a group that is recommended to receive a COVID -19 vaccine (e.g., healthcare
personnel), they may choose to be vaccinated.” In addition, “When making a decision,
pregnant people and their healthcare provide rs should consider the level of COVID -19
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Determining RSV Burden and Outcomes in Pregnant Women and Older Adults
Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 10of 60community transmission, the patient’s personal risk of contracting COVID -19, the risks of
COVID -19 to the patient and potential risks to the fetus, the efficacy of the vaccine, the side
effects of the vaccine, and the lack of data about the vaccine during pregnancy.”49 In an effort
to better define transplacental antibody transfer of both RSV and SARS -CoV -2 antibodies
across gestational ages, Substudy 5 has been incorporated as part of this ROAPS amendment.
It is expected that enrollment for Substudy 5 as defined in Methods Section may begin around
or after the start of enrollment for the COVID VE Substudy 6 and aims to enroll health y women
who present at EUH or EUHM for delivery , regardless of RSV or COVID status.
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Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 11of 601.2.COVI D-19 Amendment for COVID VE / Sub-study 6
In December 2019 the Wuhan Municipal Health Committee identified an outbreak of
pneumonia that was ultimately identified as a novel pathogen named SARS -CoV -2. The
disease caused by SARS -CoV -2 is called Coronavirus disease 2019 (COVID -19). On March
11, 202 0 the WHO declared COVID -19 a pandemic. As of March 8, 2021, >29 million cases
and 530,000 deaths had occurred in the US.50Morbidity and mortality have disproportionately
affected older adults and racial and ethnic minorities.51Since the emergence of SARS -CoV -
2, additional mutations in the virus have been observed including D614G, B.1.1.7 (which
emerged in the UK), P1 (which emerged in South America), and B.1.351 (which emerged in
South Africa).
Currently , there are over 170 vaccines in preclinical development and 60 vaccines that have
entered into clinical trials .52In the US, 6 candidate vaccines have had vaccine doses purchased
by Operation Warp Speed to advance promising candidate vaccines rapidly toward licensure,53
and 2 mRNA vaccines [Moderna (mRNA- 1273), Pfizer (BNT162b2)] received FDA EUA in
December 2020. BNT162b2 is amRNA vaccine recommended as 2 doses 21 days apart that
encodes the full-length, membrane -anchored S glycoprotein of SARS -CoV -2 with two
introduced proline mutations to lock it in the prefusion conformation.54-56It was co -developed
by BioNTech SE and Pfizer, Inc. The vaccine showed an acceptable safet y profile in a Phase
1/2 study .57Data supporting the FDA EUA came from a pivotal Phase 3 clinical trial.47 The
BNT162b2 study vaccinated over 43,000 participants, and vaccine was 95% effective in
prevention of COVID -19 in comparison to placebo.58It also was highly effective against
severe cases (9 in placebo: 1 in vaccine). Millions of BNT162b2 doses have now been
administered under EUA to individuals at high risk including healthcare workers, nursing
home residents, and other high -risk groups (e.g., ≥65 years of age).
Although clinical trials provide initial vaccine efficacy in a highl y controlled setting, real world
estimates of COVID -19 vaccine effectiveness (VE) are needed since this can vary
substantially .58
The optimal methodology for VE studies uses the “test-negative design ” (TND) in which
vaccination rates among test-positive individuals (“cases”) are compared with vaccination
rates among test-negative individuals (“controls”). VE is calculated as: (1-odds ratio for
vaccination) x 100.59A test-negative case-control study design using a molecular assay is
important in estimating VE accurately and rapidly,60and can control for differences that mi ght
exist due to access to care.60-63Test-negative controls have been demonstrated to accuratel y
estimate VE theoreticall y and through retrospective reanal ysis of prospectively collected data
of vaccine efficacy from ra ndomized controlled trials.60-63
Such studies have been used extensively for influenza.64-71The ROAPS study was modifie d
during the Spring of 2020 toretrospectively characteriz ethe emergence of novel respiratory
pathogens (e.g., SARS -CoV -2)in these adults (Version 4.0) . Beginning the summer of 2020,
all admitted patients to EUH and EUHM are receiving standard of care (SOC) testing for
SARS -CoV -2 using a molecular test upon hospital admission to EUH and EUHM. Reasons
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Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 12of 60for this include identification of SARS -CoV -2 infection prior to hospital admission
(community -onset) that is presenting presy mptomatically , asymptomaticall y, or atypically.
This provides a unique opportunity to evaluate the VE of COVI D-19 vaccination with
BNT162b2 against hospital admission due to ARI in adults ( Sub-Study #6 ).
Critical to VE studies is correctly determining the vaccination status for all ca ses and controls
enrolled in this study . To determine vaccination status, review of government -issued COVID -
19 vaccination cards, medical records from relevant healthcare providers (e.g., primary care,
public health department), health- insurance providers , pharmacies, and any local, state, or
national adult immunization registries will need to occur for each enrolled patient. For each
potential source of vaccination, a record of whether BNT162b2 (or other COVID -19 vaccine)
was received, including the date(s) of administration and the number of doses received, will
be obtained.
It is also critical to control for potential bias and confounding that may exist in the absence of
randomized assignment of vaccine and blinded follow-up. Thus, in addition to constructing
crude OR and VE estimates, logistic regression modeling to assess BNT162b2 VE after
adjustment for time of enrollment, recruitment site, and other potentially confounding
sociodemographic, clinical factors (e.g., comorbidities, history of SARS -CoV -2 infection), and
behavioral and lifesty le factors will be performed. It is particularly critical as potential for
receipt of vaccine will be rapidly changing over time. As such, it will be necessa ry to control
tightly the ‘vaccine priority group’ of enrolled subjects along with the window for enrollment
to limit the risk of findings being due to vaccine access. In addition, the risk of SARS -CoV -2
exposure is anticipated to rapidly change over time, so it will be critical to identify and control
for timing of illness. The approach to this will be by multivariable anal ysis.
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Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 13of 602.STUDY OBJECTIVES
For clarity Sub-Studies 1 -5 are presented first followed by Sub -Study 6
2.1 Sub- Studies 1- 5 reflect ROAPS RSV and only non-COVID VE Objectives
2.2 Sub- Study 6 reflects only COVID VE Objectives
2.1.ROAPS RSV AND SUB -STUDIES 1 – 5 OBJECTIVES
2.1.1. Primary Objective
To determine the population -based incidence of RSV -related hospitalizations in pregnant
women and adults ≥50 years of age.
2.1.2. Secondary Objectives
1)To describe the epidemiology and clinical presentation of RSV -related hospitalizations
in pregnant women and adults ≥50 years of age.
2)To describe the outcomes of RSV -related hospitalizations in pregnant women and
adults ≥50 y ears of age.
3)To compare the population -based incidence of hospitalization, epidemiology, clinical
presentation, and outcomes observed in RSV -positive pregnant women and adults ≥50
years of age versus those with influenza.
4)To compare RSV ant ibodies in cord blood and maternal serum at various wGA.
5)To compare SARS -CoV -2 antibodies in cord blood and maternal serum at various
wGA.
2.1.3. Exploratory Objectives
1)To determine the rates of seroresponse to RSV between acute and convalescent
serology and the concordance with molecular test results in hospitalized pregnant
women and adults ≥50 years of age.
2)To determine the prevalence of RSV and other viral pathogens (including SARS -CoV -
2) in healthy control population s of pregnant women and adults ≥50years of age.
3)To compare the rate of RSV and other viral pathogen detections among enrolled control
populations with the rate of RSV and other viral pathogen detections among
hospitalized pregnant women and adults ≥50 y ears of age.
4)To describe the clinical and epidemiologic characteristics of patients hospitalized with
ARI in whom specific pathogens are identified, including those who are co -infected.
5)To determine the rate s, risk factors for, and outcomes of RSV -related pneumonias.
6)To correlate RSV viral load with clinical symptomatology and outcomes in a subset of
enrolled patients (Sub -Study #1).
7)To collect clinical specimens for future anal yses.
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Requiring Hosp italization
Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 14of 608)To assess the risk of RSV infection/re -infection through 1 year after enrollment in a
subset of patients enrolled in the primary study (Sub -Study #2).
9)To describe the durability of the serological response to RSV through 1 year after
enrollment in a subset of patients enrolled in the primary study (Sub- Study #2).
10)To determine rates of influenza vaccination and influenza vaccine effectiveness against
influenza -related hospitalizations inpregnant women and adults ≥50 years of age
hospitalized with ARI .
11)To determine rates of RSV andother viral pathogens among adults 18 – 49 years of
age admitted with congestive heart failure (CHF) or chronic obstructive pulmonary
disease (COPD) exacerbations (Sub- Study #3).
12)To assess the performance characteristics of cough specimens submitted for the
detection of RSV and other viral pathogens.
13)To assess the cellular immune response to RSV at baseline and in follow -up in a subset
of RSV positive patients and controls (Sub-Studies #1, 2, and 4).
14)To assess the risk of RSV infection/re -infection throu gh almost 3 years after enrollment
in a subset of patients enrolled in the primary study (Sub -Study #4).
15)To describe the durability of the serological response to RSV through almost 3 years
after enrollment in a subset of patients enrolled in the primary study (Sub -Study #4).
16)To determine the population -based incidence of SARS -CoV -2-related hospitalizations
in pregnant women and adults ≥50 years of age .
17)To describe the epidemiology and clinical presentation of SARS -CoV -2-related
hospitalizations in pregnant women and adults ≥50 years of age.
18)To describe the outcome s of SARS -CoV -2-related hospitalizations in pregnant women
and adults ≥50 y ears of age.
19)To compare the population -based incidence of hospitalization, epidemiology, clinical
presentation, and outcomes observed in SARS -CoV -2-positive pregnant women and
adults ≥50 years of age versus those with influenza , RSV, or other respiratory viral
pathogens .
20)To describe the seroprevalence of antibodies to SARS- CoV -2 among subjects infected
with SARS -CoV -2, oth er circulating coronaviruses, and other respiratory viruses.
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 15of 602.2.COVID VE / SUB -STUDY 6 OBJECTIVES
Objectives Endpoints
Prim ary Prim ary
Objective 1: To estimate the
effectiveness of 2 doses of BNT162b2
(i.e., fully vaccinated) against
hospitalization for ARI* due to
SARS -CoV- 2 infection.VE calculated as 1 minus the OR comparing the odds of
being fully vaccinated (2 doses) w ith BNT162b2 for
hospitalized cases and controls, multiplied by 100%.*
Secondary Secondary
Objective 2: To describe the
effectiv eness of only 1 dose of
BNT162b2 (i.e., partially vaccinated)
against hospitalization for due to
SARS -CoV- 2 infection.VE calculated as 1 minus the OR comparing the odds of
being partially vaccinated with BNT162b2 (only 1 dose)
for hospitalized cases and controls, multiplied by 100%.*
Objective 3: To describe the
effectiveness of ≥1 dose of BNT162b2
(i.e., ever vaccinated) against
hospitalization for ARI due to SARS -
CoV- 2 infection.VE calculated as 1 minus the OR comparing the odds of
ever being vaccinat ed (≥1 dose) w ith BNT162b2 for
hospitalized cases and controls, multiplied by 100%.*
To evaluate the effectiveness of
BNT162b2 against ARI hospitalization
stratified by prevalent or important
viral strains.BNT162b2 VE estimates by prevalent or important virus
variants.
To evaluate the effectiveness of
BNT162b2 against severe
hospitalization -related outcomes (e.g.,
ICU admission, mechanical
ventilation, and death).BNT162b2 VE estimates against severe outcomes
including ICU admission, mechanical ventilation, and
death.
Tertiary/Exploratory Tertiary/Exploratory
To further describe the effectiveness
of BNT162b2 stratified by various
patient characteristics (e.g., age, sex,
race/ethnicity, chronic medical
conditions, history of SARS -CoV -2
infection, long -term care facility
residence, pregnancy status, and
receipt of influenza vaccine).BNT162b2 VE estimates by age group.
BNT162b2 VE estimates by sex.
BNT162b2 VE estimates by race/ethnicity.
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 16of 60Objectives Endpoints
BNT162b2 VE estimates by presence of chronic medical
conditions, history of SARS -CoV -2 infection, pregnancy
status.
BNT162b2 VE estimates by receipt of influenza vaccine in
the last year.
BNT162b2 VE estimates among long -term care facility
residents.
BNT162b2 VE estimates by time since vaccination
(durability).
BNT162b2 VE estimates by time between first and second
dose among those who received 2 doses.
To describe the proportion of patients
with ARI where SARS -CoV- 2 was
identified.Proportion of ARI hospitalizations where SARS -CoV -2 is
identified.
To summarize the proportion of
patients who receive 0, 1, or 2 doses of
BNT162b2.
To summarize the time betw een
administration of the first and second
dose of BNT162b2 among patients
who received 2 doses.
To summarize the time since
vaccination with BNT16 2b2 (most -
recent dose) from study enrollment. Proportion of patients who receive 0, 1, and 2 doses of
BNT162b2
Average and median time between receipt of the first and
second dose BNT162b2 among patients who received two
doses.
Average and median time bet ween study enrollment and
receipt of last dose among patients receiving BNT162b2.
To describe demographic, clinical,
and laboratory (i.e., viral strain)
characteristics and disease severity of
any BNT162b2 vaccine failures.Describe age, gender, race/ethnicity, clinical
characteristics, and severity (ICU admission, ventilator,
death) of any patients who received BNT162b2 and test
positive for SARS -CoV- 2.
Sequence isolates of available SARS -CoV- 2 viral variants
and identify whether these are due to major viral variants
(e.g., B.1.351).
To describe COVID- 19 disease
severity for vaccinated and
unvaccinated cases.Describe disease severity for vaccinated and unvaccinated
cases (e.g., average hospital LOS, 30 -day readm ission, the
proportion requiring I CU admission or mechanical
ventilation, death).
* ARI as defined by WHO as an acute respiratory infection that occurred within the last 10
days and required hospitalization with history of fever or measured fever of ≥38 C °AND
cough. Because many COVID -19 patients do not necessarily have fever (~15%) or cough
(~15%), we will vary this definition in sensitivity analyses.51
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 17of 603.METHODS
For clarity , Sub-Studies 1 – 5 (ROAPS RSV and all non-COVID VE methods) are presented
first followed b y Sub -Study 6 (COVID VE onl y).
Schedule of Events for Sub -Studies 1-6 can be found in the following Appendices:
Appendix A: Schedule of Events – ROAPS Acutely Ill Cases
Appendix B: Schedule of Events – Sub-Study #4
Appendix C: Schedule of Events –Health y Controls
Appendix D: Schedule of Events –Sub-Study #5
Appendix E: Schedule of Events -COVID VE Sub -Study #6
3.1.ROAPS RSV Sub -Studies #1 – 5 andAll Non- COVID VE Methods
To accomplish Primary, Secondary #1 –3, and Exploratory Objectives #1, 4 – 7:
We will prospectively identify and enroll pregnant women and adults ≥50 y ears of age
who meet the case definition of acute respir atory tract infection (ARI) and are admitted
for inpatient care. This will include those who are admitted for observation or remain
in the ED for ≥24 hours. Nasophary ngeal/orophary ngeal (NP/OP )swab s as well as
cough specimens, will be obtained from all enrolled patients as soon as possible after
admission (see specimen collection section for specific guidelines) and blood will be
obtained. A study questionnaire detailing clinical and epidemiology information will
be completed via patient and/or healthcare power of attorney interview and medical
chart review. This will include an assessment of Activities of Daily Living (ADL),
Quality of Life (QOL), frailty , and data to determine the other disease -specific scores
(for older adults) and a pregnancy -related questionnaire for pregnant women. In order
to ensure that specimens are collected in a timely manner, we will aim for 7 days a
week enrollment using study nurses and other qualified personnel. Enroll ed patients
also will have standard of care (SOC) results and specimens scavenged and will be
asked to return for convalescent serology 21 – 60 days(goal 21 – 45 day s)after initial
presentation. Home visits may be used if needed, but follow -up at Emory will be highly
encouraged. If ARI symptoms develop after hospital discharge but before the follow -
up appointment for convalescent serology , an additional follow -up visit will occur prior
to the convalescent visit. If s ymptoms are present at the convalescent visit, NP and OP
swabs as well as cough specimens will be obtained at the convalescent visit. Data will
be anal yzed separatel y for pregnant women and adults ≥50years of age.
Modifications Beginning in Season 3:Beginning the summer of 2020, all admitted
patients to EUH and EUHM are receiving standard of care (SOC) testing for SARS-
CoV-2 upon hospital admission. Reasons for this include identification of SARS -CoV-
2 infection prior to hospital admission (community -onset) that is presenting
presymptomatically, asymptomatically, or atypically. Beginning inSeason 3 (2020 –
21), we will salvage SOC specimens sent from admitted patients meeting enrollment
criteria (we will not obtain additional NP/OP swabs or cough specimens beyond those
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Version: 10MAR2021; Page 18of 60collected as SOC except as detailed below for those enrolled in Substudies 1, 2 and 4) .
We are requesting a waiver of all element of informed consent for review of medical
records and collection of SOC specimens from patients meeting eligibility criteria . A
small subset will be prospectively consented and enrolled into Substudies 1, 2, and/or
4 (e.g., those that have SOC testing that are RSV positive, influenza positive, or PCR -
negative controls) . This is important as the COVID -19 pandemic has impacted
resources available (e.g., PPE) to approach all admitted patients making it impractical
to conduct the study as had occurred in Seasons 1+2. These salvaged SOC specimens
will then be tested with study -specific BioFire RVP testing retrospectively 3 weeks or
more after hospital discharge and potentially with future Pfizer assays (e.g., dedicated
PCR) .These results will not be available to the patient or patient care teams (the result
will no longer be clinically relevant from these specimens). Patient intervi ews will not
be conducted except on those subjects enrolled in Substudies 1, 2, or 4. Patients will
not have follow -up or direct contact with the research staff unless enrolled in
Substudies 1, 2, or 4.
To accomplish the Secondary Objectives #4 – 5 (Sub -Study #5): We will identify
and enroll pregnant women admitted to EUH M for a one-time inpatient visit at the time
of delive ry. A subset of these will have been enrolled in the Emory Cord Blood research
study (EmPOWR), the Cleveland Core Bank, or other rese arch entities obtaining cord
blood. These women will be approach to co-enroll into ROAPS. Cord blood will be
collected and saved at the time of birth and SOC maternal serum will be salvaged from
the laboratory . Cord blood and maternal serum antibody levels will be compared at the
time of delivery between various wGA for both RSV and also SARS -CoV -2. If
insufficient cord blood is available, residual infant SOC sera may be salvaged from the
laboratory (if available).
To accomplish the Exploratory Objective s #2-3:We will prospectively identify and
enroll pregnant women and adults ≥50 years of age without recent illness or
hospitalizations. These adults will also have NP/OP swabs , cough specimens and blood
obtained on enrollment . They will also be asked to return for follow -upserology 21 –
60days (goal 21 – 45 days) after initial enrollment. If ARI symptoms develop after
enrollment, but before the follow -up appointment for follow -up serology , an additional
follow -up visit will occur prior to the convalescent visit. I f symptoms are present at the
convalescent visit, NP and OP swabs will be obtained at the follow -up visit. To the
extent feasible, efforts will be made to match the age,gender , and co -morbidities to the
cohort of hospitalized and enrolled older adults. Pregnant women controls will be
matched to cases roughly on age, race/ethnicity ,time, and weeks gestational age
(wGA). Data will be analyzed separatel y for pregnant women and adults ≥50years of
age.
Modifications Beginning in Season 3: Beginning i n Season 3, a control population of
healthy outpatients will NOT be enrolled due to th e COVID -19 pandemic.
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 19of 60To accomplish Exploratory Objectives #6 and 13 (Sub -Study #1): We will serially
sample a subset of adults every other day who have RSV identified on standard of care
testing and controls (e.g., those with influenza, those that are SO C PCR- negative) with
NP/OP swabs along with obtaining information about the resolution of symptoms from
the patient interview. This will only occur until hospital discharge, follow -up will occur
according to the main study except that those enrolled in thi s optional substudy will
also have NP/OP swabs obtained at the convalescent visit. If these Sub-Study adults
agree, they will also have PBMCs collected at enrollment, approximately day 7 of
symptoms (if this occurs after the enrollment visit), and at the c onvalescent visit.
Modifications Beginning in Season 3: None.
To accomplish Exploratory Objectives #8-9 (Sub -Study #2): We will enroll in
follow -up a subset of patients beyond the follow -up visit at Days 21 –60. This will
include RSV positive (either through RSV SOC testing or through study -specific
BioFire testing) and roughl y matched RSV negative patients enrolled into this study
that will be identified and asked to complete follow -up by the study team. They will
be asked to return for a NP/OP swab , cough specimen and blood draw for any
symptoms consistent with ARI (see I nclusion Criteria #5c) and for follow -up blood
draw just prior to the onset of the next RSV season. The study team will make contact
with them every 2 weeks between enroll ment into Sub-Study #2 and the final visit to
ascertain for interval ARI. If these Sub-Study adults agree, they will also have PBMCs
collected at their final Sub -Study #2 visit.
Modifications Beginning in Season 3: Those identified with study -specific BioFire
testing will not be approached for enrollment into Sub-Studies 2 and/or 4. These
subjects will not have follow -up NP/OP swab testing cough specimen collection
performed. Similar to the overall study, a small subset (e.g., individuals that have SOC
testing that are RSV positive, influenza positive, and are PCR -negative controls) will
be prospectively consented and enrolled into Substudies 1, 2, and/or 4.
To accom plish Exploratory Objective #10: We will obtain vaccination histories from
patients that meet enrollment criteria for the Primary, Secondary, and Exploratory
Objectives #1, 4 – 7 . We will use a test negative design to determine influenza vaccine
effectiveness (VE). Sensitivity analyses will be used to determine VE by varying the
definition of ARI and subgroup anal yses will be performed (e.g., different age groups,
co-morbidities, multiple seasons of influenza vaccination).
Modifications Beginning in Season 3: This exploratory objective will now be limited
to obtaining vaccination history only from the medical record and central electronic
registries (patients and medical provider s will not be contacted for records).
To accomplish Exploratory Objective #11 (Sub -Study #3): We willenroll 18 – 49
year old adults who otherwise meet all of the Inclusion and Exclusion Criteria ( Except
for Inclusion Criterion #1) who are admitted with COPD or CHF exacerbations
(Inclusion Criteria #5a OR 5b ). These will be followed similarly to the Primary ,
Secondary , and Exploratory Objectives #4 – 7 above.
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Short Title: RSV in Older Adults and Pregnant Women Study
(ROAPS)
Version: 10MAR2021; Page 20of 60Modifications Beginning in Season 3:The same modification will occur as for
Primary, Secondary, and Exploratory Objectives #1, 4 – 7 (see above) in that a waiver
of informed consent will be requested to test SOC specimens and review medical
records .
To accomplish Exploratory Objective #12: We will collect cough specimens from
adults that can provide cough specimens for viral testing. We will test these specimens
for evidence of RSV and other viral pathogens. The results of the viral testing of these
cough specimens will be compared with other RVP SOC testing, Biofire RVP testing,
and serolog y to determine the performance characteristics of this sample type.
Modifications Beginning in Season 3: Beginning inSeason 3, cough specimens will
NOT be obtained in the study.
To accomplish Exploratory Objectives #13 and 14 (Sub -Study #4): Similar t o Sub -
Study #2, we will enroll and follow -up a subset of patients bey ond the follow -up visit
that occurs just prior to the RSV season in Sub-Study #2. This will include RSV
positive and RSV negative patients enrolled into this study . They will be asked to
return for a NP/OP swab, cough specimen and blood draw for any symptoms consistent
with ARI (see Inclusion Criteria #5c) and for follow -up blood draw just prior to the
onset of the subsequent 2 RSV seasons (last visit occurring almost 3 years after initi al
enrollment). The study team will make contact with them every 2 w eeks between
enrollment into Sub -Study #4and the final visit to ascertain for interval ARI. PBMCs
will be collected from them on a yearly basis.
Modifications Beginning in Season 3: Subs tudy #4 will continue in Season 3, but will
not include cough specimens. All other study procedures will occur as detailed above.
To accomplish Exploratory Objectives #16-20:We will identify SARS -CoV -2
positive patients among those who meet enrollment criteria for the primary study.
Similar to the primary and secondary objectives, we will test collected
nasophary ngeal/oropharyngeal ( NP/OP )swabs as well as cough specimens and blood
specimens b y PCR and antibody assay s. We will also assess clinical and epidemiology
information including assessment of Activities of Daily Living (ADL), Quality of Life
(QOL), frailty , and data to determine the other disease -specific scores (for older adults)
and a pregnancy -related questionnaire for pregnant women.
Modifications Beginning in Season 3: The same modification will occur as for
Primary, Secondary, and Exploratory Objectives #1, 4 – 7 (see above) in that a waiver
of informed consent will be requested to test SOC specimens and review medical
records .SOC specimens will have already been tested by SOC SARS- CoV-2 PCR
testing. W e will not obtain questionnaires on these COVID -19 positive patients.
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 21of 603.2.COVID VE Sub -Study #6 Methods
To accomplish the Objectives for Sub-Study #6: COVID VE, the following approach and
definitions will be utilized. An NP or nasal swab to test for the presence of SARS- CoV -2 by
NAAT will be required for all study participants as a study -related procedure (if not performed
as standard of care). NAAT will be performed in an approved local laboratory . Whole-genome
sequencing will be performed on SARS -CoV2- positive swabs from enrolled patients when
possible from study specimens and/or SOC specimens when availa ble.
Cases will be defined as patients who meet selection criteria and:
1.Test positive for SARS -CoV -2 via NAAT performed upon sample(s) collected as a
study -related procedure upon admission/enrollment, OR
2.Tested positive by NAAT* from samples collected ≤14 days prior to
admission/enrollment.
* All efforts will be made to confirm test results from specimens prior to admission as
a NAAT test. If a positive test cannot be confirmed as a NAAT, it will still be included.
We will examine the proportion of cases identified in the 14 days prior to
admission/enrollment (Criteria #2 above). If this is a substantial component of the total
number of cases, we will consider a sensitivity analysis using only samples collected
upon admission/enrollment (Criteria #1 above only).
Patients who have positive results for SARS -CoV -2 from samples taken ≥72 hours after
hospital admission/enrollment will be considered to have nosocomial COVID -19 and will be
excluded from the primary analysis. The impact of excluding these patients on VE estimates
will be examined in sensitivity analyses. Laboratory confirmation is defined by NAAT,
however, results from viral culture, direct or indirect fluorescent antibody staining, or rapid
antigen testing will be collected and analy zed in sen sitivity anal yses.
3.2.1. Definition of Test -Negative Controls
All other patients who met study inclusion criteria (e.g., at least one NP or nasal swab that was
tested for SARS -CoV -2 using NAAT) but for whom SARS -CoV -2 is not identified from
NAAT will serve as test -negative controls.
3.2.2. Vaccination
A natural (“real -life”) history of vaccination with BNT162b2 will be obtained for both cases
and controls from government -issued COVID -19 vaccination cards, medical and billing
records collected from relevant healthcare providers (e.g., primary care, publi c health
department), health -insurance providers, pharmacies, and any local, state, or national
immunization registries for each enrolled patient. For each potential source of vaccination, a
record of whether BNT162b2 was received, including the date(s) ofadministration and number
of doses received, will be obtained. Self-reported COVID -19 vaccination status will be also
captured as part of the patient interview and will be anal yzed in sensitivity anal yses.
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Version: 10MAR2021; Page 22of 60The primary exposure of interest is history of vaccination with BNT162b2. For the primary
objective, patients will be considered vaccinated if they have documented evidence of
receiving the second dose of BNT162b2 ≥7 days before ARI symptom onset. When evaluating
the effectiveness of one dose of BNT162b 2, patients will be considered vaccinated if they have
documented evidence of receiving the first dose of BNT162b2 ≥14 day s before ARI s ymptom
onset. Four levels of the primary exposure variable will be assessed:
1.Fully vaccinated defined as 2 doses of BNT162b2 received with ≥7 day s between receipt
of the 2nd dose and ARI symptom onset. This group will serve as the ‘exposed’ group
evaluated in the primary objective. Patients who received only 1 dose or 2 doses of
BNT162b2 with <7 days between receipt of the 2nd dose and ARI symptom onset and will
be excluded from this analysis. In sensitivity analyses, VE will also be calculated for 2
doses of BNT162b2 received with ≥14 days between receipt of the 2nd dose and ARI
symptom onset .
2.Partially vaccinated defined as 1 dose (only ) of BNT162b2 received with ≥14 days
between receipt of the 1st dose and ARI symptom onset. This group will serve as the
‘exposed’ group as a secondary endpoint. Patients who received 2 doses or 1 dose of
BNT162b2 with <14 days between rece ipt of the 1st dose and ARI symptom onset will be
excluded from this analysis.
3.Ever vaccinated defined as ≥1 dose of BNT162b2 received with ≥14days between receipt
of the 1st dose and ARI symptom onset. Patients who received 1dose of BNT162b2
received with <14 days between receipt of the 1st dose and ARI symptom onset will be
excluded from this analysis. This group will serve as the ‘exposed’ group as a secondary
endpoint.
4.Never vaccinated defined as never received BNT162b2. This group will serve as the
reference exposure group (i.e., ‘unexposed’ group) in all VE anal yses.
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Version: 10MAR2021; Page 23of 60Table: Definitions of study population, exposure, cases, and test -negative controls for
primary and secondary study objectives
Objective Study Population Exposure* CaseTest-
negative
Control
Prim ary Objective
1patients ≥18 y ears of
age hospitalized for
ARI Fully vaccinated
defined as 2 doses of BNT162b2 received
with ≥7 day s between receipt of the 2nd
dose and ARI symptom onset.SARS -
CoV- 2
identified
by NAATSARS -
CoV- 2
NOT
identified
by NAAT
Secondary Objectives
1patients ≥18 y ears of
age hospitalized for
ARIPartially vaccinated
defined as 1 dose (only) of BNT162b2
received w ith ≥14 days between receipt of
the 1st dose and ARI symptom onset.SARS -
CoV- 2
identified
by NAATSARS -
CoV- 2
NOT
identified
by NAAT 2patients ≥18 y ears of
age hospitalized for
ARIEver vaccinated
defined as 1 or 2 doses of BNT162b2
received w ith ≥14days between receipt of
the 1st dose and ARI symptom onset.
ARI= acute respiratory illness; NAAT= nucleic acid amplification test; SARS -CoV-2= severe acute respiratory
syndrome coronavirus 2.
*Patients who never received BNT162b2 or another SARS -CoV-2 vaccine will serve as the reference exposure
group (i.e., ‘unexposed’ group) in all VE analyses. For the primary objective, patients will be considered
vaccinated if they have documented evidence of receiving the second dose of BNT162b2 ≥7 days before ARI
symptom onset. When evaluating the effectiveness of one dose ofBNT162b2, patients will be considered
vaccinated if they have documented evidence of receiving the first dose of BNT162b2 ≥14 days before ARI
symptom onset.
Patients who receive any other licensed or investigational SARS -CoV -2 vaccine or COVID -
19 prophy lactic agent other than Pfizer’s BNT162b2 prior to enrollment will be excluded from
the anal ysis.
Odds of being fully vaccinated with BNT162b2 for cases and test-negative controls will be
constructed and compared using odds ratios (OR) and 95% confidence i ntervals (CI). VE will
be calculated as 1−OR multiplied by 100%. Like all observational designs, the TND still
requires assessment for bias and confounding that may exist in the absence of randomized
assignment of vaccine and blinded follow -up. Thus, in ad dition to constructing crude OR and
VE estimates, logistic regression modeling to assess BNT162b2 VE after adjustment for time
of enrollment, recruitment site, and other potentially confounding sociodemographic, clinical
factors, and behavioral and lifesty le factors will be performed.
Informed consent will be obtained prior to enrollment for all participants. Patients will be
consented and have an interview performed that will occur as close to enrollment as possible
and will participate in 1 visit. Data from the hospitalization and outcomes (e.g., vital status,
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Version: 10MAR2021; Page 24of 60discharge disposition) will be collected through 30 days post enrollment (V2) via medical
record review. No additional direct patient contact will necessaril y occur at this visit.
3.2.3. Patient Sociodemographic Characteristics, Clin ical History, and Health
Behaviors and Lifestyle
Sociodemographic and clinical characteristics for each participant will be collected and
described. Importantly , these characteristics will be used to assess and control for potential
confounding in adjusted VE models. Factors assessed for confounding will include individual -
level variables related to participant sociodemographic characteristics (i.e., time and site of
enrollment, age, sex, race, ethnicit y, and socioeconomic status), clinical history and disease
severit y (i.e., presence of chronic medical or immunocompromising conditions, history of
SARS -CoV -2 infection body mass index [BMI ], nursing home residency or other healthcare
facility exposure in the past 3 months, and antibiotic use in previous 14 da ys), health and
lifesty le behaviors (e.g., smoking status, weekl y exposure to children <5 years of age, current
drug abuse, workplace exposure to COVI D-19 , and adherence to social distancing measures ),
and vaccination history (e.g., influenza vaccine in la st year, pneumococcal vaccine[s] in last 5
years, any prior SARS -CoV -2 vaccine). These are factors that we have either found to be
important covariates in previous work, have been identified in other risk factor literature, or
are variables that may be associated with the exposure as well as outcome (i.e. prior positive
SARS -CoV -2 PCR test, etc.).72-77
Prior infection with SARS- CoV -2 will be assessed for all patients. Clinical characteristics
describing the presence or absence of underly ing immunocompromising and chronic medical
conditions will also be collected. History of immunocompromising conditions will include a
history of human immunodeficiency virus/acquired immune deficiency syndrome
(HIV/AIDS), leukemia, lymphoma, Hodgkin’s Disease, generalized malignancy (excluding
skin cancer), diseases requiring treatment with immunosuppressive drugs including long term
corticosteroids or radiation therap y, nephrotic s yndrome, chronic renal failure (including end -
stage renal disease), organ transplantation, multiple myeloma, sickle cell disease, functional or
anatomic asplenia, and immune deficiency or other conditions consistent with an
immunocompromised state. Other chronic medical conditions and health behaviors to be
evaluated will include: hypertension, obesity , chronic heart disease (including heart failure,
coronary artery disease, cardiom yopath y, and pulmonary hypertension), diabetes (including
type 1, type 2, or gestational), stroke, asthma (moderate or severe persistent), chronic lung
disease (such as chronic obstructive pulmonary disease [COPD, including emph ysema and
chronic bronchitis], idiopathic pulmonary fibrosis, and cystic fibrosis), chronic kidney disease
(with dialysis), chronic liver disease (in cluding cirrhosis), alcoholism, or cigarette smoking. A
classical and updated Charlson comorbidity index (cCCI78and uCCI79) will be calculated for
each patient based on history of chronic medical and immunocompromising conditions. These
are factors that we have either found to be important covariates in previous work, have been
identified in other risk factor literature, or are variables that may be associated with the
exposure as well as outcome. Outcome data including duration of hospital ization, ICU
admission and duration, and mechanical ventilation and duration, will be collected through last
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Version: 10MAR2021; Page 25of 60hospital contact or day 30 after enrollment (e.g., discharged home, discharged to rehabilitation,
death, still hospitalized at day 30).
3.2.4. Sensitivit y Analyses
The following sensitivity anal yses will be performed:
1)Including self- reported vaccination without documentation.
2)Peak COVID -19 circulation when ≥5% of COVID- 19 PCRs are positive
3)Hospitalization <7 day s of sy mptom onset
4)Hospitalization <14 day s of symptom onset
5)Controls positive for other viruses
6)Controls negative for other viruses
7) Cases with a control virus (e.g., rhinovirus) to evaluate for confounding in the
model.65,80,81
8) Excluding those with prior SARS -CoV -2 infection
9)SARS -CoV -2 positivity excluding test results obtained prior to hospitalization
10)Vary ing the definition of ARI (e.g., fever, cough).
11)VE calculated for 2 doses of BNT162b2 received with ≥14 day s (rather than ≥7 day s)
between receipt of the 2nddose and ARI symptom onset.
Additional sensitivity analy ses may also be performed including altering the approach from a
multivariable to a propensity -based anal ysis.
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Version: 10MAR2021; Page 26of 604.STUDY POPULATION
4.1.ROAPS RSV and COVID VE ARI
The study sites are Emory Unive rsity Hospital (EUH) and Emory University Hospital Midtown
(EUHM). EUH is located on the Emory University campus in northeast Atlanta. EUHM is
located in Midtown Atlanta, separated by about 5 miles from EUH. The Georgia Department
of Public Health District 3 (HD3) is an 8 county region that comprises Atlanta proper and the
inner ring of surrounding counties [Fulton, DeKalb, Gwinnett, Cobb, Douglas, Clay ton,
Rockdale, and Newton Counties (see Figure Atlanta Regional Map )]. We will establish
population -based active surveillance of pregnant women and adults ≥50 years of age for RSV
among HD3 residents. We previously have used ICD9-based coded data to establish the
population base served by hospitals in both adult and pediatric EPIC study enrollments of
communit y-acquired pneumonia.8,82 ICD9 data from Oct –December 2013 showed that EUH
and EUHM totaled 9.58% of HD3 hospital admissions (ARI ICD9 codes available for this
analysis were 466, 480-88, 518.5, and 518.81). This will be our preferred method for
determining the population -based incidence since it was used in EPIC.8,82Using data from the
EIP Active Bacterial Core Surveillance network from 2012 – 2014, EUH/EUHM comprised
11.1% of admissi ons in the HD3 region for invasive H. influenzae , Group B Streptococcus,
and S. pneumoniae . Thus, data from multiple sources confirm that EUH and EUHM comprise
about 9.5 – 11.1% of HD3 region admission.
We will use these two geographicall y separate hospitals to minimize potential biases that might
exist with a single location (e.g.,
patient population, referral biases,
and admission biases) that could
impact RSV estimates.
For ROAPS RSV and
Sub-Studies 1-5: We will
condu ct population -based
surveillance among
pregnant women and adults ≥50 years of age requiring hospitalization with ARI by
performing active surveillance at EUH and EUHM.
For COVID VE (Sub -Study #6): We will conduct population -based surveillance
among adults ≥18 years of age requiring hospitalization with ARI to determine COVID
VE by performing active surveillance at EUH and EUHM.
We will review the two hospitals’ emergency departments for potential admissions of adult
patients with ARI daily during the influenza season using a combination of clinical research
associates (CRAs) and nurse coordinators. Screening in the emergency departments will begin
immediately upon starting the day shift to capture some of the ARI patients waiting for a bed
from the overnight shift. All admissions from the preceding 24 hours will be screened for ARI
admissions. The Cerner Powerchart system ,which is the electronic medical record (EMR) that Data on Emory University Hospital and Emory
Univers ity Hospital Midtown
Hospital ED
Bed
sAnnual
ED
VisitsInpatient
BedsAnnual
Inpatient
Admissions
Emory U niversity
Hospital Midtown
(EUHM)35 57,000 511 23,205
Emory U niversity
Hospital (EUH)21 36,000 579 23,710
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Version: 10MAR2021; Page 27of 60is used at EUH and EUHM, will allow screening by hospital location and by time from hospital
admission. This will facilitate identification of potentially eligible patients. Additionally , SOC
specimens that are sent to themicrobiology laboratory will be reviewed to determine whether
they are associated with a hospitalized patient who meets study enrollment criteria. We also
will work with the Emory Data Warehouse to screen
electronically for patients who are not identified by either
of these two standard methodologies.
It will be crucial to demonstrate that there is minimal
enrollment bias and that any biases that occur are adjusted
for. We know from prior experience in the EPIC adult study
that elderly and sicker patients with ultimately worse
outcomes (mechanical ventilation and death) were less
likely to consent and enrol l.8Basic epidemiological and
outcome information will be obtained on all screened
patients to help identify biases and to adjust the analy sis if
biases are identified (See Appendix F and Appendix G ).
4.1.1. ROAPS SUB -STUDY 5 Study Population
For the Exploratory Objective s#2-3: We will enroll healthy pregnant women and adults ≥50
years of age who are residents of HD3 as control population s. These adults will be recruited
from outpatient clinics and/or from advertisements to this population.
Modifications Begin ning in Season 3:Beginning inSeason 3, a control population of healthy
outpatients will NOT be enrolled due to the COVID- 19 pandemic.
4.1.2. ROAPS RSV Sample Size
As this study is a descriptive study , sample size is based on feasibility instead of power for
hypothesis testing. We identified 1055 admissions/y ear and 936 admissions/y ear to EUH and
EUHM ,respectively (1991 combined admissions/y ear) in all adults using classic ARI codes
that were used in adult EPIC incidence calculations (480-486, 487.0, and 510).8Three prior
influenza seasons (2012 –2015) have had 1300 –1700 adults tested for influenza as SOC at
EUH/EUHM combined, but we know that many adults with ARI sare not tested for influenza.
To accomplish Sub-Study #3, we also will enroll adult patients of any age (≥18 years of age)
with ‘chronic obstructive pulmonary disease (COPD) exacerbations’ and ‘congestive heart
failure (CHF) exacerbations’ who are not included in these codes. Based upon an overall
eligible number of 2,500, g iven an anticipated enrollment rate of 70% and approximately 75%
of these being ≥50years of ageor admitt ed with COPD or CHF exacerbations , we anticipate 2013 Total HD3 Population
AGE GROUP White -NH Black- NH Hispanic Asian/P. Is Unknown/Oth er TOTAL
40-64 YEARS 594,162 491,681 103,356 84,195 3,197 1,276,591
65+ YEARS 228,600 109,517 13,183 18,305 744 370,349
Adults ( ≥40 Years) 822,762 601,198 116,539 102,500 3,941 1,646,940
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Version: 10MAR2021; Page 28of 60enrolling around 1,300 HD3 adults/y ear with ARI-related admissions , COPD, or CHF which
should result in 60-140 enrolled RSV- positive adults/y ear.
We know that there are 52,291 live births in HD3 in 2012. EUHM had 3,716 live births in
2014 (7.1% of the HD3 catchment). We roughl y anticipate that 5 –10% of these will have had
an acute ARI in the 2 weeks prior to hospital admission (anticipate enrolling 186 – 372 pregnant
women). Controls for the pregnant wom en will be enrolled that are similar to the cases with an
anticipated ratio of 1:1 resulting in 186 – 372 enrolled pregnant women controls/season (see
MOP for additional details about matching strategy ).
We will ideally enroll about 10 healthy controls/ week in the older adults for 30 weeks. This
would result in about 300 enrolled healthy controls/season. Modifications Beginning in
Season 3:Beginning in Season 3, a control population of healthy outpatients will NOT be
enrolled due to the COVID-19 pandemic.
At present, our best estimates of total enrollments would be between 1,500 and 1700 sick
adults/y ear with an additional 485 – 670 health y controls.
4.2.ROAPS Inclusion / Exclusion Criteria
Participant eligibility should be reviewed and document ed by an appropriately qualified member of the
investigator’s study team before participants are included in the study.
4.2.1. ROAPS RSV Inclusion / Exclusion Criteria for the Acutely Ill Cases
Inclusion Criteria for the Primary, Secondary #1 –3, and Explorato ry Objectives #1,
4 –7 (Acutely Ill Cases)
1.≥50 y ears of age OR pregnant at admission or post -partum ≤ 14 day s
2.Hospitalized (or admitted to an observation unit for ≥24 hours, or remaining in the ED
for ≥24 hours) at either EUH or EUHM,
3.Enrollment between mid-September and mid-April (if ongoing laboratory -confirmed
cases of influenza or RSV are continuing outside these boundaries then the enrollment
window may be extended),
4.Resident of HD3,
5.Admitted with
a.CHF exacerbation OR
b.COPD exacerba tion OR
c.ARI symptoms (nasal congestion, rhinorrhea, sore throat, hoarseness, new or
increased- from -baseline cough, sputum production, dy spnea, wheezing) OR
d.Admitting diagnosis suggestive of ARI (Pneumonia, Upper respiratory
infection, Bronchitis, Influenza , Cough, Asthma, Viral respiratory illness,
Respiratory distress, AND/OR Respiratory failure.
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Version: 10MAR2021; Page 29of 60Exclusion Criteria for the Primary, Secondary #1 – 3, and Exploratory Objectives #1,
4 –7 (Acutely Ill Cases)
1)Onset of s ymptoms >14 day s prior to admission,
2)Prior enrollment in this study within the last 28 day s,
3)Total duration of acute care hospitalization >3 days (also applies if transferred into
EUH or EUHM from another acute care hospital. Transfer from nursing home or short
term care facility are NOT conside red acute care hospitals here).
4.2.2. Sub-Study #5 Inclusion and Exclusion Criteria for the Secondary Objectives #4
(pregnant women)
Inclusion criteria for Secondary Objectives #4 – 5 Sub-Study #5 (pregnant
women)
1)≥18 y ears of age and pregnant,
2)Anticipated delivery or delivery of infant.
Exclusion criteria for Secondary Objectives #4 – 5 Sub-Study #5 (pregnant
women)
1)Non-enrollment into the cord blood research study ,
4.2.2.1. Inclusion and Exclusion Criteria for the Healthy Controls (Exploratory
Objec tive #2- 3)
Season 3 Modifications: In Season 3, a control population of healthy outpatients will NOT
be enrolled due to the COVID -19 pandemic.
Inclusion Criteria for Exploratory Objectives #2 -3 (Healthy Controls):
1)≥50 y ears of age OR pregnant,
2)At a routine outpatient appointment or a health y volunteer without acute illness,
3)Enrollment between mid-September and mid-April (if ongoing laboratory -confirmed
cases of influenza or RSV are continuing outside these boundaries then the enrollment
window may be exten ded),
4)HD3 resident.
Exclusion Criteria for Exploratory Objectives #2- 3 (Healthy Controls):
1)ARI symptoms, CHF symptoms, or COPD sy mptoms within the preceding 14 day s or
the 7 day s after the enrollment visit,*
*Since the presence of these symptoms in the 7 days after the visit will not be known
prospectively, subjects will be retrospectively excluded if they develop symptoms in the
7 days after enrollment.
2)Acute care hospitalization <28 day s prior to enrollment,
3)Prior enrollment in this study during the same season.
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Version: 10MAR2021; Page 30of 604.2.3. ROAPS RSV Inclusion and Exclusion Criteria for the 18- 49 year olds with COPD
or CHF Exacerbations (Exploratory Objective #11)
Inclusion Criteria for Exploratory Objective #11
1)Age 18 –49 years,
2)Hospitalized (or admitted to an observation unit for ≥24 hours, or remaining in the ED
for ≥24 hours) at either EUH or EUHM,
3)Enrollment between mid-September and mid-April (if ongoing laboratory -confirmed
cases of influenza or RSV are continuing outside these boundaries then the enrollment
window may be extended),
4)Resident of HD3,
5)Admitted with
CHF exacerbation OR
COPD exacerbation
Exclusion Criteria for Exploratory Objective #11
1)Onset of s ymptoms >14 day s prior to admission,
2)Prior enrollment in this study within the last 28 day s,
3)Total duration of acute care hospitalization >3 days (also applies if transferred into
EUH or EUHM from another acute care hospital. Transfer from nursing home or short
term care facility are NOT con sidered acute care hospitals here).
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Version: 10MAR2021; Page 31of 604.3. COVID VE Inclu sion / Exclusion Criteria
Inclusion Criteria
1)Age 18 years or older.
2)Admitted to hospital for ARI* at a participating site.
3)Previously provided a standard of care specimen (NP or nasal swab) on thishospital
admission or willing and able to provide specimen (NP or nasal swab) and comply
with all data collection requested.
4)Capable of providing informed consent (or LAR capable and willing to give
informed consent), which includes compliance with the requirements and
restrictions listed in the protocols.
Exclusion criteria
1)Any participant who received SARS -CoV -2-directed antiviral treatment within the
past 30 days, or COVID -19 monoclonal antibody therap y or COVID -19
convalescent serum therapy within the past 90 days prior to collection of required
study -related procedures for the detection of SARS -CoV -2 (i.e., NP or nasal swab).
2)Previous enrollment in this study within the past 30 day s.**
3)Any contraindication to have a NP or nasal swab (if specimen was not collected as
SOC).
*ARI for study enrollment will be defined as:
a.ARI symptoms (nasal congestion, rhinorrhea, sore throat, hoarseness, new or
increased- from -baseline cough, sputum production, dyspnea, wheezing) OR
b.Admitting diagnosis suggestive of ARI (Pneumonia, Upper respiratory
infection, Bronchitis, Influenza, Cough, Asthma, Viral respiratory illness,
Respiratory distress, AND/OR Respiratory failure.
The ARI definition for analysis will include the WHO definition (e.g., acute symptoms
of fever and cough) and variations since about 15% of patients admitted with COVID -
19 do not have fever or cough.51
** Thus, patients can contribute >1 ARI event to the study if a subsequent ARI event
for the same patient occurred >30 days after the previous event.
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Version: 10MAR2021; Page 32of 605.ROAPS RSV CASE FINDI NG, ENROLLMENT, AND PROCEDURES
INCLUDING SPECIMEN C OLLECTION
Case ascertainment will occur at EUH or EUHM through emergency departments , outpatient
clinics, hospital admitting departments, and labor and delivery at EUHM . At each site,
dedicated study staff will review electronic emergency department records and hospital
admission patient logs to screen for patients meeting the clinical case definition that would be
appropriate to approach for potential enrollment. If a patient meets the enrollment criteria,
informed consent will be obtained before enrollment into the study . Modifications beginning
in Season 3 : Beginning i n Sea son 3, a control population of healthy outpatients will NOT be
enrolled due to the COVID- 19 pandemic.
In order to optimize the quality of specimens, patients will be identified and enrolled in the
study as early as is possible. Patients who are enrolled in the study also will be interviewed
and their medical charts will be reviewed to complete the study CRF that focuses on clinical
and epidemiologic information. This will include an assessment of frailt y, and data collection
to determine the Charleston Comorbidity Index, AHA CHF score (in those with underl ying
CHF), and the MMRC score (in those with underly ing COPD). Ideally, patients will be
interviewed at the time of enrollment but if the patient is too ill at that time, study staff will
follow -up with the patient during their hospitalization to complete the study CRF. At the time
of enrollment, a NP and OP swab will be obtained from all patients. Patients who refuse the
collection of an NP swab will have the option to have a midturbinate obtained or ifthey also
refuse the midturbinate swab then a nasal swab obtained. Subjects that refuse both a NP swab
and a midturbinate swab may still be enrolled if they have had a SOC NP swab obtained.
Residual standard of care specimens will be collected from the laboratory (e.g., blood, NP SOC
swab, urine). Phlebotomy will be performed to obtain 10mL of blood. Subjects may still be
enrolled if they refuse the study phlebotom y.
Season 3 Modifications: Modifications will occur for Primary , Secondary, and Exploratory
Objectives #1, 4 – 7 (see above) furthermore, as needed a waiver for all elements of informed
consent will allow research staff to review medical records and test SOC specimens for those
patients meeting eligibility criteria. When at all possible, the participant/L AR will be
approached for written or oral consent. SOC specimens will have already been tested by SOC
SARS -CoV -2 PCR testing. Additional specimens and salvage of SOC specimens will only be
perform ed for those enrolled Substudies 1, 2, and 4.
5.1.Convalescent Serology
In order to collect convalescent sera on patients at the appropriate time, arrangements will be
made for a follow -up visit 21 to 60days (ideall y 21 – 45 days) after the day of enrollment.
Phlebotomy will be performed to obtain 10mL of blood. For patients who are still hospitalized,
this visit could occur while hospitalized. For patients who will return, incentives and reminders
will be used to help ensure patients return for the convalescent sera sample.
Modifications Beginning in Season 3: Convalescent serology and salvage of SOC specimens
will only be performed for those enrolled Substudies 1, 2, and 4.
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Version: 10MAR2021; Page 33of 605.2.ROAPS RSV Laboratory Procedures
NP and OPswabs , midturbinate, nasal, and cough specimens will have laboratory testing
performed for a variety of viruses (SARS -CoV -2, adenovirus, coronaviruses, human
metapneumovirus, influenza viruses, parainfluenza viruses 1-3, respiratory syncytial virus, and
rhinovirus ) and bacteria ( Chlamydia, Mycoplasma) . For patients who require thoracentesis or
collection of lower respiratory tract samples (e.g., bronchoalveolar lavage (BAL), mini -BAL,
or endotracheal aspiration) for clinical care, residual samples will be salvaged and may be
tested for the same pathogens. Specimens will be tested ≥21 daysafter initial enrollment using
BioFire FilmArray Respiratory Viral Panel (RVP) . Additional testing as part of the future use
exploratory endpoint may be performed on specimens collected as part of this study .Pathogens
not specifically tested for during the study but that are discovered during routine clinical care
(e.g., Streptococcus pneumoniae , Staphylococcus aureus ) will be noted in the case report form
and may be collected by the study team. Respiratory and serum specimens may be tested by
both Emory and Pfizer laboratories. Specimen handling and labeling details will be included
in a study -specific Manual of Operating Procedures (MOP). Please see the MOP for more
specific specimen collection guidelines and laboratory algorithms.
PBMCs collected from Sub-study #1, 2, and 4 participants if subjects agree to this. These
PBMCs will be collected in CPT tubes and will be processed according to existing SOPs. Cells
may be used i mmediately or may be saved (moving to liquid nitrogen storage within 2 weeks
of processing) for future cellular analy ses.
Modifications Beginning in Season 3:Beginning in s eason 3 specimens that are known to be
from SARS -CoV -2 negative patients will be processed at usual BSL2 enhanced levels.
Beginning in season 3 specimens from patients positive for SARS -CoV -2 or unknown will be
processed at a higher level of Biosafet y according to existing preapproved Biosafet y protocols
in Evan Anderson’s laborator y.
5.3.ROAPS RSV Ethical Considerations and Sub -Studies #1 – 5
A waiver of documentation/signature will be used to obtain basic information for the purpose
of recruitment on potentially eligible adults . Following recruitment, informed consent will be
obtain edand a signature will be obtained. For patients who are unable to consent due to
medical reasons, either a written or verbal consent will be obtained b y the study staff from the
legal representative of the patient. Cases or their proxies will be contacte d and interviewed b y
study staff (seeAppendix I : Screening Log). ).
Season 3 Modifications: Weare requesting a waiver of all elements of informed consent for
the review of medical records and for the collecti on of residual SOC specimens from patients
meeting eligibility criteria . When at all possible, a written or oral consent will be provided to
the participant/LAR with or without signature. A small subset will be prospectively
consented and enrolled into Substudies 1, 2, and/or 4.This is important as the COVID -19
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Version: 10MAR2021; Page 34of 60pandemic has impacted resources available (e.g., PPE) to approach all admitted patients
making it impractical to conduct the study as had occurred in Seasons 1+2.
Patient privacy and confidentia lity will be maintained throughout this study . Project paperwork
(e.g., signed consent, some CRF data) will remain in a locked, secure location, available onl y
to a minimum number of local project staff, and will not be reused or disclosed to any other
person or entit y except as required by law, or for authorized oversight of the research project.
Reports will only present data in aggregate form. Identifiers will be destroy ed at the earliest
opportunity , unless there is a public health or research justific ation for retaining the identifiers
or they are required to by law. No personal identifiers will leave Emory .
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Version: 10MAR2021; Page 35of 606. COVID VE / SUB- STUDY #6 DATA ANALYSIS AN D REPORTING OF RESUL TS
6.1.COVID VE Analysis Population s
6.1.1. Per-Protocol Population
The Per -Protocol Populat ion will include all participants who:
1. Meet all inclusion and exclusion criteria,
2. Have a final diagnosis consistent with ARI *,
3. Meet the definition of either case or test-negative control from the text of COVID
VE Sub- Study #6 Methods (section 3.2);
4. Have a record of SARS -Cov-2 vaccination history available from government -
issued COVID -19 vaccination cards, medical and billing records colle cted from
relevant healthcare providers (e.g., primary care, public health department), health -
insurance providers, pharmacies, and any local, state, or national immunization
registries
5. Did not receive any other newl y-licensed or investigational SARS -CoV -2 vaccine
or COVID -19 prophy lactic agent other than Pfizer’s BNT162b2.
*For the purposes of the primary COVID VE analysis, the WHO definition of ARI will
be used: an acute respiratory infection that occurred within the last 10 days and
required hospitalization with history of fever or measured fever of ≥ 38 C° AND cough.
Because many COVID -19 patients do not necessarily have fever (~15%) or cough
(~15%), we will vary this definition in sensitivity analyses.51
6.2.Statistical Analysis
6.2.1. Estimated Crude (Unadjusted) VE
Odds of having received BNT162b2 (fully, ever, and partiall y vaccinated) for cases and test-
negative controls will be constructed and compared using ORs and 95% CIs. VE will be
calculated as 1−OR multiplied by 100%. Corresponding 95% CIs will be calcula ted using the
Wald method.
6.2.2. Estimating Adjusted VE
In addition to constructing crude OR and VE estimates, logistic regression modeling to assess
BNT162b2 VE after adjustment for potentially confounding factors will be performed.
Variables described in the text of COVI D VE Sub-Study #6 Methods (section 3.2); will be
entered in the logistic regression model in backward stepwise manner. Only variable(s) that
change the estimated OR for BNT162b2 by ≥10% (i.e., confounder)83will remain in the final
VE model. A 2-sided alpha of .05 will be used for logistic regression modelling. Corresponding
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Version: 10MAR2021; Page 36of 6095% CI s will be calculated using the Wald method. I n addition to results from the final model,
univariate VE results will be presented for each independent variable that is assessed for
potential confounding, as the resu lts from a fully-adjusted model. When assessing the impact
of underly ing chronic medical conditions, the uCCI (Quan et al.)79will serve as the primary
approach. Sensitivity analyses using the cCCI78and individual comorbidities in adjusted
models will be performed.
6.2.3. Handling Missing Data
Crude estimates of VE will be based on the observed, determinate SARS- CoV -2 test result s
and BNT162b2 vaccination status. For adjusted VE evaluations, patients with all available
covariates will be included in the logistic regression model. If there is a substantial amount of
missing data (>10%) for any variables deemed necessary to include in our final analy ses,
sensitivity anal ysis will be performed using multiple imputation for missing covariates (under
the assumption of missing at random) to understand the impact of excluding patients with
missing information in adjusted models.
6.2.4. Analysis Timings
The COVID -19 pandemic continues to cause substantial morbidity and mortality with new
data becoming rapidly available. As such, flexibility and a rapid response to the changing
dynamics of disease is needed. We plan to conduct informal interim analyses to inform
decision making which may be presented or published. Any interim anal yses will be described
in a SAP. Analy ses for the primary , secondary , and exploratory outcomes will be analyzed
when available following L PLV of the study .
6.2.5. Hypothesis T esting
The overall study t ype-I error is 5%. For the primar y objective, h ypothesis testing will be used
to assess if 2 doses of BNT162b2 are effective in preventing ARI requiring admission to
hospital where SARS -CoV -2 is identified. The primary null hy pothesis (H 0) vsthe alternative
hypothesis (H1) is H0: VE≤ 20% vsH1: VE> 20%, where VE is 1–OR multiplied by 100%, and
the OR is equal to the odds of being fully vaccinated (i.e., 2 doses with ≥7 days since the second
dose since time of admission/enrollment) with BNT162b2 for ARI cases requiring
hospitalization where SARS -CoV -2 is identified relative to the odds of being full y vaccinated
(i.e., 2 doses) with BNT162b2 for ARI cases requiring hospitalization where SARS -CoV -2 is
not identified. For the primary objective, BNT162b2 will be considered effective for
preventing ARI requiring hospitalization where SARS -CoV -2 is identified if the lower bound
of the 95% confidence interval for the estimated VE is >20%.
No hy pothesis testing will be applied to secondary or exploratory objectives.
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Short Title: RSV in Older Adults and Pregnant Women Study
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Version: 10MAR2021; Page 37of 606.2.6. Sample Size Determination
This will be an event -driven study based on the number of cases identified. Study sample size
is based on the primary endpoint (BNT162b2 VE against ARI requiring hospitalization where
SARS -CoV -2 is identified). The required sample size will depend primarily on i) the
proportion of all-cause ARI requiring hospitalization caused by SARS -CoV -2 (which
determines the number of cases identified and the ratio of cases to controls in the primary
analysis), ii) the average uptake of BNT162b2 in the study population over the duration of the
study , and iii) the assumed VE of BNT162b2 against ARI requiring hospitalization where
SARS -CoV -2 is identified. Sample size calculations were based on the following fixed
assumptions:
Two-sided, t ype-I error of 5%
90% power
Log (OR) following approximated normal distribution
Assumed true BNT162b2 (2 doses) VE varying from 70‒90% to prevent ARI requiring
hospitalization was modeled
5% of all-cause ARI episodes requiring hospitalization will test positive for SARS -
CoV -2. A range of 5–30% was also modeled given the attack rate of COVID -19 may
vary based on social distancing and shelter -in-place measures, underl ying levels of
population immunity , and other factors.
Average BNT162b2 uptake in controls over the study period was allowed to vary in sample
size calculations (range: 10–90%) and will depend on potential future vaccination uptake
scenarios and timing of the conduct of the study . Final study enrollment size will also depend
on the proportion of enrolled patients excluded from the Per Protocol Population because i)
vaccination records could not be obtained, ii) they received a newly -licensed or investigational
SARS -CoV -2 vaccin e other than BNT162b2, or iii) they received BNT162b2, but did not
receive the full 2-dose schedule. Appendix Jpresents sample size calculations for various
scenarios of BNT162b2 uptake and the proportion of all-cause ARI where SARS -CoV -2 is
identified. Depending on the uptake of BNT162b2 and the proportion of ARI hospitalizations
where SARS -CoV -2 is identified at the time of the study , approximately 3,000 to 12,000
persons ≥18 years of age will be enrolled. Emory expects to enroll approximately 3,000
patients/y ear at the 2 participating hospitals. A Statistics Center will monitor BNT162b2
uptake among controls and the proportion of all-cause ARI where SARS -CoV -2 is identified
to inform decisions on the sample size req uired to reach an effectiveness endpoint.
Sample size requirements for the final analy sis population to detect COVID -19 vaccine VE
>20% assuming true VE=70 ‒90% with 90% power and type-I error of 5% (2-sided) under
various BNT162b2 uptake scenarios (1 to 15% of ARI events requiring hospitalization due to
SARS -CoV -2) –please see Appendix J .
Methodology for summary and statistical analyses of the data collected in this study is outlined
here and will be further detaile d in statistical anal ysis plan (SAP). The SAP may modify what
is outlined in the protocol where appropriate, however, any major modifications of the primary
endpoint definitions or their anal yses will also be reflected in a protocol amendment.
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Version: 10MAR2021; Page 38of 607.ROAPS AND SUB-STUDIES 1-5 DATA ANALYSIS AND REPORTIN G OF
RESULTS
As this is a descriptive study , data may be summarized on an ongoing basis. Analy ses include
estimations of incidence, frequency of pathogen -specific etiologies, and descriptive clinical
epidemiolog y of hospitalized patients and their associated precision (e.g. 95% CIs) . All of the
analyses will be descriptive.
For incidence rates, hospital market share data (of EUH and EUHM), percentage of eligible
subjects enrolled from the screening log, and thepercentage of SOC RSV positive cases
enrolled/percentage of RSV positive SOC RSV positive cases on the screening log will be used
to determine the multiplier for calculating the total estimated cases of RSV in HD3. Together
with the corresponding total population denominator in HD3 (i.e. total population of
pregnancy , total population of adults ≥50 years of age) the estimated number of hospitalized
RSV cases per 1,000 people will be determined in HD3. For the primary and secondary
endpoints, a case of RSV will be considered an y patient with a positive molecular test for RSV
from any specimen ty pe (either study PCR or molecular PCR) or RSV seroconversion (4 fold
rise in titer between acute and convalescent sera).
All of the epidemiological, clinical, and outcome related data will be descriptively summarized
by proportion and counts, or by means, median, and ra nge as appropriate, along with 95% CI
wherever is needed. We will estimate the association of RSV detection with symptoms using
the odds of detecting RSV in case versus control specimens (Exploratory Objectives 2 and 3)
and estimate attributable risk in ≥50 age group and pregnant women. Interim and final results
will be presented at scientific meetings and published in peer -reviewed literature.
Results of research laboratory testing conducted only for this study may be shared with
patients only at/after the Day 21-60 visit as by that time results will not be clinically
relevant (RSV, COVID -19 are a self -limited viral illness for which medications have not
been proven to be useful) . This will be done to help facilitate determination of whom
should be followed in the Sub-study #2 that will continue until the subsequent RSV
season. Enrollment intothis primary study will not affect the treating physician’s ability
to obtain S tandard of Care (SOC) respiratory viral testing.
Modifications Beginning in Season 3:No research laboratory testing will be shared with
subjects.
7.1.Justification
This study will not directly benefit those persons enrolled in this study . However, the overall
results will potentially benefit the US popula tion as a whole by increas ingour understanding
of RSV , influenza, and COVID -19in pregnant women and older adults which could guide
public health policy for RSV vaccine development and implementation.
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Version: 10MAR2021; Page 39of 607.2.Data Entry and Management
Staff at each site will enter clinical, epidemiological , and laboratory data based on the study
CRF into a REDCap database that correlates with a ca se report form. This database will meet
all regulatory standards and requirements. It is anticipated that initially documentation will
occur on paper CRFs (source) . Once the REDCap database is fully built and tested, direct data
entry may occur to REDCap (source). Timing of this transition will be clarified in the MOP.
The REDCap database for the COVID VE Sub-Study 6will be revised from the original
ROAPS REDCap database to collect the required variables.
8.COMPLIANCE WITH GOOD CLINICAL PRACTICE
8.1.Ethical Conduct of the Study
This study will be conducted in accordance with the Declaration of Helsinki on Ethical
Principles for Medical Research Involving Human Participants, adopted by the General
Assembly of the World Medical Association (1996 & 2008). In addition, the study will be
conducted in accordance with the protocol, the principles of the International Conference on
Harmonization (ICH) guideline on Good Clinical Practice and applicable local regulatory
requirements and laws.
8.2. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
The Investigator will have prospective approval of the study protocol, protocol amendments,
informed consent forms, and other relevant documents (e.g., advertisements, if applicable,
from the IRB/IEC). All correspondence with the IRB/IEC should be retained in the
Investigator File. Copies of IRB/IEC approvals should be forwarded toPfizer. The only
circumstance in which an amendment may be initiated prior to I RB/IEC approval is where the
change is necessary to eliminate apparent immediate hazards to the participants. I n that event,
the Investigator must notify the IRB/IEC and Pfize r in writing within 5 working day s after the
implementation.
8.3.Participant Information and Consent
All parties will ensure protection of participant personal data and will not include participant
names or initials on any Sponsor forms, reports, publications , or in any other disclosures.
Participant names, address, birth date and other identifiable data will be replaced by a
numerical code consisting of a numbering system provided by Pfizer to de-identify the trial
participant. In case of data transfer, Pfiz er will maintain high standards of confidentiality and
protection of participant personal data.
The Investigator must ensure that each study participant, or his or her legal representative, is
fully informed about the nature and objectives of the study and possible risks associated with
participation. For eligible participants included in vulnerable populations (e.g., illiterate,
elderl y, cognitive or physical impairments) that may require a third party to complete the
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Version: 10MAR2021; Page 40of 60informed consent process, sites must defer to their institution’s requirement for obtaining
informed consent. The institution’s policy must be provided to the Sponsor for approval prior
to first patient first visit.
The Investigator, or a person designated by the Investigator, will obtain informed consent from
each participant or the participant's legal representative before any study specific activity is
performed. The informed consent document(s) used during the informed consent process must
be reviewed by the Sponsor, approved by the IR B/IEC before use, and available for inspection.
The Investigator will retain the original of each participant's signed consent form.
8.4.Participant Recruitment
Due to the epidemiological nature of the study , participant recruitment will include, at the
minimum, a daily review of admissions databases for potential participants, as well as
healthcare -provider -to-healthcare -provider communication regarding the study .
Participants may be identified from multiple sources, for example: inpatient departments,
general medical wards, pulmonary or respiratory disease wards, infectious disease wards, or
intensive care units.
To maximize enrollment, the site should establish a ARI surveillance system to capture all
eligible persons with suspected ARI who meet the selection criteria and are willing to give
consent. The surveillance system must account for participants presenting to the healthcare
facility 24hours a day , 7 da ys a week for 365 days per y ear.
9.SAFETY
Adverse Events and Serious Adverse Events
In this study , the “product under stud y” refers to the Pfizer -BioNTech COVID -19 vaccine and
is referred to as such when appropriate in the text below.
The investigator ( or designee) is responsible for detecting, documenting, and recording events
that meet the definition of an AE or SAE and remains responsible to pursue and obtain adequate
information both to determine the outcome and to assess whether the event meets the criteria
for classification as an SAE or caused the participant to discontinue the study .
The awareness date is the date that the sponsor/investigator becomes aware of the presence of
all 4 minimum reporting criteria (i.e. an identifiable subject, an id entifiable reporter, an event
meeting SAE or special exposure definition, and a suspect Pfizer product)
The time period for actively eliciting and collecting AEs and SAEs (active collection period)
will begin when the first protocol -required procedure (swa b sample) is performed at Visit 1
and will conclude 15 minutes after the procedure is performed.
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Version: 10MAR2021; Page 41of 60If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consen t is withdrawn.
During the active collection period, each participant will be proactively questioned about the
occurrence of AEs in a nonleading manner. AEs identified during the active collection period
may be based on symptoms or other complaints reported to the Investi gator (or designee) by
the participant or may be based on clinical findings made by the Investigator (or designee).
SAEs that are explicitly related to the product under study (BNT162b2) must be reported to
the Pfizer Drug Safet y Unit (DSU) within 24 hour s of awareness throughout the entire study
period, if the investigator should become aware. In addition, the investigator may be requested
by Pfizer Safet y to obtain specific follow -up information in an expedited fashion.
The sponsor/investigator may incidentally become aware of reportable events, as described
above, through unsolicited patient report (e.g., the study participant contacts the investigator
or study staff outside of the active collection period or the Investigator becomes aware of
events explicitly related to the Pfizer product under study , BNT162b2). Special exposure
scenarios, including Exposure During Breastfeeding [EDB], Occupational/Environmental
exposure, medication errors and overdose related to Pfizer product under study (BNT162b2),
will be reported to the DSU within 24 hours of awareness. Definitions and reporting
instructions are included in the Safety Reporting Reference Manual.
Exposure during pregnancy (EDP) to the product under study (BNT162b2) is not reportable as
an individual safet y report since these will be summarized as endpoints of the study.
Lack of Effectiveness (LOE) for BNT162b2 is a study endpoint. It will not be reported as
individual SAE reports. Effectiveness will be summarized in the CSR. Potential COVI D-
19/MI S-C/Acute Respiratory Illnesses and their sequelae that are consistent with the clinical
endpoint definition should not be recorded as AEs.
The definitions of an AE, SAE, Research Related Injury (RRI), LOE and special exposure
scenarios can be found in t he Safety Reporting Reference Manual. The investigator is required
to assess whether any AE occurring during the active collection period may be related to
participation in the study .All AEs that occur during the active collection period (i.e., serious
and non -serious, including those attributed to a protocol- required procedure identified as RRI)
are collected in the clinical study database.
Should a participant, in the investigator’s opinion, suffer a medically important research related
injury caused byparticipation in the study , the Pfizer clinical study team must be notified
immediately by telephone or email.
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Version: 10MAR2021; Page 46of 6069. Clippard J, Thaker SN, Monto AS, et al. Relative Vaccine Effectiveness of Live-
Attenuated Versus Inactivated Influenza Vaccines in Children and Adolescents Aged 2-18
Years in Two Seasons -US Flu VE Network. IDWeek 2014; 2014 October 8 -12, 2014;
Philadelphia, PA. p. Oral Presentation 650.
70. Caspard H, Gaglani M, Clipper L, et al. Effectiveness of live attenuated influenza
vaccine and inactivated influenza vaccine in children 2-17 years of age in 2013 -2014 in the
United States. Vaccine 2016;34:77 -82.
71. Petrie JG, Ohmit SE, Cheng CK, et al. Influenza Vaccine Effectiveness Against
Antigenically Drifted Influenza Higher Than Expected in Hospitalized Adults: 2014 -2015.
Clin I nfect Dis 2016;63:1017-25.
72. Tartof SY, Qian L, Hong V, et al. Obesit y and Mortality Among Patients Diagnosed
With COVI D-19: Results From an Integrated Health Care Organizat ion. Ann Intern Med
2020;173:773-81.
73. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult
inpatients with COVID -19 in Wuhan, China: a retrospective cohort study . Lancet
2020;395:1054-62.
74. Webb Hooper M, Napoles AM, Perez-Stable EJ. COVI D-19 and Racial/Ethnic
Disparities. JAMA 2020;323:2466-7.
75. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and
critical illness among 5279 people with coronavirus disease 2019 in New York City:
prospecti ve cohort study . BMJ (Clinical research ed 2020;369:m1966.
76. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus
Disease 2019 (COVID -19) Outbreak in China: Summary of a Report of 72314 Cases From the
Chinese Center for Diseas e Control and Prevention. JAMA 2020;323:1239 -42.
77. COVID -19 and People with Certain Medical Conditions. (Accessed March 2, 2021, at
https://www.cdc.gov/coronavirus/2019 -ncov/need -extra -precautions/people- with-medical -
conditions.html .)
78. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying
prognostic comorbidit y in longitudinal studies: development and validation. J Chronic Dis
1987;40:373 -83.
79. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity
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Am J Epidemiol 2011;173:676-82.
80. Anderson EJ,Carosone -Link P, Yogev R, Yi J, Simoes EAF. Effectiveness of
Palivizumab in High -risk Infants and Children: A Propensity Score Weighted Regression
Analy sis. Pediatr Infect Dis J 2017;36:699-704.
81. Yildirim I, Kao CM, Suntarattiwong P, et al. A Retrospec tive Test- Negative Case-
Control Study to Evaluate Influenza Vaccine Effectiveness in Preventing Hospitalizations in
Children. Clin I nfect Dis 2021.
82. Jain S, Williams DJ, Arnold SR, et al. Community -acquired pneumonia requiring
hospitalization among U.S. children. N Engl J Med 2015;372:835 -45.
83. Mickey RM, Greenland S. The impact of confounder selection criteria on effect
estimation. Am J Epidemiol 1989;129:125 -37.
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Version: 10MAR2021; Page 47of 6011.APPENDICES
11.1. Appendix A:Schedule of Events –ROAPS Acutely Ill Cases
Study Visit Enrollment All:
DailyOptional
Substudy 1:
Every other day
whilehospitalize
dARI Illness
before
Convalescent
Visit*Convalescent Optional Substudy
2: Telephone call
q2 weeks Optional
Substudy 2: ARI
illnessOptional Substudy
2: Final Visit8
Study Day Windows11 Daily Every other day +/ -1 day 22 -60 Day 23 –615
through to final
visitDay <365 (just prior
to next RSV season)
STUDY PROCEDURES
Obtain Informed Consent X
Review Eligibility Criteria X
Patient Interview9X X1X X X X X
Review of Medical Record X X X X3X3X3
Record Concomitant Medications X X X X3X3X3
SPECIMEN COLLECTION
Obtain nasopharyngeal (NP) swab6,9X X X X2X X2
Obtain oropharyngeal (OP) swab9X X X X2X X2
Obtain cough specimen (if possible)9X X X2X X2
Obtain acute serum7,9X X
Obtain follow -up serum9X X X
Collect residual SOC blood9X {X} {X} {X} {X} {X}
Collect residual NP or OP SOC swabs X {X}
Collect residual SOC urine9X {X} X {X} {X} {X} {X}
Collect other residual SOC specimens4,
9X {X} X {X} {X} {X} {X}
PBMC collection: Optional Sub -Study
#1, if agreeable to this48 mLDay 7 symptoms: 32 mL (if
different than enrollment)40 mL 48 mL
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Version: 10MAR2021; Page 48of 60SOC: Standard of care; NP: Nasopharyngeal; OP: Oropharyngeal; { } If available ; *Visit will occur only if patient develops new ARI illness prior to the Convalescent Visit (D 22 –60)
1Record resolution date of signs and symptoms from patient interview
2A NP and OP swab /cough sample will be obtained at the follow -up visi t only if the patient develops active ARI symptoms prior to the Convalescent Visit.
3The follow -up visit could occur while still hospitalized. Final outcomes and medications (e.g., duration of hospitalization) will be col lected from the medical record unt il hospital discharge even
if this occurs after the follow -up visit.
4Including SOC testing from other specimen types (e.g., BAL, Endotracheal tube aspirate, thoracentesis).
5The Optional Substudy 2 visit for ARI illness may occur repeatedly before the s ubsequent RSV season (the Final Visit at Day<365).
6Patients who refuse the collection of an NP swab will have the option to have a midturbinate or nasal swab obtained.
7Patients who refuse the collection of acute serum, will have additional residual SOC specimen collected.
8 The Optional Substudy 2 Final Visit may occur at the same time as the Option Substudy 4 Enrollment Visit. If this occurs, the serum and the PBMCs w ill only be collected once. If these occur
on different dates, then serum and PBMCs will be collected at both visits.
9 Modifications Beginning in Season 3 : Beginning the summer of 2020, all admitted patients to EUH and EUHM are receiving standard of care (SOC) testing for SARS -CoV-2 upon hospital
admission. Reasons for this include identification of SARS -CoV-2 infection prior to hospital admission (community -onset) that is presenting presymptomatically, asymptomatically, or atypically.
Beginning in Seaso n 3, we will salvage SOC specimens sent from admitted patients meeting enrollment criteria (we will not obtain additional NP/ OP swabs or cough specimens beyond those
collected as SOC except as detailed below for those enrolled in Substudies 1, 2 and 4). Weare requesting a waiver of informed consent for collection of SOC specimens and review of medical
records from patients meeting eligibility criteria. A small subset will be prospectively consented and enrolled into Substudi es 1, 2, and/or 4. This is impor tant as the COVID -19 pandemic has
impacted resources available (e.g., PPE) to approach all admitted patients making it impractical to conduct the study as had occurred in Seasons 1+2. These salvaged SOC specimens will then
be tested with study -specific Bio Fire RVP testing retrospectively 3 weeks or more after hospital discharge. These results will not be available to the patient or patient care teams (the result will no
longer be clinically relevant from these specimens). Patient interviews will not be conducted except on those subjects enrolled in Substudies 1, 2, or 4. Patients will not have follow -up or direct
contact with the research staff unless enrolled in Substudies 1, 2, or 4.
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Version: 10MAR2021; Page 49of 6011.2. Appendix B: Schedule of Events –Sub-Study #4
Study Visit Substudy 2 Final Visit/
Enrollment Substudy 4*Telephone call q2
weeks ARI illness Year #2 Visit Year #3 Final Visit
Study Day Windows1<365 from initial enrollment <730 from initial
enrollment<1095 from initial
enrollment
STUDY PROCEDURES
Obtain Informed Consent X
Review Eligibility Criteria X
Patient Interview X X X X X
Review of Medical Record X X3X3X3
Record Concomitant Medications X X3X3X3
SPECIMEN COLLECTION
Obtain nasopharyngeal (NP) swab4X2X X2X2
Obtain oropharyngeal (OP) swab X2X X2X2
Obtain cough specimen (if possible) X2X X2X2
Obtain serum X X X X
Collect residual SOC blood X {X} /{X} {X}
Collect residual SOC urine X {X} {X} {X}
Collect other residual SOC specimens X {X} {X} {X}
PBMC collection: if agreeable to this 48 mL 48 mL 48 mL
1Record resolution date of signs and symptoms from patient interview
2A NP and OP swab /cough sample will be obtained only if the patient develops active ARI symptoms prior to the Visit.
3Final outcomes and medications will also be collected from the medical record.
4 Patients who refuse the collection of an NP swab will have the option to have a midturbinate (preferred) or nasal swab obtained .
* The Optional Substudy 2 Fina l Visit may occur at the same time as the Option Substudy 4 Enrollment Visit. If this occurs, the serum and the PBMCs will on ly be collected once. If these occur
on different dates, then serum and PBMCs will be collected at both visits.
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Version: 10MAR2021; Page 50of 6011.3. Appendix C: Sched ule of Events –Healthy Controls*
Study Visit Enrollment Final
Study Day Windows11 22 - 60
STUDY PROCEDURES
Obtain I nformed Consent X
Review Eligibility Criteria X
Patient I nterview X X
Review of Medical Record X X1
Record Concomitant Medications X X1
SPECIMEN COLLECTION
Obtain nasophary ngeal (NP) swab X X2
Obtain orophary ngeal (OP) swab X X2
Obtain cough specimen (if possible) X X2
Obtain acute serum X
Obtain follow- up serum X
SOC: Standard of care; NP: Nasopharyngeal; OP: Oropharyngeal; { } If available
1To determine whether an ARI may have occurred betw een enrollment and convalescent visits.
2A NP and OP swab w ill be obtained at the follow -up visit only if the patient develops interim ARI symptoms.
*Note that beginning in Season 3 healthy controls will not be enrolled.
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Version: 10MAR2021; Page 51of 6011.4. Appendix D: Schedule of Events –Sub-Study #5
Study Visit 1
Study Day Windows Enrollment
STUDY PROCEDURES
Obtain Informed Consent X
Review Eligibility Criteria X
Patient Interview X
Review of Medical Record X
Record Concomitant Medications X
SPECIMEN COLLECTION1
Collect residual SOC blood X
Collect cord blood from time of delivery X
Collect other residual SOC specimens
(mother and infant) X
1Cord blood, SOC blood or other SOC specimens may be collected from time of admission to the hospital and throughout the hospital stay.
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Version: 10MAR2021; Page 52of 6011.5. Appendix E: Schedule of Events –COVID VE Sub -Study #6
Visit IdentifierV1 Screening
EnrollmentV2 Vital Status Assessment / Data
Collection Only
Visit Window Day 1 -3post admission Up to 30 days post admission
Informed consent X
Patient interview for d emographic characteristics, risk factors, and life -event data
collection ^X
Specimen collection (NP or nasal swab) * X
SARS -CoV -2 NAAT testing * X
Data from SOC NAAT testing for SARS -CoV -2 X
Data from SOC sample culture –(blood, urine, or respiratory culture (if applicable) X
Vital status assessment aX
Collection of data describing all potential sources of vaccination history to be
investigated b X X
Medical Record review and collection of medical history / hospitalization data cX
Adverse event reportingdX X
^ Patient interview may occur on the day or enrollment or shortly thereafter depending upon patient/LAR capacity to undergo i ntervie w at that time.
* If not performed as standard of care (SOC)
aVital status will be assessed using medical record data and does not involve patient participation.
b This process may continue beyond 30 days to identify all potential sources of vaccine history information. Alternatively, if all data are available, verified and
recorded at V1 then this w ill not be requested at later visits (V2).
cMedical record review will include, but not be limited to, all medical records related to the current hospitalization to asse ss underlying patient data,
comorbidities, and outcomes of the hospitalization (e.g., duration of hospitalization, ICU admission, mechanical ventilation, survival, disposition).
dAdverse event reporting is required as specified in Section 9.
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Version: 10MAR2021; Page 53of 6011.6. Appendix F: Study Patient Flow – Acutely Ill Cases ROAPS RSV and COVID VE*
* Note changes throughout the protocol for alterations in Season 3.
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Version: 10MAR2021; Page 54of 6011.7. Appendix G: Patient Flow – Healthy Controls*
* Note that healthy controls will not be enrolled in Season 3.
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Version: 10MAR2021; Page 55of 60
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Version: 10MAR2021; Page 56of 6011.8. Appendix H: Proposed Definitions for Chest Radiography Confirmed Pneumonia
To accomplish Exploratory Aim # 5, we will use the following definitions of pneumonia in interpreting SOC chest radiographs. To be
diagnosed with pneumonia, subjects must meet the clinical case definition andhave an abnormal chest radiograph (within 72 hours of
admission), defined as: presence of consolidation, other infiltrate, and/or pleural effusion . Based on WHO criteria, these are defined
as:
Consolidation : A dense or fluffy opacity that occupies a portion or whole of a lobe or the entire lung that may or may not contain air
bronchograms. Atelectasis of an entire lobe that produces a dense opacity and a positive silhouette sign with the mediastinal border i s
considered consolidation.
Other Infiltrate : Linear and patchy densities (interstitial infiltrate) in a lacy pattern involving both lungs, featuring peribronchial
thickening and multiple areas of atelectasis which may be difficult to distinguish from con solidation.
Pleural effusion : Presence of fluid in the lateral pleural space between the lungs and chest well; in most cases, this will be seen at the
costophrenic angle or as a lay er of fluid adjacent to the lateral chest wall; this does not include flui d seen in the horizontal or oblique
fissures.
Additional definitions for descriptive terminology :
Air Bronchogram –The air containing bronchus which becomes visible when the surrounding lung parenchy ma is opacified
due to air space consolidation or volu me loss. Generall y, the bronchial tree is in contiguity with water density pulmonary
parench ymal structures, generall y believed to be a reflection of air space disease (alveolar, acinar).
Bronchial Wall Thickening – Peribronchial thickening: peribronchial inflammatory edema or peribronchial inflammation
which causes peribronchial “cuffing” that is usually a manifestation of bronchitis, asthma, reactive airway disease, or viral
lower respiratory tract infection, and is a non -specific finding.
Bronchioliti s, uncomplicated –moderate to marked hy peraeration (generalized air trapping), bronchial wall thickening, with or
without minimal parahilar linear opacities, in the appropriate clinical setting. This condition does not meet the criteria f or
enrollment.
Bronchiolitis, complicated – moderate to marked hy peraeration, bronchial wall thickening, perihilar linear opacities, and
patch y areas of peribronchial parench ymal opacit y or atelectasis of an entire segment or lobe. Some observers may refer to
these findings as viral pneumonia or viral bronchopneumonia. This condition does meet criteria for “Other Infiltrate”.
Bronchopneumonia –A descriptive term which refers to shaggy bronchial inflammatory changes which involve the adjacent
air spaces; a subjective of term which means different things to different observers, and should be avoided if possible.
Alveolar (air space) Disease –a disorder in which the air spaces of the lung become filled with water density material such as
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Version: 10MAR2021; Page 57of 60edema, pus or blood, all of which produce identical radiographic appearances. Alveolar disease is generall y ill-defined and
fluffy , tends to coalesce and may involve large areas of lobe or lung.
Interstitial Disease –an increase in diffuse linear markings in the lung parenchy ma which does not cause air bronchograms, but
may be reflected in a reticulonodular pattern, a “ground -glass” or cloudy appearance, a honeycomb lung, and may be either
nodular or linear in appearance. The findings of interstitial disease when seen on high resoluti on computed tomography
include bronchial wall thickening, thickened interlobular septa, ground -glass opacity, nodules and reticular densities of
varying sizes.
Pulmonary Edema –Leakage of fluid from the pulmonary microvasculature into the interstitium, fr om any cause, results in
interstitial pulmonary edema. Edema is a t ypical interstitial pattern and may be manifested by Kerley A and B lines which are
due to fluid in the interlobular septa. Alveolar edema is usually preceded by interstitial edema, and fills acinae and air spaces,
producing more ill -defined homogenous shadows of water density .
Atelectasis –collapse of lung parench yma either due to airway obstruction or pleural fluid or mass effect. Atelectasis reflects
volume loss of vary ing amounts of lu ng parench yma and may be linear, subsegmental, segmental, lobar, or entire lung.
Significant lung collapse is generall y associated with nearb y lung compensatory over inflation.
11.9. Appendix I: Screening Log
Example here, actual screening log is likely to be in REDCap
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Version: 10MAR2021; Page 59of 6011.10. Appendix J :COVID VE Sample Size
Requirements for the final anal ysis population to detect BNT162b2 VE >20% assuming true VE= 70‒90% with 90% power and ty pe-I
error of 5% (2 -sided) under various BNT162b2 uptake scenarios (5 to 30% of ARI hospitalization sdue to SARS -CoV -2)
Assume true VE=70%
5% of ARI is SARS -CoV -2 positive 15% of ARI is SARS -CoV -2 positive 25% of ARI is SARS -CoV -2 positive 30% of ARI is SARS -CoV -2 positive
BNT162
UptakeControls CasesTot
EvalTot
Enroll*Controls CasesTot
EvalTot
Enroll*Controls Cases Tot EvalTot
Enroll*Controls Cases Tot EvalTot
Enroll*
10 6769 356 7125 11875 2104 371 2475 4125 1171 390 1561 2602 938 402 1340 2233
20 3266 172 3438 5730 1022 180 1202 2003 573 191 764 1273 461 198 659 1098
30 2108 111 2219 3698 665 117 782 1303 377 126 503 838 304 130 434 723
40 1540 81 1621 2702 491 87 578 963 281 94 375 625 229 98 327 545
50 1213 64 1277 2128 392 69 461 768 228 76 304 507 187 80 267 445
60 1015 53 1068 1780 335 59 394 657 199 66 265 442 165 71 236 393
70 909 48 957 1595 308 54 362 603 187 62 249 415 157 67 224 373
80 905 48 953 1588 318 56 374 623 200 67 267 445 171 73 244 407
90 1174 62 1236 2060 435 77 512 853 287 96 383 638 251 108 359 598
Assume true VE=80%
5% of ARI is SARS -CoV -2 positive 15% of ARI is SARS -CoV -2 positive 25% of ARI is SARS -CoV -2 positive 30% of ARI is SARS -CoV -2 positive
BNT162
UptakeControls CasesTot
EvalTot
Enroll*Controls CasesTot
EvalTot
Enroll*Controls CasesTot
EvalTot
Enroll*Controls Cases Tot EvalTot
Enroll*
10 4945 260 5205 8675 1518 268 1786 2977 832 277 1109 1848 661 283 944 1573
20 2325 122 2447 4078 717 127 844 1407 396 132 528 880 315 135 450 750
30 1455 77 1532 2553 452 80 532 887 252 84 336 560 201 86 287 478
40 1024 54 1078 1797 321 57 378 630 181 60 241 402 146 63 209 348
50 770 41 811 1352 245 43 288 480 140 47 187 312 114 49 163 272
60 608 32 640 1067 197 35 232 387 115 38 153 255 95 41 136 227
70 505 27 532 887 169 30 199 332 102 34 136 227 85 36 121 202
80 455 24 479 798 160 28 188 313 101 34 135 225 86 37 123 205
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Version: 10MAR2021; Page 60of 6090 513 27 540 900 196 35 231 385 132 44 176 293 116 50 166 277
Assume true VE=90%
5% of ARI is SARS -CoV -2 positive 15% of ARI is SARS -CoV -2 positive 25% of ARI is SARS -CoV -2 positive 30% of ARI is SARS -CoV -2 positive
BNT162
UptakeControls CasesTot
EvalTot
Enroll*Controls CasesTot
EvalTot
Enroll*Controls CasesTot
EvalTot
Enroll*Controls Cases Tot EvalTot
Enroll*
10 4275 225 4500 7500 1294 228 1522 2537 698 233 931 1552 549 235 784 1307
20 1955 103 2058 3430 594 105 699 1165 322 107 429 715 253 108 361 602
30 1183 62 1245 2075 361 64 425 708 197 66 263 438 155 66 221 368
40 798 42 840 1400 245 43 288 480 135 45 180 300 107 46 153 255
50 568 30 598 997 176 31 207 345 98 33 131 218 78 33 111 185
60 417 22 439 732 132 23 155 258 74 25 99 165 60 26 86 143
70 313 16 329 548 101 18 119 198 59 20 79 132 49 21 70 117
80 241 13 254 423 83 15 98 163 51 17 68 113 43 18 61 102
90 212 11 223 372 82 14 96 160 56 19 75 125 50 21 71 118
*Assumes 40% of enrolled participants will be unevaluable (i.e., excluded from the Per Protocol Population because i) vaccina tion records could not be obtained,
ii) they received a newly -licensed or investigational SARS -CoV- 2 vaccine other than COVID -19 vaccine , or iii) they received COVID -19 vaccine , but did not
receive the full 2 -dose schedule.
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