Low Intervention Study of the Effectiveness Of 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Against Vaccine Type Pneumococcal Hospitalised Community Acquired Pneumonia (CAP) in Adults 60 Years and Older Using A Test Negative Design Study in A Well-Defined Area of the South of Madrid Region
Conditions: Community Acquired Pneumonia (CAP)
Sponsor: Pfizer

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Study Information
Title
A Low Intervention Study of the Effectiveness Of
13-Valent Pneumococcal Conjugate Vaccine (PCV13)
Against Vaccine Type Pneumococcal Hospitalised
Community Acquired Pneumonia (CAP) in Adults
60 Years and Older Using A Test Negative Design Study
in A Well-Defined Area of the South of Madrid Region
Study Phase
Not applicable
Protocol number
B1851202
Protocol version identifier
V3.0
Date
03 February 2022
Research question and 
objectives
To determine the effectiveness of PCV13 to prevent 
hospitalised vaccine-type (VT)-pneumococcal CAP
among adults aged 
test-negative design study, overall and among
immunocompetent persons only
Authors
Pfizer S.L.U
Avenida de Europa, 20-B
Parque Empresarial La Moraleja 
28108 Alcobendas (Madrid) Spain 
Phone numbers:
E-mail address:
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing,
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................................... 3 
LIST OF FIGURES ................................................................................................................................... 4 
1. 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
2. 
RESPONSIBLE PARTIES COUNTRY COORDINATING INVESTIGATORS ...................... 7 
3. 
SUMMARY ................................................................................................................................. 7 
4. 
AMENDMENTS AND UPDATES ........................................................................................... 13 
5. 
MILESTONES ........................................................................................................................... 16 
6. 
SCHEDULE OF ACTIVITIES .................................................................................................. 16 
7. 
RATIONALE AND BACKGROUND ...................................................................................... 19 
8. 
RESEARCH QUESTION AND OBJECTIVES ........................................................................ 24 
9. 
RESEARCH METHODS .......................................................................................................... 27 
9.1. Study Design .................................................................................................................................... 27 
10. 
STUDY PROCEDURES ............................................................................................................ 33 
10.1. 
Surveillance Process .................................................................................................................. 33 
10.2. 
Screening/Enrolment Log .......................................................................................................... 34 
10.3. 
Visit 1 Day 1 (Screening/Enrolment) ......................................................................................... 35 
10.4. 
Visit 2 Day 30 (Final Diagnosis and Event Outcome) ............................................................... 39 
10.5. 
Visit 3 Day 180 (Vital Status Assessment) ................................................................................. 41 
11 
ASSESSMENTS ........................................................................................................................ 41 
11.1. Additional Research ....................................................................................................................... 41 
11.2 
. Biological Samples ................................................................................................................... 42 
11.3 
. Imaging Assessments - Chest Radiography ............................................................................. 46 
12. 
DATA ANALYSIS/STATISTICAL METHODS ..................................................................... 46 
12.1. 
Study Size ................................................................................................................................... 46 
12.2. 
Data Management ...................................................................................................................... 53 
12.3. 
Case Report Forms/Data Collection Tools/Electronic Data Record ......................................... 54 
12.4. 
Data Analysis ............................................................................................................................. 55 

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12.5. 
Interim Analysis ......................................................................................................................... 57 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................... 57 
14. 
LIMITATIONS OF THE RESEARCH METHODS ................................................................. 58 
15. 
PROTECTION OF HUMAN SUBJECTS................................................................................. 58 
15.1. 
Patient Information and Consent ............................................................................................... 58 
15.2. 
Patient Withdrawal..................................................................................................................... 59 
15.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .................................... 60 
15.4. 
Ethical Conduct of the Study ...................................................................................................... 60 
16. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS (AEs)/ADVERSE  
REACTIONS ............................................................................................................................. 60 
16.1. 
Adverse Events ........................................................................................................................... 62 
16.2. 
Research-Related Injury (RRI) ................................................................................................... 63 
16.3. 
Reporting of Selected Exposures and AEs Related to Pfizer Products ...................................... 63 
16.4. 
Definition of Serious Adverse Events (SAEs) ............................................................................. 64 
16.5. 
Selected Exposures to Pfizer Product that Require Reporting to Pfizer Safety ......................... 64 
17. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ................ 65 
17.1. 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ........................ 65 
17.2. 
Publications by Investigators ..................................................................................................... 65 
18. 
REFERENCES ........................................................................................................................... 67 
19. 
LIST OF TABLES ..................................................................................................................... 70 
20. 
LIST OF FIGURES .................................................................................................................... 70 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ........................................................................ 70 
ANNEX 2. ADDITIONAL INFORMATION ........................................................................................ 70 
 
LIST OF TABLES 
 
Table 1. 
 Pneumococcal Adult Vaccination in Madrid as of January 2018 ....................................... 22 
Table 2. 
PCV13 and PPV23 Uptake in Madrid Region Per Age (September 2019) ........................ 23 
Table 3.       
 ..................... 29 
Table 4. 
Incidence of Hospitalised Pneumonia Cases in Adults 60 Years and Older ....................... 48 

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Table 5. 
Codes for Hospitalised Pneumonia Under ICD-10 ............................................................. 49 
Table 6. 
Sample Size Scenarios for VE Calculations At Interim ...................................................... 50 
Table 7. 
Categorization of Risk Factors by Immunocompetence3 .................................................... 52 
Table 8. 
Summary of Study AE Reporting Requirementsa ............................................................... 60 
LIST OF FIGURES 
Figure 1. 
Map of Study Locality ........................................................................................................ 27 

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1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
CAP 
Community Acquired Pneumonia 
CAPA 
Acronym for an epidemiological study assessing the burden of 
hospitalised community-acquired pneumonia (CAP) due to 
Streptococcus pneumoniae in adults in Spain using urinary antigen 
detection (UAD) testing 
CAPITA 
Community-acquired Pneumonia Immunisation Trial in Adults 
CDC 
United States Centres for Disease Control and Prevention 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CRB-65 
Confusion Urea Respiratory Rate Blood Pressure 
CST 
Clinical Study Report 
CT 
Computed Tomography 
CXR 
Chest X-ray 
eCRF 
Electronic Case Report Form 
FiO2 
Fraction of inspired Oxygen 
FSFV 
First Subject First Visit 
ICD 
International Disease Classification 
ICU 
Intensive Care Unit 
IEC 
Independent Ethic Committee 
ID 
Identification 
IPD 
Invasive Pneumococcal Disease 

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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ISCIII 
Instituto de Salud Carlos III 
LSLV 
Last Subject Last Visit 
OR 
Odds Ratio 
PCR 
Polymerase Chain Reaction 
PCL 
Pfizer Central Laboratory 
PCV13 
13-valent Pneumococcal Conjugate Vaccine 
PCV20 
20-valent Pneumococcal Conjugate Vaccine 
PI 
Principal Investigator 
PPV23 
23-valent Pneumococcal Polysaccharide Vaccine 
PSI 
Pneumonia Severity Index 
RIP 
Regional Immunisation Program 
RL 
Reference Laboratory 
RRI 
Research Related Injury 
RSV 
Respiratory Syncytial Virus 
SISPAL 
 Información en Salud Pública y Alimentación  (in Spanish) 
SP 
Streptococcus pneumoniae, S. pneumoniae 
SpO2 
Oxygen saturation level 
SOC 
Standard Of Care 
TND 
Test Negative Design 
UAD 
Urinary Antigen Detection 
US 
United States 
VE 
Vaccine Effectiveness 
VT 
Vaccine Type 

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2. RESPONSIBLE PARTIES COUNTRY COORDINATING INVESTIGATORS
Name, 
degree(s)
Job Title
Affiliation
Address
Jose Yuste, PhD Head of Department
Pneumococcal 
Reference 
Laboratory
Centro Nacional de 
Microbiología, Instituto de 
Salud Carlos III (ISCIII)
Juan Emilio 
Losa, MD, 
PhD
Head of Infectious
Disease Department
Department of 
Internal Medicine
Hospital Universitario 
Fundación Alcorcón,
Alcorcón (Madrid)
Victor Moreno,
MD
Head of Internal 
Medicine Department
Department of 
Internal Medicine
Hospital Universitario de 
Móstoles, Móstoles (Madrid)
Teresa Álvarez 
de Espejo, MD,
PhD 
Assistant Medicine 
Doctor
Department of 
Internal Medicine
Hospital Universitario Rey 
Juan Carlos, Móstoles 
(Madrid)
3. SUMMARY
A Low Intervention Study of the Effectiveness Of 13-Valent Pneumococcal Conjugate
Vaccine (PCV13) Against Vaccine Type (VT) Pneumococcal Hospitalised Community
Acquired Pneumonia (CAP) in Adults 60 Years and Older Using A Test Negative 
Design Study (TND) in A Well-Defined Area of the South of Madrid Region.
Version 3.0, dated 03 February 2022.
Main author:
, Pfizer S.L.U, Spain.
Rationale and background 
The approval of the 13-valent pneumococcal conjugate vaccine (PCV13) for both adults 
and children offers the opportunity to prevent pneumococcal disease in the two groups of
population with highest incidence rates, namely children <5 years of age and the elderly.
In the Community of Madrid, PCV13 is recommended and reimbursed for all adults over

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60 years of age not previously vaccinated with 23-valent pneumococcal polysaccharide 
vaccine (PPV23) nor PCV13 since January 2018.  For this age group a single dose of 
PCV13 is recommended. In addition, it is recommended that 
 years with a 
chronic disease such as Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart 
failure, regardless of previous vaccination status, will receive one dose of PCV13.  
Sequential immunisation with both vaccines (PCV13+PPV23) is recommended for high-
risk immunocompromised patients 
 years of age.  This recommendation is supported 
by results of the CAPA study (Epidemiological study assessing the burden of hospitalised 
community-acquired pneumonia [CAP] due to Streptococcus pneumoniae (SP) in adults 
in Spain using urinary antigen detection [UAD] testing) that showed a significant 
proportion (9%) of hospitalised all-cause CAP cases were caused by PCV13 serotypes in 
adults 18 years and older.1 
The paediatric heptavalent pneumococcal conjugate vaccine (PCV7) was first available in 
Spain in June 2001 and incorporated in the Madrid regional immunisation programme (RIP) 
in 2006, remaining in the private market for other regions. From mid-2010 through 2016, 
Spanish regions introduced the 13-valent conjugate vaccine (PCV13) in their RIPs. 
Adult vaccination with the 23-valent polysaccharide (PPV23) officially started in 2004, and 
with PCV13 in 2016 for some cohorts. Most adult pneumococcal vaccination occurs during 
annual influenza vaccination campaigns. Pneumococcal vaccination for adults in the Madrid 
region changed as of January 2018.  An overview of pneumococcal adult vaccination is 
described in Table 1. 
Note that for persons 
 years with past PPV23 administration, only those with underlying 
disease or at high risk will be given PCV13, and others without risk factors will not receive 
another pneumococcal vaccination (Table 1).  
 years age group, the 
population with PCV13 will be enriched for those with risk factors, and this will need to be 
accounted for in the analysis as a source of confounding (ie, confounding by indication). 
Current PCV13 and PPV23 average uptake in Madrid Region as of March 2019 is 
described in Table 2, with a peak for PCV13 in people of 63 years old (see Table 2). People 
of over 60 years in the whole of Madrid region are 1,511,750 as of January 2018 (Instituto 
Nacional de Estadística, INE, www.ine.es). 
The Regional Health System 
 en Salud 
Pública y 
(SISPAL) [in English 
 System for Public Health and 
 which includes information on previous vaccination history, including influenza, 
PPV23 and PCV13 vaccination, with lot number and date of administration per person. 
Pneumococcal vaccination status will be based on whether receipt of 
 
PPV23 could be confirmed by electronic registries. All available vaccination data will be 
collected from the registry on subjects and time from vaccination will be incorporated in the 
analysis phase.  Patients will be included regardless of the timing of their vaccination relative 
to their qualifying pneumonia admission but will be excluded from vaccine effectiveness 

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(VE) and serotype distribution analysis if they received pneumococcal vaccination 
days
before hospitalisation for CAP because of risk of false positive UAD test. We will obtain 
previous influenza vaccination status (within the last year) via electronic registries as well.
Respiratory syncytial virus (RSV) has long been recognized as a problematic respiratory 
pathogen causing illness in children, but the scope and impact of RSV in adults is less well-
defined.  Severe disease occurs especially among those with compromised cardiac, pulmonary, 
or immune systems and in the elderly but estimates of the RSV disease burden requiring 
hospitalization in adults are limited.   Previous studies have suggested that up to 10% of adults 
presenting with acute respiratory illness during the winter have RSV. Further, Pfizer is 
.

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Research question and objectives  
 
Primary Objective 
 
To determine the effectiveness of PCV13 to prevent hospitalised VT-pneumococcal 
 years in Madrid using a TND, overall and among 
immunocompetent persons only. 
 
Secondary Objective(s) 
To describe the distribution of SP serotypes using blood, high-quality respiratory 
cultures, and a serotype-specific UAD assay among adults 60 years of age and older 
with CAP. 
To determine the proportion of persons with respiratory pneumococcal carriage 
among adults 60 years of age and older presenting with CAP by testing saliva 
specimens using both conventional culture and the sensitive molecular method of 
polymerase chain reaction (PCR) for the detection of two target genes (lytA and ply). 
To describe the proportion of participants with CAP and with S. pneumoniae ( 
SP+CAP) who present with underlying at-risk and high-risk medical conditions. 
To describe the frequency and type of antibiotic resistance among SP isolates, overall 
and by specimen type. 
Exploratory Objectives 
To estimate incidence rates for hospitalised CAP and SP+CAP (both overall and 
radiologically confirmed) in the surveillance region within the limitations of the 
expected under ascertainment of hospital-based screening process and current 
diagnostic testing. 
To compare the effectiveness of PPV23 to that of PCV13 in preventing cases of 
hospitalised VT-
 years using a test- 
negative study design, overall and among immunocompetent persons only. 
To compare pneumococcal serotype results from high-quality respiratory specimens 
(standard of care), UAD1/2 (study procedure), and saliva specimens taken for 
carriage testing (study procedure). 
To estimate incidence rates for hospitalised CAP among adults aged 
 years with 
underlying at-risk and high-risk medical conditions, in aggregate and for individual 
risk conditions within the limitations of the expected under ascertainment of hospital- 
based screening process and current diagnostic testing. 

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Additional 2019 Novel Coronavirus Disease 2019 (COVID-19)-related Exploratory 
Objectives 
To determine if the frequency of pneumococcal infection differs between hospitalised 
CAP patients with COVID-19 infection compared to those without COVID-19 
infection, overall and stratified by age, sex, and pneumococcal risk status. 
Among the subset of hospitalised CAP patients with COVID-19 identified, to 
determine if the proportion who experience severe clinical outcomes (eg, intensive 
care unit [ICU] stay, mechanical ventilation, prolonged hospitalisation, and 
sequelae) differs between those with pneumococcal co-infection compared to those 
without pneumococcal co-infection, overall and stratified by age, sex, and 
pneumococcal risk status. 
Using a test-negative design to determine the VE of PCV13 against severe COVID-
19 clinical outcomes among COVID-19 positive hospitalised CAP patients, overall 
and among immunocompetent persons only. 
To assess if pneumococcal carriage differs for those with current or past COVID-
19 infection, overall and stratified by age, sex, and pneumococcal risk status. 
 
Additional 2022 Respiratory Syncytial Virus (RSV) Exploratory Objective 
 
To determine the proportion of persons with RSV infection among adults 60 years 
of age and older presenting with CAP by testing saliva specimens using the PCR 
method. 
Study design 
This study is a low interventional, prospective, multicentre, hospital-based study involving 
adults 60 years of age and older hospitalised with CAP at participating sites. Hospital 
surveillance data will be used for incidence rates calculations. Vaccine effectiveness will be 
calculated using a TND. The approximate study duration will be 4 years.  
 
Population 
This study will prospectively enroll adults, aged 60 years and over, who are hospitalised 
with CAP in one of the study hospitals: Hospital Universitario de Móstoles, Hospital 
Universitario Fundación de Alcorcón, and Hospital Rey Juan Carlos de Móstoles (as of 
February 2022, additional sites may be included at a later date). 
Variables 
Please see Section 10 for full listing.  In summary, the screening step will collect 
demographic information, eligibility for the study, whether consented, any standard of care 

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(SOC) test results.  If consent is given, then further data collection and enrolment would 
include: medical and vaccination history, smoking and alcohol use, details of current illness 
including all symptoms, treatment, severity score, vital signs and test results. 
At follow up, confirmation of CAP or alternative diagnosis, event disposition and vital status 
would be recorded at two visits: 30 and 180 days after hospital admission. 
 
Data sources 
Data will be collected from the hospital, including radiology and laboratory results, as well 
as primary care medical records. 
Study size 
The required sample size depends on the accrual of immunocompetent VT-CAP cases, the 
VE point estimate, percentage of individuals vaccinated, as well as other factors.  Based on 
current estimates, the overall number of subjects to be enrolled is expected to be between 
2,000 and 5,500 and required time for enrolment will be between 1.7 and 4 years, depending 
on the values for the parameters mentioned above and enrolment rates. See Section 12.1.2 
for full information on these calculations. As the required number of enrolled subjects is 
highly dependent on the proportion of CAP subjects that have VT pneumococcal CAP and 
the proportion of the population vaccinated, the required sample size may be adjusted based 
on ongoing information from UAD testing results and vaccine exposure data if needed. An 
interim analysis will be conducted after accrual of 170 VT-cases but, given additional 
subjects may be needed to allow for adequate statistical power, at least 4 years of enrolment 
is planned. 
Data analysis 
Vaccine Effectiveness will be calculated as follows.  Odds of having received PCV13 for 
cases and controls will be constructed and compared using odds ratios (OR) and 95% 
Confidence interval (CIs).  We will calculate VE as 1-OR x 100.  In addition to constructing 
crude OR and VE estimates, we will also perform propensity score matching cases and 
controls using potentially confounding factors for VE, and then construct a conditional 
logistic regression to assess PCV13 and PPV23 VE.  For the other study objectives, 
descriptive analysis will be carried out, presenting the absolute and relative frequencies of the 
qualitative variables and the main measures of centralization and dispersion in case of 
quantitative variables. CAP incidence rates per 100,000 inhabitants of the study age group 
will be assessed based on CAP events captured on screening log during the recruitment 
period in the participating sites.  Methodologies for the statistical analyses of the data 
collected in this study are outlined here and will be provided in detailed in the full study 
protocol and statistical analysis plan (SAP). 

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Milestones 
Milestone 
Planned date 
Completion of feasibility assessment 
Q2 2020 
Start of data collection, First Subject First 
Visit (FSFV)
March 2021 
End of data collection, Last Subject Last 
Visit (LSLV) 
Q1 2025 
Interim analysis 
After approximately 170 immunocompetent VT- 
CAP cases available for analysis [~Q2 2022]
Study results 
Q2 2025 
Final study report 
Q3 2025 
4. AMENDMENTS AND UPDATES 
Document History 
Document 
Version 
Date 
Substantial or 
Administrative 
Amendment 
Protocol section(s) 
changed 
Rationale 
Original 
protocol 
26 May 
2020 
 
 
Not applicable 
 
(N/A) 

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Amendment 
1 
13 April 
2021 
Substantial 
amendment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol authors: 
Information about the 
authors is updated 
 
-Section 2: the name of 
the principal 
investigators and sites 
participating in the study 
is updated. 
 
 
- Section 3: Update of 
version and authors and 
errata correction. 
 
 
- Section 5: Update of 
study milestones dates. 
 
- Section 6, 7, 8: errata 
correction. 
Changes in personnel 
responsible for the study 
Change of participating 
site: Hospital de 
Fuenlabrada is replaced 
by a new site, Hospital de 
Móstoles 
Updated timelines, taking 
into account the actual 
start date of the study. 

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- Section 9: Update of 
data for the new 
participating site and 
update of population 
data for both sites. 
 
 
 
 
 
 
-Section 9.1.1 
Inclusion criteria 
wording, modified to 
the designated 
surveillance area of 
participating hospitals.
 
- Section 10.2 
Vaccination history. 
 
- Section 10.3 and 10.4 
Visit 2 and 3. 
 
-Section 12.1.2. Erratum
correction. 
 
-References: Update 
reference 12.
Inclusion of new site with
updated population data. 
Data are also updated 
with the available figures 
as of 2021 for the 
previous site, to 
homogenize the sources 
of information in the two 
participating sites. 
Replacement of Hospital 
de Fuenlabrada with a 
new site, Hospital de 
Móstoles. 
Update to include COVID 
vaccination. 
Detail cause of death. 
Updated reference for 
latest population figures. 
Amendment 
2 
03 Feb 2022 Substantial 
amendment 
Protocol authors: 
Information about the 
authors  contact details 
is updated. 
 
-Section 2: the name of 
the principal 
investigators and sites 
participating in the study 
is updated. 
 
 
- Section 3: Update of 
study version. 
Changes in personnel 
responsible for the study.
Addition of one new 
participating site: 
Hospital Universitario 
Rey Juan Carlos de 
Móstoles in order to 
increase recruitment. 

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-Section 7. Rationale for 
the addition of 
Respiratory Syncytial 
Virus (RSV) testing. 
 
- Section 8: Update of 
exploratory objectives. 
 
 
 
 
 
- Section 9: Update of 
data for the new 
participating site. 
 
- Section 9.1.1: 
Deletion of inclusion 
criterion #4. 
 
 
 
-Section 10. Study 
procedures first 
paragraph deleted. 
 
-Section 10.2: Addition 
of RSV vaccination 
history. 
 
-Minor wording and 
grammatical changes.
Addition of RSV testing. 
 
 
Inclusion of new 
exploratory objective: 
RSV PCR testing in 
saliva samples collected 
for pneumococcal testing.
Inclusion of new site. 
 
 
 
Residents and non-
geographical catchment 
area will be included to 
increase enrolment. 
 
It was repeated. 
 
 
 
Control of confounding. 
5. MILESTONES 
Milestone 
Planned date 
Completion of feasibility assessment 
Q2 2020 
Start of data collection (FSFV) 
March 2021 
End of data collection (LSLV)
Q1 2025
Interim Analysis 
After approximately 170 immunocompetent VT-CAP 
Study results 
Q2 2025 
Final study report 
Q3 2025 
6. SCHEDULE OF ACTIVITIES 
Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed 

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information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
schedule of activities table (and record this information in repeating forms within Visit 1) in 
order to conduct evaluations or assessments required to protect the well-being of the subject. 
Procedure/Assessment 
Visit 1 Day 1h 
Visit 2 Day 30 
Visit 3 Day 180 
Visit Window 
Within 48 hours of 
admissiona 
30 to 45 days after 
admissionb 
180 to 195 days after 
admission 
Setting 
In person 
Telephone calla and/or 
medical record review 
Telephone call and/or 
medical record review 
Verification of inclusion/exclusion 
criteria 
X 
Informed Consent 
X 
Demographics 
X 
Behavioural factors considered 
potential risks for disease 
X 
Antibiotic treatment within 14 days 
prior to admission 
X 
Specific Medical History 
X 
Details of current illness 
X 
CRB-65 score Pneumonia Severity 
Index score 
X 
Healthcare facility exposure in past 
3 months 
X 
 
 
Charlson Comorbidity Index data 
 
 
Xg 
Record results of SOC tests 
X 
 
 
Record results of SOC 
pneumococcal, Coronavirus disease 
2019 (COVID-19) and RSV testing 
X 
Xd 
 
Record hospitalisation-related data 
including vital signs 
X 
Xe 
 
Urine samplec 
X 
 
 
Saliva sample (selected sites) 
X 
 
 
Pneumococcal Conjugate Vaccine 
vaccination record 
X 
 
 
23-valent Pneumococcal 
Polysaccharide Vaccine (PPV23) 
vaccination record 
X 
 
 

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Procedure/Assessment 
Visit 1 Day 1 
Visit 2 Day 30 
Visit 3 Day 180 
Visit Window 
Within 48 hours of 
admissiona 
30 to 45 days after 
admissionb 
180 to 195 days after 
admission 
Setting 
In person 
Telephone calla and/or 
medical record review 
Telephone call and/or 
medical record review 
Influenza and RSV vaccination 
record 
X 
Final diagnosis for event 
X 
Selected adverse event monitoringf 
X 
X 
X 
Vital Status 
X 
X 
a. Participants should ideally be enrolled as soon as feasible (ie, within 24 hours of admission on normal weekdays) but 
may be enrolled later if admitted on the weekend and/or if person cannot consent during that time period (eg, if 
intubated). 
b. Visit 2 may be performed in person in lieu of a telephone call if patient being seen at study hospital for standard of care 
visit. 
c. If subject readmitted within 14 days of the qualifying hospitalisation, that follow up hospitalisation will be considered 
part of the same event as the initial hospitalisation.  An additional urine sample will be taken upon readmission. 
d. Any additional results from standard of care pneumococcal and viral respiratory testing, including COVID-19 and 
RSV, not captured during Visit 1 Day 1 could be recorded at Visit 2 Day 30 (and data can be entered on Visit 1 
eCRF). 
e. Any additional information on hospitalisation data electronic case report form (eCRF) items not captured during Visit 
1 Day 1 could be recorded at Visit 2 Day 30. 
f. Please see full details of which adverse events to record in Section 16 Table 8. 
g. Information to calculate Charlson Comorbidity Index (CCI) will be collected. Diagnosis codes such as International 
Classification of Diseases (ICD) discharge codes may be provided as a separate file linked by participant number to 
calculate CCI or data will be collected via eCRF at Day180 or prior visit. 
h. SOC assessments (for example, details of current illness, vital signs, radiology exams, microbiological testing and 
others) could be performed before hospital admission or enrolment (Date of Visit) and captured in eCRF. 

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7. RATIONALE AND BACKGROUND 
The Madrid health authority has recommended the administration of 13-valent pneumococcal 
conjugate vaccine (PCV13) in the adult population.  This has provided the opportunity to 
maximize the benefit of pneumococcal vaccination in preventing pneumococcal disease in 
the population groups with highest incidence rates, children <5 years of age and the elderly.2 
The effectiveness of PCV13 in preventing both invasive and non-invasive pneumococcal 
disease (IPD) has been demonstrated in children in different countries.3,5   PCV13 efficacy for 
the prevention of vaccine-type community-acquired pneumonia (VT-CAP) and IPD was 
established in the Community-acquired Pneumonia Immunisation Trial in Adults (CAPITA) 
aged 65 and older.6   However, there are still few available real-life effectiveness estimates in 
adults. 
As a result of the CAPITA trial and the evidence that despite herd protection induced by the 
PCV13 infant vaccination program in the United States (US) roughly 10% of all adult CAP 
was still caused by PCV13 serotypes, in September 2014 the US Centres for Disease Control 
and Prevention (CDC) Advisory Committee on Immunisation Practices revised their 17-year-
old pneumococcal vaccination recommendation for older adults to include PCV13 use for all 
adults aged 
 years.  A recent study in the US evaluating the real-life effectiveness of 
PCV13 in adults over 65 to prevent CAP has shown a 72.8% effectiveness to prevent VT-
CAP in this population. This study was done using a test-negative design.7 
The paediatric heptavalent pneumococcal conjugate vaccine (PCV7) was first available in 
Spain in June 2001 and incorporated in the Madrid  RIP in 2006, remaining in the private 
market for other regions. From mid-2010 through 2016, Spanish regions introduced the 13-
valent conjugate vaccine (PCV13) in their RIPs. 
PCV13 was introduced in Spain in June 2010 for immunisation of healthy children but, in 
contrast to most European countries, it was not included into the national immunisation 
programmes and was given only when funded by parents until 2015 2016, except in two 
Regions, Madrid and Galicia (into the national immunisation programsince June 2010 and 
January 2011, respectively). 
In the Community of Madrid, PCV13 replaced the 7-valent (PCV7) in the fully 
government-funded RIP in May 2010 (2+1 schedule), but was later on excluded in May 
2012 and reintroduced into the RIP in March 2015 for infants born after January 2015 
(including catch-up doses for children following vaccination programmes that had already 
started).8   Vaccine uptake reached 95% in periods with public-funded pneumococcal 
vaccination but fell to 67% in the only private funding period.8 Overall, incidence rates 
(IR) of IPD in children less than 15 years of age decreased by 70% (p<0.001) in 2016 
compared to the PCV7 period (2007-2010), due to 91% reduction in the IR of PCV13-type 
IPD (p<0.001).8   Following universal vaccination with PCV7/PCV13 in infants in the 
Community of Madrid, the IR of PCV7-type IPD in adults 60 years and older significantly 
decreased by 61% in 2013-2015 (IR: 1,25 per 105) compared to the PCV7 period (2008-
2010, IR: 2.07 per 105) and also PCV13-non PCV7 type IPD by 47% (p<0.05; 2013-2015 

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IR: 3.45 per 105 vs 7.33 per 105 in 2008-2010).9   IPD caused by serotype 3 was the second 
most prevalent serotype among all IPD cases (2013-2015 IR: 1.61 per 100,000 
population).9   No significant changes in the overall IPD in 60 years and older were 
observed (2013 2015 IR: 17.09 per 105 vs 17.97 per 105 in 2008-2010). The incidence of 
IPD due to serotypes 8, 9N, 10A, 23B and 24F significantly increased in the 2013-2015 
period. Serotypes 8 and 9N accounted for 51% in the population aged 5 to 59 years and 
serotypes 8 and 22F for 25% in the population aged 60 years and older.9   Similar trends were 
observed in 2017 with an overall IPD incidence rate in adults 65 years and older of 26.45 
cases per 105 inhabitants.10 
Adult vaccination with the 23-valent polysaccharide (PPV23) officially started in 2004, and 
with PCV13 in 2016 for some cohorts. Most adult pneumococcal vaccination occurs during 
annual influenza vaccination campaigns. 
In January 2018, the new recommendations and funding for PCV13 that were approved in the 
Community of Madrid, confirmed that all adults over 60 years of age not previously 
vaccinated either with PPV23 or PCV13, should receive one dose of PCV13 and those over 
18 years with a chronic disease such as Chronic Obstructive Pulmonary Disease (COPD), 
diabetes, heart failure, regardless of previous vaccination status, should receive one dose of 
PCV13. Sequential immunisation with both vaccines (PCV13+PPV23) was recommended for 
adults with high risk immunocompromising conditions.11    This recommendation was based 
on the burden of non- bacteraemic CAP in adults and the assumption based on the CAPA 
study (Epidemiological study assessing the burden of hospitalised CAP due to Streptococcus 
pneumoniae in adults in Spain using UAD testing) that there is still a significant burden due 
to PCV13 serotypes among all hospitalised CAP in adults 18 years and older (9%).1   As of 
September 2019, 
around 8% of adults 60 years and older have been vaccinated with PCV13 (Table 3), 
this proportion is expected to increase in the following months/years. 
The Regional Health System operates a database known as SISPAL which includes 
information on previous vaccination history, including influenza, PPV23 and PCV13 
vaccination with lot number and date of administration per person. Pneumococcal 
vaccination status will be based on whether receipt of 
 dose of PCV13 or PPV23 could be 
confirmed by electronic registries. We will obtain previous influenza vaccination status 
(within the last year) via electronic registries as well. 
The aim of this study is to evaluate the PCV13 VE against hospitalised VT-pneumococcal 
CAP among adults 
 years in the Community of Madrid (total population as of 
January 2018) of 6,578,079 inhabitants, of which 1,511,750 were aged 60 years and 
older).12 
 
Rationale for the addition of Respiratory Syncytial Virus (RSV) testing 
 
Respiratory syncytial virus has long been recognized as a problematic respiratory pathogen 
causing illness in children13, 14, 15  but the scope and impact of RSV in adults is less well-

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defined.  Severe disease occurs especially among those with compromised cardiac, pulmonary, 
or immune systems and in the elderly16,17,18,19,20 but estimates of the RSV disease burden 
requiring hospitalisation in adults are limited.   Previous studies have suggested that up to 10% 
of adults presenting with acute respiratory illness during the winter have RSV.21,22,23,24,25
Further, Pfizer is 
.
1 Data stemming from the SISPAL system, directly communicated by the Regional Health Authority.

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Table 1.
Pneumococcal Adult Vaccination in Madrid as of January 2018
Age group
New schedule
What was administered
before 2018?
Without previous 
vaccination
years without risk 
factors
PCV13
PPV23
(except birth cohorts
1956 57: 
PCV13+PPV23)
Adults 
years) with
underlying disease
PCV13
PPV23
+
Revaccination at 60 years
Persons of any age and
high risk
PCV13+PPV23
(8 weeks apart)
+
Revaccination in
5 years with PPV23
PCV13+PPV23
+
Revaccination in 5 years
with PPV23
With previous
vaccination (at least
1 dose of PPV23)
PCV13 (at least
1 year apart)
PCV13 (at least
1 year apart)
+
Revaccination in
5 years with PPV23

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Table 2. 
PCV13 and PPV23 Uptake in Madrid Region Per Age (September 2019) 
Age 
PCV13 
PPV23 
Cohort size 
60 
7.43% 
6.18% 
73,865 
61 
15.40% 
8.67% 
71,294 
62 
23.58% 
19.17% 
67,364 
63 
25.72% 
27.39% 
67,235 
64 
11.34% 
36.99% 
66,110 
65 
11.71% 
43.03% 
62,288 
66 
12.16% 
45.89% 
61,535 
67 
11.17% 
47.46% 
63,514 
68 
10.56% 
47.66% 
66,411 
69 
11.50% 
60.02% 
59,676 
70 
12.97% 
71.83% 
55,635 
71 
13.09% 
63.87% 
57,778 
72 
11.61% 
67.09% 
55,496 
73 
11.89% 
75.37% 
53,122 
74 
14.31% 
88.89% 
44,381 
75 
15.70% 
94.90% 
39,960 

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8. RESEARCH QUESTION AND OBJECTIVES 
Primary Objective(s): 
Primary Endpoint(s): 
To determine the effectiveness of PCV13 to 
prevent hospitalised vaccine-type (VT)-
 
years in Madrid using a test- negative design
study, overall and among immunocompetent
persons only. 
VE calculated as 1 minus the OR 
comparing the odds of having received
PCV13 for cases and controls, 
multiplied by 100%, overall and 
restricted to immunocompetent 
subjects only. 
Secondary Objective(s): 
Secondary Endpoint(s): 
To 
describe 
the 
distribution 
of 
S. 
pneumoniae serotypes using blood, high-
quality respiratory cultures, and a serotype-
specific urinary antigen detection (UAD) 
assay among adults 60 years of age and 
older with CAP. 
Proportion of CAP events for each 
pneumococcal serotype, PCV-13, and 
20-valent pneumococcal conjugate 
vaccine (PCV20) serotypes among all 
CAP subjects with UAD1/2 testing 
(overall) and among all CAP subjects 
with a pneumococcus identified. 
To determine the proportion of persons with 
respiratory pneumococcal carriage among 
adults 60 years of age and older presenting 
with CAP by testing saliva specimens using 
both conventional culture and the sensitive 
molecular method of PCR for the detection 
of two target genes (lytA and piaB). 
Proportion of CAP events where the 
pneumococcus was identified from 
saliva by culture or PCR divided by all 
CAP events where the subject had a 
valid saliva specimen test result. 
To describe the proportion of participants 
with CAP and with SP+CAP who present 
with underlying at-risk and high-risk medical
conditions. 
Proportion of CAP subjects with 
underlying at-risk and high-risk 
medical conditions, overall and 
restricted to those with pneumococcus 
isolated from blood, high-quality 
respiratory cultures, and a serotype- 
specific UAD assay. 
To describe the frequency and type of 
antibiotic resistance among S. pneumoniae 
isolates, overall and by specimen type. 
Proportion of S. pneumoniae isolates 
with antibiotic resistance identified by 
SOC testing, overall and by resistance 
type. 

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Exploratory Objectives 
Exploratory Endpoints 
To estimate incidence rates for hospitalised 
CAP and SP+CAP (both overall and 
radiologically confirmed) in the surveillance 
region within the limitations of the expected 
under ascertainment of hospital-based 
screening process and current diagnostic 
testing. 
Number of CAP events identified by 
screening log divided by number of 
 years in surveillance 
region. 
To compare the effectiveness of PPV23 to 
that of PCV13 in preventing cases of 
hospitalised VT- pneumococcal CAP among
 years using a test-negative 
study design, overall and among 
immunocompetent persons only. 
Final adjusted VE point estimate for 
PPV23 subtracted from final adjusted 
VE subtracted for PCV13, overall 
and among immunocompetent 
persons only. 
To compare pneumococcal serotype results 
from high-quality respiratory specimens 
(standard of care), UAD1/2 (study 
procedure), and saliva specimens taken for 
carriage testing (study procedure). 
Percent agreement in serotype results 
between specimen types for events that
have both types available.  (Three 
comparisons: 1. high-quality 
respiratory culture [standard of care 
specimen] versus UAD1/2; 2. UAD1/2 
versus saliva carriage sample; 3. 
High-quality respiratory culture versus
saliva carriage sample). 
To estimate incidence rates for hospitalised 
CAP among adults aged 
 years with 
underlying at-risk and high-risk medical 
conditions, in aggregate and for individual 
risk conditions within the limitations of the 
expected under ascertainment of hospital- 
based screening process and current 
diagnostic testing. 
Number of CAP events identified by 
screening log multiplied by the 
proportion of CAP subjects with 
specific risk condition(s) divided by 
the estimated number of persons 
 ears in surveillance region with the
same specific risk condition(s), in 
aggregate for at-risk and high-risk 
conditions and for individual risk 
groups if the size of risk group is 
adequate for a stable estimate. 

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Additional COVID-19 Exploratory Objectives 
Additional COVID-19 Exploratory 
Endpoints 
To determine if the frequency of 
pneumococcal infection differs between 
hospitalised CAP patients with COVID-19 
infection compared to those without 
COVID-19 infection, overall and stratified 
by age, sex, and pneumococcal risk status. 
Percentage of CAP events with 
pneumococcal infection identified by 
any means (eg, UAD, BinaxNOW®, 
bacterial culture) among CAP events 
associated with a positive COVID-19 
test compared to percentage of CAP 
events with pneumococcal infection 
identified by any means (eg, UAD, 
BinaxNOW®, bacterial culture) among 
CAP events associated with a negative 
COVID-19 test, overall and stratified 
by age, sex, and pneumococcal risk 
status.
Among the subset of hospitalised CAP 
patients with COVID-19 identified, to 
determine if the proportion who experience 
severe clinical outcomes (eg, ICU stay, 
mechanical ventilation, prolonged 
hospitalisation, and sequelae) differs 
between those with pneumococcal co-
infection compared to those without 
pneumococcal co-infection, overall and 
stratified by age, sex, and pneumococcal risk
status. 
Among CAP subjects with COVID-19
infection, percentage of CAP subjects 
with severe clinical outcomes (overall 
and by individual outcome) among 
those with pneumococcal co-infection 
identified by any means (eg, UAD, 
BinaxNOW®, bacterial culture) 
compared to percentage of CAP 
subjects with serious clinical outcomes
among those without pneumococcal 
co-infection identified by any means 
(eg, UAD, BinaxNOW®, bacterial 
culture), overall and stratified by age, 
sex, and pneumococcal risk status. 
Using a test-negative design to determine 
the VE of PCV13 against severe COVID-
19 clinical outcomes among COVID-19 
positive hospitalised CAP patients, overall 
and among immunocompetent persons only. 
VE calculated as 
1 minus the OR comparing the odds of
having received PCV13 for cases and 
controls, multiplied by 100%, overall 
and among immunocompetent persons
only, adjusted for confounders. (Cases
= COVID-19-positive CAP subjects 
with severe clinical outcomes; Controls
= COVID-19-positive CAP subjects 
without severe clinical outcomes). 

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To assess if pneumococcal carriage differs 
for those with current or past COVID-19 
infection, overall and stratified by age, sex, 
and pneumococcal risk status. 
Percentage of CAP events with 
pneumococcal carriage among CAP 
events associated with a positive 
COVID-19 test compared to 
percentage of CAP events with 
pneumococcal carriage among CAP 
events associated with a negative 
COVID-19 test, overall and stratified 
by age, sex, and pneumococcal risk 
status. 
 
Additional RSV Exploratory Objective 
Additional RSV Exploratory 
Endpoints 
To determine the proportion of persons with 
RSV infection among adults 60 years of age 
and older presenting with CAP by testing 
saliva specimens using the PCR method). 
Proportion of CAP events where RSV 
was identified from saliva by PCR 
divided by all CAP events where the 
subject had a valid saliva specimen 
test result. 
Note: Saliva samples will be taken only in selected sites. 
 
9. RESEARCH METHODS 
9.1. Study Design 
This is a low interventional, prospective, multicentre, hospital- based study in adults aged 60 
years of age and older hospitalised with CAP at participating sites.  Hospital surveillance 
data will be used for incidence calculations and a TND for VE calculations. Vaccine 
effectiveness will be calculated using a TND. The approximate study duration will be 4 
years. 
In the South of Madrid there are two municipalities that belong to the network of King Juan 
Carlos I University (Figure 1): 
Móstoles is a city located in the southwest of the Madrid region. Its total population is 
210,309 people,12 57,042 of them are people aged 60 years or older. For secondary care, the 
population that receives medical care at the Hospital Universitario de Móstoles includes 137,552 

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inhabitants which represents 65.4% of the total population of the town. There is another hospital,
Hospital Universitario Rey Juan Carlos included in the study in February 2022, that covers the 
remaining population. The Hospital Universitario de Móstoles has 332 beds, while the Hospital 
Universitario Rey Juan Carlos has 358 beds.
Alcorcón is a city located in the Southwest of Madrid region. Its total population is
172,384 people,12 45,535 of them are people of 60 years or older. The population receives 
medical care at its only hospital, called Hospital Universitario Fundación Alcorcón, which
is the only public hospital in Alcorcón.  The hospital has 400 beds.
As of 1st January 2020, the total population of these two municipalities (Alcorcón and
Móstoles) was 382,693 people, 103,844 of them were of 60 years and older that represents
6.5% of the total population of Madrid Region (in total: 1,593,526 inhabitants in this age
group) (Table 3). In Spain, every town or village is obliged by law to maintain and update
the census
municipal de
An automated and electronic population 
registry is continuously updated (eg, with new people registering, leaving the village, or
dying). Thus, these population denominators are not intercensus extrapolations but actual
counts.  An internal audit of the population by Dr.
has shown the populations are 
comparable to the averages across Spain.

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Table 3.
Geographic Catchment Area (January 2020)
Population of
60 years and older
Percentage of people of 60 
years and older
Hospital Universitario de 
Móstoles, Móstoles
35,106
25.5%
Hospital Universitario Rey 
Juan Carlos, Móstoles
Hospital Universitario 
Fundación Alcorcón, 
Alcorcón
46,802
27,1%
Note: Hospital Universitario de Móstoles and Hospital Universitario Rey Juan Carlos have the same geographic 
catchment area.
Figure 1.
Map of Study Locality
PCV13 effectiveness against hospitalised VT-Pneumococcal CAP will be assessed using a
TND, which is a modified case-control study. In the TND, researchers are not aware of
but later classify the participants into cases or 
controls according to the test results. Cases are participants testing positive for PCV13
serotypes by any method, including routine culture from blood, high-quality respiratory
culture, or serotype-specific UAD1. For the analysis, PCV13 serotypes will be defined as all 
serotypes contained in PCV13 (ie, 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F).

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Controls are hospitalised patients with pneumonia meeting the inclusion and exclusion 
criteria but testing negative for PCV13-type infection or related serotypes.  Vaccine 
effectiveness is calculated as follows: 
VE = (1 
100%. 
TND validity is predicated on the core assumption that the intervention (vaccine) has no 
effect on other non-targeted aetiologies resulting in similar illness/disease incidence in the 
vaccinated and unvaccinated.  Compared with conventional case-control or cohort designs, 
the TND is less susceptible to bias caused by differences in health-care- seeking behaviour 
among cases and controls and the use of non-specific outcome measurements.  However, 
TND is prone to selection bias, residual confounding due to healthy vaccinee effects and 
risk-based vaccination strategies, bias due to indirect effects of the vaccine, and 
misclassification of false-negative cases and controls, these concerns will be addressed, 
discussed and acknowledged as limitations of the study. 
Further, statistical adjustments will be undertaken to control for confounding (eg, 
propensity score matching). 
An interim analysis is planned after accrual of 170 VT-cases but depending on the VE point 
estimate, the proportion of CAP cases that are vaccine serotype, and the frequency of PCV-
13 vaccination in the study population, additional subjects may be needed to allow for 
adequate statistical power. On this basis, approximately 4 years of enrolment is planned. 
If the anticipated PCV20 is approved during the enrolment of cases for VE analysis as 
expected (projected to be in use no sooner than late 2022), subjects with PCV20 exposure 
will be excluded from the cases and the controls for the PCV13 VE analysis.  Initial PVC20 
use is expected to primarily involve those aging into the over 60 age group, and substantial 
number of persons with a history of PCV13 vaccination are expected to remain in that age 
group population. 
Laboratory testing.  The Central laboratory will conduct BinaxNOW® (Alere, Walthman, 
MA) and the serotype-specific UAD1 and 2 assays (Pfizer, Inc) to test urine samples from all 
enrolled participants as the study-related procedures.  Results from SOC tests performed on 
enrolled subjects will be also collected, including respiratory, blood, and pleural fluid 
cultures and urine pneumococcal antigen testing.  All pneumococcal isolates will undergo 
serotyping. 
Pneumococcal Carriage and RSV infection assessments.  In addition, patients at selected 
study sites will provide a saliva sample to test for pneumococcal carriage and RSV infection 
but, if they decline this procedure at the time of collection, they will not be excluded from the 
study.  Samples will be processed for pneumococcal detection by the standard, conventional 
culture diagnostic approach and molecular methods. RSV will be detected by molecular 
methods only. 
Incidence assessment.  Population-based incidence of CAP will also be estimated in this 
study.  Nearly all CAP hospitalisations in the surveillance regions are expected to involve the 
study hospitals.  Every effort will be taken to identify all pneumonia patients admitted to 

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study hospitals. Patients with pneumonia who are not enrolled will be recorded on the 
screening log, which will be the basis of the count of CAP events for incidence estimates. 
Where appropriate population-based denominators are available, incidence rates for at-risk and 
high-risk conditions will be generated in aggregate and by condition for more frequent 
conditions. Nevertheless, incidence estimates will be conservative, given established multiple 
risks for under ascertainment of pneumonia events in studies in this setting (for example, due 
to misdiagnosis, chest X-ray [CXR] false negative, or hospitalisation on a different inpatient 
ward). Non-
incidence estimations. 
COVID-19 and pneumococcal infection. The World Health Organization declared COVID- 
19 a pandemic during the finalization of this protocol (March 11, 2020). On this basis, 
additional exploratory objectives related to the relationship between COVID-19 and 
pneumococcal infection were added.  If COVID-19 continues to occur at a sufficient 
frequency in the surveillance region during enrolment to allow for a meaningful analysis, 
these objectives will be pursued using COVID-19 infection status based on standard of care 
testing.  Further, if a high incidence of COVID-19 infections is burdening the  hospitals at 
the anticipated time of study start or at some point during study enrolment period, enrolment 
will be delayed or halted to allow involved staff to focus on COVID-19 clinical care. 
 
This study will prospectively enroll adults, aged 60 years and over, who are hospitalised 
with CAP in one of the study hospitals: Hospital Universitario de Móstoles, Hospital 
Universitario Fundación de Alcorcón, and Hospital Rey Juan Carlos de Móstoles (as of 
February 2022, additional sites may be included at a later date). 
9.1.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Age 
 years. 
2. Evidence of pneumonia within first 48 hours of hospital admission based on: 
a.
Documented pneumonia diagnosis or clinical suspicion of pneumonia* at the time 
of enrollment OR; 
b. Radiologic findings consistent with pneumonia (eg, increased pulmonary density 
due to infection and/or alveolar infiltrates [multilobar, lobar, or segmental]) AND 
presence of 
 symptoms: 
i. fever (oral temperature >38.0°C or tympanic temperature >38.5°C); 
ii. hypothermia (<35.5°C measured by a healthcare provider) within 24 hours 
before enrollment; 

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iii. chills or rigors; 
iv. pleuritic chest pain; 
v. new or worsening cough; 
vi. sputum production; 
vii. dyspnea (shortness of breath); 
viii. tachypnea (respiratory rate >20/min); 
ix. malaise; or 
x. abnormal auscultatory findings suggestive of pneumonia (rales or evidence of 
pulmonary consolidation including dullness on percussion, bronchial breath 
sounds, or egophony). 
3. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
*Note: Pneumonia may be clinically suspected, based on any combination of radiologic and 
laboratory findings as well as signs, symptoms and other clinical findings, regardless of a 
formal admission diagnosis or other diagnoses assigned during hospitalization and other 
acute or chronic comorbidities, including other pulmonary diagnoses. 
9.1.2. Exclusion Criteria 
Patients meeting any of the following criteria will not be included in the study: 
4. Any patient who develops signs and symptoms of pneumonia after being hospitalized 
for 
 hours (either at current hospital, another transferring hospital, or a 
combination of these). 
5. Previously enrolled subjects readmitted 
days after discharge for their study 
qualifying admission. 
6. At the time of enrolment, pneumonia has been excluded as the diagnosis or another 
diagnosis confirmed. 
9.1.3. Variables 
Please see listing of data collection per visit, Section 10. 
9.1.4. Data Sources 

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In the Madrid Region, the primary and secondary medical care records are formally linked for 
routine clinical use. The information related to vaccine administration will be extracted from 
a population-based computerized vaccination registry that belongs to the Regional Health 
System, namely SISPAL (http://www.sanidadmadrid.org/saludpublica/e-sispal, restricted 
access). SISPAL vaccination registry provides nominal records (name, sex, date of birth) of 
every vaccine administered (vaccine, lot, date of administration) in the public or private 
sector to the entire population living in the Madrid Region and provides access to the 
information for every health care practitioner working in the public sector after request. The 
electronic database was created in 2005 but contains information on vaccination prior to 
2005, transferred from manual records. Self-reported vaccination history will not be used as 
it has been demonstrated that vaccine self-reported data could significantly overestimate the 
vaccine coverage when compared with SISPAL database.28 
10. STUDY PROCEDURES 
10.1. Surveillance Process 
10.1.1. Surveillance Manual 
The Surveillance Manual should describe and identify the following: 
Description of the informed consent process, including the staff roles responsible for 
informed consent. 
Description of the study-level Surveillance Officer role, which will be responsible for 
coordinating all enrolment activities at the participating sites. Additionally, site-level 
surveillance coordinators may be utilized. 
Identification of key personnel in each hospital that will assist with enrolment. This 
list should include the key posts at each ward who will serve as important sources of 
information for identification of inpatients with pneumonia.  Ideally, numerous 
sub-investigators and site staff across various departments/wards will be involved to 
ensure constant and complete surveillance. 
Surveillance team structure, training and engagement should be addressed. 
Description of the process for sample collection. 
Establishment of communication and collaboration mechanisms between the 
surveillance staff and the local laboratory that will manage samples. 

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Development of validated links with the testing laboratories for result reporting, if 
possible. 
Description of the laboratory testing procedures for SP, and methods for safe 
shipping and handling of the samples. 
A detailed step-by-step description of the screening process.  This should include a 
description of how staff will be contacted to identify patients being admitted with 
pneumonia. This can also include how hospital admissions records, patient medical 
records, radiology reports and microbiology reports will be reviewed to identify 
patients being admitted with pneumonia. 
A step-by-step process of enrolment, including procedures used to identify patients 
being admitted with pneumonia, consent, enrolment, specimen collection, review of 
medical records of enrolled individuals, participant follow-up. 
The use of the screening and enrolment log, which will record all identified 
hospitalised patients admitted with pneumonia, whether or not they are eligible for 
the study, and whether or not the eligible individuals were enrolled. 
Enrolment will ideally be within 24 hours of admission to the hospital on weekdays 
but may be enrolled later if admitted on the weekend and/or if person cannot consent 
during that time period (eg, if intubated).  When a potentially eligible patient has 
been identified for the study (see screening criteria), the pneumonia hospitalisation 
registry (screening log) will be completed by staff trained to work on the study and 
then later the patient will be offered participation in the study. 
10.2. Screening/Enrolment Log 
The study screening log will be completed by site personnel and be forwarded to the 
sponsor or its representatives weekly for the required study monitoring and follow-up. 
The registry will include the following information as permitted by the Independent 
Ethics Committee (IEC) and may include: 
Screening date; 
Hospital site and ward; 
Sex; 
Nationality; 
Surveillance area resident (yes/no); 
Eligibility  if not eligible, why; 

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Consented (yes/no); 
Date of consent (day/month/year); 
If declined, reason not consented; 
Study participant ID; 
Date of admission to hospital (day/month/year); 
Year of birth; 
Pneumonia confirmed by Chest radiology (yes/no); 
ICU admission (yes/no); 
Samples collected. 
10.3. Visit 1 Day 1 (Screening/Enrolment) 
All relevant patients who are eligible via inclusion in the screening process will be offered 
enrolment to the consented study.  The study would be explained by a healthcare professional 
who will also answer any questions the patient has before taking written informed consent to 
participate in the study.  Once consent has been given, data and samples will be collected per 
the SCHEDULE OF ACTIVITIES in Section 6. 
If the patient meets all the inclusion criteria and none of the exclusion criteria, they 
will be informed of this study and asked for written informed consent (see Section 
15.1). 
Once informed consent is obtained, a participant number will be assigned to the 
patient. The participant number will contain no initials or any other personal data that 
may identify the patient.  Hospitalised participants that are recruited more than once 
as new cases (see Inclusion Criteria, Section 9.1.1) will be assigned a new participant 
number.  Multiple events for a single participant will be linked in the electronic Case 
Report Form (eCRF) (for example, capturing prior study number(s) in the eCRF for 
the new event(s)). 
Collect Adverse Events (AEs) and Research Related Injury (RRI) as outlined in Section 
16. 
Collection of urine for pneumococcal testing per Section 11.2.3. 
Collection of saliva sample at selected study sites per Section 11.2.4. 
Specifically, at this visit the following data will be recorded in the eCRF: 

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Date informed consent is obtained. 
 
Eligibility of the subject.  It will be confirmed that the participant meets all inclusion 
criteria and no exclusion criteria to be eligible for the study. 
Demographic data: date of birth; sex, nationality, country of birth. 
Surveillance area resident: Do you live in the study catchment area? (yes/no). 
Residence setting (eg, nursing home, long-term care facility for those with disability 
or dependency, private residence, or other). 
Weekly exposure to children <5 years of age. 
Body Mass Index (BMI) (height and weight). 
Smoking status (current/previous/never). 
Alcohol/drug use. 
Vaccination history. 
Pneumococcal, last date of administration for PCV13 and PPV23.  PCV20 
immunisation will also be collected once available in the region. 
Influenza vaccination in last year, date of administration. 
COVID-19 vaccination, dates and vaccines types. 
 
RSV vaccination, dates and vaccine types. 
Hospitalisation data: 
Dates and time of admission/discharge for qualifying admission. 
ICU stay (yes/no). 
Number of days in ICU. 
Mechanical ventilatory support (invasive and non-invasive), if used and type. 
Number of days of mechanical ventilator use. 
Acute respiratory distress syndrome (ARDS) diagnosis during illness. 

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Readmission within 14 days of discharge (If yes, dates of admission/discharge). 
Symptoms of qualifying pneumonia illness mentioned in inclusion criteria. 
Date of illness onset. 
Vital signs (initial respiratory rate, pulse oximetry, blood pressure, heart rate). 
 
Level of oxygen supplementation during pulse oximetry measurement (FiO2). 
SOC chest radiography results (eg, CXR and computed tomography [CT] 
scan), including if consistent with pneumonia per standard outlined in Section 
11.3. 
SOC microbiology test results including test and specimen type: 
Blood cultures. 
Respiratory microbiology testing, including bacterial (eg, PCR and culture), viral 
testing (eg, RSV, influenza, and COVID-19), and Gram stain results. 
All standard of care COVID-19 testing during the qualifying illness will 
be recorded with result. 
Pneumococcal testing (eg, BinaxNOW® or another pneumococcal antigen urine 
test). 
Other body fluid/tissue sterile under normal conditions. 
CAP severity/prognosis scale (Confusion Respiratory Rate Blood Pressure [CRB-65] 
and Pneumonia Severity Index [PSI]) on presentation to hospital if information 
available from SOC testing to calculate score: 
CRB-65 score [Contributing data elements: age, blood pressure, presence of 
confusion, and respiratory rate]. 
PSI score. Contributing data elements are: 
Altered mental status. 
Nursing home residency. 
pH and partial pressure of arterial O2 (PaO2) from atrial blood or arterialised 
venous blood OR oxygen saturation level (SpO2) measured by pulse oximetry 

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and FiO2 during that assessment. 
Blood urea nitrogen. 
Serum sodium concentration. 
Plasma glucose concentration. 
Hematocrit. 
Presence of pleural effusion. 
Relevant medical history: 
COPD. 
Asthma. 
Congestive Heart Failure. 
Coronary Artery Disease (CAD). 
Chronic Kidney Disease. 
Diabetes (with or without complications). 
Liver Disease. 
Immunosuppressant Drug Therapy. 
Autoimmune Disorders. 
Immunodeficiency. 
Human Immunodeficiency Virus (HIV). 
Acquired Immunodeficiency Syndrome (AIDS). 
Cancer/Malignancy, Solid Tumor only. 
Cancer/Malignancy, Hematologic only. 
Organ Transplantation. 
Cerebrovascular accident (Stroke). 
Number of previous pneumonia events in year prior to admission. 

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Healthcare facility exposure in past 3 months, includes inpatients stays, dialysis 
centers or long-term care, skilled-nursing, assisted-living, rehabilitation, or other 
healthcare facilities. 
Antibiotic treatment within 14 days prior to admission. 
 
10.4. Visit 2 Day 30 (Final Diagnosis and Event Outcome) 
The participant will be followed-up by telephone at 30 to 45 days after hospital admission. 
The date of the visit, the 
 study-qualifying suspected 
CAP event will be recorded in the eCRF.  If patient returns to study hospital for a standard 
 
of care clinic visit for another reason, the visit may occur in person. RRIs will be collected if 
encountered during the collection of visit-related information or if the patient is contact by 
phone. 
The following data will be recorded in the study eCRF: 
Any additional results from standard of care pneumococcal and viral 
respiratory testing, including COVID-19 and RSV, that was not captured during 
Visit 1. 
Additional information on hospitalisation data eCRF items not captured during 
Visit 1. 
Principal investigator (PI) or designee should make an outcome assessment of final 
diagnosis based on any information available over the hospitalisation of the patient. 
This may include both study and SOC exams, procedures and tests.  This data point 
can be recorded on Day 30 or sooner if available. Final diagnosis categories will 
include: 
CAP-radiologically confirmed; 
CAP-not radiologically confirmed (eg, clinical CAP); 
CAP-no chest radiology done; or 
Other diagnosis (not CAP). 
Acute Bronchitis. 
Exacerbation of COPD. 
Empyema/lung abscess. 
Other Acute Lower Respiratory Infection. 

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Acute pulmonary exacerbation of congestive heart failure. 
Non-infectious process. 
Event disposition at 30 days after admission: 
Fatal/deceased. 
 
Not recovered/not resolved. 
Recovered/resolved. 
Recovered/resolved with sequelae. 
Recovering/resolving. 
Unknown. 
Vital Status (ie, deceased or living), including date and cause of death if deceased. 
RRIs per Section 16.2 and selected exposures and AEs related to Pfizer products per 
Section 16.3. 
Case Definition for Radiologically Confirmed CAP 
Patients in whom the treating physician clinically suspected pneumonia who meet the 
following 2 criteria will be considered to have radiologically confirmed CAP: 
1. Has a radiologic finding that is consistent with pneumonia (eg, pleural effusion, 
increased pulmonary density due to infection, the presence of alveolar infiltrates 
[multilobar, lobar or segmental] containing air bronchograms); AND 
2. Illness involves 
 symptoms: 
a.
fever (oral temperature >38.0°C/100.4°F or tympanic temperature 
>38.5°C/101.2°F) within 24 hours before enrolment; 
b. hypothermia (<35.5°C measured by a healthcare provider) within 24 hours of 
enrolment; 
c.
chills or rigors; 
d. pleuritic chest pain; 
e.
new or worsening cough; 

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f.
sputum production; 
g. dyspnea (shortness of breath); 
h. tachypnea (respiratory rate >20/min); 
i.
malaise; 
 
j.
abnormal auscultatory findings suggestive of pneumonia (rales or evidence of 
pulmonary consolidation including dullness on percussion, bronchial breath 
sounds, or egophony). 
10.5. Visit 3 Day 180 (Vital Status Assessment) 
The participant will be followed-up by telephone at 180 to 195 days after hospital admission 
to assess vital status at Day 180 (ie, alive or dead).  If investigator is definitively aware of 
vital status through other means (eg, access to vital statistics records or patient visit in 
electronic record after Day 180), this source may be used to determine vital status in lieu of a 
phone call. RRIs will be collected if encountered during the collection of vital status or if the 
patient is contact by phone. 
The following data will be recorded: 
Vital Status at 180 days after admission (ie, deceased or living), including date 
and cause of death if deceased. 
Information to calculate Charlson Comorbidity Index (diagnosis codes such as 
International Classifications of Diseases [ICD] discharge codes may be provided 
as a separate file linked by participant number to calculate CCI or data will be 
collected via eCRF at this or prior visit). 
Record RRIs per Section 16.2 and selected exposures and AEs related to Pfizer 
products per Section 16.3. 
11 
ASSESSMENTS 
Collection of clinical data. The study staff will complete a eCRF for each participant at 
each visit, as detailed above. The eCRF will be completed reviewing the medical records of 
the patient, the results of the tests performed, and interviewing the participant. Once the 
eCRF is completed, it will be signed and dated by the investigator verifying the information 
contained therein. 
11.1. Additional Research 
Not applicable. 

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11.2. Biological Samples 
11.2.1. Blood and Respiratory Samples 
All blood and respiratory specimens collected as part of SOC for culture (eg, blood, pleural 
fluid, transtracheal aspirate, bronchoalveolar lavage or other respiratory tract specimen) will 
undergo bacterial culture at the local site laboratory for the identification of SP according to 
their standard methodology.  Best practices for blood culture collection involved obtaining 2 
sets of blood cultures before antibiotic administration if possible.  The blood culture should 
be collected and timed according to the 
 using different sampling 
sites.  Anaerobic and aerobic samples should be collected. 
Whenever possible, blood should be collected from peripheral veins. Results of blood 
cultures (including antibiotic susceptibility) from this SOC bacterial culture testing will 
be recorded in the eCRF. 
For sputum specimens collected as part of standard of care testing, specimen quality will be 
 of care Gram stain results. Only bacterial culture 
results from high-quality sputum specimens will be use in case categorisation for the VE 
analysis, but all pneumococcal isolates will be serotyped regarding of specimen quality. 
Serotyping, Antimicrobial Resistance and Molecular Biology Testing of the Isolates 
Pneumococcal bacterial isolates from SOC specimens will be shipped and analyzed in the 
Pneumococcal Reference Laboratory from the Centro Nacional de Microbiología which 
belongs to the Instituto de Salud Carlos III (ISCIII).  In no case will there be any 
interference with the autonomous regional pneumococci monitoring systems at the sites 
participating in the study. 
The ISCIII reference laboratories provide data and information of sanitary interest on the 
microorganisms that cause infectious diseases, environmental pollutants situation and the 
development of new technologies and/or surveillance strategies and control in accordance 
with the priorities established by the Ministerio de Sanidad, Consumo y Bienestar Social 
(MSCBS) following the recommendations of the European Centre for Disease Prevention 
and Control (ECDC).  The pneumococcal reference laboratory is located in Majadahonda 
which is a city in Madrid region, it carries out a passive surveillance and receive the isolates 
from hospitals of all the Spanish regions. 
Identification and Serotyping 
All isolated pneumococcal strains will be stored frozen in skimmed milk at a temperature of - 
40ºC or lower in the Department of Microbiology of each participating site until delivery to 
the reference laboratory (RL) at ISCIII.  From a fresh culture (18-24h) in blood agar a dense 
suspension will be obtained (all plate growth will be recorded) in a vial with 0.5 ml of sterile 
skimmed milk (Skim Milk, Oxoid).  The vial will be immediately frozen at -40ºC. 
The pneumococcus strains should be frozen as soon as possible and with the minimum 
number of runs. 

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The strains will be thawed in the site where they are isolated before being sent at room 
temperature to the RL.  The strains may be sent in the following ways: 
On blood agar plates or tubes, after abundant seeding (without incubation). 
Incubation will be performed on reception at the RL.  If plates are used, only one strain 
should be seeded per plate. 
 
Transport media tubes are preferable.  The whole quantity of a fresh culture should be 
collected from a blood agar plate by dragging with a swap and sent at room 
temperature in the transport media. 
To prevent the loss of strains for reasons of viability during transportation, or other reasons, 
the microbiology laboratory of each site will keep a frozen sample for up to 6 months for 
study purposes.  The frozen vials, plates or the tubes with transport medium will be identified 
by the site personnel using a label containing a study code and the subject identifier (site no. 
and participant no.) from which the isolate comes.  In addition, a copy of the label containing 
the same codes used to identify the isolate will be attached to the study form for submission 
of strains to the RL.  When preparing the pack with the strains, the safety rules applicable in 
Spain will be followed and standardised packages will be used.  Strains will be sent to the 
ISCIII at regular intervals (every 1-2 months, depending on the volume of strains) using a 
courier service.  Once the samples/strains have been received at the ISCIII a subculture will 
be performed in the appropriate medium (blood agar or chocolate agar) in order to ensure the 
viability and purity of the organisms. 
For pneumococcal serotyping at the ISCIII, it will be used the Capsular Sequence Typing 
(CST) methodology.16   The CST is a well-established molecular method to genotype the 
capsular locus in order to assess the serotype.  It has been accepted as a generic method for  
typing SP among the different European Pneumococcal Reference Laboratories that belong 
to ECDC through the Invasive Bacterial Disease network (IBD-labnet). The primers used in 
the CST are based on the publicly available sequences of the capsular genes of the more than 
90 known pneumococcal serotypes.17  Capsular Sequence Typing (CST) is based on a part of 
the sequence of the wzh gene of the capsular locus.  The 3 forward and 4 reverse primers 
used in the CST are based on the publicly available sequences of the capsular genes of the 90 
known pneumococcal serotypes described by Bentley et al.17   The primers contain an M13-
tail, which facilitates sequencing with universal M13-primers. After sequencing of 506 base 
pairs of the wzh gene, a capsular type can be assigned.  The capsular type is a composite 
assignment; the first part of the assignment is based on the phenotype assessed by 
conventional serotyping and the second part of the assignment is the consecutive number of 
the capsular type belonging to the same serotype. 
Antimicrobial Susceptibility Testing 
The measurement of the minimum inhibitory concentration (MIC) of each isolate will be 
performed at the using a broth microdilution method (Sensititre,Trek Diagnostic Systems 

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LTD, East Grinstead, United Kingdom) according to the The European Committee on 
Antimicrobial Susceptibility Testing (EUCAST)2 guidelines. For pneumococci Cation- 
Adjusted Mueller-Hinton Broth (CAMHB) broth will be used, with 2.5-5% lacquer horse 
blood (LHB).  The following antimicrobials will be evaluated: penicillin, amoxicillin, 
cefotaxime, erythromycin, clindamycin, tetracycline, and levofloxacin. 
 
2      http://www.eucast.org/clinical_breakpoints/. 

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The laboratory investigator of the ISCIII or designee will be responsible for completing a
record with the results of serotyping and susceptibility to be submitted to the sponsor
regularly. These records will not include any personal data of the participants from whom
the isolates were obtained.
11.2.2. Detection of Serotype-specific Pneumococcal Urine Antigen and BinaxNOW®
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 validated UAD 1 assay are the 13 polysaccharide antigens used in 
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® SP test is a commercially available, Food and Drug Administration (FDA)
approved assay for the detection of SP in the urine and cerebrospinal fluid (CSF) from 
patients with pneumonia or meningitis.  The BinaxNOW® SP test is an in vitro rapid 
immunochromatographic 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. Residual 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
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
material is performed.
11.2.3. Pneumococcal Carriage and RSV Infection Testing
The saliva samples will be placed in individual bags for transport and will be kept at room
temperature until delivery. Samples will be delivered once or twice a week (preferably at the 
beginning of the week; Mondays or Tuesdays) to improve the culture efficiency. The samples 
will be referred to the ISCIII for conventional culture and molecular biology study (for 
culture-negative samples).  Briefly, swabs with the saliva samples will be streaked onto blood
agar plates containing gentamicin to select SP and avoid the growth of bacteria from the 
microbiota.  For culture-negative samples, characterization of SP will be performed through a
real-time PCR assay for the detection of pneumococcus target genes lytA and piaB. Once 
pneumococcus is confirmed, a CST methodology will be used to identify the serotype.

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Additional PCR testing for RSV will be performed on the same saliva sample. 
The PI of the ISCIII or designee will be responsible for completing a record with the results 
of the microbiological tests on the nasopharynx to be submitted to the sponsor regularly.  
These records will not include any personal data of the participants from whom the isolates 
were obtained. 
11.3. Imaging Assessments - Chest Radiography 
Patients hospitalised with CAP who have chest imaging studies normally performed as 
standard care (eg, CXR, CT, magnetic resonance imaging [MRI)]). Results of all imaging 
performed for this episode of CAP will be recorded on the eCRF. Radiologist review and 
interpretation will be documented on the eCRF. Radiologically confirmed CAP will be 
those considered to have a radiologic finding that is consistent with pneumonia (eg, pleural 
effusion, increased pulmonary density due to infection, the presence of alveolar infiltrates 
[multilobar, lobar or segmental] containing air bronchograms). 
12. DATA ANALYSIS/STATISTICAL METHODS 
12.1. Study Size 
12.1.1. Defining Cases and Test-negative Controls 
For the analysis of the primary endpoint, we will define cases as events involving 
hospitalised for CAP in whom PCV13 serotypes are identified by any method including 
UAD1 or routine culture of blood, pleural fluid, or other high-quality respiratory tract 
specimen. PCV13 VT serotypes are as follows: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F and 23F. Only sputum isolates from high-quality specimens (see Section 11.1) will be 
considered in assigning case status.  All other episodes of CAP that met the inclusion criteria 
for the study, but for whom PCV13 or related serotypes are not identified from any source 
(ie, non-vaccine type [NVT] only) will serve as test-negative controls.  Subjects with 
vaccine-related serotypes (eg, 6C) will be excluded from controls for the primary analysis. 
Subjects with VT serotype who also have an NVT or vaccine-related serotypes will be 
classified as cases.  Subjects may only contribute one CAP event to any given VE analysis. 
For PPV23 VE, cases will be those with one of 23 serotypes in PPV23: 1, 2, 3, 4, 5, 6B, 7F, 
8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F (including 
those where a NVT or vaccine-related serotype is also identified). Events with vaccine- 
related serotypes (either alone or in combination with an NVT) will be excluded from the 
controls for the primary analysis.  Controls will be those with only nonvaccine serotypes (ie, 

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all other serotypes). Subjects with VT serotype who also have an NVT or vaccine-related 
serotypes will be classified as cases. 
In sensitivity analyses, we will estimate PCV13 and PPV23 VE using different control group. 
In this case, controls will be defined as non-VT pneumococcal CAP (Broome method).13 
That is, controls will be patients in whom pneumococcus is detected by blood/pleural/high- 
quality sputum culture, BinaxNOW®, or UAD1/2 positive; but VT or vaccine-related 
serotypes are not identified from culture or UAD1/2. (ie, serotypes identified are not VT or 
related serotypes).  In the second sensitivity analysis, we will define controls as CAP patients 
in whom pneumococcus was not detected by any method (culture, UAD, or BinaxNOW®), 
similar to a recently published TND.14 
If PCV20 use is initiated in the surveillance area during the study, PCV20 vaccinated persons 
would be excluded from both case and control groups for the PCV13 VE analysis. 
12.1.2. Study Size Estimates 
The required sample size depends on the accrual of immunocompetent VT-CAP cases, the 
VE point estimate, percentage of individuals vaccinated, as well as other factors.  Based on 
calculations outlined below in detail, the overall number of subjects to be enrolled is 
expected to be between 2,000 and 5,500 and will require between 1.7 and 4 years of 
enrolment period. 
Hospitalised pneumonia cases have been forecasted here based on the incidence of all-cause 
hospitalised CAP in the Madrid Region derived from the Spanish Conjunto Mínimo Básico 
de Dato (CMBD) 
(https://pestadistico.inteligenciadegestion.mscbs.es/publicoSNS/comun/ArbolNodos.aspx) 
for the year 2015.  CMBD is the Spanish centralized hospital discharge database that covers 
nearly the entire Spanish population and includes more than 95% of admissions to hospitals 
of the National Health System, thus providing a complete record of all hospitalisations at 
National level and by Region.  To estimate the incidence of hospitalised pneumonia cases in 
adults 60 years and older, we use the seven ICD-9 codes for pneumonia (480, 481, 482, 483, 
484, 485 and 486) that resulted in 22,487 hospitalisations per year with an incidence rate of  
1.5 per 100 adult older than 60 years in the Region of Madrid (Table 4). 

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Table 4. 
Incidence of Hospitalised Pneumonia Cases in Adults 60 Years and Older 
Madrid Region, CMBD 2015a 
60-64y 
65-74 y 
>74y 
Total Cases/Incidence rate per 105 
480 viral 
9
25
37
71/4.98
481-pneumococcal 
110
345
1192
1,647/115.53
482-Other bacteria 
96
316
707
1,119/78.49
483-Other organism 
7
13
20
40/2.81
484-Other 
17
36
53
106/7.44
485-Broncopneumonia 
52
136
583
771/54.08
486-Non specify 
1,094
3,508
14,131
18,733/1,314
Total 
1,385
4,379
16,723
22,487/1,577.37
a. The ICD codes in this column as well as 487.0, 510, 513 will be used to retrospectively screen for missed CAP events 
to ensure completeness of surveillance. 
The equivalent codes for hospitalised pneumonia under ICD-10 (Table 5) are as follows: 

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Table 5. 
Codes for Hospitalised Pneumonia Under ICD-10 
ICD-10 codesa 
J12 
Viral pneumonia, unspecified 
J09.X1 
Influenza due to identified novel influenza virus with 
pneumonia 
J10.00 
 
J10.01 
J10.08 
Influenza due to other identified influenza virus with 
unspecified type of pneumonia 
Influenza due to other identified influenza virus 
with the same other identified influenza virus 
pneumonia. 
Influenza due to other identified influenza virus 
with other specified pneumonia. 
J11.00 
 
J11.01 
J11.08 
Influenza due to unidentified influenza virus with 
unspecified type of pneumonia. 
Influenza due to unidentified influenza virus with 
other respiratory manifestations. 
Influenza due to unidentified influenza virus with 
specified pneumonia. 
J13 
Pneumonia due to Streptococcus pneumoniae 
J14 
Pneumonia due to Hemophilus influenzae 
J15 
Unspecified bacterial pneumonia 
J16 
Pneumonia due to other infectious organisms, not elsewhere 
classified 
J17 
Pneumonia in diseases classified elsewhere 
J18 
Bronchopneumonia, unspecified organism 
a.
The ICD codes in this column as well as J1100, J129, 5100, 5109, and 5130 will be used to retrospectively screen for 
missed CAP events to ensure completeness of surveillance. 
For this study surveillance region, we expect approximately 1800 all-cause CAP patients in 
the age group of the study are hospitalised yearly based on 2018 data. This would represent 
162 PCV13-type cases per year overall considering 9% of VT-CAP cases as per the CAPA 
study1 and 648 PCV13-type cases in 4 years of expected duration of the study. 
Approximately, 36% of CAP admissions are expected to be immunocompromised persons, 
so we expect ~104 immunocompetent CAP cases annually (~416 over 4 years).20   The 
following table (Table 6) estimates accrual of cases and controls for the VE analysis for 
immunocompetent subjects varying the key inputs.  For these calculations, 2.5% alpha 
was used to split alpha allocated between interim analysis and final analysis (ie, 2.5% to 
each analysis). 

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Table 6. 
Sample Size Scenarios for VE Calculations At Interim 
Scenario by
input varied
Vaccine
Coverage
Among
Controls
Projected 
Vaccine 
Effectiveness
Vaccinetype
(VT) 
Serotype
Prevalence
Case:Control
Ratio based on 
VT Serotype
Prevalence 
Needed
Cases 
Expected
non-VT 
Controls 
Total 
Evaluable
subjects
Enrolled,b
n 
% CAP 
inpatients
enrolled 
CAP 
inpatients
needed,c n
Years to Enrolld
Expected
VE  
1
15% 
70% 
9% 
1:10 
117 
1165 
1282 
1349 
70% 
1928
1.7 
2a
15% 
60% 
9% 
1:10 
170 
1692 
1862 
1960 
70% 
2800
2.4 
 
3
15% 
50% 
9% 
1:10 
259 
2584 
2843 
2993 
70% 
4275
3.7 
 
4
15% 
40% 
9% 
1:10 
427 
4261 
4688 
4935 
70% 
7050
6.1 
% CAP 
VT 
5
15% 
60% 
7% 
1:13 
167 
2160 
2327 
2449 
70% 
3499
3.0 
6
15% 
60% 
11% 
1:8 
173 
1380 
1553 
1635 
70% 
2335
2.0 
 
8
15% 
60% 
13% 
1:7 
176 
1224 
1400 
1474 
70% 
2105
1.8 
% Vax 
9
10% 
60% 
9% 
1:10 
252 
2516 
2768 
2914 
70% 
4162
3.6 
10
20% 
60% 
9% 
1:10 
129 
1283 
1412 
1486 
70% 
2123
1.8 
90% 
Power 
11
15% 
60% 
9% 
1:10 
208 
2070 
2278 
2398 
70% 
3426
3.0 
% 
enrolled 
12
15% 
60% 
9% 
1:10 
170 
1692 
1862 
1960 
50% 
3920
3.4 
13
15% 
60% 
9% 
1:10 
170 
1692 
1862 
1960 
30% 
6533
5.7 
a.
Base case values are highlighted in gray; 2.5% alpha was used for all scenarios and 80% power was used for all 
scenarios except #11.  All calculations done with OpenEpi, Version 3, open-source calculator (Sample Size- 
Unmatched Case Control Study; available @ https://www.openepi.com/SampleSize/SSCC.htm) and used Fleiss 
method with continuity correction, which is consistent with estimates based on Fischer's exact test.  For these 
calculations, 2.5% alpha was used to split alpha allocated between interim analysis and final analysis (ie, 2.5% to each 
analysis). 
b.
Includes projected 5% of subjects with no valid pneumococcal serotype specimen result. 
c.
 is based on the percentage of CAP patients enrolled in prior column, which 
accounts for loss of potential subjects who declined participation or were not offered participation due to incomplete 
surveillance. 
d.
Estimate 1800 CAP admissions annually in the surveillance area and 36% would be immunocompromised, leaving 
~1150 immunocompetent CAP admissions annually and ~104 vaccine-type pneumococcal CAP cases. 
In conclusion, assuming 9% VT-CAP, Scenario 1 sample size would be reached in 1.7 years 
after enrolling 1349 immunocompetent subjects (~2107 subjects overall), Scenario 2 (base 
case) in 2.4 years after enrolling 1960 immunocompetent subjects (~3063 subjects overall), 
and Scenario 3 in 3.7 years after enrolling 2993 subjects (~4,677 subjects overall). An 
increase in percentage of cases that VT-serotype to 
vaccinated proportion to 
20% would reduce the time to accrue the needed cases for the interim analysis to 2 years or 
less.  Lower proportion of VT-serotypes, lower VE point estimate, lower percentage of 
PCV13-vaccinated persons, or lower number of patients enrolled or subjects with valid urine 
specimens could all increase the time to achieve the needed number of vaccine serotype CAP 
cases.  As the required number of enrolled subjects is highly dependent on the proportion of 
CAP subjects that have VT pneumococcal CAP and the proportion of the population 
vaccinated, the required sample size may be adjusted based on ongoing information from 
UAD testing results and vaccine exposure data if needed.  An interim analysis will be 
conducted after accrual of 170 VT-cases (scenario 2 above), but, given additional subjects 
may be needed to allow for adequate statistical power, 4 years of enrolment is planned, 
which would bring the number of subjects enrolled to 5,400 (based on 1,800 potential 
subjects annually and 70% enrolled). 
If the anticipated PCV20 is approved during the enrolment of cases for VE analysis as 

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expected (projected to be in use no sooner than late 2022), subjects with PCV20 exposure 
will be excluded from both the cases and the controls for the PCV13 VE analysis. We expect 
substantial number of persons with a history of PCV13 vaccination to remain in the 
population in this age group and, thus, event accrual for VE analysis would not be 
significantly impact immediately following the PCV20 launch. 
12.1.3. Analysis Populations 
12.1.3.1. Vaccine Effectiveness CAP Population (Primary Analysis Population) 
The Primary Analysis Population will include all participants who: 
1. Meet all inclusion and exclusion criteria. 
2. Have a final diagnosis consistent with CAP (CAP-Radiologically Confirmed; CAP- 
Not Radiologically Confirmed or CAP-no chest radiology done). 
3. Meet the definition of either case or test-negative control from Section 12.1.1. 
4.
 combined years of pneumococcal vaccination history available. 
5. Did not receive any pneumococcal vaccination 
 days prior to urine sample 
collection. 
6. Have not received PCV20 if available in surveillance region during study. 
This population will be analysed overall and restricted to immunocompetent subjects which 
will be all subjects not noted to the immunocompromised in Table 7. 

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Table 7. 
Categorization of Risk Factors by Immunocompetence3 
Risk factor 
Categorization 
Age 
60 + 
Diabetes mellitus 
immunocompetent 
Alcoholism 
immunocompetent 
Chronic heart disease 
immunocompetent 
Chronic liver disease 
immunocompetent 
Chronic lung disease 
immunocompetent 
Smoking 
immunocompetent 
Congenital or acquired asplenia 
immunocompromised 
Cerebrospinal fluid leak 
immunocompetent 
Cochlear implant 
immunocompetent 
Congenital or acquired immunodeficiencies 
immunocompromised 
HIV infection 
immunocompromised 
Chronic renal failure 
immunocompromised 
Nephrotic syndrome 
immunocompromised 
Leukemia 
immunocompromised 
Hodgkin's disease 
immunocompromised 
Lymphoma 
immunocompromised 
Generalize malignancy 
immunocompromised 
Iatrogenic immunosuppression 
immunocompromised 
Solid organ transplant 
immunocompromised 
Multiple myeloma 
immunocompromised 
Antineoplastic chemotherapy 
not specified 
Occupational risk with exposure to metal fumes 
not specified 
Bone marrow transplantation 
immunocompromised
Neurologic diseases (eg, cerebral palsy and 
seizures) 
not specified 
Prior IPD 
immunocompetent
These populations will serve as the primary analysis population for the primary endpoint and the secondary 
objective of calculating VE for PPV23. 
 
3 Official Regional Immunisation Programme in the Community of Madrid, 2019. 

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12.1.3.2. Five-year PPV23-naïve Population 
The Five-year PPV23-naïve Population is a subset of the Primary Analysis Population and 
will include participants from the Primary Analysis Population that have not received 
PPV23 within the last 5 years. To better understand the impact of PPV23 use on PCV13 
VE, the primary endpoints will be analysed in this population in addition to the primary 
analysis population as a sensitivity analysis. 
12.1.3.3. Radiologically Confirmed CAP Population 
The VE populations endpoints will be analysed in this population as a sensitivity analysis to 
determine the impact of requiring radiographic confirmation for the diagnosis of CAP.  All 
requirements 
 events must have a final 
-radiologically 
 with the definition provided in 
Section 10.2. 
12.1.3.4. Serotype Distribution CAP Population (Secondary Analysis Population) 
The Primary Analysis Population will include all events who: 
1. Participant meets all inclusion and exclusion criteria. 
2. Event has final diagnosis consistent with CAP. 
3. Did not receive any pneumococcal vaccination 
days prior to event urine sample 
collection. 
4. Event with valid UAD1/2 test results or other pneumococcal serotype result (eg, from 
bacterial isolate). 
Events with same serotype result involving rehospitalisation 
days will be considered 
same event for this analysis. 
12.1.3.5. Incidence CAP Population (Exploratory Analysis Population) 
The calculation of incidence will include all CAP events identified on the screening log as 
 either prospectively or 
retrospectively through ICD discharge code review. 
12.1.4. Endpoints 
See Section 8 for details of endpoints per study objective. 
12.2. Data Management 
An electronic database will be created for this study.  Details of the database creation are 
included in the Data Management Plan. 

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12.3. Case Report Forms/Data Collection Tools/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A eCRF is required and should be completed for each included subject. The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
eCRFs are securely stored at the study site in encrypted electronic and/or paper form and 
will be password protected or secured in a locked room to prevent access by unauthorized 
third parties. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
eCRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRFs are true. Any corrections to entries made in the eCRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the eCRFs must match those charts. 
In some cases, thee CRF may also serve as the source document. In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the eCRF, and for which the eCRF will stand as the source document. 
12.3.1. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed 
informed consent [/assent] documents, copies of all eCRFs, safety reporting forms, source 
documents, detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports). The 
records should be retained by the investigator according to the International Council for 
Harmonisation (ICH) guidelines, according to local regulations, or as specified in the clinical 
study agreement (CSA), whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 

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Investigator records must be kept for a minimum of 15 years after completion completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
12.4. Data Analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed and maintained by the sponsor.  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. 
 
12.4.1. Vaccine Effectiveness 
If either PCV13 or PPV23 coverage is <10% or >90%, we will assess whether valid VE 
estimates can be generated for the involved vaccine.  If appropriate, we will proceed as 
follows; odds ratio of having received PCV13 and PPV23 for cases and controls with 95% CI 
for odds ratio will be calculated. See details on case and control assignment in Section 
12.1.1. We will calculate VE as 1-OR x 100.  In addition to constructing crude OR and VE 
estimates, we will perform unconditional logistic regression modelling to assess VE after 
adjustment for potentially confounding factors.  Because of the risk-based approach to catch 
up vaccination in the over 60 cohort, we will also perform a second adjusted analysis, 
selecting non-vaccine-type controls similar the VT-serotype cases based on propensity score 
matching.  Further, we will use a two-sided alpha of .025 for all analyses if final VE analysis 
is not conducted at the interim analysis.  If interim analysis is final VE analysis, a two-sided 
alpha of .05 will be used in the final tables.  A second model will be developed excluding 
immunocompromised persons to evaluate VE without those that may not be able to respond 
to the vaccine.  Only adjusted estimates will be considered the final VE.  Time from 
vaccination will be accounted for in the adjusted analyses.  The comparison of the estimates 
of the effectiveness between PCV13 and PPV23 will be performed using the z-score test. 
The null hypothesis will be that there is no difference between the two estimates. 
For the other study objectives, descriptive analysis will be carried out, presenting the 
absolute and relative frequencies of the qualitative variables and main measures of 
centralisation and dispersion in case of quantitative variables. Comparisons between 
proportions will be performed using 
 test, the Fisher's exact test, or the Likelihood Ratio 
test, as appropriate.  For quantitative variables, the Student's t-test or the Analysis Of 
Variance (ANOVA) test will be used, and when data did not show normality in the 
Kolmogorov-Smirnov test, the Kruskal-Wallis and Mann-Whitney tests will be used. 

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12.4.2. CAP Incidence Rate 
Incidence rates (IR) per 100,000 inhabitants of the study age group will be calculated with 
their respective 95% confidence intervals. 
Numerator: The numerator will include all CAP events  both involving study subjects and 
other unconsented patients captured on screening log 
geographical catchment area.  Frequent retrospective review of admissions assigned 
pneumonia ICD discharge codes will be undertaken monthly to ensure no CAP events are 
missed from the screening log.  Efforts will also be made to assess how many persons from 
the district were hospitalised for pneumonia outside of the surveillance region. 
For SP+CAP, the proportion of CAP events among study subjects with pneumococcus 
identified by any means, will be multiplied by the calculated CAP incidence rate.  For 
radiologically confirmed CAP, the proportion of CAP events among study subjects that is 
radiologically confirmed will be multiplied by the calculated CAP incidence rate. Other 
more complex adjustment processes will also be explored if there is adequate detail captured 
in the screening log, such as calculation the proportion with pneumococal infection within 
specific risk/age strata or multiple imputation. 
Denominator: Annual population data over 60 years old and estimated person-years data for  
this age group will be obtained from INE (National Statistical Institute).  To determine 
denominators (catchment area), calculations will be made based on the following parameters: 
age-specific strata of the total population in the region of Madrid; age-specific strata of total 
hospital discharges in the region of Madrid; age-specific strata of hospital discharges of the 
Móstoles (2 hospitals) and Alcorcón (1 hospital).  Catchment area is calculated as the 
proportion of the Móstoles and Alcorcón hospital discharges compared to total hospital 
discharges in the region of Madrid. These percentages are then applied to the total 
population of the region of Madrid and hence, catchment population in the Móstoles and 
Alcorcón hospitals by age group are estimated.  If population denominators for adults aged 
 years are available for underlying at-risk and high-risk medical conditions, incidence 
will be calculated specifically for these risk groups in aggregate and for individual risk 
conditions that are of sufficient size as outlined in the SAP. 
While every effort will be taken to prospectively and retrospectively capture pneumonia 
events, incidence estimates will be considered conservative, given established multiple risks 
for under ascertainment of pneumonia events in studies in this setting (for example, due to 
misdiagnosis, CXR false negative, or hospitalisation on a different inpatient ward). 
 
12.4.3. Additional COVID-19 and RSV Exploratory Analyses 
Additional statistical methods and data analysis for the COVID-19 and RSV exploratory 
analyses will be described in the SAP.  These analyses will be undertaken if COVID-19 
continues to occur at a sufficient frequency during enrolment in the surveillance region to 
allow for a meaningful analysis. 

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12.5. Interim Analysis 
An interim analysis will be conducted after accrual of the number of cases required to assess 
VE with expected VE of 60% (scenario 2 above, Table 5). Currently, this is expected to 
require ~170 evaluable VT cases. Because the study will assess VE among all subjects and 
limited to the immunocompetent, we will need 170 evaluable immunocompetent VT cases 
available at the interim analysis. As per Table 5, this would expect to take approximately 2.4 
years (Q1 2023) to enrol the needed cases, and, given the required time for UAD testing, the 
study team would be aware of this in Q2 2023.  The target number of cases for the interim 
may be adjusted based on UAD testing results and vaccine exposure data obtained during the 
conduct of the study.  If VE point estimate is lower than 60% at the interim analysis, the 
required number of cases will be re-assessed. 
Other descriptive analyses of eCRF and laboratory data may be done on an ad hoc basis 
throughout the enrolment period. 
13. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) and/or Good Pharmacoepidemiology Practices (GPP), as relevant, are being 
followed.  The monitors may review source documents to confirm that the data recorded on 
eCRFs are accurate.  The investigator and institution will allow Pfizer monitors/auditors or 
its agents and appropriate regulatory authorities direct access to source documents to perform 
this verification. This verification may also occur after study completion. 
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the 
 medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
For studies conducted at non-Pfizer investigator sites, it is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 

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14. 
LIMITATIONS OF THE RESEARCH METHODS 
The actual proportion of participants who would follow their healthcare practitioner 
vaccination recommendation is not known, so this aspect might influence the size of the 
vaccinated group and therefore the global results. 
Differential enrolment based on clinical status (eg, severity of illness) and age can introduce 
bias in the global results obtained, likely an underestimation of incidence. 
Under ascertainment of incidence estimates is expected, given established multiple risks for 
under ascertainment of pneumonia events in studies in this setting (for example, due to 
misdiagnosis, CXR false negative, or hospitalisation on a different inpatient ward). 
15. 
PROTECTION OF HUMAN SUBJECTS 
15.1. Patient Information and Consent 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data on any 
sponsor forms, reports, publications, or in any other disclosures, except where required by 
applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data 
transferred to Pfizer or other authorized parties will be identified by this single, 
subject-specific code. The investigator site will maintain a confidential list of subjects who 
participated in the study, 
 
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
the clinical study agreement (CSA) and applicable 
privacy laws. 
The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws. 

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The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection. 
The investigator must ensure that each study subject or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the 
 personal data. The investigator further must 
ensure that each study subject or his or her legally acceptable representative is fully informed 
about his or her right to access and correct his or her personal data and to withdraw consent 
for the processing of his or her personal data. 
Whenever consent is obtained from a 
 (legally acceptable representative, the 
 assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC. If the investigator determines 
that a 
capacity is so limited that he or she cannot reasonably be 
consulted, then, as permitted by the IRB/EC and consistent with local regulatory and legal 
 be waived with source documentation of the reason 
assent was not obtained. If the study subject does not provide his or her own consent, the 
source documents must record why the subject did not provide consent (eg, minor,  
decisionally impaired adult), how the investigator determined that the person signing the 
consent was the su
 acceptable representative, the consent 
 
to the study subject (eg, parent, spouse), and that the 
 assent was obtained or waived. 
If assent is obtained verbally, it must be documented in the source documents. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject (or 
 
 
assent, when applicable,) before any study-specific activity is performed (unless a waiver of 
informed consent has been granted by an IRB/EC). The investigator will retain the original 
document. 
15.2. Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons.  In any circumstance, every effort should be made to document 
subject outcome, if applicable. The investigator should inquire about the reason for 
withdrawal and follow-up with the subject regarding any unresolved AEs. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
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15.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent[/assent] documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained in the investigator file.  Copies of IRB/IEC approvals should 
be forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation. 
15.4. Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organisations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
16. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS (AEs)/ADVERSE  
REACTIONS 
 
Table 8. 
Summary of Study AE Reporting Requirementsa 
Safety event 
Recorded on the Case Report 
Form 
Reported on the CT 
SAE Report Form 
Report Form to Pfizer 
Safety within 24 hours 
of awareness 
SAE 
1. All SAEs occurring within 
15 minutes of study sample 
collection (ie, study urine or 
saliva specimens). 
 
2. SAEs determined to be related 
to a Pfizer product during entire 
study period. 
 
3. Research-related injuries during
entire study period. 
Only SAEs determined to
be related to a Pfizer 
product. 

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Non-serious AE 
AEs occurring within 15 minutes 
after study sample collection (ie, 
study urine or saliva specimens).
None. 

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Safety event 
Recorded on the Case Report 
Form 
Reported on the CT 
SAE Report Form 
Report Form to Pfizer 
Safety within 24 hours 
of awareness
Scenarios involving 
exposure to a Pfizer 
product, including exposure 
during pregnancy or breast 
feeding, medication error, 
overdose, misuse, 
extravasation, and 
occupational exposure. 
All involving exposure to a Pfizer 
product (regardless of whether 
associated with an AE), except 
occupational exposure, during 
entire study period. 
All (regardless of 
whether associated with 
an AE) involving 
exposure to a Pfizer 
product. 
 
Note: Any associated AE 
(either serious or non-
serious) is reported 
together with the 
exposure scenario. 
a. 
See full detail on reporting requirements and definitions in Protocol Section 16.1, Section 16.2, and 16.3. 
16.1. Adverse Events 
An AE is defined as any untoward medical occurrence and can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
whether or not related 
n the study. 
This study includes qualifying diagnostic or monitoring procedures required per protocol to 
collect clinical data needed to meet the study objectives, which are not standard-of-care but 
that do not pose more than a minimal risk or burden to the study participant. The qualifying 
procedures in this study are: 
Qualifying diagnostic or monitoring procedure(s) 
Recording Time Period 
Urine collection 
15 minutes 
Saliva sample collection
15 minutes
Any AE that occurs up to 15 minutes after a study-related urine or saliva sample collection 
must be recorded. 
The investigator is required to assess whether the AE may be related to the 
 
participation in the study.  All AEs (ie, serious and non-serious, including those attributed to 
a qualifying procedure identified as RRI) are collected in the clinical study database. 
The investigator must pursue and obtain information adequate to determine the outcome of 
the AE and to assess whether it meets the criteria for classification as an RRI requiring 
immediate notification to Pfizer as described below.

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16.2. Research-Related Injury (RRI) 
Should a participant, in the 
suffer a medically important RRI caused 
by their participation in the study, the designated Pfizer clinician or medical monitor must be 
notified immediately and the AE documented in the eCRF. 
A medically important RRI is any untoward medical occurrence 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); 
Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an injury is an important 
medical event.  An important medical event may not be immediately life-threatening and/or  
result in death or hospitalisation.  However, if it is determined that the event may jeopardise 
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. 
An investigator may be requested by the designated Pfizer clinician or medical monitor to 
obtain specific additional follow-up information in an expedited fashion.  In general, this will 
include a description of the injury in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant treatments, vaccines, and/or illnesses, 
must be provided.  In the case of a participant death, a summary of available autopsy findings 
must be submitted as soon as possible to Pfizer or its designated representative. 
 
16.3. Reporting of Selected Exposures and AEs Related to Pfizer Products 
If during the conduct of this study, the investigator or study staff becomes aware (for 
example, during the course of medical record review or through spontaneous, non-solicited 
reports from the patient) of an serious AE that has been noted to be related to a Pfizer 
product or certain exposures to a Pfizer product, these events must be reported to CT SAE 
Report Form Report Form to Pfizer Safety (local Drug Safety Unit) within 24 hours of 
awareness (immediately if fatal or life-threatening). This includes reports related to PCV13 
as well as other Pfizer drugs. These AEs should also be recorded in the eCRF. For each 
subject, the safety event reporting period for these events begins at the time of 
informed consent and lasts through the end of the observation period of the study (Visit 3). 
The investigator or his/her staff might become aware of such events during the participant 
interview (for example, participant spontaneously mentions a serious vaccine 

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or drug reaction related to a Pfizer product) or during study-related medical record review 
(for example, reads a medical note that mentions a diagnosis of a serious vaccine or drug 
reaction involving a Pfizer product).  The investigator may be requested by Pfizer Safety to 
obtain specific follow-up information in an expedited fashion.  This information is more 
detailed than that recorded on the eCRF.  Additional information on safety reporting will be 
provided in the Study Reference Manual. 
16.4. Definition of Serious Adverse Events (SAEs) 
A SAE is any untoward medical occurrence in a patient administered a medicinal or 
nutritional product (including pediatric formulas) at any that: 
Results in death; 
Is life-threatening; 
Requires inpatient hospitalisation or prolongation of hospitalisation (see below for 
circumstances that do not constitute AEs); 
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
Results in congenital anomaly/birth defect. 
Or that is considered to be: 
An important medical event. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalisation.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
16.5. Selected Exposures to Pfizer Product that Require Reporting to Pfizer Safety 
The selected Pfizer product exposures that require reporting to Pfizer Safety/local Drug 
Safety Unit even in the absence of an AE are as follows: exposure during pregnancy or 
breast feeding, medication error, overdose, misuse, extravasation, and occupational 
exposure.  Additional information on these definitions will be provided in the Study 
Reference Manual. 

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17. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
17.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
 
17.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
PI of the results of the study based on information collected or generated by the PI, whether 
or not the results are favorable to the Pfizer product.  However, to ensure against inadvertent 
disclosure of confidential information or unprotected inventions, the investigator will 
provide Pfizer an opportunity to review any proposed publication or other type of disclosure 
of the results of the study (collectively, 
 before it is submitted or otherwise 
disclosed. 
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicenter study, the investigator agrees that the first publication is to 
be a joint publication covering all investigator sites, and that any subsequent publications by 
the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - 
 
Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 

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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA. 
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control. If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues. 

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18. REFERENCES 
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Madrid, Spain 2018. Available from: 
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date%253A201801010000-201812312359. Accessed: June 26, 2019. 
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Invasive pneumococcal disease. Annual Epidemiological Report for 2017. European 
Centre for Disease Prevention and Control. Stockholm, Sweden 2019. [Available from: 
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Accessed: June 26, 2019. 
3.
Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MP, Miller E. Effect of the 
13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in 
England and Wales 4 years after its introduction: an observational cohort study. Lancet 
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4.
Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C, Bennett NM, et al. 
Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive 
pneumococcal disease in children and adults in the USA: analysis of multisite, 
population-based surveillance. Lancet Infect Dis. 2015;15(3):301-9. 
5.
Angoulvant F, Levy C, Grimprel E, Varon E, Lorrot M, Biscardi S, et al. Early impact 
of 13-valent pneumococcal conjugate vaccine on community-acquired pneumonia in 
children. Clin Infect Dis. 2014;58(7):918-24. 
6.
Bonten MJ, Huijts SM, Bolkenbaas M, Webber C, Patterson S, Gault S, et 
al.Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl 
J Med. 2015;372(12):1114-25. 
7.
McLaughlin JM, Jiang Q, Isturiz RE, Sings HL, Swerdlow DL, Gessner BD, et 
al.Effectiveness of 13-valent pneumococcal conjugate vaccine against hospitalization 
for community-acquired pneumonia in older US adults: A test-negative design. Clin 
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8.
Picazo J, Ruiz-Contreras J, Casado-Flores J, Negreira S, Baquero F, Hernandez- 
Sampelayo T, et al. Effect of the different 13-valent pneumococcal conjugate 
vaccination uptakes on the invasive pneumococcal disease in children: Analysis of a 
hospital-based and population-based surveillance study in Madrid, Spain, 2007-2015. 
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9.
Latasa Zamalloa P, Sanz Moreno JC, Ordobas Gavin M, Barranco Ordonez MD, Insua 
Marisquerena E, Gil de Miguel A, et al. Trends of invasive pneumococcal disease and 
its serotypes in the Autonomous Community of Madrid. Enferm Infecc Microbiol 
Clin.2018;36(10):612-20. 
10.
Boletín epidemiológico de la Comunidad de Madrid. Madrid, Spain. Dirección General 
de Salud Pública, Consejería de Sanidad; 2018. Available from: 
http://www.comunidad.madrid/publicacion/ref/20209. Accessed: June 26, 2019. 
11.
Nota informativa sobre vacunación frente a Neumococo en el adulto. Madrid, 
Spain.Consejería de Sanidad, Dirección General de Salud Pública; 2018. Available from: 
http://www.madrid.org/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&b 
lobheadername1=Content- 
disposition&blobheadername2=cadena&blobheadervalue1=filename%3DNota+informa 
tiva+Neumo13- 
Enero18f.pdf&blobheadervalue2=language%3Des%26site%3DPortalSalud&blobkey=i 
d&blobtable=MungoBlobs&blobwhere=1352946849880&ssbinary=true. 
Accessed: June 26, 2019. 
 
12.
Statistics of the Continuous Register. Population by sex, municipalities and age (year 
to year). Instituto Nacional de Estadística (INE); 2020. Available from: 
https://www.ine.es/jaxiT3/Tabla.htm?t=33847&L=0. Accessed: March 25, 2021. 
13.
Arriola, C. S., Kim, L., Langley, G., Anderson, E. J., Openo, K., Martin, A. M., ... & 
Chaves, S. S. (2020). Estimated Burden of Community-Onset Respiratory Syncytial 
Virus Associated Hospitalizations Among Children Aged< 2 Years in the United States, 
2014 15. Journal of the Pediatric Infectious Diseases Society, 9(5), 587-595. 
14.
Rha BCA, Lively JY, et al. Respiratory syncytial virus-associated hospitalizations among 
young children 2015 2016. Pediatrics. 2020;146(1):e20193611 
15.
Ramilo, O., & Mejias, A. (2020). Measuring the Burden of RSV in Children to Precisely 
Assess the Impact of Preventive Strategies. Pediatrics, 146(1). 
16.
Ivey, K. S., Edwards, K. M., & Talbot, H. K. (2018). Respiratory syncytial virus and 
associations with cardiovascular disease in adults. Journal of the American College of 
Cardiology, 71(14), 1574-1583. 
17.
Falsey, A. R., et al. (2005). "Respiratory syncytial virus infection in elderly and high-risk 
adults." N Engl J Med 352(17): 1749-1759. 
18.
Chatzis, O., Darbre, S., Pasquier, J., Meylan, P., Manuel, O., Aubert, J. D., ... & Asner, S. 
A. (2018). Burden of severe RSV disease among immunocompromised children and 
adults: a 10 year retrospective study. BMC infectious diseases, 18(1), 1-9. 
 
 

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19.
Ackerson, B., Tseng, H. F., Sy, L. S., Solano, Z., Slezak, J., Luo, Y., ... & Shinde, V. 
(2019). Severe morbidity and mortality associated with respiratory syncytial virus versus 
influenza infection in hospitalized older adults. Clinical Infectious Diseases, 69(2), 197-
203. 
20.
Branche, A. R., Saiman, L., Walsh, E. E., Falsey, A. R., Sieling, W. D., Greendyke, W., ... 
& Finelli, L. (2021). Incidence of respiratory syncytial virus infection among hospitalized 
adults, 2017 2020. Clinical Infectious Diseases. 
21.
Dowell, S. F., Anderson, L. J., Gary Jr, H. E., Erdman, D. D., Plouffe, J. F., File Jr, T. M., 
... & Breiman, R. F. (1996). Respiratory syncytial virus is an important cause of 
community-acquired lower respiratory infection among hospitalized adults. Journal of 
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Thompson, W. W., Shay, D. K., Weintraub, E., Brammer, L., Cox, N., Anderson, L. J., & 
Fukuda, K. (2003). Mortality associated with influenza and respiratory syncytial virus in 
the United States. Jama, 289(2), 179-186. 
23.
Falsey, A. R., Hennessey, P. A., Formica, M. A., Cox, C., & Walsh, E. E. (2005). 
Respiratory syncytial virus infection in elderly and high-risk adults. New England Journal 
of Medicine, 352(17), 1749-1759. 
24.
Falsey, A. R., McElhaney, J. E., Beran, J., Van Essen, G. A., Duval, X., Esen, M., ... & 
Taylor, S. (2014). Respiratory syncytial virus and other respiratory viral infections in older 
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209(12), 1873-1881. 
25.
Jain, S., Self, W. H., Wunderink, R. G., Fakhran, S., Balk, R., Bramley, A. M., ... & 
Finelli, L. (2015). Community-acquired pneumonia requiring hospitalization among US 
adults. New England Journal of Medicine, 373(5), 415-427. 
26.
Broome CV, Facklam RR, Fraser DW. Pneumococcal disease after pneumococcal 
vaccination: an alternative method to estimate the efficacy of pneumococcal vaccine. N 
Engl J Med. 1980;303(10):549-52. 
27.
Suzuki M, Dhoubhadel BG, Ishifuji T, Yasunami M, Yaegashi M, Asoh N, et 
al.Serotype-specific effectiveness of 23-valent pneumococcal polysaccharide vaccine 
against pneumococcal pneumonia in adults aged 65 years or older: a multicentre, 
prospective, test-negative design study. Lancet Infect Dis. 2017;17(3):313-21. 
28.
Jimenez-Garcia R, Hernandez-Barrera V, Rodriguez-Rieiro C, Carrasco Garrido P, 
Lopez de Andres A, Jimenez-Trujillo I, et al. Comparison of self-report influenza 
vaccination coverage with data from a population based computerized vaccination 
registry and factors associated with discordance. Vaccine. 2014;32(35):4386-92. 
 
 

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29.
Elberse KE, van de Pol I, Witteveen S, van der Heide HG, Schot CS, van Dijk A, et 
al.Population structure of invasive Streptococcus pneumoniae in The Netherlands in the 
pre-vaccination era assessed by MLVA and capsular sequence typing. PLoS 
One.2011;6(5):e20390. 
30.
Bentley SD, Aanensen DM, Mavroidi A, Saunders D, Rabbinowitsch E, Collins M, et 
al. Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal 
serotypes. PLoS Genet. 2006;2(3):e31. 
31.
Huijts SM, Pride MW, Vos JM, Jansen KU, Webber C, Gruber W, et al. Diagnostic 
accuracy of a serotype-specific antigen test in community-acquired pneumonia. Eur 
Respir J. 2013;42(5):1283-90. 
32.
Pilishvili T, Bennett NM. Pneumococcal disease prevention among adults: Strategies 
for the use of pneumococcal vaccines. Vaccine. 2015;33 Suppl 4:D60-5. 
33.
Sousa D, Justo I, Domínguez A, Manzur A, Izquierdo C, Ruiz L, et al. Community- 
acquired pneumonia in immunocompromised older patients: incidence, causative 
organisms and outcome. Clin Microbiol Infect. 2013;19(2):187-92. 
19. LIST OF TABLES 
Table 1. 
Pneumococcal Adult Vaccination in Madrid as of January 2018 
Table 2. 
PCV13 and PPV23 Uptake in Madrid Region Per Age (September 2019) 
Table 3. 
Population of Adults 60 Years and Older Living in Participating 
 
Geographic Catchment Area (January 2018) 
Table 4. 
Incidence of Hospitalised Pneumonia Cases in Adults 60 Years and Older  
Table 5. 
Codes for Hospitalised Pneumonia Under ICD-10 
Table 6. 
Sample Size Scenarios for Vaccine Effectiveness Calculations At Interim 
Table 7. 
Categorisation of Risk Factors by Immunocompetence 
Table 8. 
Summary of Study Adverse Event Reporting Requirements 
20. LIST OF FIGURES 
Figure 1. 
Map of Study Locality 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
Not applicable. 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable.