Examining Vaccine Effectiveness (VE) of Flublok Relative to Standard Dose Inactivated Influenza Vaccine Among Kaiser Permanente Northern California Members Aged 18-64 Years
Conditions: Influenza, Pneumonia, Lower Respiratory Tract Infection, Acute Myocardial Infarction, Congestive Heart Failure, Stroke
Sponsor: Kaiser Permanente

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Examining vaccine effectiveness (VE) of Flublok® Quadrivalent 
(Influenza Vaccine) relative to standard dose inactivated 
influenza vaccine among Kaiser Permanente Northern 
California members aged 18-64 years 
 
Phase IV, multi-center, modified-cluster randomized study to assess the effectiveness of Flublok 
Quadrivalent vaccine compared to standard dose inactivated influenza vaccine in adults  
 
Study Protocol 
Study Code: 
VAP00003  
Development Phase: 
Phase IV  
Sponsor: 
Kaiser Permanente Northern California 
Kaiser Permanente Vaccine Study Center 
1 Kaiser Plaza, 16th Floor 
Oakland, CA 94612 
Product(s): 
Flublok Quadrivalent vaccine 
Standard-Dose Inactivated Influenza Vaccine (SD-IIV)* 
* to be determined prior to influenza season 
Form / Route: 
Liquid/Intramuscular injection (0.5 mL) 
Indication For This Study: 
Comparative vaccine effectiveness of 2018-2019 and 2019-2020 
formulations of Flublok Quadrivalent vaccine and SD-IIV in adults 18 
through 64 years of age 
Manufacturer: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Principal Investigator: 
Nicola Klein, MD, PhD 
 
Contributing Investigators: 
Bruce Fireman, MA 
Ned Lewis, MPH 
Laurie Aukes, RN 
John Hansen, MPH 
Amber Hyman, MPH 
Project Manager and Study 
Leader 
 
Amber Hyman, MPH 
  
Version and Date of the Protocol: 
Version 2.0 dated 8 May 2020 
 
ClinicalTrials.gov: 
NCT03694392 
 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 

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History of Protocol Versions 
Table 1: Previous versions of the protocol 
Version* 
Date 
Comments 
0.1 
18 July 2018 
Draft Protocol sent to Sanofi from KPVSC 
0.2 
3 Aug 2018 
Revised draft protocol sent to Sanofi from KPVSC 
0.3 
11 Sept 2018 
Revised draft protocol sent to Sanofi from KPVSC 
1.0 
3 Oct 2018 
Final protocol sent to Sanofi from KPVSC 
* Versions in bold font have been approved by the Independent Ethics Committee(s) (IEC[s]) / Institutional Review 
Board(s) (IRB[s]) and used in the study. 
 

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Table of Contents 
History of Protocol Versions ............................................................................................. 2 
List of Tables ...................................................................................................................... 6 
Synopsis .............................................................................................................................. 7 
Table of Study Procedures ................................................................................................ 9 
List of Abbreviations ....................................................................................................... 10 
1 
Introduction........................................................................................................ 11 
1.1 
Background ....................................................................................................... 11 
1.2 
Background of the Product ................................................................................. 13 
1.3 
Potential Benefits and Risks ............................................................................... 13 
1.3.1 
Potential Benefits to Subjects........................................................................... 13 
1.3.2 
Potential Risks to Subjects ............................................................................... 13 
1.4 
Rationale for the Study ...................................................................................... 14 
2 
Study Objectives ................................................................................................. 14 
2.1 
Primary Objective .............................................................................................. 14 
2.2 
Secondary Objectives......................................................................................... 14 
2.3 
Exploratory Objectives ...................................................................................... 15 
3 
Investigators and Study Organization ............................................................... 16 
4 
Independent Ethics Committee / Institutional Review Board .......................... 16 
5 
Investigational Plan ............................................................................................ 16 
5.1 
Description of the Overall Study Design and Plan .............................................. 16 
5.1.1 
Study Design ................................................................................................... 16 
5.1.2 
Justification of the Study Design...................................................................... 16 
5.1.3 
Study Plan ....................................................................................................... 17 
5.1.4 
Vaccine Distribution Procedures ...................................................................... 18 
5.1.5 
Planned Study Calendar ................................................................................... 19 
5.2 
Study Population................................................................................................ 20 
5.2.1 
Recruitment Procedures ................................................................................... 20 
5.2.2 
Informed Consent Procedures .......................................................................... 20 
5.2.3 
Screening Criteria ............................................................................................ 20 
5.2.4 
Inclusion Criteria ............................................................................................. 20 

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5.2.5 
Exclusion Criteria ............................................................................................ 20 
5.2.6 
Medical History ............................................................................................... 20 
5.2.7 
Contraindications for Subsequent Vaccinations ............................................... 21 
5.2.8 
Classification of Subjects Who Discontinue the Study ..................................... 21 
5.2.9 
Follow-up of Discontinuations ......................................................................... 21 
5.2.10 
Follow-up and Reporting of Pregnancies ......................................................... 21 
5.3 
Modification of the Study and Protocol .............................................................. 21 
5.4 
Interruption of the Study .................................................................................... 22 
6 
Vaccines Administered....................................................................................... 22 
6.1 
Identity of the Investigational Product(s)............................................................ 22 
6.1.1 
Identity of Study Product(s) ............................................................................. 22 
6.1.1.1 
Composition .................................................................................................. 22 
6.1.1.2 
Preparation and Administration ..................................................................... 22 
6.1.1.3 
Dose Selection and Timing ............................................................................ 23 
6.1.2 
Identity of Comparator SD-IIV Product(s) ....................................................... 23 
6.1.2.1 
Composition .................................................................................................. 23 
6.1.2.2 
Preparation and Administration ..................................................................... 23 
6.1.2.3 
Dose Selection and Timing ............................................................................ 23 
6.2 
Identity of Other Product(s) ............................................................................... 23 
6.3 
Product Logistics ............................................................................................... 24 
6.3.1 
Labeling and Packaging ................................................................................... 24 
6.3.2 
Product Shipment, Storage, and Accountability ............................................... 24 
6.3.2.1 
Product Shipment .......................................................................................... 24 
6.3.2.2 
Product Storage ............................................................................................. 24 
6.3.2.3 
Product Accountability .................................................................................. 24 
6.3.3 
Replacement Doses ......................................................................................... 24 
6.3.4 
Disposal of Unused Products ........................................................................... 25 
6.3.5 
Recall of Products............................................................................................ 25 
6.4 
Blinding and Code-breaking Procedures ............................................................ 25 
6.5 
Randomization and Allocation Procedures ......................................................... 25 
6.6 
Vaccine Administration Compliance .................................................................. 26 
6.7 
Concomitant Medications and Other Therapies .................................................. 26 
7 
Management of Samples .................................................................................... 26 
8 
Endpoints and Assessment Methods ................................................................. 26 
8.1 
Primary Endpoints and Assessment Methods ..................................................... 26 
8.1.1 
Relative Vaccine Effectiveness of Flublok Quadrivalent vaccine ..................... 26 
8.2 
Secondary Endpoints and Assessment Methods ................................................. 27 

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8.2.1 
Relative Vaccine Effectiveness of Flublok ....................................................... 27 
8.3 
Exploratory Endpoints and Assessment Methods ............................................... 28 
8.3.1 
Relative Vaccine Effectiveness of Flublok ....................................................... 28 
9 
Reporting of Serious Adverse Events ................................................................ 29 
9.1 
Initial Reporting by the Investigator ................................................................... 29 
9.2 
Follow-up Reporting by the Investigator ............................................................ 30 
9.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ............ 30 
9.4 
Assessment of Causality .................................................................................... 30 
9.5 
Reporting SAEs to Health Authorities and IECs / IRBs...................................... 30 
10 
Data Collection and Management ..................................................................... 30 
10.1 
Data Collection .................................................................................................. 30 
10.2 
Data Management .............................................................................................. 31 
10.3 
Data Review ...................................................................................................... 31 
11 
Statistical Methods and Determination of Sample Size .................................... 31 
11.1 
Statistical Methods............................................................................................. 31 
11.2 
Sample Size and Power Calculations.................................................................. 32 
12 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities .............. 33 
12.1 
Ethical Conduct of the Study / Good Clinical Practice........................................ 33 
12.2 
Source Data and Source Documents ................................................................... 33 
12.3 
Confidentiality of Data and Access to Subject Records ...................................... 34 
12.4 
Monitoring, Auditing, and Archiving ................................................................. 34 
12.4.1 
Monitoring ...................................................................................................... 34 
12.4.2 
Audits and Inspections ..................................................................................... 34 
12.4.3 
Archiving ........................................................................................................ 34 
12.5 
Financial Contract and Insurance Coverage........................................................ 34 
12.6 
Stipends for Participation ................................................................................... 35 
12.7 
Publication Policy .............................................................................................. 35 
13 
Reference List ..................................................................................................... 36 
14 
Signature Page.................................................................................................... 37 
15 
Appendices ......................................................................................................... 38 
 

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List of Tables 
Table 1: Previous versions of the protocol.....................................................................................2 
 

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Synopsis 
Company: 
Sanofi Pasteur, Inc. 
Products: 
Flublok Quadrivalent (Influenza Vaccine) 
Active Substances: 
• 
45 µg hemagglutinin (HA) per virus strain per dose 
Title of the Trial: 
Examining vaccine effectiveness (VE) of Flublok® Quadrivalent (Influenza 
Vaccine) relative to standard dose inactivated influenza vaccine (SD-IIV) 
among Kaiser Permanente Northern California members aged 18-64 years 
Development Phase: 
Phase IV 
Coordinating Investigator: 
Nicola Klein, MD, PhD 
Study Sites: 
Kaiser Permanente Northern California 
Planned Study Period: 
August 2018 to May 2022 
Study Design, Schedule of Study 
Procedures, and Methodology: 
Multi-center, modified-cluster randomized study 
Early Safety Data Review: 
N/A 
Interruption of the Study: 
N/A 
Observational Objectives: 
To estimate the relative vaccine effectiveness of Flublok Quadrivalent 
vaccine versus SD-IIV in adults 18-64 years against select endpoints 
(specified below) 
Observational Endpoints: 
PCR-confirmed influenza, hospitalized influenza, hospitalized community-
acquired pneumonia, and cardio-respiratory events 
Planned Sample Size: 
~2,400,000 
Duration of Participation in the 
Study: 
N/A; this is an observational, data-only study 
Licensed Study Product 1: 
Flublok Quadrivalent vaccine 
 Form: 
Single 0.5 mL dose  
 Composition: 
• 
45 mcg HA of each of influenza types and subtypes A (H1N1), A 
(H3N2), and two B lineages (B/Yamagata and B/Victoria) 
• 
sodium chloride (4.4 mg) 
• 
monobasic sodium phosphate (0.195 mcg) 
• 
dibasic sodium phosphate (1.3 mg), and polysorbate 20 (Tween®20) 
(27.5 mcg) 
• 
may also contain residual amounts of baculovirus and Spodoptera 
frugiperda cell proteins (≤ 19 mcg), baculovirus and cellular DNA (≤ 
10 ng), and Triton X-100 (≤ 100 mcg)  
 Route: 
Liquid/Intramuscular injection (0.5 mL) 
 
 
Licensed Study Product 2: 
To be determined prior to each influenza season 
 Form: 
Single 0.5 mL dose 
 Composition: 
• 
15 mcg HA of each of influenza types and subtypes A (H1N1), A 
(H3N2), and one or two B lineages (trivalent or quadrivalent, 
respectively, of B/Yamagata and/or B/Victoria) 

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• 
Additional composition details will vary, determined by national Kaiser 
Permanente vaccine procurement 
 Route: 
Liquid/Intramuscular injection (0.5 mL) 
  
 
Inclusion Criteria: 
Adults 18-64 years who receive Flublok or standard dose inactivated 
influenza vaccine during the 2018-2019, 2019-2020, and 2020-2021 
influenza seasons be determined prior to each influenza season 
Exclusion Criteria: 
Adults 18-64 years who do not receive Flublok or SD-IIV during the 2018-
2019, 2019-2020, and/or 2020-2021 influenza seasons 
Statistical Methods: 
• 
The relative vaccine effectiveness will be calculated based on the 
formula rVE = 1 – relative Hazard Ratio (rHR), where rHR is estimated 
from a fully adjusted Cox Regression model (further described in 
Section 11.1).  
 

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Table of Study Procedures 
Not applicable. 
 

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List of Abbreviations 
AESI 
Adverse Event of Special Interest 
CDC 
Centers for Disease Control and Prevention 
EMR 
Electronic Medical Record 
HR 
Hazard Ratio 
SD-IIV 
Standard-Dose Inactivated Influenza Vaccine 
SD-IIV4 
Standard-Dose Quadrivalent Inactivated Influenza Vaccine 
ICD-10 
International Classification of Diseases, 10th Revision 
ILI 
Influenza-Like Illness 
IRB 
Institutional Review Board 
KPNC 
Kaiser Permanente Northern California 
KPVSC 
Kaiser Permanente Vaccine Study Center 
PCR 
Polymerase Chain Reaction 
QIV 
Quadrivalent Influenza Vaccine 
RCT 
Randomized Control Trial 
RR 
Relative Risk 
rVE 
Relative Vaccine Effectiveness 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Event 
VAERS 
Vaccine Adverse Event Reporting System 
VE 
Vaccine Effectiveness 
 

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1 
Introduction 
1.1 
Background 
Influenza viruses types A and B belong to the genus Orthomyxoviridae and are characterized as 
enveloped, negative-strand, segmented ribonucleic acid (RNA) viruses. The viral envelope 
contains 2 virus-coded glycoprotein spikes, the hemagglutinin (HA) and neuraminidase (NA) 
proteins, which are key antigens in the host response to influenza virus in both natural 
infection and vaccination. A third protein, M2, is a minor envelope component of the A-strain 
viruses. 
Influenza is transmitted through inhalation of virus-containing droplets from infected individuals. 
The incubation period is usually 1 to 2 days. The virus multiplies in the ciliated columnar 
epithelium of the upper- and lower-respiratory tract, causing cellular necrosis and sloughing. 
Virus shedding typically begins just before illness onset (within 24 hours), rapidly peaks, and 
remains elevated for 1 to 2 days before rapidly declining to low levels. Usually, virus shedding 
lasts a total of 5 to 10 days. 
There is considerable variation in the severity of illness in different individuals, partly due to age, 
general health, and immune status relative to previous influenza infections and vaccination. The 
classic symptoms include rapid onset (12 hours or less) of malaise, fever, myalgia, headache, and 
a non-productive cough or sore throat. Most symptoms last several days, but malaise and cough 
may last for a week or more. Complications of influenza include primary viral pneumonia, 
secondary bacterial pneumonia, and exacerbation of underlying medical conditions such as 
chronic obstructive pulmonary disease and congestive heart failure.  
While influenza affects all age groups, seniors, children younger than 5 years of age, and persons 
with underlying health problems are at increased risk for complications. Members of high-risk 
groups who become ill with influenza are more likely than the general population to require 
hospitalization complications of the infection (e.g., pneumonia and cardiovascular events). 
Groups considered at higher risk for influenza-related complications include persons aged ≥65 
years due to immunosenescence and adults 50–64 years of age and older because they are likely 
to have chronic medical conditions that put them at increased risk for severe influenza illness. 
Antigenic variation is an important feature of the influenza virus. The viral HA and NA surface 
antigens are subject to continuous and sequential evolution within immune or partially immune 
populations. Antigenic drift results from mutation(s) affecting the RNA segment coding for either 
HA or NA, but more commonly HA. As a result, there is alteration in protein structure involving 
1 or a few amino acids, resulting in minor changes in antigenicity. Antigenic variants within a 
subtype (e.g., H1 or H3) emerge and through natural selection gradually become the more 
predominant circulating virus strain, while the preceding antigenic variant is suppressed by 
specific immunity in the population. In contrast to antigenic drift, antigenic shift represents the 
emergence of completely new subtypes, typically through gene reassortment with other 
circulating strains and acquisition of antigenically different gene sequences. Antigenic shift 
occurs at irregular intervals and may lead to pandemics. While influenza B appears to be more 
genetically stable than influenza A, the dominant circulating B strain typically varies from season 
to season. For over a decade, both Yamagata and Victoria lineages have co-circulated during each 

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season with varying prevalence. The large antigenic divergence between the 2 influenza B 
lineages limits antigenic cross-reactivity, and immunity to 1 B lineage does not provide adequate 
protection against the other. Accordingly, switching from a trivalent vaccine to a quadrivalent 
vaccine is expected to prevent additional morbidity and mortality associated with mismatched 
influenza B strains that may occur with trivalent vaccines. With this in mind, Flublok 
Quadrivalent vaccine were developed. 
Vaccination with influenza vaccine is the primary method for preventing influenza and its severe 
complications. It has been shown to be effective in reducing influenza-associated morbidity and 
mortality in groups at increased risk for influenza-related complications such as infants and young 
children and persons 50 years of age and older. Of note, immune responses to the vaccine are 
lower in seniors than those in young healthy adults. Strategies to improve immune responses to 
the vaccine in the elderly population could provide significant additional reductions in influenza-
associated morbidity and mortality. One approach is to increase the dose of HA in vaccines. 
Previous studies evaluating the immune responses in terms of hemagglutination inhibition (HAI) 
antibodies with higher doses of HA per strain in different influenza vaccines support a dose-
response effect. 
Flublok Quadrivalent vaccine is a recombinant HA influenza vaccine indicated for active 
immunization against disease caused by influenza A subtype viruses and type B viruses contained 
in the vaccine for adults 18 years of age and older. Use of recombinant DNA techniques to 
produce vaccine antigen expressed in cell culture is a method that avoids growing the influenza 
viruses in embryonated hen’s eggs. Recombinant technology also allows control over the 
sequence of the full-length HA produced. The recombinant proteins are highly purified and the 
vaccine contains no egg protein, preservatives, or antibiotics, any of which may produce 
hypersensitivity reaction in some individuals. 
Flublok Quadrivalent vaccine contains 45 µg HA per virus strain per dose, 3 times the amount of 
HA compared to standard-dose inactivated quadrivalent influenza vaccine (SD-IIV4). The high 
purity of a recombinant antigen enables administration of a higher concentration of HA antigen 
without an increase in adverse effects in humans. This higher dose of antigen may be a particular 
advantage to older adults whose immune responses to influenza vaccines can be suboptimal. 
During this study, Flublok Quadrivalent or SD-IIV will be administered according to the 
guidelines in the Prescribing Information materials and only to persons for whom it is indicated. 
The 2018–2019, 2019–2020, and 2020–2021 formulations of recombinant influenza vaccine 
(Flublok Quadrivalent vaccine) and SD-IIV will be evaluated as described below. 
The overall objective of this study is to describe the effectiveness of Flublok Quadrivalent vaccine 
compared to SD-IIV in adults 18 through 64 years of age.  
 

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1.2 
Background of the Product 
Previous Clinical Experience: Flublok Vaccine 
Flublok vaccine (trivalent formulation) was first approved in the United States on 16 January 
2013 for use in adults 18–49 years of age. Licensure was based on results of a randomized 
controlled efficacy trial of Flublok vs placebo in 2344 subjects. The age indication was expanded 
to include all adults 18 years of age and older in 2014 based on safety and immunogenicity data 
from 2 studies; the first was conducted among 869 adults 65 years of age and older and the second 
was conducted among 602 adults 50–64 years of age. 
Flublok Quadrivalent Vaccine 
On 07 October 2016, the FDA licensed Flublok Quadrivalent vaccine for adults 18 years of age 
and older. This approval was based on 2 studies conducted during the 2014–2015 influenza 
season: (1) an immunogenicity and safety study of Flublok Quadrivalent vaccine versus SD-IIV4 
in 1350 adults 18–49 years of age and (2) an efficacy, immunogenicity, and safety study of 
Flublok Quadrivalent vaccine versus SD-IIV4 in 9003 adults 50 years of age and older. In the 
former study (of adults 18–49 years of age), immunogenicity of Flublok Quadrivalent vaccine 
was non-inferior to that of the SD-IIV4 comparator for 3 of the 4 antigens; the response to the B 
Victoria lineage strain did not meet the non-inferiority criteria but the response was low in both 
vaccine groups, making comparisons uninterpretable. In the latter efficacy study of adults 50 
years of age and older, Flublok Quadrivalent vaccine, compared to the SD-IIV4 comparator, 
demonstrated 30% to 43% greater efficacy in preventing laboratory-confirmed, protocol-defined 
influenza-like-illness caused by any viral type or subtype. 
The most common local adverse reactions (ARs) to Flublok Quadrivalent vaccine include 
tenderness and pain at the injection site. The most common systemic reactions include headache, 
fatigue, myalgia, and arthralgia, with most events being mild to moderate in severity. Safety 
profiles of Flublok influenza vaccine and inactivated influenza vaccine (trivalent and quadrivalent 
comparisons) were demonstrated to be similar in clinical trials. 
1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
Not applicable. This is not clinical trial. The present study is a prospective study using EMR data 
that are collected as part of routine clinical care. 
1.3.2 
Potential Risks to Subjects 
Not applicable. This is not clinical trial. The present study is a prospective study using EMR data 
that are collected as part of routine clinical care. 

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1.4 
Rationale for the Study 
Interventions that prevent influenza have a positive impact on other consequences of influenza 
infection, including influenza-related hospitalizations, complications, and deaths. An improved 
vaccine for the prevention of influenza in older adults is expected to have significant impact on 
public health. In an efficacy, immunogenicity, and safety study of Flublok Quadrivalent vaccine 
versus SD-IIV4 among 9,003 adults 50 years of age and older, Flublok Quadrivalent vaccine, 
compared to SD-IIV4, demonstrated 30% to 43% greater efficacy in preventing laboratory-
confirmed, protocol-defined influenza-like-illness caused by any viral type or subtype. 
According to the Centers for Disease Control and Prevention, recombinant technology potentially 
offers additional flexibility over egg- and cell-propagated vaccines. Flublok Quadrivalent vaccine 
is specifically manufactured to achieve an exact genetic match to the HA of each influenza strain 
selected by the World Health Organization and the US Food and Drug Administration for 
inclusion in the annual seasonal influenza vaccine. In addition, recombinant-based influenza 
vaccines have the promising benefit to offer better protection by avoiding potential viral 
adaptation observed with egg- and cell-propagated influenza vaccines. The primary objective of 
the current study is to evaluate the relative vaccine effectiveness (rVE) of Flublok Quadrivalent 
vaccine compared to SD-IIV. 
2 
Study Objectives 
2.1 
Primary Objective 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against all PCR-confirmed influenza. 
The endpoint for the primary objective is presented in Section 9.1.4. 
2.2 
Secondary Objectives 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed hospitalized influenza. 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against hospitalized community-acquired pneumonia. 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against hospitalized cardio-respiratory events combined (e.g., pneumonia, other 
lower respiratory infections, acute myocardial infarction, congestive heart failure, stroke).  
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed influenza A.  
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed influenza B.  
• Sub-analyses of the above outcomes as feasible by the following pre-existing conditions: 
1. Cardiovascular preexisting conditions composite, which may include: 
myocardial infarction, cerebrovascular accident, atrial fibrillation, arrhythmias, 

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coronary artery disease, valvular heart disease/valvuloplasty, chronic/congestive 
heart failure and/or congenital heart defects, CABG, angioplasty/stents, 
cardioversion, pacemaker, implantable cardioverter defibrillator, LVAD, heart 
transplant, hypertensive disease 
2. Respiratory preexisting conditions composite, which may include: COPD 
and/or pulmonary HTN 
3. Cardiorespiratory preexisting conditions composite: combined pre-existing 
conditions (a) and (b) above 
4. Obesity: based on available height/weight data for a calculated BMI ≥30 or an 
obesity diagnosis (e.g., ICD-10 E66.9) 
5. Diabetes: based on a diagnosis of diabetes 
 
The endpoint(s) for the secondary objective(s) are presented in Section 9.2.4. 
2.3 
Exploratory Objectives 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against exploratory outcomes such as: 
a. Diagnosed with influenza (includes [1] adults with a PCR-positive influenza and 
[2] adults clinically-diagnosed with influenza in any setting but not tested); this 
outcome will exclude those with a clinically-diagnosed influenza but are tested and 
PCR-negative)  
b. All-cause hospitalizations 
c. All-cause mortality 
 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in other age ranges of 
vaccinees — aged 18–64 years and aged 18–49 years — against outcomes such as (but not 
limited to):  
a. All PCR-confirmed influenza 
b. All PCR-confirmed influenza A and influenza B (separate rVE estimates) 
c. PCR-confirmed hospitalized pneumonia 
d. Hospitalized community-acquired pneumonia 
e. Hospitalized cardio-respiratory events combined 
f. All-cause hospitalization 
g. All-cause mortality 
 
• Sub-analyses of the primary and secondary outcomes of sub-groups defined by pre-
existing conditions (as described above in Section 2.2) will be conducted among adults 
18–49 years as feasible  
 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV among adults aged 
18–64 years for PCR-confirmed influenza A subtypes (A(H1N1)pdm09 and A(H3)) and 
lineage for type B influenza (B/Victoria, B/Yamagata) as feasible 
 
The endpoint(s) for the observational objective(s) are presented in Section 9.3.4. 

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3 
Investigators and Study Organization 
This study will be conducted at Kaiser Permanente Northern California (KPNC), which is an 
integrated health care system with a membership population of approximately 4 million in 2018, 
including approximately 2.5 million adults between 18 to 64 years of age. The eligible population 
for this study includes all persons 18 to 64 years of age. KPNC members receive nearly all their 
care at KPNC facilities, which includes approximately 65 medical clinics and 27 hospitals. 
Diagnoses, laboratory tests, vaccines, and medications are all captured in KPNC’s electronic 
medical record (EMR) and clinical databases. 
4 
Independent Ethics Committee / Institutional Review Board 
Kaiser Permanente Vaccine Study Center (KPVSC) received IRB approval on April 3, 2018, to 
conduct the following prospective randomized observational study: “Examining vaccine 
effectiveness (VE) of Flublok Quadrivalent (Influenza Vaccine) relative to standard dose 
inactivated influenza vaccine among Kaiser Permanente Northern California members aged 18-64 
years (Sanofi Pasteur).”  
Because the present study is a prospective study using EMR data that are collected as part of 
routine clinical care, no informed consent will be required. Protected Health Information (PHI) 
will be used by the KPVSC team (i.e., Principal Investigator, Statistician, Data Manager, Data 
Analysts, Project Manager), but no PHI will be made available to anyone outside of KPVSC. All 
data reported to Sanofi Pasteur will be de-identified in accordance with Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). Further, no individual-level data will be 
reported to Sanofi Pasteur. 
5 
Investigational Plan 
5.1 
Description of the Overall Study Design and Plan 
5.1.1 
Study Design 
To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV against all PCR-confirmed 
influenza in vaccinees aged 18–64 years, this study will compare the incidence of PCR-confirmed 
influenza among Flublok Quadrivalent vaccinees versus SD-IIV vaccinees. Our primary 
comparison will be focused on adults aged 50–64 years at KPNC during the 2018–2019, 2019–
2020, and 2020–2021 influenza seasons. We will also assess all adults aged 18–64 years for both 
influenza seasons.  
5.1.2 
Justification of the Study Design 
Please refer to Section 11.1 for details. 

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5.1.3 
Study Plan 
This study will employ a design whereby KPVSC will ensure that all clinics in KPNC will receive 
alternating shipments of Flublok Quadrivalent vaccine or SD-IIV. All KPNC facilities will follow 
a schedule that alternates which vaccine is supplied to each influenza clinic throughout the 3-year 
study period.  
We will block facilities and randomize within blocks (see Section 5.1.4), ensuring that roughly 
half the facilities within each block initially administer Flublok Quadrivalent vaccine and the 
other half administer a SD-IIV. After the initial supply, the half that started with Flublok 
Quadrivalent vaccine will be supplied with a SD-IIV, and the half that started with a SD-IIV will 
be supplied with Flublok Quadrivalent vaccine (see Figure 1). The supply of each clinic will then 
alternate between the two vaccines; that is, Flublok Quadrivalent vaccine alternating with a SD-
IIV with each delivery of vaccine to the clinics.  
 
 
 
Data Extraction 
Pertinent data will be extracted from the KPNC databases to create study datasets in the required 
file format for analysis (e.g., Excel spreadsheets, SAS datasets). Databases from which data will 
be extracted include various encounters (inpatient, outpatient, hospitalizations, emergency 
department, etc.), laboratory tests, documentation of immunizations (e.g., influenza vaccination 
history), and clinical outcomes and diagnoses, as well as demographic and membership data. 
The data analyst will perform validation of the study data throughout the data management 
process by utilizing the following types of checks as applicable:  
• Internal consistency checks (e.g. data undergo range checks, including consistency of 
dates of birth with vaccination dates, checks for completeness and missing values, etc.) 
• External data checks (e.g. data from one database may be compared with data from other 
databases) 
• Error checks written for specific databases. 

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5.1.4 
Vaccine Distribution Procedures 
Based on prior annual influenza vaccine use, we anticipate that KPNC will administer influenza 
vaccines to approximately 800,000 individuals aged 18–64 years, including 350,000 persons aged 
50–64 years each season. 
Approximately 400,000 doses of Flublok Quadrivalent vaccine and 400,000 doses of comparator 
SD-IIV will be administered to adults aged 18–64 years in each of the influenza seasons 2018–
2019, 2019–2020, and 2020–2021.  
There are approximately 70 facilities that receive individual influenza vaccine shipments from the 
KPNC Central Pharmacy (the exact number varies slightly each year; see Figure 2 for an example 
of the flow). KPNC Central Pharmacy begins “autoshipments” to the Medical Centers and their 
satellite facilities’ main pharmacies in August in preparation for annual influenza vaccination 
clinics. For purposes of this study, medical center facilities include all associated satellite sites. 
KPNC Central Pharmacy determines the amount of vaccines to be shipped each day to the 
medical center facilities based upon vaccine use the previous year at each facility. For example, 
since Oakland Medical Center administered ~5% of all vaccines during the 2017–2018 influenza 
season, they would receive 5% of the daily shipment of vaccines during the subsequent 2018–
2019 influenza season. Facilities may also request additional vaccine as needed. 
 
Once the facilities receive adequate influenza vaccines to distribute to all of their influenza 
vaccination clinics, they will prepare vaccine allotments for specific patient populations within 
each clinic (e.g., adult medicine, OB/GYN). We propose to randomize these facilities to distribute 
(and therefore administer) either Flublok Quadrivalent vaccine or a SD-IIV initially to all of their 
influenza vaccination clinics. Roughly half the facilities will first distribute Flublok Quadrivalent 
vaccine to be administered by their associated departments and clinics, while the other half will 
first distribute a SD-IIV for administration by their associated departments and clinics. The 
facilities will follow a weekly alternating schedule (with some variation due to usage) that 
indicates which vaccine is to be internally distributed to associated departments and clinics for the 
entire influenza season. Historically, >75% of vaccinations to adults aged 18–64 are administered 
prior to Thanksgiving.  

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Because the study design specifies that roughly equivalent amounts of Flublok Quadrivalent 
vaccine and SD-IIV will be administered at every KPNC facility throughout the influenza season, 
KPVSC will monitor on a weekly basis that Flublok Quadrivalent vaccine and SD-IIV are being 
distributed as much as possible in a balanced way (see Section 11.1 for further details).  
In order to randomize which facilities will initially administer Flublok Quadrivalent vaccine and 
which will start with a SD-IIV, we will block facilities by size and service area. For example, 
there may be 4 facilities per block, and within the block, 2 facilities start with Flublok 
Quadrivalent vaccine and 2 facilities start with a SD-IIV.  
Staff Training: Pharmacy Staff, Influenza Clinic Injection Nurses, and Nurse Managers 
KPVSC will work closely with the KPNC Central Pharmacy, the KPNC influenza program 
manager, the pharmacy staff, and influenza coordinators at the ~70 facilities to ensure that staff 
are aware of the study and are trained to carry out the study protocol. Randomization will be 
controlled by KPVSC, and the individual pharmacies will then distribute the vaccine to the 
departments and clinics based on the schedule determined by KPVSC. We will conduct trainings 
with the pharmacy staff, influenza coordinators, and department managers so that all relevant staff 
are aware that Flublok Quadrivalent vaccine or a SD-IIV should be routinely administered to 
everyone 18–64 years of age without any preference for one vaccine over the other, and that 
vaccine use should be based only on what is available in the clinic at the time of vaccination. 
In particular, we will emphasize that the injection nurse administering the vaccine should not 
preferentially choose one vaccine over the other, but instead use what is available in the 
refrigerator or portable cold storage box for the day. Based on routine influenza clinic operations, 
there is little potential for bias at the level of vaccine administration level (e.g., an injection nurse 
preferentially choosing one vaccine over the other), especially early in the season, when large 
numbers of influenza vaccine are administered on any given day; injection nurses are unlikely to 
spend time searching for a specific formulation based on preference. Further, by following the 
alternating vaccine supply schedule, we will reduce the likelihood that both Flublok Quadrivalent 
vaccine and SD-IIV are simultaneously available in the clinic. By having only one vaccine 
available for adults aged 18–64 years (Flublok Quadrivalent vaccine or SD-IIV), we hope to 
reduce the likelihood that an injection nurse is able to choose one vaccine over the other.  
Because influenza vaccine is used at a very rapid pace once influenza clinics officially begin 
administering vaccine, the departments and clinics may request vaccine replenishment prior to the 
next distribution in order to ensure adequate supply. For this reason, it may be possible that a 
particular clinic will have both Flublok Quadrivalent vaccine and a SD-IIV available.  
On a weekly basis, we will also monitor both the distribution of vaccine from KPNC Central 
Pharmacy to the facility pharmacies, as well as influenza vaccine administration. If we detect 
imbalances at either of these points, we will work closely with the affected facility(s) to attempt to 
correct the imbalance. Additional details may be found in Section 11.1. 
5.1.5 
Planned Study Calendar 
The following dates are approximate. The actual dates may differ if there are manufacturing 
delays that affect Flublok Quadrivalent vaccine or SD-IIV vaccine(s). 
Planned study period (total): August 2018 to May 2022  

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Anticipated first study member influenza vaccination date: September 16, 2018 
Planned vaccination periods: August 2018 to April 2019, August 2019 to April 2020, August 
2020 to April 2021 
Planned date of draft study report: February 2022 
Planned date of final study report: May 2022 
5.2 
Study Population 
5.2.1 
Recruitment Procedures 
Eligible adults aged 18–64 years will receive either Flublok Quadrivalent vaccine or a SD-IIV in 
the course of routine influenza vaccination during each of the two influenza seasons of the study 
period.  
5.2.2 
Informed Consent Procedures 
Not applicable. Because the present study is a prospective study using EMR data that are 
collected as part of routine clinical care, no informed consent will be required.  
5.2.3 
Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria to be eligible for the study: 
• Between the ages of ≥18 and <65 years at the time of influenza vaccination 
• Receive either Flublok Quadrivalent vaccine or SD-IIV at a KPNC facility during the 
study period from August 2018 through April 2021 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from the study to the extent 
possible: 
• Children <18 years old 
• Adults ≥65 years old 
5.2.6 
Medical History 
Prior to receiving an influenza vaccination (either Flublok Quadrivalent vaccine or SD-IIV), 
patients will be screened using an influenza vaccination screening form as part of a routine pre-
vaccination assessment.  

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5.2.7 
Contraindications for Subsequent Vaccinations 
Severe hypersensitivity or adverse reaction to a previous dose of Flublok Quadrivalent vaccine or 
a SD-IIV.  
5.2.8 
Classification of Subjects Who Discontinue the Study 
As this is not a clinical trial, there is not the possibility that a patient discontinues the study prior 
to completion. There is the possibility, however, that a patient is no longer a KPNC member at 
some point in the follow-up period following vaccination. Membership will be taken into account 
at the analysis stage to ensure that patients have adequate follow-up times.  
5.2.9 
Follow-up of Discontinuations 
Not applicable. 
5.2.10 Follow-up and Reporting of Pregnancies 
We will include KPNC members who receive Flublok Quadrivalent vaccine or SD-IIV vaccine(s) 
while aged 18–64 years. Follow-up for outcomes based on PCR-confirmed influenza will include 
only the first positive PCR test (for influenza) per influenza season, and only if it is ≥14 days 
after vaccination, and follow-up will continue either through April 30 of each influenza season or 
until exit from KPNC, whichever occurs earlier. In the KPNC system, influenza PCR tests are 
used for clinical purposes, thus the “trigger” for an influenza PCR test is based on clinical 
presentation. The decision to test is up to each physician. KPNC also monitors the influenza 
season, which can affect the total amount of influenza testing at any point in the season.  
Pregnancy is not an exclusion criterion for this study. Patients who are ≥18 years old and pregnant 
at the time of vaccination will be included in the analysis. Pregnant patients will be followed in 
the same way they normally would for routine influenza vaccination.  
As described in Section 10.1, in the event that KPVSC reviews individual patient charts within the 
EMR and there is written notation in the medical record indicating that a health care provider 
attributed a serious or unexpected adverse event to Flublok Quadrivalent vaccine, KPVSC will 
report the adverse event possibly related to Flublok Quadrivalent vaccine.  
5.3 
Modification of the Study and Protocol 
Any amendments to this study protocol must be discussed with and approved by Sanofi Pasteur. If 
agreement is reached concerning the need for an amendment, it will be approved in writing by 
Sanofi Pasteur, and the amended version of the protocol will replace the earlier version. Any 
substantial amendments (e.g., those that affect the conduct of the study, the safety of the subjects, 
or the analysis of the data) require KPNC IRB approval.  
During the period for which KPNC IRB approval has already been given, KPVSC is responsible 
for ensuring that changes to an approved study are not initiated without KPNC IRB review and 
approval, except as needed to eliminate apparent immediate hazards to subjects. 

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5.4 
Interruption of the Study 
The study may be discontinued if data about Flublok Quadrivalent vaccine or comparator 
resulting from this or any other studies become available; or for administrative reasons; or on 
advice of Sanofi Pasteur, KPVSC, the KPNC IRB, or the governing regulatory authorities in the 
US where the study is taking place. 
If the study is prematurely terminated or suspected, Sanofi Pasteur shall promptly inform KPVSC, 
the KPNC IRB, and the regulatory authorities of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. If applicable, KPNC will follow internal 
protocols for notifying patients who may have received Flublok in the course of routine patient 
care. 
6 
Vaccines Administered 
6.1 
Identity of the Investigational Product(s)  
6.1.1 
Identity of Study Product(s) 
Flublok Quadrivalent vaccine is indicated for active immunization against disease caused by 
influenza A subtype viruses and influenza type B viruses contained in the vaccine. Flublok 
Quadrivalent vaccine is a sterile solution supplied in prefilled, single-dose syringes, 0.5 mL.  
6.1.1.1 
Composition 
Flublok Quadrivalent vaccine is formulated to contain 180 mcg HA per 0.5 mL dose with 45 mcg 
HA of each of the following influenza types and subtypes: A (H1N1), A (H3N2), and two B 
lineages (B/Yamagata and B/Victoria). 
A single 0.5 mL dose of Flublok Quadrivalent vaccine contains sodium chloride (4.4 mg), 
monobasic sodium phosphate (0.195 mcg), dibasic sodium phosphate (1.3 mg), and polysorbate 
20 (Tween®20) (27.5 mcg). Each 0.5mL dose of Flublok Quadrivalent vaccine may also contain 
residual amounts of baculovirus and Spodoptera frugiperda cell proteins (≤ 19 mcg), baculovirus 
and cellular DNA (≤ 10 ng), and Triton X-100 (≤ 100 mcg).  
Flublok Quadrivalent vaccine contains no egg proteins, antibiotics, or preservatives. The single-
dose, pre-filled syringes contain no natural rubber latex. 
6.1.1.2 
Preparation and Administration 
Prior to administration, all Flublok Quadrivalent vaccine must be inspected visually for cracks, 
broken seals, correct label content, and extraneous particulate matter and/or discoloration, 
whenever solution and container permit. If any of these conditions exist, the vaccine must not be 
administered and another dose of Flublok Quadrivalent vaccine is to be used, and the event is to 
be reported to Sanofi Pasteur. 

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To administer the vaccine, invert the pre-filled syringe containing Flublok Quadrivalent vaccine 
gently prior to affixing the appropriate size needle for intramuscular administration. The preferred 
site for injection is the deltoid muscle. Flublok Quadrivalent vaccine should not be mixed in the 
same syringe with any other vaccine. 
6.1.1.3 
Dose Selection and Timing 
Not applicable. 
6.1.2 
Identity of Comparator SD-IIV Product(s)  
SD-IIV is defined as all standard-dose quadrivalent inactivated egg-based influenza vaccines 
administered intramuscularly during the course of this study in KPNC facilities. 
The comparator SD-IIV vaccine(s) that will be used each year is determined and ordered at the 
national KP level; thus KPVSC does not have influence over what comparator SD-IIV vaccine(s) 
are purchased.  KPVSC will be notified of which comparator vaccine will be used within KPNC. 
The comparator influenza vaccine(s) will be acquired through national KP’s usual procurement 
processes. 
6.1.2.1 
Composition 
Comparator SD-IIV influenza vaccine(s) will be used, as determined by national KP procurement. 
SD-IIV vaccine(s) are formulated to contain 15 mcg HA or 60 mcg HA (trivalent or quadrivalent 
formulation, respectively) per 0.5 mL dose with 15 mcg HA of each of the following influenza 
types and subtypes: A (H1N1), A (H3N2), and one or two B lineages (trivalent or quadrivalent 
formulation, respectively; trivalent will contain either a B/Yamagata or B/Victoria strain as per 
FDA guidance). The specific final formulation will be dependent on comparator SD-IIV 
vaccine(s) that will be ordered and used each year as determined at the national KP level. 
6.1.2.2 
Preparation and Administration 
The procedures for preparing and administering the comparator SD-IIV influenza vaccine(s) will 
be prepared and administered as per the manufacturer’s package insert. 
6.1.2.3 
Dose Selection and Timing 
Not applicable. 
6.2 
Identity of Other Product(s) 
Not applicable. 

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6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
All vaccines will be supplied with their manufacturer’s commercial labeling and packaging. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
Sanofi Pasteur will contact the Investigator or a designee to determine the dates and times of 
delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (i.e., verification of the temperature recorders). If 
there is an indication that the cold chain was broken, this person should immediately quarantine 
the product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur 
to use the product. 
6.3.2.2 
Product Storage 
All temperature monitoring, including storage and shipment within KPNC sites, of Flublok 
Quadrivalent vaccine, will be per KPNC pharmacy’s internal standard operating procedures. 
KPVSC itself will not directly monitor nor manage temperature excursions if they arise. 
Any excursion of temperature during the initial shipment of Flublok Quadrivalent vaccine 
performed by Sanofi Pasteur shall require a full evaluation and shall be documented, reviewed, 
and approved by Sanofi Pasteur/Protein Sciences in accordance with its internal procedures. If 
there is a temperature excursion, KPNC must quarantine the clinical supply until the Sanofi 
Pasteur evaluation is complete. 
Any excursion of temperature during storage or shipment performed by KPNC will require a full 
evaluation by KPNC, and shall be documented, reviewed, and approved by KPNC in accordance 
with its internal standard operating procedures. If KPNC requests additional evaluation needed for 
decision making from Sanofi Pasteur, Sanofi Pasteur will provide assistance in accordance with 
its internal procedures. 
6.3.2.3 
Product Accountability 
When patients receive Flublok Quadrivalent vaccine (or SD-IIV), the vaccine administrator will 
record the vaccination information into their medical record, including the formulation, dose, lot 
number, and date of vaccination. 
6.3.3 
Replacement Doses 
If replacement doses are required, KPNC will contact Sanofi Pasteur to resolve as appropriate. 

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6.3.4 
Disposal of Unused Products 
Unused or wasted products will be destroyed in accordance with the instructions in the KPNC 
Operating Guidelines. Product accountability will be verified throughout the study period. 
6.3.5 
Recall of Products 
Should Flublok Quadrivalent vaccine be recalled by a Health Authority or withdrawn from the 
market by Sanofi Pasteur, Sanofi Pasteur is responsible to immediately notify KPNC and KPNC 
shall cease to use Flublok Quadrivalent vaccine. 
KPNC is responsible for the implementation of the recall or withdrawal of Flublok Quadrivalent 
vaccine and the destruction of the identified batches as per authorization from Sanofi Pasteur. 
KPNC shall be responsible to provide Sanofi Pasteur with all relevant documentation related to 
the recall operation. 
Following a product recall, Sanofi Pasteur shall supply additional Flublok Quadrivalent vaccine 
for replacement for continuation of the conduct of the study. 
6.4 
Blinding and Code-breaking Procedures 
Not applicable. 
6.5 
Randomization and Allocation Procedures 
Subjects will not be individually randomized. A modified-cluster randomization scheme by 
facility will be deployed. 
This study will employ a design whereby KPVSC will ensure that all clinics in KPNC will receive 
alternating distribution of Flublok Quadrivalent vaccine or SD-IIV. All KPNC facilities will 
follow a schedule that alternates which vaccine is supplied to each influenza clinic throughout the 
3-year season period.  
We will block facilities and randomize within blocks (see Section 5.1.4), ensuring that roughly 
half the facilities within each block initially administer Flublok Quadrivalent vaccine and the 
other half administer a SD-IIV. After the initial supply, the half that started with Flublok 
Quadrivalent vaccine will be supplied with the SD-IIV, and the half that started with SD-IIV will 
be supplied with Flublok Quadrivalent vaccine (see Figure 1). The supply of each clinic will then 
alternate between the two vaccines; that is, Flublok Quadrivalent vaccine alternating with SD-IIV 
with each delivery of vaccine to the clinics.  

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6.6 
Vaccine Administration Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified KPNC personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site as per KPNC standard operating procedures 
6.7 
Concomitant Medications and Other Therapies 
Not applicable. 
7 
Management of Samples 
Not applicable. 
8 
Endpoints and Assessment Methods 
8.1 
Primary Endpoints and Assessment Methods 
8.1.1 
Relative Vaccine Effectiveness of Flublok Quadrivalent vaccine 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against all PCR-confirmed influenza. 
 

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The rVE will be calculated based on the following formula: 
𝑟𝑟𝑟𝑟𝑟𝑟 = 1 −𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 𝑅𝑅𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 (𝑟𝑟𝑟𝑟𝑟𝑟) 
where rHR is estimated from the fully adjusted Cox Regression model (described in Section 
11.1). 
Diagnoses, laboratory tests, vaccines, and medications are all captured in the electronic medical 
record (EMR) and clinical databases. Member-reported race/ethnicity is available for 
approximately 85% of members, while the remaining are imputed using the RAND BISG 
algorithm.  
All microbiological testing is conducted at KPNC laboratories that have used real-time PCR tests 
for influenza since 2006. PCR results are categorized as positive for influenza A; positive for 
influenza B; or negative for both. In the KPNC system, influenza PCR tests are used for clinical 
purposes, thus the "trigger" for an influenza PCR test is based on clinical presentation. The 
decision to test is up to each physician. KPNC monitors the influenza season which can affect the 
total amount of influenza testing in adults. Once the KPNC laboratories complete the PCR testing, 
the test result is updated in the patient’s EMR. 
The majority of KPNC’s influenza cases are seen in the outpatient setting. Most of the remaining 
cases are treated in the ED with a very small portion admitted to hospital 
Please refer to Section 5.1.1 for details pertaining to the assessment of rVE. 
8.2 
Secondary Endpoints and Assessment Methods 
8.2.1 
Relative Vaccine Effectiveness of Flublok 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed hospitalized influenza. 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against hospitalized community-acquired pneumonia. 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against hospitalized cardio-respiratory events combined (e.g., pneumonia, other 
lower respiratory infections, acute myocardial infarction, congestive heart failure, stroke).  
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed influenza A.  
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against PCR-confirmed influenza B.  
• Sub-analyses of the above outcomes as feasible by the following pre-existing conditions: 
6. Cardiovascular preexisting conditions composite, which may include: 
myocardial infarction, cerebrovascular accident, atrial fibrillation, arrhythmias, 
coronary artery disease, valvular heart disease/valvuloplasty, chronic/congestive 
heart failure and/or congenital heart defects, CABG, angioplasty/stents, 
cardioversion, pacemaker, implantable cardioverter defibrillator, LVAD, heart 
transplant, hypertensive disease 
7. Respiratory preexisting conditions composite, which may include: COPD 
and/or pulmonary HTN 

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8. Cardiorespiratory preexisting conditions composite: combined pre-existing 
conditions (a) and (b) above 
9. Obesity: based on available height/weight data for a calculated BMI ≥30 or an 
obesity diagnosis (e.g., ICD-10 E66.9) 
10. Diabetes: based on a diagnosis of diabetes 
 
The rVE will be calculated based on the following formula: 
𝑟𝑟𝑟𝑟𝑟𝑟 = 1 −𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 (𝑟𝑟𝑟𝑟𝑟𝑟) 
where rHR is estimated from the fully adjusted Cox Regression model (described in Section 
11.1). 
Data on the secondary endpoints will be extracted from the KPNC databases that contain 
encounters on patient hospitalizations. ICD-10 codes will be extracted based on the discharge 
diagnoses recorded in the patients’ EMR. The specific codes used to identify community-acquired 
pneumonia and cardio-respiratory events will be further specified in the SAP.  
 
Please refer to Section 8.1.1 for details pertaining to PCR assessment, and Section 5.1.1 for details 
pertaining to the assessment of rVE. 
8.3 
Exploratory Endpoints and Assessment Methods 
8.3.1 
Relative Vaccine Effectiveness of Flublok 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in vaccinees aged 50–
64 years against exploratory outcomes such as: 
a. Diagnosed with influenza (includes [1] adults with a PCR-positive influenza and 
[2] adults clinically-diagnosed with influenza in any setting but not tested); this 
outcome will exclude those with a clinically-diagnosed influenza but are tested and 
PCR-negative)  
b. All-cause hospitalizations 
c. All-cause mortality 
 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV in other age ranges of 
vaccinees — aged 18–64 years and aged 18–49 years — against outcomes such as (but not 
limited to):  
a. All PCR-confirmed influenza 
b. All PCR-confirmed influenza A and influenza B (separate rVE estimates) 
c. PCR-confirmed hospitalized pneumonia 
d. Hospitalized community-acquired pneumonia 
e. Hospitalized cardio-respiratory events combined 
f. All-cause hospitalization 
g. All-cause mortality 
 

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• Sub-analyses of the primary and secondary outcomes of sub-groups defined by pre-
existing conditions (as described above in Section 2.2) will be conducted among adults 
18–49 years as feasible  
 
• To estimate the rVE of Flublok Quadrivalent vaccine versus SD-IIV among adults aged 
18–64 years for PCR-confirmed influenza A subtypes (A(H1N1)pdm09 and A(H3)) and 
lineage for type B influenza (B/Victoria, B/Yamagata) as feasible 
 
Data on the exploratory endpoints will be extracted from the KPNC databases that contain 
relevant encounters on patient hospitalizations and mortality. ICD-10 codes will be extracted 
based on the discharge diagnoses recorded in the patients’ EMR. The specific codes used to 
identify diagnoses of interest will be further specified in the SAP. 
  
Please refer to Section 8.1.1 for details pertaining to PCR assessment, and Section 5.1.1 for details 
pertaining to the assessment of rVE. 
9 
Reporting of Serious Adverse Events  
9.1 
Initial Reporting by the Investigator 
Serious or unexpected adverse events (see 21 CFR 314.80) that may be related to Flublok, 
including any follow-up information, will be reported promptly to Sanofi Pasteur, national 
regulatory authorities (e.g., to the Vaccine Adverse Event Reporting System [VAERS]), and the 
KPNC Institutional Review Board, in accord with any applicable requirements.  
 
KPVSC will perform the study in compliance with all applicable local and international 
pharmacovigilance laws and regulations. Although the conduct of the study is entirely the 
responsibility of KPVSC, Sanofi Pasteur/Protein Sciences as the manufacturer of Flublok 
Quadrivalent vaccine has legal obligations to report safety information to various regulatory 
authorities. Accordingly, in the event that individual charts are reviewed and there is written 
notation in the medical record indicating that a health care provider attributed a SAE, SUSAR, or 
AESI to any product manufactured by Sanofi Pasteur/Protein Sciences used in the conduct of the 
research, KPVSC agrees to report all SAEs, SUSAR, and AESIs possibly related to Flublok 
Quadrivalent vaccine. Pharmacovigilance reports to Sanofi Pasteur will be provided at the address 
provided below within 3 working days of KPVSC’s awareness that a reportable SAE, SUSAR, or 
AESI has occurred to one of the two following addresses. 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: CL-CPV-Receipt@sanofi.com 
• By express mail, to the following address: 
Global Pharmacovigilance and Epidemiology, Sanofi Pasteur Inc., 
1 Discovery Drive, Swiftwater, PA, 18370-0187, USA 
 

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The reporting obligations as defined in the Study Agreement are the following: 
 
• Adverse events of special interest (AESI): anaphylactic reactions/hypersensitivity, 
pericarditis, Guillain-Barre Syndrome, neuritis, convulsion, encephalomyelitis/transverse 
myelitis, thrombocytopenia, syncope, vasculitis 
• Suspected Unexpected Serious Adverse Events (SUSAR): an adverse event, the nature or 
severity of which is not consistent with the applicable product information, such as a fatal 
outcome 
• New Safety Findings 
9.2 
Follow-up Reporting by the Investigator 
Any follow-up information received by the investigator regarding an SAE or AESI must be 
reported in the same procedure as explained in Section 9.1 (within 3 working days of KPVSC’s 
awareness).  
9.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE / AESI that occurs after a subject has completed the study but that is likely to be related 
to Flublok Quadrivalent vaccine must also be reported as soon as possible. In such a case, the 
reporting procedure to be followed is identical to that described in Section 9.1. 
9.4 
Assessment of Causality 
Not applicable for this EMR-based study.  
9.5 
Reporting SAEs to Health Authorities and IECs / IRBs 
Please refer to Section 9.1. KPVSC will perform the reporting of SAEs to Health Authorities and 
IECs / IRBs in compliance with all applicable local and international pharmacovigilance laws and 
regulations. 
10 Data Collection and Management 
10.1 Data Collection  
Pertinent data will be extracted from the KPNC databases to create study datasets in the required 
file format for analysis (e.g., Excel spreadsheets, SAS datasets). Databases from which data will 
be extracted include various encounters (inpatient, outpatient, hospitalizations, emergency 
department, etc.), laboratory tests, documentation of immunizations (e.g., influenza vaccination 
history), and clinical outcomes and diagnoses, as well as demographic and membership data. 

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10.2 Data Management 
The data analyst will perform validation of the study data throughout the data management 
process by utilizing the following types of checks as applicable:  
• Internal consistency checks (e.g. data undergo range checks, including consistency of 
dates of birth with vaccination dates, checks for completeness and missing values, etc.) 
• External data checks (e.g. data from one database may be compared with data from other 
databases) 
• Error checks written for specific databases. 
10.3 Data Review 
Please refer to Section 10.2. 
11 Statistical Methods and Determination of Sample Size 
11.1 Statistical Methods 
Since we are not randomizing at the individual patient level, there is no vaccine being assigned to 
any patient. The intent is to balance Flublok versus SD-IIV comparisons by balancing the 
shipments and delivery of the vaccines by clinic and calendar week.  
The preliminary analyses will compare the incidence of each of the outcomes in Flublok 
Quadrivalent vaccinees versus SD-IIV vaccinees. We plan to test the null hypothesis that Flublok 
is not any more effective than the comparator (i.e., a superiority test), using a 2-sided test, p<0.05. 
The primary analyses will use Cox regression to obtain an adjusted estimate of the relative hazard 
ratio (rHR) for each outcome, adjusted for age, sex, race/ethnicity, facility, and time-since-
vaccination. The rHR at any point in the follow-up period is the instantaneous relative risk (RR) at 
that time (i.e., we are estimating rVE by (1–rHR), and testing the null hypothesis that rHR=0). In 
addition, we may adjust for an available comorbidity score and/or a measure of prior exposure to 
influenza vaccines (e.g., exposure to flu vaccine in the prior year, or number of flu shots in the 
past three years). 
Risk sets will be conditioned (i.e., stratified) on calendar day, using a calendar timeline for the 
Cox regression. We expect many people to be vaccinated both years, and some might get 
“breakthrough” influenza both years. Getting Flublok in one year should be entirely unrelated to 
getting Flublok in another year, so robust standard errors are not needed. We will check our 
assumption that the vaccine received in one year is not related to vaccine received the next year.  
For each type of outcome, follow-up would end at the first outcome event in a season but could 
restart the next year when the individual is vaccinated again. 
We do not know whether prior vaccination (i.e., booster or priming effect) affects VE of either 
Flublok Quadrivalent vaccine or SD-IIV, but we hypothesize that prior vaccination might be an 
effect modifier but not a potential confounder because what patients are vaccinated with in prior 
years should not be associated with what vaccine they receive in any of the 3 study seasons. We 

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will test to ascertain if, as expected, there is (1) no correlation between prior vaccination (before 
the study period) and vaccination during the 3 study seasons, and (2) no correlation between the 
type of vaccine received in one season and the type of vaccine received in any other study 
season(s). If we find that there is a relationship in either of these scenarios, we can treat prior 
vaccination (“prior” meaning before the study commenced, or “prior” as in vaccination in the first 
study season relative to the second study season) as a potential confounder. We would add 
variables that adjust for whether a patient was vaccinated during the past year(s), as well as which 
vaccine type they received. Further, if prior vaccination does modify VE, we may have adequate 
power to assess whether there is a boosting effect given our large sample size. 
There is little possibility of confounding that may occur between patients tested versus those who 
are not tested. While not everyone with suspected influenza will be tested, the randomization 
process in vaccine supply (Flublok Quadrivalent vaccine versus SD-IIV) should result in an equal 
distribution of those who are and are not tested between the two vaccine groups throughout the 
season. We will attempt to mitigate possible bias and confounding as much as possible upfront by 
implementing our plans for supplying clinics with alternating shipments of vaccines. Because 
factors related to testing should be balanced, there is no reason to believe that the likelihood of 
being tested will be related to whether a person received Flublok Quadrivalent vaccine or SD-IIV.  
We will also be monitoring the balance of potential confounders that may be related to influenza 
and to PCR testing in order to confirm that we are achieving the balance intended by our quasi-
randomized shipment of vaccines to clinics. Once vaccinations begin, we will monitor on a 
weekly basis the balance of Flublok vaccinees versus SD-IIV vaccinees with respect to facility, 
sex, and age group (18–49 years and 50–64 years). Additional demographic variables such as race 
and ethnicity may also be monitored. We will also monitor balance with respect to comorbidities 
such as chronic obstructive pulmonary disease (COPD), asthma, and diabetes (to be specified 
further in the SAP). If we find that any facility is using Flublok or SD-IIV more (or less) than 
needed to achieve balance, we will work with the influenza program manager to adjust what is 
being administered. If despite our efforts, there is still imbalance, we can address these 
imbalances at the analysis stage, adjusting for, or stratifying by, the relevant covariates.  
We plan to assess the outcomes that occur ≥14 days after vaccination up through April 30 of each 
influenza season. It is possible that patients enter, exit, and re-enter the KPNC population during 
the study period. At the analysis stage, we will make the most appropriate determination for how 
to handle such cases.   
For outcomes not based on PCR-confirmed influenza (e.g., hospitalized pneumonia and cardio-
respiratory events), we will develop an algorithm (to be described in the Statistical Analysis Plan) 
to measure the intensity of influenza circulation to guide when to start and stop following for such 
events (e.g., as determined by the algorithm, hospitalized pneumonia during June when influenza 
is not circulating would not be included). 
11.2 Sample Size and Power Calculations 
We calculated the least rVE that is detectable with 80% power in a 3-year study for several aims. 
As described in Section 11.1, we plan to test the null hypothesis that Flublok is not any more 
effective than the comparator (i.e., a superiority test), using a 2-sided test, p<0.05. Our allocation 

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ratio of 1:1 implies that each year, KPNC would give Flublok Quadrivalent vaccine to 400,000 
members aged 18–64 years, and SD-IIV to another 400,000 similar KPNC members.    
Each row of the tables in the Appendices (Section 15) shows power for a possible scenario for a 
given outcome and a specific age range. The expected incidence of the outcome in vaccinees who 
received SD-IIV (based on incidence observed in the 2016–2017 influenza season) is in column 4; 
the relative risk (estimated by the relative hazard ratio) associated with getting Flublok 
Quadrivalent vaccine versus a comparator is in column 5; the corresponding rVE in column 6; and 
the power in the last column. These power calculations estimate our power to test the null 
hypothesis that Flublok Quadrivalent vaccine VE does not differ from SD-IIV(s).  
Because the comparison group will not be unvaccinated—they are getting SD-IIV—we will be 
estimating and testing rVE: i.e., the percent reduction in the incidence of “breakthrough cases” 
(e.g., influenza episodes in vaccinees) that results from the use of Flublok Quadrivalent vaccine 
rather than the SD-IIV vaccines. 
As an example, for the outcome of PCR-confirmed flu diagnosis, the first row of the first table 
indicates that power is very high (>0.99) to detect a rVE of 0.30 (which amounts to a 30% rVE) in 
a 3-year study of vaccinees aged 18–64 years, assuming that influenza incidence in the 
comparator arm will be the same as it was in the 2016–2017 influenza season. Comparing rows 5 
and 6 of the first table, our power to detect a rVE of 10% rather than 5% against test-positive 
influenza in those aged 18–64 years increases to 0.96 from 0.45.   
Depending on priorities and data availability, we may potentially conduct subgroup analyses of 
rVE, including the subgroups defined by: 
 
• influenza type A and B 
• selected diagnoses or conditions (e.g., in 50–64 year olds, rVE of those with specified 
comorbid conditions, such as cardiac, pulmonary, and metabolic comorbidities) 
• time periods and/or time-since-vaccination within a season  
• specific comparator SD-IIV(s) (if more than one comparator is used) 
12 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
12.1 Ethical Conduct of the Study / Good Clinical Practice 
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
12.2 Source Data and Source Documents 
The source data are stored in the KPNC EMR.  

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12.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the study, the Investigator will sign a fully executed agreement, including 
confidentiality, with Sanofi Pasteur. Sanofi Pasteur personnel (or designates) will not have any 
access to subject records for the present study. All data reported to Sanofi Pasteur by KPVSC will 
be deidentified and aggregated. 
12.4 Monitoring, Auditing, and Archiving 
12.4.1 Monitoring  
Not applicable.  
12.4.2 Audits and Inspections 
The KPVSC has been using essentially the same system to manage data since 1985.  Data 
management for data-only studies are performed by KPVSC almost entirely using the SAS 
system. Programs to manage data are used repeatedly, updating the SAS code as needed for 
protocol adherence.    
Many utility macros have been created and maintained for use with the VSC data management 
programs. These stored compiled macros are available to KPVSC Data Analysts / Programmers 
for their use in constructing and testing programs. 
Changes made to programs after the start of a study are documented as notes in the header/margin 
of the program or in the appropriate revision control system. Changes are applied only to copies 
of programs, and the original source is retained indefinitely. It is incumbent upon the Data 
Analyst / Programmer in charge of a particular task to document all programs and work 
performed; this includes code used as well as logs and listings produced.   
Programming for vaccine studies at the KPVSC adheres to standards across all projects to ensure 
the preservation of code, logs, and listings, as well as good programming in data processing and 
transparency in methodology. 
12.4.3 Archiving 
KPNC databases created from KPNC EMRs are available for research purposes to KPVSC Data 
Analysts / Programmers for the duration that the project is open/approved by the KPNC IRB. 
Once the study is closed, the data are archived for future reference and regulatory compliance. 
  
12.5 Financial Contract and Insurance Coverage 
Not applicable.  

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12.6 Stipends for Participation 
Not applicable.  
12.7 Publication Policy 
Each Party may publish and publicly present the final aggregated results of the Research Project, 
provided that KPVSC’s investigator will lead all such publications and presentations. Sanofi 
Pasteur/Protein Sciences will not manipulate or reanalyze the results of the Research Project in 
any way. No less than thirty (30) days prior to submission to a publisher or any external forum, 
each Party shall provide the other party with a copy of any proposed publication or presentation 
for review and comment, which review shall be limited to determining whether the publication or 
presentation includes the disclosure of Confidential Information or patentable subject matter. 
Publications or presentations shall not include Protected Health Information" or "PHI," or the 
Confidential Information of the other Party (other than the final aggregated research results of the 
Research Project) without the written permission of such Party. If the reviewing Party believes 
that patentable subject matter is disclosed in the manuscript or presentation and so notifies the 
publishing Party in writing within the thirty (30) day review period, said publication will be 
withheld for a reasonable period of time (but not to exceed sixty (60) days) until all applicable 
patent filings are completed. With respect to public presentations, each Party shall use reasonable 
efforts to provide review and comments more promptly than the full period of review specified in 
this Section, if requested by the submitting Party.    
Qualification for authorship and contributorship shall be determined in accordance with the 
“Uniform Requirements for Manuscripts Submitted to Biomedical Journals,” published by the 
International Committee of Medical Journal Editors (ICMJE). Publications shall carry appropriate 
acknowledgment of funding support from Sanofi Pasteur and a disclaimer that the contents are the 
responsibility of the authors and do not necessarily represent the official views of Institution.  
 

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13 Reference List 
 
 

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14 Signature Page 
I have read this protocol, and I agree to conduct this trial according to the procedures outlined in 
the protocol, to comply with its requirements, related to ethical and safety considerations, and to 
comply with applicable regulations and Good Clinical Practice. 
 
 
 
 
 
 
 
 
 
 
Nicola Klein, MD, PhD 
 
 
Date 
Principal Investigator 
 

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15 Appendices 
 
Power of 3-yr study comparing FluBlok v Comparators 
Power to detect relative VE against 5 types of outcome events 
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority) 
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
 
 
 
age=18-64 outcome=flu, test+ 
 
 
 
 
row 
 
 
N expectd 
3 yrs 
FluBlok 
 
 
N expectd 
3 yrs 
Comprtr 
 
proportion of 
comparators 
who have the 
outcome 
 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
1 
1,200,000 
1,200,000 
0.00218 
0.70 
0.30 
>.99 
2 
1,200,000 
1,200,000 
0.00218 
0.75 
0.25 
>.99 
3 
1,200,000 
1,200,000 
0.00218 
0.80 
0.20 
>.99 
4 
1,200,000 
1,200,000 
0.00218 
0.85 
0.15 
>.99 
5 
1,200,000 
1,200,000 
0.00218 
0.90 
0.10 
0.96 
6 
1,200,000 
1,200,000 
0.00218 
0.95 
0.05 
0.45 
 
age=18-64 outcome=hosp, flutest+ 
 
 
 
 
row 
 
 
N expectd 
3 yrs 
FluBlok 
 
 
N expectd 
3 yrs 
Comprtr 
 
proportion of 
comparators 
who have the 
outcome 
 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
7 
1,200,000 
1,200,000 
0.00089 
0.70 
0.30 
>.99 
8 
1,200,000 
1,200,000 
0.00089 
0.75 
0.25 
>.99 
9 
1,200,000 
1,200,000 
0.00089 
0.80 
0.20 
>.99 
10 
1,200,000 
1,200,000 
0.00089 
0.85 
0.15 
0.95 
11 
1,200,000 
1,200,000 
0.00089 
0.90 
0.10 
0.66 
12 
1,200,000 
1,200,000 
0.00089 
0.95 
0.05 
0.22 
 
 

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Power of 3-yr study comparing FluBlok v Comparators 
Power to detect relative VE against 5 types of outcome events 
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority) 
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
 
age=18-49 outcome=flu, test+ 
 
 
 
 
row 
 
 
N expectd 
3 yrs 
FluBlok 
 
 
N expectd 
3 yrs 
Comprtr 
 
proportion of 
comparators 
who have 
the outcome 
 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
13 
680,301 
680,301 
0.00229 
0.70 
0.30 
>.99 
14 
680,301 
680,301 
0.00229 
0.75 
0.25 
>.99 
15 
680,301 
680,301 
0.00229 
0.80 
0.20 
>.99 
16 
680,301 
680,301 
0.00229 
0.85 
0.15 
>.99 
17 
680,301 
680,301 
0.00229 
0.90 
0.10 
0.82 
18 
680,301 
680,301 
0.00229 
0.95 
0.05 
0.29 
 
age=18-49 outcome=hosp, flutest+ 
 
 
 
 
row 
 
 
N expectd 
3 yrs 
FluBlok 
 
 
N expectd 
3 yrs 
Comprtr 
 
proportion of 
comparators 
who have 
the outcome 
 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
19 
680,301 
680,301 
0.00065 
0.70 
0.30 
>.99 
20 
680,301 
680,301 
0.00065 
0.75 
0.25 
0.98 
21 
680,301 
680,301 
0.00065 
0.80 
0.20 
0.88 
22 
680,301 
680,301 
0.00065 
0.85 
0.15 
0.64 
23 
680,301 
680,301 
0.00065 
0.90 
0.10 
0.33 
24 
680,301 
680,301 
0.00065 
0.95 
0.05 
0.12 
 
 

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Power of 3-yr study comparing FluBlok v Comparators 
Power to detect relative VE against 5 types of outcome events 
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority) 
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
 
age=50-64 outcome=flu, test+ 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
25 
519,699 
519,699 
0.00205 
0.70 
0.30 
>.99 
26 
519,699 
519,699 
0.00205 
0.75 
0.25 
>.99 
27 
519,699 
519,699 
0.00205 
0.80 
0.20 
>.99 
28 
519,699 
519,699 
0.00205 
0.85 
0.15 
0.95 
29 
519,699 
519,699 
0.00205 
0.90 
0.10 
0.66 
30 
519,699 
519,699 
0.00205 
0.95 
0.05 
0.22 
 
age=50-64 outcome=hosp, flutest+ 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
31 
519,699 
519,699 
0.00120 
0.70 
0.30 
>.99 
32 
519,699 
519,699 
0.00120 
0.75 
0.25 
>.99 
33 
519,699 
519,699 
0.00120 
0.80 
0.20 
0.96 
34 
519,699 
519,699 
0.00120 
0.85 
0.15 
0.79 
35 
519,699 
519,699 
0.00120 
0.90 
0.10 
0.44 
36 
519,699 
519,699 
0.00120 
0.95 
0.05 
0.15 
 
age=50-64  outcome=PneumoniaHosp,Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
37 
519,699 
519,699 
0.00248 
0.70 
0.30 
>.99 
38 
519,699 
519,699 
0.00248 
0.75 
0.25 
>.99 
39 
519,699 
519,699 
0.00248 
0.80 
0.20 
>.99 
40 
519,699 
519,699 
0.00248 
0.85 
0.15 
0.98 
41 
519,699 
519,699 
0.00248 
0.90 
0.10 
0.74 
42 
519,699 
519,699 
0.00248 
0.95 
0.05 
0.25 
 
 
 

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Power of 3-yr study comparing FluBlok v Comparators 
Power to detect relative VE against 5 types of outcome events  
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority)  
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
 
age=50-64 outcome=CVD hosp, Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
43 
519,699 
519,699 
0.00620 
0.70 
0.30 
>.99 
44 
519,699 
519,699 
0.00620 
0.75 
0.25 
>.99 
45 
519,699 
519,699 
0.00620 
0.80 
0.20 
>.99 
46 
519,699 
519,699 
0.00620 
0.85 
0.15 
>.99 
47 
519,699 
519,699 
0.00620 
0.90 
0.10 
0.99 
48 
519,699 
519,699 
0.00620 
0.95 
0.05 
0.53 
 
age=50-64 outcome=all hosp, Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
49 
519,699 
519,699 
0.05000 
0.70 
0.30 
>.99 
50 
519,699 
519,699 
0.05000 
0.75 
0.25 
>.99 
51 
519,699 
519,699 
0.05000 
0.80 
0.20 
>.99 
52 
519,699 
519,699 
0.05000 
0.85 
0.15 
>.99 
53 
519,699 
519,699 
0.05000 
0.90 
0.10 
>.99 
54 
519,699 
519,699 
0.05000 
0.95 
0.05 
>.99 
 
 
 
 
 
 
 

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Power of 3-yr study comparing FluBlok v Comparators  
Power to detect relative VE against 5 types of outcome events  
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority)  
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
age=ChronicDis,50-64 outcome=flu, test+ 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
55 
103,940 
103,940
0.00286 
0.70 
0.30 
0.98 
56 
103,940 
103,940
0.00286 
0.75 
0.25 
0.9 
57 
103,940 
103,940
0.00286 
0.80 
0.20 
0.73 
58 
103,940 
103,940
0.00286 
0.85 
0.15 
0.48 
59 
103,940 
103,940
0.00286 
0.90 
0.10 
0.24 
60 
103,940 
103,940
0.00286 
0.95 
0.05 
0.09 
 
age=ChronicDis,50-64 outcome=hosp, flutest+ 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
61 
103,940 
103,940
0.00200 
0.70 
0.30 
0.91 
62 
103,940 
103,940
0.00200 
0.75 
0.25 
0.78 
63 
103,940 
103,940
0.00200 
0.80 
0.20 
0.58 
64 
103,940 
103,940
0.00200 
0.85 
0.15 
0.36 
65 
103,940 
103,940
0.00200 
0.90 
0.10 
0.18 
66 
103,940 
103,940
0.00200 
0.95 
0.05 
0.08 
 
age=ChronicDis,50-64  outcome=PneumoniaHosp,Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
67 
103,940 
103,940
0.00744 
0.70 
0.30 
>.99 
68 
103,940 
103,940
0.00744 
0.75 
0.25 
>.99 
69 
103,940 
103,940
0.00744 
0.80 
0.20 
0.99 
70 
103,940 
103,940
0.00744 
0.85 
0.15 
0.87 
71 
103,940 
103,940
0.00744 
0.90 
0.10 
0.53 
72 
103,940 
103,940
0.00744 
0.95 
0.05 
0.17 
 
 
 

Kaiser Permanente Vaccine Study Center 
  
 
Confidential/Proprietary Information 
Page 43 of 43 
Power of 3-yr study comparing FluBlok v Comparators 
Power to detect relative VE against 5 types of outcome events  
By age group (or chronic disease status) and outcome 
2-sided alpha=0.05 (likelihood ratio chi-sq test for superiority)  
800,000 vaccinees expected per yr: 400K fluBlok v. 400K comparators 
 
age=ChronicDis,50-64 outcome=CVD hosp, Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
73 
103,940 
103,940
0.01860 
0.70 
0.30 
>.99 
74 
103,940 
103,940
0.01860 
0.75 
0.25 
>.99 
75 
103,940 
103,940
0.01860 
0.80 
0.20 
>.99 
76 
103,940 
103,940
0.01860 
0.85 
0.15 
>.99 
77 
103,940 
103,940
0.01860 
0.90 
0.10 
0.9 
78 
103,940 
103,940
0.01860 
0.95 
0.05 
0.36 
 
age=ChronicDis,50-64 outcome=all hosp, Dec-March 
row 
N expectd 
3 yrs 
FluBlok 
N expectd 
3 yrs 
Comprtr 
proportion of 
comparators 
who have 
the outcome 
RR = 
1 minus 
relative 
VE 
Relative VE: 
% of 
breakthru 
cases 
prevented 
Power 
(prob. of 
rejecting Ho 
if rel_VE 
is true) 
79 
103,940 
103,940
0.10000 
0.70 
0.30 
>.99 
80 
103,940 
103,940
0.10000 
0.75 
0.25 
>.99 
81 
103,940 
103,940
0.10000 
0.80 
0.20 
>.99 
82 
103,940 
103,940
0.10000 
0.85 
0.15 
>.99 
83 
103,940 
103,940
0.10000 
0.90 
0.10 
>.99 
84 
103,940 
103,940
0.10000 
0.95 
0.05 
0.97