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PRIVATE AND CONFIDENTIAL Avon CAP Study Protocol
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UOB ConfidentialUOB Confidential
Avon Community Acquired Pneumonia Study (Avon CAP):
APan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study
Protocol Version 2.2
Protocol Date 30/01/2021
Sponsor University of Bristol
Funder Pfizer
Study Co -ordinating Centre Bristol Children’s Vaccine Centre
School of Population Health Sciences
University of Bristol
Level 6 , Education and Research Centre
Upper Maudlin St
Bristol
BS2 8AE
Chief Investigator Professor Adam Finn
David Baum Chair and Consultant in Paediatric
Infectious Diseases
University of Bristol and Bristol Royal Children’s
Hospital
Level 6, UHB Education Centre,
Upper Maudlin Street, Bristol BS2 8AE
[email protected]
[email protected]
Telephone: 0117 342 0172
Primary Investigator Dr Catherine Hyams
NIHR Academic Clinical Fellow
Respiratory Medicine
Academic Respiratory Unit
Southmead Hospital,
Bristol, BS10 5NB
[email protected]
Co-Primary Investigator Dr Izak Heys
Consultant in Infectious Diseases/AMU
Southmead Hospital,
Bristol, BS10 5NB
[email protected]
Co-Primary Investigator Dr Rajeka Lazarus
Consultant in Infectious Diseases and
Microbiology
University Hospitals Bristol and Weston NHS
Foundation Trust
Bristol
BS2 8HW
Research Manager Dr Jennifer Oliver
Research Programme Manager
Bristol Children’s Vaccine Centre
Level 6, UHB Education Centre,
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UOB ConfidentialUOB ConfidentialUpper Maudlin Street, Bristol BS2 8AE
[email protected]
Collaborator Leon Danon
Department of Engineering Mathematics,
University of Bristol,
Ada Lovelace Building,
University Walk,
Bristol,
BS8 [email protected]
,
Collaborator Jo Southern, PhD
Clinical Scientist
[email protected]
Collaborator Beth Begier, MD, MPH
Senior Director Pneumococcal Vaccines. Global
Medical Development & Scientific Affairs.
Mobile number: +1 -551-999-1677
[email protected]
Collaborator Robin Hubler, MS
Clinical Scientist
[email protected]
Collaborator Bradford Gessner, MD
Global Pneumococcal Lead.
Mobile number: +1 (907) 3419741 E -mail
address: [email protected]
Collaborator Sharon Gray, MS
Vaccines Clinical Affairs Lead.
Mobile number: +1 (484) 3543745 E -mail
address: [email protected]
Collaborator Harish Madhava, MD
RSV Scientific Affairs
[email protected]
Collaborator Fred Angulo, DVM PhD
Medical Development and Scientific/Clinical
Affairs
Pfizer Vaccine
Collaborator John M. McLaughlin, PhD
Global Epidemiology & Scientific Affairs
Lead for Pipeline Vaccines, Pfizer
[email protected]
Sponsor Project Reference Number 2020 -2991
ISRCTN registry number
IRAS ID Number 283899
REC Number 20/EE/0157
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UOB ConfidentialUOB ConfidentialThis protocol describes the Avon CAP study and provides information about procedures for entering
participants. Every care was taken in drafting this protocol, but corrections or amendments may be
necessary in the future. Any amendments will be circulated to and approved by investigators in the
study.
The study will adhere to the principles outlined in the UK Policy Framework for Health and Social Care
Research . It will be conducted in compliance with the protocol, the Data Protection Act 2018 and other
regulatory requirements as appropriat e.
Study queries
Clinical and general queries should be directed to the Chief Investigator (Prof Adam Finn) via: 0117
342 0172 ; Primary Investigator (Dr Catherine Hyams) via 07966 208708; or the Clinical research team
on 0117 414 8114 or 0117 342 0160 .
Sponsor
The University of Bristol is the research sponsor for this study. For further information regarding
sponsorship queries, please contact:
Research Governance Team
Research and Enterprise Development
One Cathedral Square
Bristol, BS1 5DD
Tel: +44 (0)117 42 83065 Email: research [email protected]
Study Summary
Study Title Avon Community Acquired Pneumonia Surveillance Study : A Pan -pandemic Acute Lower
Respiratory Tract Disease Surveillance Study
Short Title Avon CAP
Clinical Phase N/A
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UOB ConfidentialUOB ConfidentialStudy Design Observational
Study Participants Patients presenting to North Bristol NHS Trust or University Hospitals Bristol NHS Foundation
Trust with features of lower respiratory tract disease (LRTD)
Planned Sample Size Feasibility phase: 500 per each hospital site
Annual sample: 10 -15,000 patients per hospital site per annum
Treatment duration N/A
Follow up duration 1 -2 month sfollowing admission
Planned Study
Period3 years
Research question
and objectivesThe primary objective is to estimate population -based incidence of LRTI (including
community -acquired pneumonia hospitalizations) during and after the COVID -19 pandemic ,
overall and for the subsets associated with SARS -CoV-2, S. pneumoniae ,and respiratory
syncytial virus. Add itional epidemiological and outcomes measures will also be assessed.
Inclusion Criteria 1. Aged ≥18 years of age
2. Patients hospitalized with illness with following 2 characteristics:
a. Acute illness (i.e., present for 28days or less); AND
b. Evidence of acute LRTD:
i. Patients with current or suspected COVID -19,or previous proven COVID -19 within last
28 days ;OR
ii. Clinical or radiologic diagnosis of pneumonia or an acute LRTI ;OR
iii. New onset or worsening of ≥2 of following 8 LRTD symptoms or clinical
findings:
1. fever (>38.0°C/100.4°F) or hypothermia (<35.5°C) before or within
24 hours of enrolment
2. pleuritic che st pain;
3. cough (including nocturnal only);
4. sputum production or purulence;
5. dyspnea (shortness of breath) including orthopnea/exertional only;
6. tachypnea (respiratory rate ≥20/min);
7. abnormal auscultatory findings suggestive of LRTD
8. radiologic finding that is consistent with LRTD, including pneumonia,
and/or acute congestive heart failure .
Exclusion Criteria 1.Any patient who develops signs and symptoms of LRTD after being hospitalized for ≥48
hours ( excluding suspected/proven COVID19)
2. Previously enrolled participants readmitted ≤7 days after discharge for their study
qualifying admission (excluding suspected/proven COVID19)
3.At the time of enrolment , an LRTD -related diagnosis has been excluded or another
diagnosis confirmed (for example, patient had a fever and tachypnea due to an
intraabdominal process such as cholecystitis)
List of A bbreviations
Abbreviation Definition
A&E Accident and emergency
ARI Acute respiratory illness
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UOB ConfidentialUOB ConfidentialBNT162b2 Pfizer/Bio Ntech COVID -19vaccine
BRI Bristol Royal Infirmary
CAP Community -acquired pneumonia
CHF Congestive heart failure
COPD Chronic obstructive pulmonary disease
COVID Coronavirus disease
CRF Case report form [eCRF = electronic CRF]
CSA Clinical study agreement
CT Computed tomography
CVA Cerebrovascular accidents
CXR Chest x -ray
GCP Good Clinical Practices
ICH International Council for Harmonisation
ICU Intensive care unit
IRB/EC Independent Review Board/ Ethics Committee
LRTD Lower respiratory tract disease
MRI Magnetic resonance imaging
NP Nasopharyngeal
NSTEMI Non -ST-elevation myocardial infarction
OP Oropharyngeal
PCV7 7-valent pneumococcal conjugate vaccine
PCV13 13-valent pneumococcal conjugate vaccine
PCV20 20-valent pneumococcal conjugate vaccine
PPV23 23-valent pneumococcal polysaccharide vaccine
RSV Respiratory syncytial virus
SAP Statistical analysis plan
STEMI ST-elevation myocardial infarction
TND Test Negative Design
UAD Urinary antigen detection assay
VE Vaccine effectiveness
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UOB ConfidentialUOB Confidential1 B ackground
1.1 Acute lower respiratory tract disease
Acute lower respiratory tract disease (LRTD) encompasses pneumonia, lower respiratory tract
infection (LRTI), acute bronchitis, exacerbation of underlying respiratory disease including asthma and
chronic obstructive pulmonary disease (COPD). Throughout Europe before the COVID -19 pandemic ,
the healthcare cost of pneumonia is estimated at approxima tely €10 billion per annum, with inpatient
care accounting for €5.7 billion (European Lung White Book). The indirect costs of lost work -days
amount to €3.6 billion. Studies have shown that the incidence of pneumonia in Europe varies by
country, age and gender; however, in all studies the incidence of pneumonia increases sharply with
age. In the UK, pneumonia affects 0.5 to 1% of adults each year, and the incidence of LRTI is
considerably higher with a recent study finding an incidence of 148/1000 person -years in patients ≥
65 years of age (Millet ERC et al). Previous studies to define the disease burden attributable to acute
LRTD have used either radiological or microbiological diagnosis to confirm disease, and hence may
underestimate the true disease burden , or have been conducted using clinical coding data, which is
both retrospective and subject to the errors associated with this methodology. Furthermore, all
previous studies have been carried out before the COVID -19 pandemic, and the effect of this new
emergent respiratory pathogen on acute LRTD remains unclear.
1.2 COVID -19 infection
In 2019 a novel coronavirus -induced disease (COVID -19) emerged in Wuhan, China. A month later the
Chinese Center for Disease Control and Prevention identified a new beta -coronavirus (SARS
coronavirus 2, or SARS -CoV-2) as the aetiological agent (Zhu et al, 2019) . A worldwide pandemic is
currently occurring, and as such the disease burden of acute LRTD will increase. As the responsible
virus is a new human pathogen, relatively little is known about disease pathogenesis and the clinical
spectrum of disease which it causes, including risk factors associated with poor outcomes in developed
countries (Huang et al, 2020) .
Furthermore, the interaction between SARS -CoV-2 and other respiratory pathogens including
Streptococcus pneumoniae and Respiratory Syncytial Virus (RSV) is undefined. It is unknown if
bacterial or viral co-infection, superimposed or subsequent infection is common in patients with SARS -
CoV-2 infection. This is import ant in terms of understanding disease pathogenesis and being able to
provide appropriate vaccination strategies to try to mitigate mortality and morbidity. It remains
unclear how the disease burden of other acute LRTD will be affected, if at all, by the SARS -CoV-2
pandemic.
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UOB ConfidentialUOB ConfidentialThe UK began vaccinating its adult population in December 2020, using a Department of Health
defined risk-based strategy by age, comorbidity and key worker status. Initially ,only the BNT162b2
vaccine was used. This is a nucleoside modi fied messenger ribonucleic acid (modRNA) vaccine from
Pfizer/Biontech that encodes the full-length, membrane -anchored spike (S) glycoprotein of SARS -CoV-
2 with two introduced proline mutations to lock it in the prefusion conformation (Kariko et al.2008;
Pardi et al.2015, Wrapp et al.2020). BNT162b2 showed an acceptable safety profile in a Phase 1/2
study (Walsh et al 2020) and, in a Phase 3 trial conducted in Argentina, Brazil and the Unites States ,
was tolerable and demonstrated 95% efficacy against COVID-19(Polack et al. 2020) . At the time of
writing, BNT162b2 currently has temporary authorisation for supply under MHRA regulation 174, and
data confirming the effectiveness of the vaccine outside of the clinical trial setting are needed. Further,
additi onal COVID -19 vaccines also now have temporary authorisation for supply under regulation 174
in the UK, including from AstraZeneca and Moderna.
1.3 Streptococcus pneumoniae
Pneumococcus is a leading cause of lower respiratory tract infections among adults, including
community -acquired pneumonia (CAP) population wide (O'Brien, Wolfson et al. 2009, Said, Johnson
et al. 2013, Torres, Cillóniz et al. 2018) and among immunocomprom ised individuals (Zhang, Van
Werkhoven et al. 2018), and pneumonia among those with a history of healthcare contact such as
long -term care facility residents (Carratala, Mykietiuk et al. 2007, Chalmers, Taylor et al. 2011, Ewig,
Klapdor et al. 2012, Polver ino, Torres et al. 2013, Parrott, Nebeya et al. 2017). S. pneumoniae is also
the most frequent bacterial pathogen isolated from patients with acute bronchitis (Macfarlane,
Holmes et al. 2001, Creer, Dilworth et al. 2006) and COPD exacerbations (Wilkinson, Aris et al. 2017).
However, previous studies that described the burden of vaccine -preventable pneumococcal
pneumonia have largely focused on radiologically confirmed and microbiologically defined CAP only.
A recent review of a UK CAP incidence described underestimation of CAP using this approach,
potentially by as much as four -fold, due to study requirements for informed consent, study screening
processes, radiologic confirmation, and requirement for collection of a dedicated study urine
specimen for pneu mococcal antigen testing (Chalmers et al.,2017 ). Correspondingly, a recent vaccine -
probe study, performed in the Netherlands, documented that this limited scope appears to
underestimate the true burden of respiratory infections prevented by the 13-valent pneumococcal
conjugate vaccine (PCV13) (Gessner et al. ,2018). The vaccine -preventable disease incidence was 2 to
3.5-fold higher for clinical CAP cases versus microbiologically and radiologically confirmed vaccine -
type CAP.
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UOB ConfidentialUOB ConfidentialPneumonia study inclusion criteria are not the only source of underestimation of pneumococcal
burden –under or alternate diagnosis also contributes. Presenting complaints as well as signs and
symptoms in older patients with pneumonia are often atypical and may lead to missed or incorr ect
admission diagnoses (Henig & Kaye, 2017) . Also, pneumonia may be a secondary to or an underlying
cause of the main presenting complaint, such as in patients with altered level of consciousness,
cerebrovascular accidents (CVA), congestive heart failure (CHF), or COPD exacerbations. In these
scenarios, p neumonia may not be the primary diagnosis code recorded for the hospitalization or may
not be coded as an associated diagnosis at all. On this basis, there is a need to assess the burden of
pneumococcal di sease in the larger group of patients presenting with acute lower respiratory disease
–not just those with a formal pneumonia diagnosis. Acute lower respiratory tract disease (LRTD) in
adults includes pneumonia (all types); bronchitis; exacerbations of chronic obstructive pulmonary
disease, congestive heart failure, asthma, and other underlying pulmonary disease (e.g., cystic
fibrosis); acute respiratory distress syndrome (ARDS); and other acute lower respiratory disease, i.e.,
any condition involving acute lower respiratory pathology (i.e., effects trachea, bronchi, bronchioles,
or lungs in opinion of treating/study physician). Comprehensive assessment of all LRTD is needed to
identify the disease burden due lower respiratory tract infection.
1.4 RSV infecti ons inadults
RSV is also an important respiratory pathogen later in life, with severe disease occurring among those
with compromised cardiac, pulmonary or immune systems and in the elderly (Falsey , Hennessey et al.
2005). Estimates of the RSV disease burden requiring hospitalization in adults are limited but suggest
that up to 10% of adults presenting with acute respiratory illness (ARI) during the winter have RSV
(Dowell, Anderson et al. 1996, Thompson, Shay et al. 2003, Falsey, Hennessey et al. 2005, Falsey,
McElhaney et al. 2014, Jain, Self et al. 2015). The RSV season frequently does not completely overlap
with the influenza season which confounds the ability to define RSV’s clinical and epidemi ological
features, as viral pathogen testing is often driven by concerns regarding influenza. The limited
available data show that age and 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, dyspnoea, and wheezing may be more common (Falsey 2013,
Falsey, McElhaney et al. 2014).
1.5 Rationale for study
Accurate incidence rates of acute LRTD and its disease subsets, such as pneumonia and LRTI, remain
elusive and the impact of COVID -19 on respiratory disease burden is unclear. Accurate incidence rates
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UOB ConfidentialUOB Confidentialof vaccine -preventable infection are required to assess the potential population -level impact of
vaccination recommendati ons. As discussed, current evidence suggests that the burden of
pneumococcal and RSV lower re spiratory infections is underestimated. Further, th e current COVID -19
pandemic due to SARS -CoV-2 has dramatically increased the burden of LRTI worldwide .On this b asis,
we seek to conduct a study to measure the true burden of acute respiratory disease due to these
pathogens during and after the COVID -19 pandemic within the limitations of currently available
diagnostic testing.
This population- based multi -hospital, active prospective surveillance is designed to determine
population- based incidence rates of hospitalized adults ≥18 of age with community -acquired LRTI
(including CAP) in Bristol, England. The involved Bristol hospitals’ nearly completely capture hospita l
admissions among residents of a well delineated geographic region allowing for calculation of
population- based incidence rates of LRTI. Study data derived from surveillance activities will fully
enumerate the number of acute LRTD cases in this region .
Persons identified as having LRTD in study hospitals will be offered participati on in the consented
portion of this study involving enhanced testing for pneumococcal, RSV, and SARS -CoV-2 infection .
This will allow for more complete characterization the incidence of these infections than standard of
care testing alone.
Additionally, real world vaccine effectiveness (VE) estimates for COVID -19vaccines are needed to
demonstrate their effect in genera l populations as well as in risk groups. These canbe achieved using
a test negative design (TND) case control analys is. For the purpose of these TND analys es, cases are
individuals diagnosed with COVID -19up to 14 days prior to admission or on admission t o hospital and
controls are those in whom COVID -19was not detected in the same timeframe. Almost all data needed
to conduct these analyses are already being collected in this study, including COVID -19disease and
vaccination status from standard of care records ,alongside other medical history and current illness
details. Toallow for more complete multivariate adjustment for potential confounding differences
between the cases and controls, additional information on COVID -19-related behavioural risk factor s
will be collected from participants using a standardised questionnaire , such as occupation, frequency
ofmask use and inclusion in a social bubble. We plan to conduct VE assessments separately for
different COVID -19 vaccine product s.
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UOB ConfidentialUOB Confidential1.6 Study Context
This study will undertake surveillance of lower respiratory tract disease (LRTD) including pneumonia
in adults in a defined geographical area. This study combines NHS Hospital Trust -based surveillance of
lower respiratory tract disease (LRTD) including pneumonia in adults in a defined geographic area with
a University -sponsored research study which enhances the diagnostic accuracy in a subset of
consented patients. The surveillance will be done in two large hospitals in Bristol and may later be
expanded toinclude a third hospital in Bath. These surveillance activities will be done under NHS Trust
governance and with full ethics approval in each hospital. Although originally planned to be stand-
alone prospective, comprehensive case ascertainment of adult lower respiratory tract infections
within the NHS space, occurring as it turns out in the midst of the coronavirus pandemic, which most
commonly presents as pneumonia in adults, the work will be done alongside and overlapping with
other observational studies focussed specifically on COVID -19.
The University -sponsored embedded study will recruit a subset of the patients identified during the
surveillance activity. Patients who are enrolled, following informed consent, will have additional
investigations perf ormed for research purposes and surplus samples obtained during routine case will
also be scavenged. The surveillance activity will serve, in effect, as the screening activity for the study
as well as providing a comprehensive, anonymised dataset on the disease burden of pneumonia and
LRTD in the adult population in the Bristol urban area over a defined time period.
HRA/ethics approval for this embedded study will be sought by the University and both the data from
all consented subjects and all the anonym ised screening/surveillance datasets will be unified from the
databases held by the participating hospitals, with the agreement of those hospitals. These data will
be reported on by the University at the end of the project. The combined anonymised dataset, along
with the consented patient data and research samples, will belong to the University while the
participating hospitals will retain ownership and control over their respective databases and their
contents. Thus, the respective institutions will each have autonomy, control, governance oversight
and ethical approval jointly and collaboratively for this programme of surveillance and research.
To accurately calculate disease burden and describe acute LRTD and its subsets, it is necessary to
record all cases of adults hospitalised within the defined geographical area who meet study criteria.
This study will systematically record and describe all adult patients admitted with acute LRTD and its
subgroups, providing an accurate calculation of disease incidence , burden and outcome analysis in
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UOB ConfidentialUOB Confidentialaddition to other epidemiological analyses, including identifying risk factors for disease and poor
outcome.
This study will recruit a subset of the patients identified during the surveillance activity into a
consented arm. Patients who are enrolled, following informed consent, will have additional
investigations performed for research purposes and surplus samples obtained during routine care will
also be scavenged. Participants recruited to the embedded study will be aske d to consent to the use
of th eir data for clinical research, with a target enrolment of up to 80% of eligible admitted patients.
Patients approached with information about the consented study will subsequently fall into 3 groups:
Those who provide full con sent to the study, including access to medical data
Those who provide consent to access to medical data only (and not biological
samples)
Those who decline consent and are not enrolled in the study, and are only noted in
the screening log
Individuals who d ecline consent for access to medical data will not be recruited to this non -consented
study arm, thereby ensuring there is no contagion of the non-consented study arm. In this way, the
non-consented surveillance will only collect medical data from individu als in whom it is not practicable
to take consent.
However, as it is not practicable for the research team to approach and consent every individual
hospitalised with acute LRTD into the consented arm, this study seeks approval for data collection to
be undertaken on these individuals via a non-consented surveillance arm. We therefore will request
and obtain authorisation for access to personal data under Section 251 of the NHS Act 2006 for the
use of non-consented data. If patients are eligible, data fields from their routine clinical care would
be collected to determine features of clinical presentation and disease, including co-morbidities,
routine healthcare tests and outcomes (e.g. requirement for intensive care and/or organ support,
mortality).
The data collected during the non-consented surveillance activity will be combined with the data
obtained from the consented arm to provide a comprehensive dataset of patients with acute LRTD. In
this way, all patients and disease will be captured and described, allowing for a complete and accurate
estimation of disease incidence and burden.
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UOB ConfidentialUOB ConfidentialStudy Flow Diagram: Activities pertaining to data collection for consented study & non -consented
surveillance arms , demonstrating how they work together.
1.7 Lay summary
Acute lower respiratory tract disease affects large numbers of people worldwide. Older people are
more likely to have disease, suffering both reduced quality of life and increased mortality from
respiratory infection. Previous studies have tried to define the burden of respiratory infection in
adults, but these studies have been limited as they required patients to have either an identified cause
of disease (microbiological diagnosis) or change on a Chest X-ray(radiological diagnosis). This has led
to an underestimate in disease in adults, because other cases have not been counted.
In 2019 ,a new virus called SARS -CoV-2 (also referred to as coronavirus )that ca uses an illness known
asCOVID -19emerged and is c ausing a worldwide pandemic. As the virus is new to humans, people do
not have any immunity to it and large numbers of patients are expected to become infected. We do
not understand fully how this virus causes disease, nor the risk -factors for a poor outco me (including
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UOB ConfidentialUOB Confidentialdeath). We also do not understand how this virus interacts with other bacteria and viruses that cause
disease in humans. This is important, because if we can determine how these infections interact with
each other and the consequences for thepatients affected, we may be able to offer better vaccination
strategies to prevent disease and treatments to help patients affected. Other diseases we know are
important in adult respiratory infection are pneumococcus and RSV (a cold virus). There are po tential
new vaccines available for use in adults, but as we do not know the true amount of disease caused by
these infections, we cannot determine if using these vaccines in adults would be worthwhile.
The Avon CAP study aims to record all patients admit ted with respiratory illness at 2 hospitals in the
Bristol area. We will gather data that has already been recorded by the clinical teams treating these
patients, including demographics, co-morbidities, outcomes and the results of the investigations
undert aken by the medical team. Persons with acute respiratory illness will also be offered
participation in the consented portion of this study involving additional testing for pneumococcal and
RSV infection, which will identify more cases of such infections th anroutine testing. We will then use
these data to accurately define the true amount of disease caused by respiratory illness and be able
to determine the subgroups of disease (for example by patient co-morbidity, microbiological and
radiological diagnosi s) and determine the impact of COVID -19 on respiratory disease.
COVID -19 vaccine was introduced in the UK in December 2020, with individuals called for vaccination
by age and risk group (including certain key worker status). This study provides an ideal opportunity
to assess how effective these COVID -19vaccine sare inpreventing hospitalizations ina “real world”
setting . Real world VE estimates from this study can be compared to those from blinded, randomised
clinical trials with more limited numbers of participants. The assessment will be a case control study
comparing participants who are hospitalised with LRTI and who have been diagnosed with COVID -19
(cases) or have not been diagnosed with COVID -19(controls) on admission to hospital, or in the 14
previous days, using a method called the test negative design (TND ). Almost all the data required for
this assessment will be collected as part of the consented study, including COVID -19 disease ,
vaccination status , and sociodemo graphic and clinical characteristics of patients from standard -of-
care records held by the GP and/or hospital. The only extra information needed will be some details
about behaviours during the pandemic which will be collected via a short questionnaire. These
questions include occupation, household structure, inclusion in any social bubble and use of masks .It
is anticipated the COVID VE assessment will continue for 12 -24 months depending on vaccine uptake
and COVID -19 attack rates during the study.
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UOB ConfidentialUOB Confidential2 Sche dule of activities
Please refer to study procedures and assessments sections of the protocol for detailed information on
each procedure a nd assessment required for compliance with the protocol.
Consented Arm
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of
activities table, in order to conduct evaluations or assessments required to protect the well-being of
the participant. Collection of standard -of-care da ta will be done for all identified LRTD events in study
hospitals and entered into the surveillance databases hosted by the Trusts. This will be conducted by
appropriate members of the clinical team , and research team members will only have access to
pseud onymised data. Sample collection and interview activities shown in bold below will be
undertaken for consented participants only by members of the research team.
Table 1. Comprehensive List of Procedures by Visit for Consented -Arm , Including Visit Windows .
Procedure / AssessmentaScreening/
Enrolment VisitbFinal Assessment/
Vital Status (Data
Collection only)Convalescent Visit
(“Serology Subset”
Only)e
Visit 1 Visit 2 Visit 3
Day 1 Day 30 Day 45
Visit WindowWithin 48 hours of
admission Day 30 to 45 Day 22 to 60c
Screening (surveillance) X
Clinical symptoms X
Medical HistorycX X X
Vaccination History X X
CRB- 65 and pneumonia
severity (PSI) scoreX
Informed Consent X
Eligibility confirmation for
embedded studyX
Patient Interview , including
approved questionnairesX X
Collect urine specimen X
Collect u pper r espiratory tract
sample for SARS -CoV-2, RSV
and other pathogensdX Xd
Collect b lood specimeneX X
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UOB ConfidentialUOB ConfidentialProcedure / AssessmentaScreening/
Enrolment VisitbFinal Assessment/
Vital Status (Data
Collection only)Convalescent Visit
(“Serology Subset”
Only)e
Visit 1 Visit 2 Visit 3
Day 1 Day 30 Day 45
Obtain residual (scavenged)
standard care specimens from
clinical laboratoryX X X
Record SOC respiratory
specimen testing results X
Record SOC blood culture
resultsX
Record SOC chest imaging
resultsX
Final acute LRTD Illness
DiagnosisX
Cardiac complications X
Vital Status/Mortality X
Hospitalization duration,
readmission, & level of careX
Collect Research -related
Injur ies (RRIs) X X X
Abbreviations: SOC = standard of care; UAD = urine antigen detection assay; RSV= respiratory syncytial virus;
RRI = research -related injury ; CRB-65 = Confusion, Respiratory rate, Blood pressure, 65 years of age and older.
a. Sample collection and interview activities shown in bold above will be undertaken for consented
participants only.
b. All participants in the consented enhanced diagnostic testi ng will have confirmation of their eligibility
confirmed and be subsequently enrolled at Visit 1 / Day 1.
c. At Visit 2 and 3, relevant changes to medical history since the last visit will be documented.
d. Respiratory samples will be collected for RSV and oth er respiratory pathogen testing if such testing has
not already been ordered or completed as part of standard -of-care testing. Details on the type and
collection process for samples will be included in the laboratory manual . Another respiratory swab will b e
collected at the convalescent visit ,only if the participant experienced a new ARIafter hospital discharge .
e. For those that consent to participate in the Serology subset, a blood sample will be collected for serologic
testing. A remnant of an appropriate blood sample from standard of care testing can be used if
appropriate for this use per laboratory manual specifications. For this subset of patients, an additional
convalescent visit will take place approximately 22 –60 days after enrolment for collection of a
convalescent blood sample. However, effort should be made to schedule this visit as close to day 42 as
possible. If subject has another enrolment qualifying acute LRTD event(s) prior to their convalescent visit,
they will have acute serology specimen taken at each enrolment and only one convalescent serology visit
will be completed 42 days after last acute specimen was taken.
Non-consented arm
Collection of standard -of-care data will be done for all identified LRTD events in study hospitals and
entered into the surveillance databases hosted by the Trusts. Table 2. Comprehensive List of
Information to be collected for non -consented arm .
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UOB ConfidentialUOB ConfidentialProcedure / AssessmentFirst Data Collection Second Data Collection
Admission Outcomes and Results
Day 1 Day 30
Visit WindowWithin 48 hours of
admission Day 30 to 45
Surveillance X
Clinical symptoms X
Medical HistoryaX X
Vaccination History X
CRB- 65 and pneumonia severity
(PSI) scoreX
Record SOC respiratory specimen
testing results X
Record SOC blood culture results X
Record SOC chest imaging results X
Final acute LRTD Illness Diagnosis X
Cardiac complications X
Vital Status/Mortality X
Hospitalization duration,
readmission, & level of careX
Abbreviations: SOC = standard of care; UAD = urine antigen detection assay; RSV= respiratory syncytial virus;
RRI = research -related injury; CRB -65 = Confusion, Respiratory rate, Blood pressure, 65 years of age and older.
a. At Visit 2, relevant changes to medical history since the last visit will be documented.
2.1 Study type
Avon CAP is a prospective population -based multi -hospital epidemiological study in patients
presenting to North Bristol NHS Trust, University Hospitals Bristol and Weston NHS Foundation Trust
(hereon referred to as NBT and UHB W). Additional Trusts may be invited to parti cipate as the study
progresses, including the Royal United Hospit al NHS Trust in Bath. All LRTD events will be included to
ensure complete capture of LRTI events, which are the primary focus of the study. Bristol is a single
geographical area with multiple hospitals, general practices (GP) and long -term care facilities (LTCF),
which provide care to a defined population (the denominator) in that area.
The study collects simple demographic and clinical data on admission of patients to hospital, as well
as the results of microbiological and radiological investigations undertaken as standard -of-care
investigations in this patient group. Therefore, the stud y is non-interventional and a surveillance
exercise with an embedded consented study (see Section 1.6) .
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UOB ConfidentialUOB Confidential2.2 Patient population
The patients that will be included in the cohort are all adult patients aged ≥ 18 years presenting to
NBT and UHB Wwith clinical fe atures (signs and symptoms) of acute LRTD. This will be determined by
assessing all adult patients admitted to these 2hospitals using the screening algorithm outlined in
Section 4.
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UOB ConfidentialUOB Confidential3 Research questions and objectives
3.1 Primary outcome
To estimate population -based incidence of community -acquired LRTI hospitalizations during and
following the COVID -19 pandemic , overall and for community -acquired pneumonia.
3.2 Secondary outcomes
COVID -19/SARS -CoV-2infection
1.To estimate the population -based incidence rat es of COVID -19-related hospitalizations
2.To describe the proportion of LRTI hospitalizations (overall, standard -of-care pneumonia
diagnosis, radiologically confirmed CAP only) attributable to COVID -19, both overall and by
age/risk stratification
3.To describ e demographics, clinical and epidemiological characteristics and outcomes within
COVID -19 LRTI and the different subcategories, both overall and stratified by age/risk
4.To describe mortality rate at 30 days after admission to hospital for COVID -19LRTI and its
subcategories, overall and by age group and risk group status
5.To describe the association between COVID -19 and other respiratory pathogens, including
but not limited to S.pneumoniae , influenza and RSV, both with co -and super -imposed
infection and sec ondary respiratory infection.
6.To describe the length of hospital stay for COVID -19 LRTI hospitalizations and the proportion
of COVID -19 admissions involving an ICU stay .
7.To assess whether S. pneumoniae LRTI is associated with more severe COVID -19 clinical
outcomes (such as requiring invasive mechanical ventilation) among persons hospitalised
with COVID -19 infection.
COVID -19Vaccine Effectiveness
These measures may each be assessed per vaccine brand or manufacturer in the real- world setting .
Definitions of exposure categories and details of the planned COVID -19 VE analysis can be found in
Appendix 1.
Primary:
To estimate the effectiveness of 2 doses of COVID -19 vaccine (i.e. fully vaccinated) against
hospita lization for acute respiratory infection due to SARS -CoV-2 infection by vaccine brand or
manufacturer
Secondary:
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UOB ConfidentialUOB Confidential1.To describe the effectiveness of only 1 dose of COVID -19vaccine (i.e., partially vaccinated)
against hospitalization for due to SARS -CoV-2 infection by vaccine brand/manufacturer.
2.To describe the effectiveness of ≥1 dose of COVID -19vaccine (i.e., ever vaccinated) against
hospitalization for ARI due to SARS- CoV-2 infection by vaccine brand/manufacturer .
3.To determine the effectiveness of current and future COVID -19 vaccinations by COVID -19
variant in real- world settings
Exploratory :
1.To determine the effectiveness of current and future vaccinations against COVID -19, taking
into account factors such as patient characteristics, number of doses and d ose intervals,
timing of doses relative to disease onset, virus variant and other potential confounding
factors.
2.To describe further the effectiveness of COVID -19 vaccines against hospitalization for ARI
stratified by various patient characteristics (e.g., age, sex, chronic medical conditions, receipt
of influenza vaccine , long term care facility residence, time since vaccination and time
between doses
).
3.To summarize the proportion of hospitalized patients who receive 0, 1, or 2 doses of COVID -
19vaccine
4.To summarize the time between administration of the first and second dose of COVID -19
vaccine among hospitalized patients who received 2 doses
5.To summarize the time since vaccination with COVID -19vaccine (most -recent dose) from
illness onset
6.To describe d emographic and clinical characteristics and disease severity of any COVID -19
vaccine failures
7.To assess the impact of COVID -19 on confirmed subsequent pneumococcal LR TI
Streptococcus pneumoniae
1. To estimate the population -based incidence rates of hospitalizations for the following 12
specified LRTI subcategories:
a.all LRTI (overall, pneumococcal only, PCV13 -type, and PCV20 -type);
b.any standard -of-care pneumonia diagnosis (overall, pneumococcal only, PCV13 -
type, and PCV20 -type);
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UOB ConfidentialUOB Confidentialc.any radiologically confirmed CAP (overall, pneumococcal only, PCV13 -type, and
PCV20 -type).
2. To describe the proportion of LRTI hospitalizations (overall, standard -of-care pneumonia
diagnosis, radiologically confirmed CAP only) associated with any S. pneumoniae, PCV13,
PCV20 serotypes and by individual serotypes, both overall and stratified by age/risk
condition
3. To describe demographics, clinical and epidemiological characteristics and outcomes
within LRTI and its 12 subcategories, both overall and stratified by age/risk condition
4. To determine mortality rate at 30 days after admission to hospital for LRTI (and its 12
subcategories) , overall and by age group and risk group status
5. To describe the serotype and frequency and typ e of antibiotic resistance among S.
pneumoniae isolates
6. To describe the length of hospital stay for LRTI hospitalizations and the proportion of
LRTI admissions involving an ICU stay, overall and by 12 subcategories
RSV Infection
1.To determine the populat ion-based incidence of RSV LRTI hospitalizations both overall and
stratified by presence of underlying risk conditions
2.To describe the clinical and epidemiological characteristics and clinical outcomes of RSV -
related LRTI hospitalizations both overall and stratified by presence of underlying risk
conditions
3.To describe the proportion of LRTI caused by RSV in hospitalized patients both overall and
stratified by presence of underlying risk conditions
4.To describe the difference between the population -based incidence of hospitalization,
epidemiology, clinical presentation, and outcomes observed in RSV -positive adults versus
those with other common respiratory viruses (eg, SARS -CoV-2and influenza)
5.To determine the pathogen distribution rates of RSV ,SARS -CoV-2, and other viral pathogens
among adults admitted with congestive heart failure or chronic obstructive pulmonary
disease exacerbations
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UOB ConfidentialUOB Confidential3.3 Exploratory objectives
S.pneumoniae exploratory objectives
1.To describe the occurrence of cardiovascular events within 30 days of hospitalization for
pneumonia for standard -of-care pneumonia diagnosis and radiologically -confirmed CAP only
(overall, pneumococcal only, PCV13 -type, and PCV20 -type) including the following events:
non-ST elevation myocardial infarction (NSTEMI) , ST- elevation myocardial infarction (STEMI),
cerebrovascular accident, new episode of atrial fibrillation or other significant cardiac
arrhythmia; deep venous thrombosis or pulmonary embolism, new or worsening congestive
heart failure, and cardiovascular -related death.
2.To describe time trends in population -based incidence rates of pneumococcal- related
hospitalizations during and after COVID 19 pandemic
Respiratory syncytial virus exploratory objectives
1.To determine the rates of sero -response to RSV betwee n acute and convalescent serology
and the concordance with molecular test results
2.To determine the prevalence of RSV and other viral pathogens in control participants
without acute LRTD
3.To compare the frequency of RSV and other viral pathogen detections a mong enrolled
control participants (without acute LRTD) with the frequency of RSV and other viral
pathogen detections among LRTD events
4.To describe time trends in population -based incidence rates of RSV hospitalizations during
and after COVID 19 pandemic
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UOB ConfidentialUOB Confidential4 Rese arch methods
4.1 Study design
Adults with LRTD will be screened using population- level surveillance at study hospitals ,and collection
of standard -of-care data will be performed on all LRTD events. Patients presenting during the
recruitment period of the study, with documented or suspected COVID -19 will fulfil study eligibility
criteria, and therefore all references to LRTD also encompass documented or suspected COVID -19
cases who may not otherwise qualify as LRTD . LRTD patients will be offered participation in the
enhanced diagnostic testing portion of this study with informed consent , which will involve collection
of urine, respiratory, and in some cases blood samples, for additional testing, if necessary, for COVID -
19, pneumococcus ,and RSV as well as administration of a short patient questionnaire on COVID -
related risk behaviours . The pneumococcal testing will include serotype to allow estimation of the
proportion of the burden that is potentially vaccine preventable –either by the currently available
PCV13 or the anticipated PCV20, which is currently in the final phases of clinical development.
Information about the additional pneumococcal ,SARS -CoV-2 and RSV infection testing will be
integrated with the population -level surveillance data to allow for more accurate population -based
estimates of vaccine -preventable pneumococcal and COVID -19 and RSV- related LRTD incidence. The
epidemiologic data generated from the study may serve as the baseline for future vaccine
effectiveness studies –either for expected PCV20 or investigational RSV and SARS -CoV-2 vaccine sthat
arealso currently under development at Pfizer.
Enhanced Diagnostic Testing . Patients who meet all inclusion criteria and no exclusion criteria with
informed consent will be enrolled in enhanced diagnostic testing portion of the study. At the time of
their enrolment visit, participants will be interviewed (if possible) and aurine for pneumococcal
testing and a swab for respiratory pathogen testing will be obtained in all participants (unless refused
at time of collection or the patient’s clinical status prevents collectio n, e.g. an anuric participant
cannot provide urine). Aliquots from the urine specimen scollected from study participants will be
frozen and stored for subsequent shipment to Pfizer laboratories for urinary serotype -specific antigen
detection (UAD) and Bina xNOW® testing. Addition altesting may be conducted on these specimens or
portions of these specimens that may be stored at the Bristol Biobank only after obtaining appropriate
permissions.
All LRTD events will have additional information collected at 30 days . Additional information on the
participants’ final clinical diagnosis, vital status, and cardiovascular complications of their current
illness (pneumonia patients only) will be collected.
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UOB ConfidentialUOB ConfidentialStudy duration. The study is expected to enrol for three consec utive years with an option to extend
should additional epidemiological data be needed. Yearly or seasonal interim analyses may be
conducted.
Serology subset . All participants in theenhanced diagnostic testing group will be offered participation
in the serology subset, which will involve the following additional visits/procedures: 1) serology
specimen at enrolment visit/V1 (may be salvaged from SOC specimen if appropriate specimen
available), and 2) additional in-person visit at Day 42 to collect a blood specimen for convalescent
serology and possibly another respiratory pathoge n swab (the later only if another intercurrent acute
respiratory illness has occurred). Participation will require signature of an annex to the main study
informed consent.
UAD and Viral Testing Controls. An additional group of approximately 400 contemporaneous control
participants without acute LRTD , comparable by age group and season to subject in the enhanced
testing group , will be enrolled participation . These participants will be identified as adults who are:
1.Patients attending outpatient clinics in participating hospitals in specialties other than
respiratory or cardiology OR
2.Patients currently admitted at participating hospitals on non -medical wards with no
current acute respi ratory or cardiovascular conditions .
Control participants will provide urine for UAD and BinaxNOW testing and an upper respiratory swab
sample for RSV/ respiratory pathogen testing . UAD testing will help inform cut points for UAD positivity
in this population.
COVID -19 VE assessment is described in Appendix 1.
4.2 Active sur veillance and screening
The detailed screening methods to conduct active surveillance will be determined by the site and
described in full in a Surveillance Manual which will be cre ated and managed by the Investigator and
reviewed by Pfizer collaborators . The feasibility studies conducted prior to the surveillance study
implementation will inform the detail of surveillance activities and screening processes at both
locations.
In essence, any adult inpatients ≥ 18years old presenting to one of the participating hospitals
displaying the specified symptoms of LRTD or with a clinical diagnosis consistent with LRTD will be
included in the screening activities ,including those with exacerbations of COPD and CHF accompanied
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UOB ConfidentialUOB Confidentialby respiratory symptoms . Screening forpotential Avon CAP study participants will be undertaken by
a member of the clinical team at each hospital site, usually a nurse, allied health professional (e.g.
physiotherap ist) or doctor. This should be performed at least once a daily during the working week
(Mon -Fri), with the first screening round performed at the start of the day. Screening will involve
reviewing the medical admission take list (primarily the ‘presenting complaint/details’ section) to
screen patients for entry to the surveillance part of the study. The medical admission list is a real -time
electronic based list (internet or other IT system) which can be searched using various parameters
including admission time, enabling accurate checking of patient admissions (especially those occurring
overnight and at weekends). The medical admission take list also records details of the presenting
complaint and/or presumed diagnosis of each patient admitted to the hospi tal.
Patients admitted through the medical admission take will be excluded if they have a presenting
complaint or diagnosis that is not compatible with the study inclusion/exclusion criteria. For example,
patients with out lower respiratory pathology such as acute pancreatitis, myocardial infarction
(NSTEMI or STEMI), stroke or cellulitis would be excluded from entering the surveillance log.
Following consent, participants with LRTD events meeting the screening definition will undergo
enhanced diagnostic tests and have their clinical data pseudonymised and entered into the eCRF. All
potential participants will be approached regardless of time of admission if they are present during
established recruitment periods.
4.3Pseudonymisation
Each patient with an admission that may meet eligibility will be assigned a surveillance number within
the database. This will be assigned by the research team following the screening of the medical
admission list and will be used to pseudonymise patients. Throughout the study and on its completion,
the database will be cleaned using the NHS number to identify individuals who have more than one
qualifying admission, both within one NHS Trust and across participating study sites. These individuals
will be identified in the pseudonymised database using the surveillance number of their first study
eligible admission. The NHS number will subsequently be deleted following processing at the end of
the study. This will provide a method of ensuring that there is an accurate calculati on of disease
incidence within a defined geographical area with multiple NHS hospitals providing acute care, whilst
maintaining a pseudonymised database. A data flow diagram is included in Section 11.4.
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UOB ConfidentialUOB Confidential4.4 Patient selection
Screening inclusion criteria
Patients must meet all the following inclusion criteria to be eligible for enrolment :
1.Aged ≥18 years of age
2.Patients with illness with following 2 characteristics:
a.Acute illness (i.e., present for 28days or less); AND
b.Evidence of acute LRTD:
i.Patients wi th current orsuspected COVID -19or previous proven COVID -19
within last 28days OR
ii. Clinical or radiologic diagnosis of pneumonia or an acute LRTI OR
iii. New onset or worsening of ≥2 of following 8 LRTD symptoms or clinical
findings:
1.fever (>38.0°C) or hypothermia (<35.5°C) before or within 24 hours of
enrolment ;
2.pleuritic chest pain;
3.cough (including nocturnal only);
4.sputum production or purulence;
5.dyspnea (shortness of breath) including orthopnea or on exertion only;
6.tachypnea (respiratory rate ≥20/min) documented by healthcare
professional ;
7.abnormal auscultatory findings suggestive of LRTD (e.g.,
crepitations/ rales or evidence of pulmonary consolidation including
dullness on percussion, bronchial breath sounds, wheezing, or
egophony);
8.radiologic finding that is consistent with LRTD, including pneumonia,
and/or acute congestive heart failure (e.g., pleural effusion, increased
pulmonary density due to infection, the presence of alveolar infiltrates
[multilobar, lobar or segmental] containing air bronchograms, or
interstitial oedema).
Screening exclusion criteria
Patients meeting any of the following criteria will not be included in the study:
1.Any patient who develops signs and symptoms of LRTD after being hospitalized for ≥48 hours
(either at curre nt hospital, another transferring hospital, or a combination of these) , unless
admitted with current , previous proven ,or suspected COVID -19 infection.
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UOB ConfidentialUOB Confidential2.Previously enrolled participants readmitted ≤7 days after discharge for their study qualifying
admission, unless admitted with current , previous proven ,or suspected COVID -19 infection
3.At the time of enrolment, an LRTD -related diagnosis has been excluded or another diagnosis
confirmed (for example, patient was found to have fever and tachypnoea due to an
intraabdominal process such as cholecystitis)
Study inclusion/exclusion criteria
To participate in the enhanced diagnostic testing, individuals must meet all of the following:
1.Meet all screening inclusion criteria in section 5.2.2
2.Meet none of screening exclusion in section 5.2.3
3.Informed consent document signed and dated by patient , or the requirements for patients
unable to provide consent have been fulfilled (as detailed below)
UAD and respiratory pathogen control group
4.4.4.1 Control group inclu sion criteria
Individuals must meet all of the following inclusion criteria:
1.Age 18 years and older.
2.Informed consent document signed and dated by patient
3.Individuals who are willing and able to provide urine and respiratory swab
4.4.4.2 Control group exclusion criteria
Individuals presenting with any of the following will not be included in the control group :
1. Individuals who are investigational site staff members or relatives of those site staff member or
participants who are Pfizer employees directly involved in the conduct of the trial.
2. Individuals with suspicion of pneumonia or other respiratory infectious diseases or documented,
concomitant infectious disease.
3. Individuals residing in any long -term care facilities (for example, nursing homes orrespite care
facilities).
4. Individuals with known bronchial obstruction or a history of post -obstructive pneumonia.
(Chronic obstructive pulmonary disease (COPD) is permissible, provided there has not been an
exacerbation within the 3 months prior to enrolme nt.)
5. Individuals with primary lung cancer or another malignancy metastatic to the lungs.
6. Individuals with fever (measured temperature of ≥38.0° C measured by a healthcare provider).
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UOB ConfidentialUOB Confidential7. Individuals with significant immunosuppressive disease such as leukaemia.
8. Individuals with either pneumococcal conjugate vaccine (PCV) and/or pneumococcal
polysaccharide vaccine (PPV) administration within the past 30 days
Patient consent and enrolment
AvonCAP is a disease surveillance study for acute LRTD illness event soccurring in hospitalised patients
recording clinical data and the results of investigations performed by clinical teams as routine
standard -of-care. Therefore, specified individual patient consent is not required tocollect data on
acute LRTD events for screening .
Patients with LRTD illness event identified through screening will be offered the opportunity to
participate in enhanced diagnostic testing portion of this study . This enhanced diagnostic testing
require sinformed consent to participate and involves collection of urine, blood and upper respiratory
swabs, as well as extra interview data and access to data held in the surveillance database . Participants
will have an opportunity to review information about what would be involved in full in the patient
information leaflet and informed consent form .
This study anticipates that some patients who meet eligibility criteria may not be able to provide
consent. For example, patients requiring ventilation on intensive care, orthose with delirium or
cogn itive impairment and/or dementia may lack capacity. In this event, the research team will discuss
the patient’s capacity with the relevant clinical team and determine the opinion of the clinical team
concerning the patient’s capacity and willingness to participate . The research team will attempt to
contact afamily member, friend or unpaid carer of the patient (i.e.patient representative), in order
to discuss the stud y and determine the patient’s willingness to participate. The patient will not be
enrolled in the study if the research team, clinical team or patient representative do not feel that this
patient would be willing to participate if they had capacity, or that participating would adversely affect
their clinical treatment. We will conduct this aspe ct of the study in accordance with the Mental
Capacity Act .
Avon CAP is an observational surveillance study, and patients can,therefore ,be enrolled in other
studies or clinical trials.
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UOB ConfidentialUOB Confidential5Justification for accessing data without consent
The Avon CAP surve illance study will undertake comprehensive surveillance on all adults hospitalised
with an eligible condition (i.e. acute LRTD) without consent from all participants.
Avon CAP will undertake systematic and comprehensive surveillance of all adults hospital ized with
acute lower respiratory tract disease within a well-defined geographical area. As the demographic and
population of Bristol is well described, ascertaining the true burden of acute respiratory infection and
describing disease in the context of COVID-19 will allow this study to calculate accurate estimates of
incidence. In order to be able to determine the morbidity and mortality associated with acute lower
respiratory tract disease, it is necessary that the data collected cover the entire populati on, as missing
any cases within the study area would result in an inaccurate calculation of disease burden.
Furthermore, by capturing and detailing precise clinical data, this study will be able to stratify disease
by patient factors such as age, gender and ethnicity, as well as by risk factors, including smoking status
and pre-existing co-morbid disease including chronic respiratory and cardiovascular conditions.
Through this surveillance mechanism all acute respiratory infection in hospitalized adults will also be
described by causative pathogen and radiological diagnosis, in addition to capturing patient outcome.
The study has three important features:
1.The data will be comprehensive and complete over a defined time period for a defined
population area and therefore not subject to the potentially biased ascertainment
which weakens other large studies
2.The demographic of the study area is broad in terms of deprivation, minority groups,
urban and rural distribution and is in many ways highly representative of the
population of England, permitting results to be of value for nationwide planning.
3.The study has substantial confirmed funding which will underpin its viability and
successful conduct and is fully embedded within the clinical services of the contributin g
hospitals, while the anonymised data handling and analysis will be undertaken within
the University domain thus not competing for scarce research resources at a time of
critical need within the NIHR and NHS research infrastructures.
This comprehensive surveillance platform will enable us to truly understand and describe adult
respiratory infection in adults in the context of COVID -19. Should any vaccine providing protection
against respiratory pathogens be introduced during Avon CAP, the design of this study enables it to
act as a vaccine impact ecological study. The research team will seek to enrol as many participants as
possible in the embedded study undertaking enhanced diagnostic tests, with a target recruitment of
80% of eligible participants.
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UOB ConfidentialUOB Confidential5.1Patie nts missed by consent
This study seeks to describe and ascertain the disease burden and outcomes attributable to acute
LRTD in hospitalised adults, and by necessity the research will be undertaken on patients accessing
secondary healthcare requiring acute medical care. Some patients will be admitted ‘out of hours’ (i.e.
evenings, nights and/or weekends) and may be discharged or die before the research team have time
to approach these individuals for consent. Those who are discharged home after a short interval are
those most likely to represent mild disease. Individuals who die shortly after admission are likely to
be either elderly, frail or have extensive/severe pre-existing medical conditions. These patients are
those most likely to represent severe disease with adverse outcomes, and therefore most likely to
benefit from any public health intervention or improvement in healthcare resource allocation that
may be enabled by the insights provided by this study. However, not all elderly, frail or patients with
co-morbid disease have severe disease, and it is therefore not possible to extrapolate or generalise
the data obtained from individuals who consent to all patients admitted. To fully understand, describe
and account for acute LRTD and its subgroups of disease it is essential to undertake comprehensive
surveillance activity inclusive of all individuals requiring hospital -level care following presentation with
acute LRTD. An accurate evaluation of disease incidence, including the incidence of pneumonia, LRT I
and other disease subgroups or estimation of disease incidence by risk factor (such as age, gender,
socioeconomic status), requires the inclusion and accurate data capture of all individuals admitted
within the defined geographical area over a defined pe riod.
5.2Requirement for data points
To fulfil the study objectives, this study requires data from participants categorised as NHS number,
date of birth, postcode (to sector level), date of death and health data. These are the minimum data
required to ensure accurate ascertainment, processing and analysis. Additional fields such as the
patients’ names, addresses and/or hospital numbers may be seen by the research team in the review
of clinical records to collate data to undertake this study, but will not be extracted or saved.
In order to mee t the study objectives, the following data will be collated without consent under
appropriate approvals:
1.NHS number
2.Date of birth
3.Sector level postcode
4.Date of Death
5.Health Data
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UOB ConfidentialUOB ConfidentialThe data will be held within a database in the IT domain of each participating NHS study site, accessible
only to authorised research team members. The data will be processed and transferred to the central
University IT domain as outlined in section 10 of this protocol. The requirement for the data is
explained in the following para graphs.
5.2.1 NHS Number
The NHS number is a unique identifying number that is issued to each individual and stays with that
individual for life. It is therefore a single data point that can identify an individual both within a given
NHS Trust (or study site) and across NHS Trusts. Each NHS Trust uses a local hospital number which is
not transferrable or usable within the NHS IT system at another NHS site, and therefore this cannot
be used to avoid duplication. Participant name would not be uniquely identifiabl e within a large and
densely populated area and would require at least one additional data point for accurate
identification.
This study aims to determine the incidence of acute LRTD with a defined geographical area with the
acute care requirements of the population being served by more than one NHS Trust (or study sites).
To calculate disease incidence accurately, each individual who meets study eligibility criteria must be
counted correctly (i.e. not missed and not counted more than once for a single cli nical episode), both
within and across study sites. For example, a patient may be admitted to North Bristol NHS Trust,
discharged home a few hours later but unexpectedly deteriorate and be taken by ambulance to
University Hospital Bristol and Weston NHS Trust. In this example, the patient would have only one
episode of disease, but unless there was a mechanism to identify this individual across the study sites
they would be counted twice, and therefore lead to an inaccurate count.
5.2.2 Date of Birth
A particip ant’s date of birth is required to calculate patient age at admission, age at death (if occurring
within 30 days of study admission) and age at discharge. This is important to allow stratification of
individuals affected by acute LRTD by age, with evidence suggesting disease increases with age.
Vaccination strategy in the UK is currently stratified by age, with individuals over 65 years qualifying
for PneumoVax® (PPV -23) vaccination and seasonal influenza vaccination. Therefore ,estimating the
disease burde n by age will provide important information about the groups most likely to benefit from
vaccination with current and novel vaccines against respiratory disease, in addition to other public
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UOB ConfidentialUOB Confidentialhealth interventions and healthcare resource allocation designed t o improve outcomes in those most
at risk.
Furthermore, current risk severity scores for respiratory disease recommended by the British Thoracic
Society, NICE and American Thoracic Society/Infectious Disease Society of America require patient age
at admiss ion. These severity scores have not been well evaluated in the context of the emergent
COVID -19 pandemic. Testing existing risk severity scores and identifying modifications that improve
their accuracy at predicting disease outcomes would lead to improved clinical care for individuals with
acute LRTD.
5.2.3 Postcode (to sector level)
Sector level postcode is required to estimate the socioeconomic status of individuals affected with
respiratory disease, and to undertake geotemporal analysis of acute LRTD allowin g for mathematical
modelling of infection. Determining which localities and socioeconomic groups are most at risk of
disease and adverse outcomes is important in determining the availability and distribution public
health care interventions, including but not limited to vaccination programmes. Furthermore, the
potential impact of other interventions designed to modify risk factors such as comorbid disease,
environmental factors and access or availability of healthcare resources can be appropriately assessed
and provided based on the data provided by this study.
Mathematically modelling disease patterns and spread in time and place allows for better
understanding of how disease outbreaks and incidence of disease occurs in a population, and will
provide a gen eralisable model that can be used both within this population and extrapolated to other
populations. This will also not only provide better understanding of disease but also provision of better
health care resources to reduce disease morbidity and mortalit y.
5.2.4 Date of Death
Date of death for participants in this study will only be recorded if occurring within 30 days of an
eligible hospital admission. The date of death is used to (1) calculate survival and mortality statistics
(2) determine if any death occurring within 30 days of admission is as an inpatient or following
discharge. This is important in determining disease burden and outcome and determining whether
mortality was as an inpatient or following discharge. This has significant impact on healthcare
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UOB ConfidentialUOB Confidentialeconomics and provision of healthcare resources. It may also highlight patient groups at particular risk
of adverse outcomes, and thereby enable targeted interventions to reduce mortality in these groups.
5.2.5 Health Data
Health data are data concerning individuals’ demograph ics (gender, ethnicity), pre-existing medical
conditions, signs and symptoms of disease on arrival at hospital, and investigation of (blood,
microbiology and radiological test results) and outcomes (e.g.requirement for intensive care and/or
organ support, length of hospital admission, etc.). Health data will be ascertained in order to
characterise acute lower respiratory tract disease including: the patients that it affects; the
presentation to hospital; its investigation, treatment and outcomes; to strati fy disease into subgroups;
and determine microbiological diagnosis. These will be used to investigate risk factors for disease and
poor outcome (including morbidity and mortality) and to calculate disease burden and incidence of
acute LRTD and its subgroups. This is important in determining the requirement and provision of
healthcare resources and the potential benefit of public health initiatives (including current and future
vaccines) in reducing morbidity and mortality
5.3 Public health benefit
Processing of th esedata will allow the study to determine:
Incidence of acute LRTD and its subgroups in the Bristol area
Risk factors for acute LRTD and its subgroups
Outcome for acute LRTD and its subgroups in Bristol
Incidence of vaccine -preventable respiratory d isease in Bristol
Identify risk factors with poor outcome, including those that may be modifiable
Identification of differences between patients and their outcome at participating hospitals
Since the characteristics of the population of Bristol are known in detail , thesedata willbe able to be
extrapolated to national level. Thesedata will therefore inform policy onpublic health interventions
to improve the health of those whose data have been systematically collated, the wider Bristol
population and the national population. Furthermore, t hese data can be analysed to provide insight s
into healthcare resource allocation, again benefitting the local population and those studied .
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UOB ConfidentialUOB Confidential5.4 Lawful Basis for data processing
GDPR Article 6.1(e) – University of Bristol public task
Article 9.2(i) –public interest in the area of public health
Article 9.2(j) –scientific research
Public task: the processing of thesedata is needed to calculate a true disease incidence for acute LRTD,
its subgroups and vaccine -preventable disease that will enable the better allocation and provision of
healthcare resources and implementation of public health initiatives to reduce morbi dity and
mortality, including but not limited to vaccination.
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UOB ConfidentialUOB Confidential6 Recruitment, data and sample collection
6.1 Patient selection
This study will be based at NBT and UHB Whospitals , and other hospital sites may be invited to
participate at a future date . Patients will be selected from normal clinical care either from the
inpatient or acute admissions setting. Furthermore, an audit of microbiological testing will be
undertaken to ensure that patients were inadvertently missed through the clinical care selection
pathway. If any additional healthcare setting s are established to manage overflow patients with
COVID -19 infection from these hospitals due to thepandemic , these additional hospital sites would
be included in this study.
6.2 Data sources
Cons ent will be obtained to access data relating to outcomes of:
Radiology tests
Microbiology tests
Clinical parameters regarding hospital admission (including co-morbidities, symptom
type and duration, admission observations, etc)
Vaccination status
Patient treatment (including requirement for ventilation, renal support, etc)
Patient outcomes (including hospital length of stay, requirement for intensive care,
haemofiltration and complications arising from their LRTD).
Consent will also be obtained to record w hich GP practice the participant is registered with, in order
to use this to generate a denominator for incidence calculation.
6.3 Sample and data collection
Data will be recorded on an e-CRF (REDCap), although a paper -based source document may be used
under exceptional circumstances (such as computer failure) which will be entered to the e-CRF. In this
instance, any paper- based records will be handled in keeping with due diligence of confidential
medical information.
Consent will also be obtained for collect ion of the following samples:
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Scavenging of Residual Standard of Care Specimens
Where possible for participants in enhanced diagnostic testing, aliquots of standard care specimens
will be scavenged (e.g., sputum, tracheal aspirate, bronchoalveolar lavage, pleural fluid, or swab for
MRSA testing ) and sent to the appropriate local or national laborator iesfor pneumococcal , RSV, and
other respiratory pathogen testing.
S. pneumoniae isolates
Any S. pneumoniae isolates from standard of care bacterial cultures (such as, blood, respiratory tract,
and pleural fluid) will be sent to the appropriate local or national laboratories for confirmation of S.
pneumoniae, and serotype identification as outlined in the Labor atory Manual.
Respiratory swabs for respiratory pathogen testing (Study Procedure)
If not already requested or completed as part of standard of care testing, arespiratory swab will be
collected as a study procedure for RSV RT-PCR and respiratory pathoge n testing as soon after study
enrolment as possible and preferably within 24 hours of study enrolment . Nasopharyngeal (NP) swab
is currently the preferred approach. If the participant declines a NP swab, an alternative respiratory
specimen such a midturbin ate nasal swab may be collected. Any sample collection will be recorded in
the CRF. Enrolled patients may decline respiratory swab collection and remain in the study. Full details
of specimen collection and processing will be outlined in Laboratory Manual. The Serology subset will
also have another respiratory swab collected at their convalescent visit if they have a new intercurrent
acute respiratory infection before Visit 3.
Urine samples
As a s tudy procedure , urine will be collected in a noninvasive manner from all participants as soon as
possible following enrolment ; it is preferred that the urine sample be collected within 24 hours
following study enrolment . Any sample collection will be recorded in the CRF. If a bladder catheter
has been placed as part of routine medical care, a fresh urine sample may be collected from the lumen
or the port. Any additional urine volume remaining after the UAD aliquots are saved, will be deposited
in Bristol biobank or divided into falcon tubes and shipped to the Pfizer central laboratory for
additional new assay development and UAD technology transfer. Urine will be frozen and stored at
the local laboratory for subsequent shipment to the Pfizer central laboratory
for UAD and BinaxNOW®
testing or transfer to biobank at Bristol University . Specific instructions for the collection, processing
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UOB ConfidentialUOB Confidentialand shipment of urine specimens will be described in the study laboratory manual. Patient unable or
unwilling to provide a urine specimen may still be enrolled in the study.
As part of a program of rigorous control and continuous assessment of UAD assay performance, and
ongoing monitoring of the studies which utilize the UAD assay, this study will collect urine samples
from approximately 400, controls without acute LRTD that will be similar in age group distribution and
month of collection to participants with acute LRTD . Analysis of these control samples will further
support that the established positivity cut-off values of the UAD assays are applicable to this
population. BinaxNow® will also be analyzed in control patients.
Schedule of Events –Controls with outAcute LRTD
Study Visit Enrolment
Study Day Windows 1
STUDY PROCEDURES
Obtain Informed Consent X
Review Eligibility Criteria X
Patient Interview , including review of cardiovascular events in prior 2 monthsaX
Review of Medical Record X
SPECIMEN COLLECTION
Urine specimen X
Obtain respiratory swab X
Obtain blood specimen (optional) X
aCollect cardiovascular events per Protocol Section 6.2 in past 2 months.
UAD 1 and UAD 2.The Pfizer UAD is a multiplex immunoassay, based on the Luminex xMAP bead
technology, with the ability to combine multiple spectrally distinct microspheres, each conjugated to
a different serotype -specific monoclonal antibody in a single well to allow the detection of all antigens
simultaneously using only a small volume of urine sample. The 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V,
14, 18C, 19A, 19F, 23F) covered in the val idated UAD 1 assay are the 13 polysaccharide antigens used
in Pfizer’s 13vPnC vaccine. The UAD 2 assay, using the same Luminex xMAP bead technology detects
11 additional serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F).
BinaxNOW® is a commerci ally available, Food and Drug Administration (FDA) approved assay for the
detection of S.pneumoniae in the urine and cerebrospinal fluid (CSF) from patients with pneumonia
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UOB ConfidentialUOB Confidentialor meningitis. The BinaxNOW® S. pneumoniae test is an in vitro rapid immunochromato graphic test
intended to be used in conjunction with culture and other methods, to aid in the diagnosis of
pneumococcal pneumonia.
Aliquots for urine samples for testing conducted by Pfizer Inc will be processed and kept frozen in an
appropriate local laboratory and will be shipped in bulk for analysis at the Pfizer Vaccines Research
and Development (VRD) laboratory, Pearl River, New York, USA. Details regarding sample processing
and shipping are provided in a separate laboratory manual. Residua l samples from urine aliquots sent
for UAD/BinaxNOW testing may be stored for future testing at Pfizer laboratories and may be kept for
up to 15 years after the study ends, at which time they will be destroyed. In addition to testing for this
study, any residual urine from these aliquots left over after the study is complete may be used for
additional research related to the development of products. Pfizer will not perform any testing of
genetic material. Residual urine samples at Pfizer may be shared with other researchers as long as
confidentiality is maintained, and no testing of the participant’s genetic material is performed .
Serology testing for serology subset participants
All participants enrolled in the Serology subset will have a blood sample collected for acute and
convalescent serologic testing, including for RSV infection . If a blood sample is drawn for standard
care, an aliquot of this specimen may be scavenged and used for serologic testing in lieu of a separate
specimen collection if it meets the requirements outline din the Laboratory Manual. If a participant
has another enrolment qualifying acute LRTD event(s) prior to their convalescent visit, they will have
acute serology specime n taken at each enrolment and only one convalescent serology visit will be
completed 42 days after last acute specimen was taken. Control participants may also have a blood
specimen taken ,and serologic testing may be conducted on th osespecimen s.
Additio nal testing for respiratory infection
This study anticipates that novel diagnostic and prognostic tests for respiratory infection may emerge
throughout the study period, including against COVID -19. Any biological specimen s(urine, serum or
blood derivatives and respiratory samples) collected as primary research or salvage samples in this
study, which are surplus to study requirements following testing as outlined in the protocol above ,
may be used for novel and emergent assays to detect, quantify and/or characterize the respiratory
infection and the immune system response to pathogens such as SARS -CoV-2.
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Biological samples
The participant may request that their samples, if still identifiable, be destroyed at any time; howev er,
any data already collected from those samples will still be used for this research. All anonymized
biological samples not required for this protocol may be deposited in the Bristol Biobank to be used
in future research and shared with other researchers ,as long as appropriate approvals are obtained .
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UOB ConfidentialUOB Confidential7 Study procedures and clinical data –Consented arm
Total duration of participation per participant will be approximately one month from date of
admission. One visit is in person (V1), and one may involve record abstraction and/or phone contact
(V2). For the Serology subset, participation will extend to approximately 6 weeks and involve an
additional in person visit.
7.1 Consented arm, Visit 1: Screening/ Enrolment (Day 1)
Screening all potential participants (adult patients with respiratory symptoms and/or suspected
COVID -19) for eligibility forthe disease surveillance and consented parts of the study. Every effort will
be made to approach, discuss, and enrol participants in the consented arm and seek their consent for
collection and use of data. Participants should be enrolled as soon as feasible after admission (no later
than 48 hours after admission if at all possible). Screening while administrative admission process is
occurring is encouraged. The enrolm ent visit will be conducted in person and include the following
activities:
Screen patients against the inclusion/e xclusion criteria of this protocol
Provision of enhanced testing information toLRTD patient, answer any questions with
particular attention to the study schedule and sample collection.
Obtain signed and dated written informed consent from participant forLRTD patients who
want to participate in enhanced diagnostic test ing. In the event that a potential participant
lacks capacity to consent to participation, study staff will follow protocols for patients unable
to provide informed consent.
Enter standard of care data into eCRF for LRTD events
For consented participants , collect and process urine , blood and respiratory specimens as
detailed in Laboratory Manual (unless refused at time of collection or the patient’s clinical
status prevents collection, e.g. an anuric participant cannot provide urine).
For consented participants , salvage standard of care r espiratory specimens for respiratory
pathogen and pneumococcal testing. See laboratory manual for details.
For consented participants , interview participant if possible, for past medical history and
eCRF elements not in medical chart , COVID risk behaviours questionnaire
For consented participants , record any serious adverse events associated with sample
collection and RRIs.
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UOB ConfidentialUOB ConfidentialIf participating in Serology subset, obtain a blood specimen for serology per specification in
laboratory manual. Salvaged SOC specimens may be used if meet specifications outlined in
the Laboratory Manual.
Non-consented arm
Screen patients against the inclusion/e xclusion criteria of this protocol
Enter standard of care data into eCRF for LRTD events
V1 data collection
Patients meeting screening criteria will have basic demographic and clinical data collected on an e -
CRF after consent . This will involve collection of the following data at visit 1:
Patient details
Eligibility checks –inclusion/ exclusion criteria components
Date of hospitalization, length of stay in hospital
Demographics (age, gender, race/ethnicity, socioeconomic status estimated by postcode ,
vaccination [e.g. influenza/ PCV13/PPV23 /COVID -19and date of relevant administration],
smoking status , alcohol/drug use )
Details of present illness (symptoms, date of onset, vital signs on admission to hospital)
oUsed antibiotics in the 14 days prior to admission
Standard -of-care test results
oRoutine biochemistry and haematology test results on admission , including C -
reactiv e protein and NT -proBNP
oBlood cultures
oRespiratory microbiology testing, including bacterial (eg, PCR and culture) and viral
testing (eg, COVID19, RSV and influenza )
oPneumococcal testing (eg, BinaxNOW urine test),
oAntibiotic resistance results for pneumoc occal isolates
oSputum Gram stain results
oCOVID -19 testing data collection will include tests from up to 14 days prior to
hospitalisation based on patient self -report and medical records
Hospitalization data:
oAdmission hospital
oDates and time of admission/discharge
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UOB ConfidentialUOB ConfidentialoICU stay (yes/no)
oNumber of days in ICU
oMechanical ventilation and days of ventilator use
oRequirement for new/increased haemofiltration
oNon -invasive ventilation requirement and days of usage
New York Heart Association (NYHA) Heart Failure Classification, Pneumonia Severity (CRB65
and PSI scores)
Relevant Medical History and Major Comorbidities
Rockw ood Frailty Score and Charlson Comorbidity Index
COVID riskbehaviours questionnaire including occupation, household structure, in clusion in
social bubble and mask wearing
7.2 Consented arm, Visit 2: Final diagnosis /Vital status assessment (Day 30)
The assessment may be completed 30 to 45 days after enrolment by phone call, medical record
review, during a follow -up standard care visit and/or other means.
At day 30 after admission, the following will be assessed and recorded in the CRF:
Record final clinical/standard -of-care diagnosis for qualifying acute LRTD illness
Vital status (alive or deceased) at Day 30 after enrolment
Cardiac complications through Day 30 after enrolment
The Principal Investigator or designee should make an assessment of fina l standard -of-care LRTD -
related diagnosis if any discrepancy exists in the record. The Investigator is to also confirm, based on
any existing or new information, if the participant had clinically and radiographically confirmed
pneumonia.
Data collection at V2:
Record RRIs
Hospital- related adverse event s(e.g.,fallsin hospital and hospital -acquired infection s)
Final standard of care/ clinical diagnosis of acute LRTD illness
Vital status at Day 30
Occurrence of cardiovascular events within 30 days of illness onset (pneumonia only):
onon-ST elevation myocardial infarction (NSTEMI)
oST-elevation myocardial infarction (STEMI)
ocerebrovascular accident
onew episode of atrial fibrillation or other clinically significant arr hythmia
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UOB ConfidentialUOB Confidentialodeep venous thrombosis or pulmona ry embolism
onew or worsening congestive heart failure
ocardiovascular- related death
7.3 Consented arm, Visit 3 [ serology subset only]: Convalescent serology assessment on Day 45
For those enrolled in the Serology subset who have signed the related ICD Annex, a follow -up visit
will be conducted approximately 45 days after enrolment (visit window: Day 22 –60). If there is a
low patient return rate for this follow -up visit, the stu dy will consider whether home visits may be
more convenient and better suited to patients in this study. If home visits are undertaken, they will
be offered to participants as a visit option, and an appropriate time will be arranged after liaison
between t he participant and research team. The procedures undertaken during home visits will
ensure that both study participants and research staff are appropriately protected in line with any
Health and Safety regulations (e.g. PPI, sharps bins, etc.).
Blood spec imen for respiratory pathogen serology including RSV will be obtained. A n upper
respiratory swab will be obtained if intercurrent acute respiratory illness has occurred
Record RRIs.
7.4 Consented arm, Patient outcome :
The follow -up information should be collected 1 month after enrolment or when the patient is
discharged from hospital (whichever occurs later). At day 30 after admission, the following will be
assessed and recorded in the CRF:
Record final clinical/standard -of-care diagnosis for qualifying a cute LRTD illness :
o CAP –radiologically or clinically confirmed, acute bronchitis/LRTI, exacerbation of
underlying chronic respiratory disease, LRTI not otherwise specified, congestive
cardiac failure, empyema/lung abscess, non-infective process , and non-respiratory
infection -related diagnosis .
Vital status at Day 30 after enrolment :
odeceased, not recovered, recovered, recovered with sequelae ,recovery ongoing,
unknown
Cardiac complications through Day 30 after enrolment :
oST-and non-ST elevation myocardia l infarction, cerebrovascular accident, new
episode of atrial fibrillation or other arrythmia , venous thromboembolism,
cardiovascular- related death
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UOB ConfidentialUOB ConfidentialThe Principal Investigator or designee willassess final standard -of-care LRTD /COVID -related diagnosis
if any discrepancy exists in the record. The Investigator is to also confirm, based on any existing or
new information, if the participant had clinically and radiographically confirmed pneumonia.
7.5 Ongoing clinical care
This is an observational epidemiological study collating and recording standard -of-care investigations
and patient details in a consented study with enhanced diagnostic tests . As such, Avon CAP should not
impact on any aspect of clinical care or other interventional trial in which the patient may be
participating.
7.6 Research -related injury reporting
Given this study only involves specimen collection using methods routinely used in clinical care (ie,
collection of urine, nasal swabs, and blood samples) , no serious adverse events are anticipated.
However, should a participant, in the investigator’s opinion, suffer a medically important RRI caused
by his or her participation in the study, the sponsor and designated Pfizer clinician or medical monitor
must b e notified immediately. A medically important RRI is any untoward medical occurrence that:
Results in death;
Is life -threatening (immediate risk of death);
Requires inpatient hospitalization or prolongation of existing hospitalization;
Results in persisten t or significant disability/incapacity (substantial disruption of the
ability to conduct normal life functions);
Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an injury is a n important medical
event. An important medical event may not be immediately life-threatening and/or result in death or
hospitalization. However, if it is determined that theevent may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above, the
important medical event should be reported as an RRI.
If, during the course of the study, the research team become aware that a participant experienced an
serious adverse event that may be attributable to an adv erse reaction of any vaccination, this will be
logged by the research team and reported to the vaccine manufacturer .
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UOB ConfidentialUOB Confidential8 Study procedures and clinical data –Non -Consented arm
Total duration of participation per participant will be approximately one month from date of
admission.
8.1 Non -consented, Surveillance Admission Data Collection (Day 1)
Screening all potential participants (adult patients with respiratory symptoms and/or suspected
COVID -19) for eligibility for the disease surveillance study . Every effort will be made to approach,
discuss, and enrol participants in the consented study arm and seek their consent for collection and
use of data. However, in patients in whom it is not practicable to do so, surveillance activity will be
undertake n as outlined below. Participants should be enrolled as soon as feasible after admission (no
later than 48 hours after admission if at all possible). Data collection will include the following
activities:
Screen patients against the inclusion/exclusion cri teria of this protocol
Enter standard of care data into eCRF for LRTD events
Admission data collection
Patients meeting screening criteria will have basic demographic and clinical data collected on an e -
CRF. This will involve collection of the following data at admission:
Patient details
Eligibility checks –inclusion/ exclusion criteria components
Date of hospitalization
Demographics (age, gender, race/ethnicity, socioeconomic status estimated by postcode,
vaccination [influenza/ PCV13/PPV23/COVID -19 and date of relevant administration],
smoking status, alcohol/drug use)
Details of present illness (symptoms, date of onset, vital signs on admission to hospital)
oUsed antibiotics in the 14 days prior to admission
Standard -of-care test results
oRoutine biochemistry and haematology test results on admission, including C -
reactive protein and NT -proBNP, and blood group
Hospitalization data:
oAdmission hospital
oDates and time of admission
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UOB ConfidentialUOB ConfidentialNew York Heart Association (NYHA) Heart Failure Classification, Pneumo nia Severity (CRB65
and PSI scores)
Relevant Medical History and Major Comorbidities
Rockwell Frailty Score and Charlson Comorbidity Index
8.2 Non -consented Patient Outcome measures
The follow -up information should be collected 1 month after enrolment or when the patient is
discharged from hospital (whichever occurs later). At day 30 after admission, the following will be
assessed and recorded in the CRF:
Microbiological investigation results
oBlood cultures.
oRespiratory microbiology testing, including bacterial (eg, PCR and culture) and viral
testing (eg, COVID19, RSV and influenza),
oPneumococcal testing (eg, BinaxNOW urine test),
oAntibiotic resistance results for pneumococcal isolates
oSputum Gram stain results
Hospitalization data:
oDates of discharge
oICU stay (yes/no)
oNumber of days in ICU
oMechanical ventilation and days of ventilator use
oRequirement for new/increased haemofiltration
oNon -invasive ventilation requirement and days of usage
Vital status at Day 30 after enrolment:
oDeceased , not recovered, recovered, recovered with sequelae, recovery ongoing,
unknown
oDate of death if under 30 days from admission
Record final clinical/standard -of-care diagnosis for qualifying acute LRTD illness:
o CAP –radiologically or clinically confirmed, acute bronchitis/LRTI, exacerbation of
underlying chronic respiratory disease, LRTI not otherwise specified, congestive
cardiac failure, empyema/lung abscess, non-infective process, and non-respiratory
infecti on-related diagnosis.
Cardiac complications through Day 30 after enrolment:
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UOB ConfidentialUOB ConfidentialoST-and non-ST elevation myocardial infarction, cerebrovascular accident, new
episode of atrial fibrillation or other arrythmia, venous thromboembolism,
cardiovascular- related deat h
Hospital related adverse events (e.g., falls in hospital and hospital -acquired infections)
The Principal Investigator or designee should make an assessment of final standard -of-care LRTD -
related diagnosis if any discrepancy exists in the record. The In vestigator is to also confirm, based on
any existing or new information, if the participant had clinically and radiographically confirmed
pneumonia.
8.3 Ongoing clinical care
This is an observational epidemiological study collating and recording standard -of-care investigations
and patient details in a consented study with enhanced diagnostic tests. As such, Avon CAP should not
impact on any aspect of clinical care or other interventional trial in which the patient may be
participating.
8.4 Research -relat ed injury reporting
Given that this study is non -interventional and covers a period during which participants are under
clinical care, Adverse Event data will not be recorded -except that which is pertinent to study data
collection -and Serious Adverse Events will not be reported unless they are related to the patient's
involvement in this study.
Any event that;
Results in death;
Is life -threatening (immediate risk of death);
Requires inpatient hospitalisation or prolongation of existing hospitalisation;
Results in persistent or significant disability/incapacity (substantial disruption of the ability
to conduct normal life functions); OR,
Results in congenital anomaly/birth de fect.
and is judged by an Investigator to be possibly, probably or definitely related to the patient's
participation in this study (i.e. the collection of their data) will be reported to the Sponsor within 24
hours and to the approving REC within 15 days o f the study team becoming aware of it.
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UOB ConfidentialUOB Confidential9 S tudy size and data analytics
9.1 Study size
Expected study size was calculated using both a retrospective coding data from 2018 -2019, and a 21 -
day prospective audit of adult patients admitted to the Acute Medical Unit at NBT. It should be noted
that both methods used to calculate estimated patient numbers were conducted in a time period
before the COVID -19 pandemic. Both methods calculated anAvon CAP patient cohort approximately
7,000 adult patients per annum at NBT, and assuming all 2hospital sites have similar patient numbers,
the envisaged patient cohort before COVID -19 was 14,000 patients per annum. However, given the
COVID -19 pandemic we expect a significantly large sample size, which is likely to approximate 23,000
patients per annum across the 2sites. Number of adults in surveillance population is approximately
630,000,
yielding expected LRTD incidence of >3,600 per 100,000 population annually (3.65 per 100
person years; 95% CI: 3.60 to 3.70) .
9.2 Pneumonia and LRTDgroup classifications
LRTD participants will be classified by standard -of-care diagnoses extracted from the medical chart
and using standardized case definitions (e.g., for radiologically confirmed CAP). Standardized case
definitions not specifically referenced in the study objectives will be included in the Statistical Analysis
Plan (SAP). Events with a final diagnosis of pneumonia by the treating clinician will be considered to
have standard -of-care pneumonia diagnosis. A case of RSV is considered any patient with positive
molecular test from any specimen type and/or RSV seroconversion defined as 4-fold rise in RSV
antibody titers between acute/convalescent samples. Participants with
pneumococc us identified
through standard of care testing ( aside from colonization specimens ) and UAD1/2 and BinaxNOW will
be considered to have pneumococcal infection . COVID -19 infection will be defined as any patient who
has current infection confirmed via laboratory diagnostic testing (molecular, serological or other
future test deemed clinically appropriate to determine current SARS- CoV-A infection). Alternatively ,
any individual who meets any future diagnostic criteria which are determined sufficient to confirm
current SARS -CoV-A infection will also be deemed to hav e COVID -19.
Radiologically confirmed pneumonia
Radiologically confirmed pneumonia will be defined as patients in whom the treating physician
clinically suspected pneumonia who meet the following 2 criteria:
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increased pulmonary density due to infection, the presence of alveolar infiltrates
[multilobar, lobar or segmental] containing air bronchograms); AND
2.Illness involves ≥2 of the following signs or symptoms:
a.fever (>38.0°C) within 24 hours before enrolment
b.hypothermia (<35.5°C) within 24 hours of enrolment
c.chills or rigors
d.pleuritic chest pain
e.new or worsening cough
f.sputum production
g.dyspnea (shortness of breath)
h.tachypnea (respiratory rate >20/min) doc umented by healthcare professional
i.malaise
j.abnormal auscultatory findings suggestive of pneumonia (crepitations/ rales or
evidence of pulmonary consolidation including dullness on percussion, bronchial
breath sounds, or egophony).
Lower respiratory tract infection
Lower respiratory tract Infection will b e defined as enrolled subject with one of the following:
1.Final clinical diagnosis consistent with LRTI (ie, pneumonia or other LRTI); OR
2.Positive laboratory test for pneumococcus, RSV, SARS -CoV-2 orany other infectious
respiratory pathogen ; OR
3.Evidence of both:
a. Active infection, ie at least 1 of the following conditions: reported fever, reported
chills, measured temperature of >38.2°C or <35°C, or an abnormal white blood cell
count or differential) AND
b.Lower respiratory tract disease (at least 1 of the following conditions: abnormal
breath sounds, documented tachypnea, cough, sputum production, or dyspnea)
Cardiovascular event sfollowing pneumonia
The rates of cardiovascular events at 30 days following pneumonia will be compared to rates among
controls without acute LRTD in the 2 months prior to their enrollment. In addition, a group of
comparable persons based on age, Charlson co-morbidity index and underlying disease will be
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UOB ConfidentialUOB Confidentialassembled through analysis of anonymized health data to assess the rate of these outcomes in this
population with pneumonia. Full details will be provided in the SAP.
Acute Respiratory Illness (ARI)
The WHO definition of ARI will be used: An acute respiratory infection with: history of fever or
measured fever of ≥ 38 C°; and cough; with onset within the last 10 days; and requires hospitalization.
(https://www.who.int/influenza/surveillance_monitoring/ili_sari_surveillance_case _definition/en/ )
9.3 Data analysis
Detailed methodology for summary and statistical analyses of data collected in this study will be
documented in a statistical analysis plan (SAP), which will be dated, filed and maintained by the
investigators. The SAP may modify the plans outlined in the protocol; any major modifications of
primary endpoint definitions or their analyses would be reflected in a protocol amendment.
9.4 Limitations of the research methods
As with any study in humans there is potential for limitations. The methodology used here in recruiting
participants, data collection and analyses will seek to minimize these , as listed below.
Denominator
The two hospitals included in the study serve much of the Bristol population. However, there is likely
some cross over at the geographical borders, for example with Bath Hospital. It is expected that this
may be directional towards Bristol, as both hospitals are tertiary referral centres so individuals may
preferentially attend in Bristol rather than Bath , which is a district general hospital. The team will have
assessed the degree of such cross over by the analysis phase so that a correction can be factored into
the denominator, but this will be by estimation.
Representativeness
Hospitalized individuals admitted with LRTD who meet the eligibility criteria will be invited to
participate in the enhanced diagnostic testing portion of the study . It is possible there could be bias in
the refusals being different from those who do take part, for example those with most severe disease .
Further, if recruitment for enhanced diagnostic testing cannot be performed at all times (eg,
weekend s,overnights , and holidays ), some patients with acute LRTD may not be able to participate in
the enhanced diagnostic testing port ion of the study on that basis. The representativeness of
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UOB ConfidentialUOB Confidentialenhanced diagnostic testing participants will be established by comparing the groups that have
accepted and declined using eCRF data .
Recruitment completeness
It is possible patients may be missed by virtue of their pathway through the hospital being atypical,
the time of admission or a human error factor. This would be a random error so should not bias the
study. Every effort will be made to identify such patients through ongoing audits for surveil lance
completeness (e.g., via radiological records, ICD discharge codes, or microbiology tests ordered). A
second factor may be the inability to collect samples from all consented participants, possibly through
their refusal or inability to provide them. This will be addressed through appropriate training of staff
in the importance of and methods to obtain as comprehensive a set as possible, while respecting
patient choice and well -being.
Data completeness
Collection of information will mainly come from medical notes, which may not always be complete.
However, the fields selected for this study wou ld come from the basic registration information and
from details that would be required in order to treat the individual so should be completed reliably.
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UOB ConfidentialUOB Confidential10 Regu latory issues
10.1 Research governance
This study will be conducted in accordance with:
• The International conference for harmonisation of good clinical practice (ICH GCP)
• The UK Policy Framework for Health and Social Care Research , and
• The Declaration of Helsinki
10.2 Ethics approval
The Health Research Authority (including review by an NHS research ethics committee )will review the
study prior to recruitment commencing. The HRA/NHS REC will be asked to approve the study
protocol, as well as any “public -facing” or “participant -facing” documentation (e.g. patient
information sheet and consent form). All the above will be approved by the Sponsor prior to
submission .
10.3 Risks and anticipated benefits for participants and society
Potential benefits for participant s:
There are no direct benefits to taking part in this study ,however ,the participant may feel that they
are contributing to the scientific knowledge about COVID -19 and vaccine preventable infections
during the pandemic which may help diagnostics , vaccine development, and future patient care.
Potential harms or risks to participants:
Biological Samples :
The collection of nasal/throat swabs, saliva, nasosorption, blood and urine samples are considered to
be minimally arduous for participants. Potential harms:
Venepuncture: taking blood samples may cause some discomfort and occasionally result in a
bruise.
Nasal swabs: participants may find this causes temporary discomfort or bleeding.
Urine collection: this poses no risk
Data collection and protection :
There are risks to study participants concerning the collection and use of data, namely potential
ident ification of study participants, inappropriate access to participants’ data, and inappropriate
transfer of participants’ data.
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UOB ConfidentialUOB ConfidentialIn order to ensure that data protection requirements concerning identifiable data collected through
this study, and the right to privacy and confidentiality are maintained, the study will:
Apply to the Clinical Advisory Group for Section 251 of the NHS Act,
Complete and adhere to Data Protection Impact Assessments
Ensure that appropriate Data Security Protection Toolkit Assessment s are undertaken by
participating organisations
That participating organisations adhere to GDPR compliance.
Further study protocols to mitigate these risks are outlined in Section 11 of this protocol.
Anticipated benefits for society
Data analysis will be conducted at interim intervals, which may allow for initial results for the primary
and secondary outcome measures at a time -point before end date. This would allow for potential
publication of important data which impacts on the clinical care of patie nts with COVID -19 and may
impact vaccination strategies to prevent adult respiratory disease and associated morbidity and
mortality. Further, this information is also intended to improve the understanding of how much LRT D
is vaccine preventable, either wit h approved vaccine s (e.g
., pneumococcal vaccines) or investigational
vaccines (e.g., RSV and COVID -19 vaccine s),which would help inform vaccine recommendations in the
future which allow for prevention of LRTIs in this population .
10.4 Sponsor approval
All study documents will be approved by the Sponsor prior to submission for regulatory approval . Any
amendments following a favourable ethical opinion, will be approved by the Sponsor prior to
submission.
10.5 NHS approval
Confirmation of capacity and capability from the local NHS Trust (NBT and UHB W)is required prior to
recruitment. Any amendments to the study documents will be approved by all necessary parties prior
to implementation .
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UOB ConfidentialUOB Confidential10.6 Investigator responsibilities
This is a multisite observational epidemiology study. The Chief Investigator (Prof Adam Finn) will be
required to ensure that local research approvals have been obtained and that any contractual
agreements required have been signed off by all parties before recr uiting any participants. The CI will
also be required to allow access to study documentation or source data, on the request, for monitoring
visits and audits performed by the Sponsor or any regulatory authority.
10.7 Consent
Consented arm
In line with applicable regulations, consent will be obtained (as specified above) for access to patient
data and to obtain clinical specimens.
Non-Consented arm
In line with applicable regulations, Confidentia lityAdvisory Group approval under Section 251 of the
NHS Act 2006 will be sought to obtain patient records without consent. This will only apply to
individuals who are eligible for the study but who could not be approached to discuss or seek consent
to participate in the consented study . Therefore, Section 251 of the NHS Act will only apply to those
individuals in whom it is not practicable to obtain consent e.g. those who died or were discharged
before the research team could approach them. For participants enrolled in the embedded enhanced
diagnost ic study arm, consent will be obtained for access to patient data. Individuals approached by
the research team to discuss and seek consent for the embedded enhanced diagnostic study will
subsequently fall into three categories:
Those who provide full consent to the study, including access to medical data
Those who provide consent to access to medical data only (and not biological
samples)
Those who decline consent and are not enrolled in the study, and are only noted in
the screening log
10.8 Confidentiality
The Chief Investigator (Prof Adam Finn), Princip alInvestigator (Dr Catherine Hyams) and Sponsor
(University of Bristol )will preserve the confidentiality of participants taking part in the study in
accordance with the Data Protection Act2018 and any other local requirements. Study documentation
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UOB ConfidentialUOB Confidentialand the study database will be anonymised using a unique identification number, generated during
enrolment. No individual participant will be identified in any publications which may arise from this
study.
10.9 Indemnity
The University of Bristol has arranged Public Liability insurance to cover the legal liability of the
University as Research Sponsor in the eventuality of harm to a research participant arising from
management of the research by the Univers ity.
The University of Bristol holds Professional Negligence insurance to cover the legal liability of the
University, for harm to participants arising from the design of the research, where the research
protocol was designed by the University.
The Univers ity of Bristol's Public Liability insurance policy provides an indemnity to our employees for
their potential liability for harm to participants during the conduct of the research.
Equivalent appropriate cover will be in place at all study sites. In additi on, investigators have the
protection of medical malpractice indemnity with the Medical Protection Society or Medical Defence
Union.
10.10 Sponsor
University of Bristol will act as the Sponsor for this study . Delegated responsibilities will be assigned
to the N HS trusts taking part in this study .
10.11 Monitoring
The study may be subject to inspection and audit by University of Bristol (under their remit as Sponsor)
and other regulatory bodies to ensure adherence to GCP and the UK Policy Framework for Health and
Social Care Research .
Monitoring is provided on behalf of University of Bristol by University Hospitals Bristol and Weston
NHS Trust, who are contracted to monitor a sample of 10% of ongoing studies annually.
10.12 Patient expenses
No incentive payment will be made to patients involved in the Avon CAP study.
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UOB ConfidentialUOB Confidential11 Data management
11.1 Data recording, storage and access
Accurate source data will be kept for all study participants. This will typically comprise the standard
demographic information, past medical history, and baseline biochemistry results.
All data will be stored securely in line with the Data Protection Act 2018 and the principles of GCP.
Electronic data will be stored on encrypted and password -protected severs. Physical records, including
consent forms, will be stored in secured and lockable cabinets. In line with local policy for non-CTIMPs,
data from this study will be retained for at least 5 years.
Appropriate Data Protection Impact Assessments will be undertaken as required for the surveillance
study and will be submitted alongside the protocol for review by the HRA and other regulators. All
necessary agreements, including Data Transfer Agreements, will be agreed between the respective
NHS Trusts and University of Bristol. All study sites and the University of Bristol will ensure an accurate
and updated Data Security and Protection Toolkit is available.
11.2 NHS Databases
A site-specific study database will be built within the NHS IT domain at each participating NHS site,
using the REDCap database management software. Study data will be entered by the study team. The
study database will only be accessible to named personnel within the study team using the password-
protected REDCap website. User access privileges will be defined within the REDCap software to
ensure that study staff are assigned an appropriate level of data access, with the minimum amount of
data access required as the default access setting. The REDCap database will be programmed to mark
identifiable fields (and therefore restrict their access or download), and to calculate fields such as
length of hospital admission, survival (up to 30 days following admission), age at admission. These
fields will be exported in the pseudonymised dataset as opposed to the specific date, thereby
removing identifiers and aggregating data.
Before transfer of data to the University IT domain, the study CI, PI or senior research team member
(such as research database manager) will undertake the following activity:
Removal of nam e from any NHS database
Removal of other potentially identifying fields from pseudonymised database (e.g.
date of death, hospital discharge date)
Splitting of the data, resulting in the production of two databases:
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UOB ConfidentialUOB ConfidentialoPseudonymised database containing pseudonymising surveillance number
and clinical data, with calculate fields
oIdentifiable data including NHS number, sector level postcode, ethnicity , date
of birth and admission date
Encryption of data and/or other data protection measures before transfer of data to
the University IT domain, for example use of Open Pseudonymiser.
11.3 University of Bristol Data
Data from each participating NHS Trust will be imported and held in two separate databases:
1.A REDCap database within a secure University IT domain, which contains only pseudonymised
data
2.A password protected database containing identifiable data, with restricted user access on a
bespoke server
This will create a single unifying research dataset, allowing for analysis of data to meet the study
objectives, whilst enabling data security measures to protect data and participants.
Once the data has been pseudonymised, the identifying data will not be utilised unless there is a
specific reason for this being needed (e.g. geotemporal analysis, identifying individuals across multiple
NHS sites). Furthermore, wherever possible data will be processed to the least specific possible in
order to address the research question being investigated –for example, patients will be aggregated
by admission year, month or week of the year, or selected using a random number generator if this is
possible. Ethnicity will be aggregated wherever possible (e.g. BAME, etc.) .
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11.5 Data monitoring
The study may be monitored by the Sponsor or other regulatory bodie s. For the purposes of audit and
compliance monitoring, clinical study data will be available to delegated members of the local study
teams, as well as to representatives of the Sponsor, relevant regulatory authorities, and the study co -
ordinating team. Particip ants in the consented arm will be consented to their study data being
released for this purpose. Pfizer or its agent may conduct visits to the study sites during study conduct
or after study completion to ensure that the protocol and Good Clinical Pr actices (GCPs) and/or Good
Pharmacoepidemiology Practices (GPP), as relevant, are being followed.
11.6 Publication policy
The Chief Investigator will have primary responsibility for the expedient preparation, review and
submission of any manuscripts, abstracts, press releases or other publications detailing the study’s
procedures or findings. We will follow the International Committee of Medical Journal Editors (ICM JE)
criteria to determine authors, and all authors who meet these criteria will be offered authorship. We
anticipate that as a collaborative project, members of each of the study organizations (University of
Bristol and Pfizer) will participate. Each organ ization will determine members that meet authorship
criteria.
Any publication will include a list of investigators, with authors being determined in line with
the ICMJE guidelines, as well as an acknowledgement of roles of the study Sponsor and Funder(s).
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UOB ConfidentialUOB Confidential12 References
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Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid- 19 Vaccine.
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dynam ics of airway pathogens in the aetiology of exacerbations in COPD." Thorax.
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UOB ConfidentialUOB ConfidentialWrapp D, Wang N, Corbett KS, et al. Cryo -EM Structure of the 2019 -nCoV Spike in the Prefusion
Conformation. bioRxiv . Feb 15 2020;doi:10.1101/2020.02.11.944462
Zhang, L., et al. (2018). Clinical and microbiological epidemiology of community acquired pneumonia
in immunocompromised adults .European Congress for Clinical Microbiology and Infectious Diseases
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Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with
Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727 -33.
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UOB ConfidentialUOB ConfidentialAPPENDIX 1 –Description of COVID- 19 vaccine effectiveness assessment
1. Analysis design
A test negative design will be used, with patients iden tified using a clinical case definition (e.g. acute
respiratory infection (ARI)). Patients are then tested for a vaccine aetiologic agent, and VE is estimated
by comparing the odds of vaccination among patients testing positive versus negative for vaccine -type
aetiology. Adjusting can be undertaken for potential confounding factors that may exist in the absence
of randomized participation and blinded follow -up.TND studies are considered a robust type of
observational study for evaluating VE against infecti ous respiratory diseases (De Serres et al 2013,
Jackson et al 2013, Lipsitch et al 2016, Sullivan et al 2014, Foppa et al 2016, Orenstein et al 2007). The
main advantages of the TND are that it helps avoid bias due to (unmeasured) healthcare -seeking
behavi or and its ease of access to a series of controls that are representative of the source population.
Previous research has shown that this simplicity does not necessarily come at the cost of validity (De
Serres et al 2013, Jackson et al 2013, Lipsitch et al2016, Sullivan et al 2014, Foppa et al 2016, Orenstein
et al 2007, Schwartz et al 2017). Full details of these analyses will be outlined in the statistical analysis
plan (SAP), which will include statistical adjustment to control confounding due to age a nd risk -based
vaccination schemas.
2. Defining Cases and Test- Negative Controls
Both cases and controls will only include subjects that meet WHO ARI case definition in Protocol
Section 9.2.4.
2.1 Detection of cases
SARS -CoV-2 will be detected by molecular techniques (i.e. nucleic acid amplification tests, NAAT) from
biological specimens collected from the naso -or oropharynx. This will be undertaken via collection of
results of routine standard -of-care testing or fro m research specimen (if not undertaken by standard-
of-care testing).
Cases will be defined as patients who meet these analysis selection criteria and:
1.Test positive for SARS- CoV-2 via NAAT performed at hospital admission or study enrollment,
OR
2.Tested positive by NAAT from samples collection ≤14 days prior to hospital admission or
study enrollment .
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UOB ConfidentialUOB Confidential2.2 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. This approach mimics the definition of test-negative controls that is commonly used
in TND studies of influenza and pneumococcal vaccines.
3. Prima ry exposure of interest
The primary exposure of interest is history of vaccination with COVID -19 vaccine. As an observational
study design, COVID -19 vaccination is not part of the study procedures, rather it would be given as
part of th e national vaccinati on campaign. The dates of administration and which vaccine was given,
by manufacturer or product, taken from medical records, will be included in the study CRF data.
COVID -19 vaccination status will be also captured as part of the patient interview and wi ll be analyzed
in sensitivity analyses.
For the primary objective, patients will be considered vaccinated if they have documented evidence
of receiving the second dose of COVID -19 vaccine ≥7 days before symptom onset. When evaluating
the effectiveness of one dose of COVID -19 vaccine, patients will be considered vaccinated if they have
documented evidence of receiving the first dose of COVID -19 vaccine ≥14 days before ARI symptom
onset.
Multiple levels of the primary exposure variable will be assessed , including :
1.Fully vaccinated defined as 2 doses of the same COVID -19 vaccine received with ≥7 days
between ARI symptom onset and receipt of the 2nd dose. This group will serve as the
‘exposed’ group evaluated in the primary objective. Patients who received 2 doses of COVID -
19 vaccine with <7 days between ARI symptom onset and receipt of the 2nd dose will be
excluded from this analysis.
2.Partially vaccinated defined as 1 dose (only) of COVID -19 vaccine received with ≥14 days
between ARI symptom onset and recei pt of the 1st dose. This group will serve as the
‘exposed’ group as a secondary endpoint. Patients who received 1 dose of COVID -19 vaccine
with <14 days between ARI symptom onset and receipt of the 1st dose will be excluded from
this analysis.
3.Ever vaccinated defined as 1 or 2 doses of the same COVID -19 vaccine received with ≥14
days between ARI symptom onset and receipt of the 1st dose. Patients who received 1 dose
of COVID -19 vaccine received with <14 days between ARI symptom onset and receipt of the
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UOB ConfidentialUOB Confidential1st dose 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 COVID -19 vaccine. This group will serve as the
reference exposure group (i.e., ‘unexposed’ group) in all VE analyses.
TABLE 1.DEFINITIONS OF STUDY POPULATION ,EXPOSURE ,CASES ,AND TEST -NEGATIVE CONTROLS FO R PRIMARY AND
SECONDARY STUDY OBJE CTIVES
Objective Study Population Exposure* CaseTest- negative
Control
Primary
Objective
(1)patients ≥18 years
of age hospitalized
for ARI Fully vaccinated
defined as 2 doses of the same
COVID -19 vaccine received with ≥7
days between ARI symptom onset
and receipt of the 2nd dose.SARS -CoV-2
identified
by NAATSARS -CoV-2
NOT identified
by NA AT
Secondary Objectives
2patients ≥18 years
of age hospitalized
for ARIPartially vaccinated
defined as 1 dose (only) of COVID -
19 vaccine received with ≥14 days
between ARI symptom onset and
receipt of the 1st dose.SARS -CoV-2
identified
by NAATSARS -CoV-2
NOT identified
by NAAT
3patients ≥18 years
of age hospitalized
for ARIEver vaccinated
defined as 1 or 2 doses of COVID -
19 vaccine received with ≥14 days
between ARI symptom onset and
receipt of the 1st dose.
NAAT= nucleic acid amplification test; SARS -CoV- 2= severe acute respiratory syndrome coronavirus 2.
* Patients who never received COVID -19 vaccine will serve as the reference exposure group (i.e., ‘unexposed’
group) in all VE analyses. For the primary obj ective, patients will be considered vaccinated if they have
documented evidence of receiving the second dose of COVID -19 vaccine ≥7 days before ARI symptom onset.
When evaluating the effectiveness of one dose of COVID -19 vaccine, patients will be considere d vaccinated if
they have documented evidence of receiving the first dose of COVID -19 vaccine ≥14 days before ARI symptom
onset.
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UOB ConfidentialUOB ConfidentialReferences for Appendix 1:
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vaccine efficacy estimates compared to the gold standard of randomised placebo -controlled clinical trials. Euro
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Foppa IM, Ferdinands JM, Chaves SS, et al. The case test -negative design for studies of the effectiveness of
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Orenstein EW, De Serres G, Haber MJ, et al. Methodologic issues regarding the use of three observational
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doi:10.1586/14760584.2014.96669
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