A Phase 3, Randomized, Observer-blinded, Active-controlled Trial to Evaluate Immunogenicity & Safety of a Recombinant Quadrivalent Nanoparticle Influenza Vaccine (Quad-NIV) With Matrix-M1™ Adjuvant Against Fluzone® Quadrivalent in Clinically Stable Adults ≥ 65 Years of Age
Phase: PHASE3
Conditions: Influenza, Human
Sponsor: Novavax

Nanoparticle Influenza Vaccine, Quadrivalent   Confidential 
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A PHASE 3, RANDOMIZED, OBSERVER-BLINDED, ACTIVE-CONTROLLED TRIAL TO 
EVALUATE THE IMMUNOGENICITY AND SAFETY OF A RECOMBINANT 
QUADRIVALENT NANOPARTICLE INFLUENZA VACCINE (QUAD-NIV) WITH 
MATRIX-M1™ ADJUVANT AGAINST FLUZONE® QUADRIVALENT IN CLINICALLY 
STABLE ADULTS ≥ 65 YEARS OF AGE 
 
Investigational Materials: 
Hemagglutinin 
Nanoparticle 
Influenza 
Vaccine, 
Quadrivalent (Quad-NIV), representing the strains 
recommended for inclusion in quadrivalent vaccines 
for the 2019 - 2020 northern hemisphere influenza 
season, ie, A/Brisbane/02/2018 (H1N1) pdm09; 
A/Kansas/14/2017 
(H3N2); 
B/Maryland/15/2016; 
B/Phuket/3073/2013; administered with Matrix-M1 
Adjuvant  
Reference Material: 
Fluzone® Quadrivalent (Sanofi Pasteur), a United 
States (US)-licensed seasonal quadrivalent influenza 
vaccine manufactured for the 2019 - 2020 influenza 
season. 
Protocol Number: 
qNIV-E-301 
Sponsor: 
Novavax, Inc. (Novavax) 
21 Firstfield Road 
Gaithersburg, MD 20878 USA 
Responsible Clinical Operations 
Manager: 
Jamie Fiske 
Clinical Project Manager, Clinical Operations 
Novavax, Inc. 
Gaithersburg, MD 20878 
Office: 240-912-1684 
Email: jfiske@novavax.com 
Version & Date: 
Version 4.0 – 31 October 2019  
Prior Version: 
Version 3.0 – 03 September 2019 
Version 2.0 – 02 July 2019 
Version 1.0 – 21 May 2019 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Novavax, Inc. and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by national 
and local laws. Persons to whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
Novavax, Inc.  
20 Firstfield Rd, Gaithersburg, MD 20878 
(240) 268-2000 

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PROTOCOL APPROVAL PAGE 
The principal investigator is responsible for ensuring that all trial site personnel, including 
sub-investigators and other staff members, conduct this trial according to this protocol, Good 
Clinical Practice (GCP) and International Conference on Harmonisation (ICH) guidelines, the 
Declaration of Helsinki, and the pertinent individual country laws/regulations and to comply 
with its obligations, subject to ethical and safety considerations during and after trial 
completion. The principal investigator also agrees not to disclose the information contained in 
this protocol or any results obtained from this trial without written authorization. 
Investigational 
Material(s): 
Hemagglutinin 
Nanoparticle 
Influenza 
Vaccine, 
Quadrivalent 
(Quad-NIV), representing the strains recommended for inclusion in 
quadrivalent vaccines for the 2019 - 2020 Northern hemisphere influenza 
season, ie, A/Brisbane/02/2018 (H1N1) pdm09; A/Kansas/14/2017 
(H3N2); B/Maryland/15/2016; B/Phuket/3073/2013; administered with 
Matrix-M1 Adjuvant  
Reference Material 
Fluzone® Quadrivalent (Sanofi Pasteur), a United States (US)-licensed 
seasonal quadrivalent influenza vaccine manufactured for the 2019 - 2020 
influenza season. 
Protocol: 
qNIV-E-301  
Date of Issue: 
31 October 2019   
 
I have read and approve the protocol specified above and agree on its content: 
Novavax, Inc. 
 
   Signed Electronically 
 
Vivek Shinde, MD  
Vice President, Clinical Development  
Novavax, Inc. 
 Date 
Signed Electronically 
 
Jamie Fiske 
Clinical Project Manager, Clinical Operations 
Novavax, Inc.  
 
 Date 
Clinical Trial Site 
 
 
 
Print Name – Principal Investigator 
 Date 
 
 
Signature 
 

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PROTOCOL CHANGE HISTORY 
Protocol Version 4.0, 31 October 2019 (revised from Version 3.0, 03 September 2019) 
The following is a summary of the changes made to this protocol. 
 
Location of Change 
Change/Modification in Version 4.0 
Section 7.1.2 
The microneutralization assay has been modified to reflect that 
the assay “will be qualified before use.” 
Section 7.2.1 
Text has been added to clarify that a limited qualification of the 
cell-mediated immunity assay will be performed prior to its use 
in clinical testing. 
Section 10.6.1 
The Day 28 unblinded data review has been clarified to include 
all primary endpoints (Hemagglutination inhibition antibody 
responses assayed with egg-propagated virus) testing of 
associated Day 28 serum samples for all 4 vaccine homologous 
influenza strains (ie, 2 influenza A and 2 influenza B strains) and 
safety data through Day 28. Data concerning secondary and 
exploratory endpoints will be included in the unblinded review 
of Days 0 and 28 as they become available. 
Protocol Version 3.0, 03 September 2019 (revised from Version 2.0, 02 July 2019) 
The following is a summary of the changes made to this protocol. 
 
Location of Change 
Change/Modification in Version 3.0 
Protocol Approval Page  
The Clinical Operations signatory has been updated to 
Jamie Fiske, Clinical Project Manager, Novavax, Inc.  
Synopsis, Section 6.1.5, 
Appendices 1 and 3 
The Day 28 Study Visit window has been expanded from 
± 2 days to ± 4 days. 
Protocol Version 2.0, 02 July 2019 (revised from Version 1.0, 21 May 2019) 
The following is a summary of the changes made to this protocol. 
 
Location of Change 
Change/Modification in Version 2.0 
Protocol Approval Page 
The Clinical Operations signatory has been updated to Michelle 
Spindler, Director of Clinical Operations, Novavax, Inc.  
Synopsis, Section 1.9 
Text has been updated to specify that testing for cell-mediated 
immunity (CMI) responses will be conducted on a subset of 
approximately 140 subjects from several pre-designated clinical 
sites (to target approximately 70 evaluable subjects per 
treatment group) at Days 0, 7, 28, and 182. 

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Location of Change 
Change/Modification in Version 2.0 
Synopsis, Sections 2.3, 
3.2.3 
An additional exploratory objective and endpoint has been 
added to reflect assessment of CMI responses in a subset of 
approximately 140 subjects from several pre-designated clinical 
sites. 
Synopsis, Section 3.1, 3.3 “Site” has been added as a stratification factor. 
Synopsis, Sections 6.1.2, 
6.1.4, Appendix 1 
Text has been added to specify additional blood draws on Days 
0, 7, 28, and 182 for a subset of approximately 140 subjects from 
pre-designated clinical sites for the purposes of testing CMI 
responses. In addition, text has been added to note that all 
subjects at several pre-designated CMI testing sites will 
participate in CMI blood sampling and the Informed Consent 
document at those sites will be adjusted accordingly. 
Synopsis, Section 10.4.2 
Text has been added to reflect analysis of exploratory CMI 
response endpoints will be performed on a subset of 
approximately 140 subjects from several pre-designated clinical 
sites (70 subjects per treatment arm) and results may be reported 
as an addendum to the main clinical study report. 
Section 7, Appendix 3 
The maximum amount of blood drawn has been updated to 168 
mL. Most subjects will provide up to 60 mL of blood in the trial. 
A subset of approximately 140 subjects from several 
pre-designated clinical sites participating in CMI assessments 
will provide up to 168 mL.   
Section 7.2 
Section has been added to describe laboratory assessments of 
CMI and T Cell responses based on intracellular cytokine 
staining. 
General 
Minor changes have been made to improve the readability and 
consistency of the document. 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .......................................................................................... 2 
PROTOCOL CHANGE HISTORY ....................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF TABLES.................................................................................................................... 8 
GLOSSARY OF ABBREVIATIONS ..................................................................................... 9 
CLINICAL PROTOCOL SYNOPSIS ................................................................................. 12 
1 
INTRODUCTION ........................................................................................................... 21 
1.1 
Influenza Virus ........................................................................................................... 21 
1.2 
Influenza Disease Burden in Older Adults .............................................................. 21 
1.3 
Licensed Vaccines Against Influenza Virus for Older Adults ............................... 22 
1.4 
Novavax’s Nanoparticle Influenza Vaccines ............................................................ 23 
1.4.1 
Quadrivalent (Quad-NIV) .................................................................................... 23 
1.4.2 
Trivalent (Tri-NIV) .............................................................................................. 23 
1.4.3 
Matrix-M1 Adjuvant ............................................................................................ 23 
1.5 
Nonclinical Investigations .......................................................................................... 24 
1.5.1 
Matrix-M1-adjuvanted Tri-NIV ........................................................................... 24 
1.5.2 
Other Matrix-M1-adjuvanted Vaccines ............................................................... 25 
1.6 
Clinical Investigations ................................................................................................ 25 
1.6.1 
Summary of Phase 2 Trial (qNIV-E-201) with Quad-NIV ................................. 25 
1.6.1.1 
Safety Through Day 28 ............................................................................... 25 
1.6.1.2 
Immunogenicity Through Day 28 ............................................................... 26 
1.6.2 
Matrix-M-adjuvanted Vaccines ........................................................................... 27 
1.7 
Trial Rationale ............................................................................................................ 27 
1.8 
Expected Risks from Vaccination with Quad-NIV With or Without Matrix-
M1 Adjuvant ............................................................................................................... 28 
1.9 
Risks Associated with Fluzone Quadrivalent .......................................................... 29 
2 
TRIAL OBJECTIVES .................................................................................................... 30 
2.1 
Primary Objectives..................................................................................................... 30 
2.2 
Secondary Objectives ................................................................................................. 30 
2.3 
Exploratory Objectives .............................................................................................. 30 
3 
TRIAL OVERVIEW ...................................................................................................... 32 
3.1 
Design .......................................................................................................................... 32 
3.2 
Trial Endpoints ........................................................................................................... 32 
3.2.1 
Primary Endpoints ............................................................................................... 32 

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3.2.2 
Secondary Endpoints ........................................................................................... 33 
3.2.3 
Exploratory Endpoints ......................................................................................... 33 
3.3 
Randomization and Blinding Procedure .................................................................. 34 
3.4 
Maintaining the Blinded Randomization Scheme ................................................... 34 
3.5 
Procedure for Unblinding Individual Subjects During the Trial .......................... 34 
3.6 
Trial Duration ............................................................................................................. 35 
4 
TRIAL TEST ARTICLES ............................................................................................. 36 
4.1 
Overview of Product and Manufacturing Process for Clinical Trial 
Material ....................................................................................................................... 36 
4.2 
Manufacture of Bulk Antigen ................................................................................... 36 
4.2.1 
Recombinant Baculovirus .................................................................................... 36 
4.2.2 
Production and Purification of Quad-NIV ........................................................... 36 
4.2.3 
Manufacture of Matrix-M1 Adjuvant .................................................................. 37 
4.3 
Description of Clinical Trial Dosage Formulation .................................................. 37 
4.4 
Fluzone Quadrivalent – Active Comparator ........................................................... 37 
4.5 
Investigational Product Packaging, Storage, and Handling .................................. 37 
4.6 
Compliance and Drug Accountability ...................................................................... 37 
5 
SELECTION OF TRIAL SUBJECTS .......................................................................... 39 
5.1 
Inclusion Criteria ....................................................................................................... 39 
5.2 
Exclusion Criteria....................................................................................................... 39 
6 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................... 41 
6.1 
Trial Visit Procedures ................................................................................................ 41 
6.1.1 
Day 0 – Screening Visit ....................................................................................... 41 
6.1.2 
Day 0 – Injection Visit ......................................................................................... 41 
6.1.3 
Day 3 (± 1 day) – Safety Telephone Contact ....................................................... 42 
6.1.4 
Day 7 (± 1 day) – Follow-up Visit ....................................................................... 42 
6.1.5 
Day 28 (± 4 days) – Follow-up Visit ................................................................... 42 
6.1.6 
Day 90 (± 7 days) – Safety Telephone Contact ................................................... 43 
6.1.7 
Day 182 (± 7 days) – Follow-up Visit ................................................................. 43 
6.1.8 
Day 364 (± 14 days) – Safety Telephone Contact ............................................... 43 
6.2 
Unscheduled Visits ..................................................................................................... 43 
6.3 
Concomitant Therapy ................................................................................................ 43 
6.4 
Declining Trial Treatments or Procedures .............................................................. 44 
6.5 
Premature Discontinuation from Trial .................................................................... 44 
6.6 
Protocol Deviations..................................................................................................... 45 
6.7 
Trial Termination ....................................................................................................... 45 
7 
TRIAL LABORATORY REQUIREMENTS............................................................... 46 

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7.1 
Serological Assessments of Immunogenicity ............................................................ 46 
7.1.1 
Hemagglutination Inhibition (HAI) Assay .......................................................... 46 
7.1.1.1 
Egg-Propagated HAI ................................................................................... 46 
7.1.1.2 
VLP-based HAI ........................................................................................... 46 
7.1.2 
Microneutralization Assay ................................................................................... 47 
7.2 
Assessments of Cell-Mediated Immunity ................................................................. 47 
7.2.1 
Assessment of T Cell Responses Based on Intracellular Cytokine Staining ....... 47 
7.3 
Retention and Use of Archived Specimens............................................................... 48 
8 
TRIAL ASSESSMENT OF SAFETY ........................................................................... 49 
8.1 
Adverse Events ........................................................................................................... 49 
8.1.1 
Solicited Adverse Events/Subject Diary .............................................................. 49 
8.1.2 
Unsolicited Adverse Events ................................................................................. 50 
8.1.3 
Vital Sign Abnormalities as Adverse Events ....................................................... 51 
8.1.4 
Medically-attended Events and Significant New Medical Conditions ................ 51 
8.2 
Serious Adverse Events .............................................................................................. 53 
8.3 
Safety Reporting Requirements and Timelines for SAEs and Certain Other 
Events .......................................................................................................................... 53 
8.4 
Severity ........................................................................................................................ 54 
8.5 
Relationship (Causality)............................................................................................. 56 
9 
TRIAL DATA MANAGEMENT................................................................................... 57 
9.1 
Recording and Collection of Data ............................................................................. 57 
9.2 
Data Quality Assurance ............................................................................................. 57 
9.3 
Monitoring .................................................................................................................. 57 
9.4 
Audit and Inspection .................................................................................................. 58 
9.5 
Adherence to and Changes to the Protocol .............................................................. 58 
9.6 
Retention of Records .................................................................................................. 58 
10 TRIAL STATISTICAL CONSIDERATIONS ............................................................. 59 
10.1 
Subject Populations .................................................................................................... 59 
10.2 
General ........................................................................................................................ 59 
10.3 
Demographics and Protocol Compliance ................................................................. 59 
10.4 
Analyses Addressing Protocol Objectives ................................................................ 59 
10.4.1 
Analyses of Primary Objectives ........................................................................... 59 
10.4.1.1 Immunogenicity ........................................................................................... 59 
10.4.2 
Analysis of Secondary and Exploratory Immunogenicity Objectives ................. 60 
10.4.3 
Analyses Concerning Safety Objectives .............................................................. 61 
10.5 
Sample Size Considerations ....................................................................................... 61 
10.6 
Plan for Statistical Summaries and Analyses .......................................................... 62 

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10.6.1 
Day 28 Unblinded Data Review .......................................................................... 62 
10.6.2 
Final Clinical Study Report ................................................................................. 63 
10.7 
Computer Methods..................................................................................................... 63 
11 TRIAL LEGAL AND ETHICAL REQUIREMENTS ................................................ 64 
11.1 
Compliance with Regulatory Requirements ............................................................ 64 
11.2 
Ethics Committee ....................................................................................................... 64 
11.3 
Informed Consent ....................................................................................................... 64 
11.4 
Required Site Documentation ................................................................................... 64 
11.5 
Subject Confidentiality .............................................................................................. 65 
11.6 
Disclosure of Information .......................................................................................... 65 
12 REFERENCES ................................................................................................................ 66 
APPENDIX 1 – QNIV-E-301 TRIAL PROCEDURES SCHEDULE ............................... 69 
APPENDIX 2 – QNIV-E-301 SUBJECT DIARY CARD (DRAFT) ................................. 70 
APPENDIX 3 – QNIV-E-301 BLOOD DRAW SCHEDULE ............................................ 71 
APPENDIX 4 – QNIV-E-301 SUBJECT MEASUREMENT TOOL ................................ 72 
 
LIST OF TABLES 
Table 1: Trial Design for qNIV-E-301 .................................................................................. 32 
Table 2:  Programmatically-Determined Protocol Deviations ............................................... 45 
Table 3: Listing of Diary Solicited Events ............................................................................ 50 
Table 4: Adverse Events of Special Interest .......................................................................... 52 
Table 5: Definition of Severity Grading for Adverse Events ................................................ 55 
Table 6:  Severity Grade Definitions for Solicited Gastrointestinal Adverse Events and 
Fever ........................................................................................................................ 55 
Table 7: Definition of Relationship for Adverse Events ....................................................... 56 
 

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GLOSSARY OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
APC 
Antigen Presenting Cells  
C 
Celsius  
CBER 
Center for Biologics Evaluation and Research 
CD 
Cluster of Differentiation or Compact Disc 
CDC 
Centers for Disease Control and Prevention  
CI 
Confidence Interval 
CMI 
Cell-Mediated Immunity 
CMO 
Chief Medical Officer  
CO2 
Carbon Dioxide 
CQA 
Clinical Quality Assurance  
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTM 
Clinical Trial Manager 
CTMS 
Clinical Trial Management System 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GBS  
Guillain-Barré Syndrome  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMR  
Geometric Mean Ratio 
GMT 
Geometric Mean Titer 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition  
HD 
High-Dose  
HEENT 
Head, Eyes, Ears, Nose, Throat  
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 

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Abbreviation or Term 
Definition 
ICH  
International Conference on Harmonisation 
IDMS 
Isotope Dilution Mass Spectrometry 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
IP 
Investigational Product  
IRB 
Investigational Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Randomization System 
LLOQ 
Lower Limit of Quantitation  
MAE 
Medically-attended Event 
MDCK 
Madin Darby Canine Kidney (cells line)  
MedDRA 
Medical Dictionary for Regulatory Activities  
μg 
Microgram 
mg 
Milligram 
MHC 
Major Histocompatibility Complex  
μL 
Microliter 
mL 
Milliliter 
μM 
Micromolar 
mM 
Millimolar 
MMP 
Methyl-α-D-mannopyranoside 
MN 
Microneutralization 
NA 
Neuraminidase or Not Applicable 
NI 
Non-inferiority  
NIV 
Nanoparticle Influenza Vaccine 
nm 
Nanometer 
NP 
Nucleoprotein  
NZW 
New Zealand White (rabbits) 
OD 
Optical Density  
PD 
Protocol Deviation  
PBMC 
Peripheral Blood Mononuclear Cell 
PP 
Per Protocol 
PS 
Polysorbate  
PT 
Preferred Term 
qNIV or Quad-NIV 
Nanoparticle Influenza Vaccine, Quadrivalent 

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Abbreviation or Term 
Definition 
RBC 
Red Blood Cell 
RSV F 
Respiratory Syncytial Virus Fusion  
SAE 
Serious Adverse Event 
SCR 
Seroconversion Rate 
SD 
Standard Deviation 
Sf 
Spodoptera frugiperda 
SNMC 
Significant New Medical Condition  
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SPR 
Seroprotection Rate or Surface Plasmon Resonance   
TCID  
Tissue Culture Infective Dose  
TGS 
Toxicity Grading Scale 
TMAE 
Trimethylaminoethyl 
TMF 
Trial Master File 
tNIV or Tri-NIV 
Nanoparticle Influenza Vaccine, Trivalent  
VLP 
Virus-Like Particle 
VRBPAC 
Vaccine and Related Biological Products Advisory 
Committee 
WHO 
World Health Organization 
w/v 
Weight to Volume  

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CLINICAL PROTOCOL SYNOPSIS 
Protocol 
Number  
qNIV-E-301 
Title  
A Phase 3, Randomized, Observer-blinded, Active-controlled Trial to Evaluate the 
Immunogenicity and Safety of a Recombinant Quadrivalent Nanoparticle Influenza Vaccine 
(Quad-NIV) with Matrix-M1™ Adjuvant Against Fluzone® Quadrivalent in Clinically Stable 
Adults ≥ 65 Years of Age. 
Sponsor and 
Clinical Phase  
Novavax, Inc., 20 Firstfield Road, Gaithersburg, MD 20878 
Phase 3  
Active 
Treatment 
Hemagglutinin Nanoparticle Influenza Vaccine, Quadrivalent (Quad-NIV), representing the 
strains recommended for inclusion in quadrivalent vaccines for the 2019 - 2020 Northern 
hemisphere influenza season, ie, A/Brisbane/02/2018 (H1N1) pdm09; A/Kansas/14/2017 (H3N2); 
B/Maryland/15/2016; B/Phuket/3073/2013 [VRBPAC 2019, WHO 2019]; administered with 
Matrix-M1 Adjuvant. 
Reference 
Materials  
Fluzone® Quadrivalent (Sanofi Pasteur), a United States (US)-licensed seasonal quadrivalent 
influenza vaccine manufactured for the 2019 - 2020 influenza season. 
Dosing and 
Regimen  
All subjects will receive an intramuscular (IM) injection on Day 0 of their assigned test article. 
Injections will contain 240 µg total hemagglutinin (HA) antigen (ie, 60 µg HA of each strain) 
co-formulated with 75 µg Matrix-M1 adjuvant; or the recommended dose of 2019 - 20 Fluzone 
Quadrivalent.  
Purpose and 
Rationale 
Novavax has developed a novel recombinant hemagglutinin (HA) quadrivalent nanoparticle 
influenza vaccine (Quad-NIV) for the prevention of disease due to influenza virus in 
adults ≥ 65 years of age, using a recombinant baculovirus and insect cell technology. With a 
nanoparticle structure, recombinant wild-type sequenced HAs, and use of Matrix-M1 adjuvant, 
Quad-NIV may offer several important advantages over existing licensed egg-derived seasonal 
influenza vaccines, including avoidance of antigenic mismatch due to egg-adaptive mutations; and 
induction of both broadly cross-reactive antibody responses against emerging drift variants of 
seasonal influenza viruses [Shinde 2018], and potent cross-reactive polyfunctional CD4+ T cells.   
In a recent Phase 2, dose-finding, formulation-optimizing trial in adults ≥ 65 years of age, multiple 
formulations of Quad-NIV, containing HA-based antigens representing the 4 influenza strains 
recommended for inclusion in the 2018 - 2019 Northern hemisphere seasonal influenza vaccine 
[VRBPAC 2018, WHO 2018] and co-formulated with Matrix-M1 adjuvant, given intramuscularly, 
induced robust hemagglutination inhibition (HAI) antibody responses against both homologous 
A/B and drifted H3N2 strains. Three formulations in particular: formulation A (60 µg HA of each 
strain in-clinic mixed with 50 µg of Matrix-M1); formulation B (60 µg HA of each strain 
co-formulated with 50 µg of Matrix-M1); and formulation C (60 µg HA of each strain 
co-formulated with 75 µg of Matrix-M1), induced comparable HAI antibody responses (using both 
egg-propagated or wild-type-VLP agglutinins as reagents) against all evaluated homologous and 
drifted H3N2 strains. In addition, all three formulations outperformed Fluzone® High-Dose on 
HAI antibody responses to all evaluated homologous and drifted H3N2 strains using the wild-type 
VLP HAI assays, which assessed the binding of vaccine-induced antibodies to HA sequences 
reflective of circulating viruses not subjected to egg adaptation. The short-term reactogenicity and 
overall safety profiles (through 182 days of follow-up) of the three formulations were also 
comparable. Formulation C (60 µg HA of each strain co-formulated with 75 µg of Matrix-M1) 
induced substantially higher median counts of homologous and drifted strain-specific 
polyfunctional CD4+ T cells at Day 7 following immunization. Finally, formulation C elicited 
significantly higher mean hemagglutination inhibition (HAI) titers than unadjuvanted Quad-NIV 
(formulation E containing only 60 µg HA of each strain) for 5 of 6 tested viral hemagglutinins. 
The totality of safety and immunogenicity data to date indicate that formulation C of Quad-NIV is 
the best candidate to advance in further clinical development.   
The Phase 2 data warrant confirmation of the non-inferiority of immunogenicity of 240 µg 
Quad-NIV containing antigens (60 µg HA of each strain) representing the 4 influenza strains 
recommended for inclusion in the 2019 - 2020 Northern hemisphere seasonal influenza vaccine 

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[VRBPAC 2019, WHO 2019], co-formulated with 75 µg Matrix-M1 adjuvant, as compared to a 
US-licensed seasonal quadrivalent influenza vaccine comparator, Fluzone Quadrivalent, to 
generate data to support licensure of Quad-NIV for the prevention of influenza disease in 
adults ≥ 65 years of age. 
Primary 
Objectives  
• 
To demonstrate the non-inferior immunogenicity of 240 µg Quad-NIV co-formulated with 
75 µg Matrix-M1 adjuvant, relative to a US-licensed comparator, Fluzone Quadrivalent, in 
clinically stable adults ≥ 65 years of age, in terms of hemagglutination inhibition (HAI) 
(assayed with egg-propagated virus) antibody responses to all Quad-NIV homologous 
influenza strains (ie, 2 influenza A and 2 influenza B strains) at Day 28 post-vaccination. 
• 
To describe the safety profile of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and the comparator in clinically stable adults ≥ 65 years of age. The safety profile 
will include solicited short-term reactogenicity; 28-day all adverse event (AE) profile; 1-year 
post-injection medically-attended adverse event (MAE), serious adverse event (SAE), and 
significant new medical condition (SNMC), including immunologically-mediated adverse 
events of special interest (AESIs). 
Secondary 
Objectives  
• 
To describe the immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and of a US-licensed comparator, Fluzone Quadrivalent, in clinically stable 
adults ≥ 65 years of age, in terms of HAI (assayed with both egg-propagated virus and 
wild-type VLP reagents) antibody responses to all Quad-NIV homologous influenza strains 
(2 influenza A and 2 influenza B strains) and at least 1 antigenically drifted A or B strain in 
terms of geometric mean titers (GMTs), geometric mean ratio (GMR), seroconversion rate 
(SCR), seroprotection rate (SPR) and the baseline adjusted ratio of GMTs between treatment 
arms at Day 28. An additional time-point at Day 182 may be tested by HAI for these outcomes 
in a subset of subjects in each treatment group. 
Exploratory 
Objectives  
• 
To evaluate the superior immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg 
Matrix-M1 adjuvant, relative to Fluzone Quadrivalent, in clinically stable adults ≥ 65 years of 
age, in terms of HAI (assayed with both egg-propagated virus and wild-type VLP reagents) 
antibody responses against all 4 vaccine homologous influenza strains (ie, 2 influenza A and 
2 influenza B strains) and 1-2 antigenically-drifted A and/or B strains at Days 0 and 28 
post-vaccination. 
• 
To describe the immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and of a US-licensed comparator, Fluzone Quadrivalent, in clinically stable 
adults ≥ 65 years of age, in terms of microneutralization (MN) responses to 
vaccine-homologous and/or antigenically-drifted influenza strains at Days 0 and 28 
post-vaccination, in terms of GMTs, GMR, SCR, and the baseline adjusted ratio of GMTs 
between treatment arms at Day 28 post-vaccination. Note: Due to the time-consuming nature 
of MN testing, this exploratory objective may be completed in a subset of participants in each 
study treatment group and/or a subset of strains after the initial study HAI data are complete 
and reported in an addendum. Laboratory staff will remain blinded as to treatment 
assignments until all projected MN tests are complete. Similarly, an additional time-point at 
Day 182 may also be tested.  
• 
To describe the quality and amplitude of cell-mediated immune (CMI) responses in healthy 
adults ≥ 65 years of age to vaccination with 240 µg Quad-NIV co-formulated with 75 µg 
Matrix-M1 adjuvant, as measured by functional T cell responses based on intracellular 
cytokine analysis. Additional markers of CMI (eg, memory B cells and/or other T cell subsets) 
may be evaluated depending on availability/recovery of cell volume. Due to the laborious 
nature of the cellular assays, they will be performed on subjects from a limited number of 
participating sites and results may be reported as an addendum to the main clinical study 
report. 
Primary 
Endpoints 
• 
Comparative HAI antibody responses (assayed with egg-propagated virus) on Day 28, 
summarized in terms of the ratio of geometric mean titers (GMTs) AND seroconversion rate 

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(SCR) difference, between subjects receiving Quad-NIV or Fluzone Quadrivalent for all 
4 vaccine homologous influenza strains (ie, 2 influenza A and 2 influenza B strains).  
Non-inferiority for each homologous strain will be demonstrated if: 
o 
The lower bound of the two-sided 95% CI on the ratio of the GMTs 
(GMTQuadNIV/GMTFluzone) is ≥ 0.67,  
AND 
o 
The lower bound of the two-sided 95% CI on the difference between the SCRs 
(SCRQuadNIV-SCRFluzone) is ≥ -10%.  
• 
Number and percentage (95% CI) of subjects with solicited local and systemic adverse events 
over the 7 days post-injection (ie, Day 0 through Day 6, inclusive); all adverse events through 
28 days post-injection (ie, Day 0 through Day 27, inclusive); and MAEs, SAEs, and SNMCs 
– including AESIs – through 1 year post-injection.  
Secondary 
Endpoints 
• 
HAI antibody titers (assayed with both egg-propagated virus and wild-type VLP reagents) at 
Days 0 and 28 specific for vaccine-homologous A and B strain(s), and antigenically-drifted 
influenza strains. An additional time-point at Day 182 may also be tested with a subset of 
subjects. Derived/calculated endpoints based on these data will include:  
o 
GMT – defined as the antilog of the mean of the log-transformed HAI titers, on Days 0 
and 28.  
o 
Geometric mean ratio (GMR) – defined as the ratio of post-vaccination to pre-vaccination 
(Day 0) HAI GMTs (GMRPost/Pre) on Day 28.  
o 
Seroconversion rate (SCR) – defined as proportion of subjects in a given treatment group 
with either a baseline reciprocal (Day 0) titer of < 10 and a post-vaccination reciprocal 
titer ≥ 40, or a baseline reciprocal (Day 0) titer of ≥ 10 and a post-vaccination titer ≥ 4-fold 
higher on Day 28.  
o 
Seroprotection rate (SPR) – defined as the proportion of subjects with a reciprocal HAI 
titer ≥ 40 on Day 28.  
o Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers).  
Exploratory 
Endpoints 
• 
Comparative HAI antibody responses (assayed with both egg-propagated virus and wild-type 
VLP reagents) on Day 28, summarized in terms of the ratio of geometric mean titers (GMTs) 
AND seroconversion rate (SCR) difference, between subjects receiving Quad-NIV or Fluzone 
Quadrivalent for all 4 vaccine homologous influenza strains (ie, 2 influenza A and 2 influenza 
B strains) and 1-2 antigenically-drifted A and/or B strains. 
Superior immunogenicity for each strain will be demonstrated if: 
o 
The lower bound of the two-sided 95% CI on the ratio of the GMTs (GMTQuadNIV/ 
GMTFluzone) is greater than 1.5,  
AND 
o 
The lower bound of the two-sided 95% CI on the difference between the seroconversion 
rates (SCRQuadNIV- SCRFluzone) is greater than 10%. 
• 
Microneutralization 
(MN) 
responses: 
Neutralizing 
antibody 
titers 
specific 
to 
vaccine-homologous A and B strain(s) and/or antigenically-drifted influenza strains, at Days 0 
and 28 post-vaccination, as measured by a microneutralization assay. An additional time-point 
at Day 182 may also be tested. Derived/calculated endpoints based on these data will include: 
o 
GMT – defined as the antilog of the mean of the log-transformed neutralizing titer for a 
given treatment group. 
o 
GMR – defined as the ratio of post-vaccination and pre-vaccination neutralizing GMTs 
within the same treatment group (designated as GMRPost/Pre).  
o 
SCR – defined as proportion of subjects in a given treatment group with either a baseline 
reciprocal titer of < lower limit of quantitation (LLOQ) and a post-vaccination reciprocal 

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titer 4-fold higher than the LLOQ, or a baseline reciprocal titer of ≥ LLOQ and a 
post-vaccination reciprocal titer ≥ 4-fold higher than the baseline titer. 
o 
Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers).  
• 
Counts and/or proportions of Days 0, 7, 28, and 182 peripheral blood effector memory T cell 
populations that secrete one or more of IL-2, CD40L, IFN-γ, and TNF-α cytokines following 
in vitro restimulation with HA in subjects selected for cellular immune response monitoring. 
Counts and/or proportions of additional markers of CMI as appropriate. 
Trial Design  
This is a Phase 3, randomized, observer-blinded, active-controlled trial to evaluate the 
immunogenicity and safety of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 Adjuvant 
against a licensed comparator in clinically stable adults ≥ 65 years of age to be conducted in the 
United States. Approximately 2650 eligible subjects will be enrolled and randomized at a 1:1 ratio 
into 1 of 2 treatment groups, as shown in the Trial Design table below. The active group (Group A) 
and the comparator group (Group B) will each consist of approximately 1325 subjects. Both groups 
will be stratified by site, age (65 to < 75 and ≥ 75 years), and history of prior year receipt of the 
2018-19 influenza vaccine. On Day 0, all subjects will receive a study treatment as indicated in the 
Trial Design table by intramuscular (IM) injection. Total injection volumes for Quad-NIV will be  
0.5 mL. Trial follow-up for each subject will span approximately 1 year from the Day 0 injection. 
It is anticipated that a percentage of the randomized trial subjects will not complete the trial. 
Subjects who withdraw or are discontinued will not be replaced. 
Trial Design for qNIV-E-301 
 
Day 0 Trial Treatment Injection 
 
Subjects Per Group 
Treatment 
Group 
Vaccine 
HA Dose per Strain, 
μg 
(H1N1/H3N2/BV/BY) 
Matrix-M1 
Adjuvant 
Dose 
Injection 
Volume 
Treatment Arm 
A 
Quad-NIV 
60, 60, 60, 60 
75 µg 
0.5 mL 
Non-dominant 
1325 
B 
2019-20 Fluzone Quadrivalent[1] 
1325 
Total Trial Subjects 
2650 
Abbreviations: Bv = B Victoria lineage; BY = B Yamagata lineage; HA = Hemagglutinin 
Note: All subjects will receive a single vaccination by IM injection in their non-dominant arm on Day 0. If the non-
dominant arm is not available for injection, then the dominant arm will be used.  
[1] Fluzone Quadrivalent will be administered at the manufacturer’s recommended dose and volume.   
Trial Visit 
Procedures 
All subjects will undergo procedures summarized in the Schedule of Events table and described in 
detail below.  
Day 0 – Screening Visit 
Clinically stable male and female volunteers, ≥ 65 years of age, who have provided written 
informed consent to participate in the trial and who are able to comply with trial requirements, will 
have the following procedures performed: review of inclusion and exclusion criteria; medical 
history, including influenza vaccination history during the previous 3 years (with emphasis on the 
2018-19 vaccine) and history of adverse reactions to prior influenza vaccines and allergies; 
medication history; physical examination of HEENT (head, eyes, ears, nose, and throat), abdomen, 
extremities, and at least inguinal, cervical, and axillary nodes, gross motor function, and skin; vital 
signs (heart rate, blood pressure, respiratory rate, and oral temperature), height, and weight; and 
assessment of concomitant medications. Note that further procedures may be performed at the 
investigator’s discretion in order to adequately screen subjects against eligibility criteria. Potential 
subjects who meet all inclusion criteria and none of the exclusion criteria (see Inclusion / Exclusion 
Criteria ) may be enrolled. Note: Subjects should be free of acute illness (defined as the presence 
of a moderate or severe illness with or without fever, or an oral temperature ≥ 38.0°C) in order to 
receive the test article injection. Subjects presenting with an acute illness on screening may return 
to the trial site within the next 7 days, provided the enrollment timelines allow, to receive their 
injection provided symptoms have resolved.  
Day 0 – Trial Treatment Injection Visit 

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All subjects who have eligibility confirmed will have blood drawn for baseline immunogenicity 
testing (eg, HAI and MN titers; 20 mL), and then be randomized to 1 of 2 treatment groups. 
A subset of approximately 140 subjects from several pre-designated clinical sites (to target 
approximately 70 evaluable subjects per treatment group) will provide additional blood samples 
(27 mL per visit) at 4 time points (ie, Days 0,7, 28, and 182) to support testing of cell-mediated 
immune responses (CMI). Note: All subjects at several pre-designated CMI testing sites will 
participate in CMI blood sampling and the Informed Consent document at those sites will be 
adjusted accordingly. 
Subjects will then receive a single IM injection of their assigned treatment into the deltoid muscle 
of the non-dominant arm. (If the non-dominant arm is not available due to post-surgical changes, 
skin changes, or prior injury, the dominant arm may be used). Subjects will be monitored in the 
clinic for approximately 30 to 60 minutes following injection with trial treatment for the occurrence 
of any local injection site or systemic reactions, including evaluation of vital signs. 
Starting on vaccination day (Day 0) and for 6 days thereafter (Day 0 through Day 6 inclusive), 
subjects will maintain diaries for daily recording of their body temperature and any adverse event 
spontaneously experienced. In addition, the following local injection site and systemic reactions 
will be solicited by diary: injection site (local) events – pain, bruising, redness, and swelling; 
general systemic events – oral temperature, chills, muscle pain, joint pain, diarrhea, nausea, 
vomiting, headache, and fatigue; and facial/respiratory systemic events – cough, difficulty 
breathing, difficulty swallowing, hoarseness, chest tightness, sore throat, wheezing, eye redness, 
and facial swelling. Subjects will also be asked to record any concomitant medications, physician 
visits, or hospitalizations associated with these solicited adverse events.   
Follow-up Telephone Contacts and In-clinic Visits 
Safety follow-up visits will be performed by scripted telephone contact on Day 3 (± 1 day) to query 
for any Grade 3 solicited or unsolicited event and/or SAE experienced and concomitant 
medications taken for these events since the last visit. Subjects who report a Grade 3 event and/or 
SAE may be asked to return to the clinic for an unscheduled visit at the investigator’s discretion. 
On Days 7, 28, and 182, a subset of approximately 140 subjects who were enrolled at several 
pre-designated clinical sites, and who provided blood for CMI responses at Day 0, will provide 
additional blood samples for post-vaccination CMI responses (27 mL per visit).  
On Day 28 (± 4 days), all subjects will return to the clinic for collection of vital signs, diary review, 
to provide blood samples for post-vaccination immunogenicity testing (20 mL), and to report any 
AEs, MAEs, SNMCs, and SAEs occurring since the last visit, and any concomitant medications 
taken. Subjects will return to the clinic again on Day 182 (± 7 days) for collection of vital signs, to 
provide blood samples for post-vaccination immunogenicity testing (20 mL), and to report any 
MAEs, SNMCs, and SAEs occurring since the last trial visit, and any concomitant medications 
taken for these events. 
Additional safety telephone contacts will occur on Days 90 (± 7 days) and 364 (± 14 days) to query 
for any MAEs, SNMCs, and SAEs occurring since the last trial visit, and any concomitant 
medications taken for these events.  
Schedule of Events: 
Trial Day:  
0 
3 
7 
28 
90 
182 
364 
Window (days): 
± 1 
± 1 
± 4 
± 7 
± 7 
± 14 
Trial Procedures 
Trial Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical/Medication 
History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
X [4] 
X [4] 
 
X [4] 
 
Vital Signs 
X [1] 
 
X 
X 
 
X 

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Serology  
X 
 
 
X 
 
X 
PBMC for CMI 
X[5] 
 
X[5] 
X[5] 
 
X[5] 
 
Trial Treatment Injection  
X 
 
 
 
 
 
Adverse Event Review [2] 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Review [2] 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Review 
 
 
 
X [3] 
 
 
End of Trial  
 
 
 
 
 
 
X 
Note: Procedures shaded in grey are performed via scripted telephone call. 
[1] Vital signs to be captured pre-vaccination and between 30 to 60 minutes post-vaccination. 
[2] All adverse events and concomitant medications taken will be collected through Day 28; thereafter, only MAEs, SAEs, 
and SNMCs and medications taken for these events will be collected.  
[3] The subject diary will be reviewed by the investigator and collected at the Day 28 visit.  
[4] If needed, a physical examination may be performed, based on the investigator’s discretion. 
[5] To be collected from a subset of approximately 140 subjects from several pre-designated clinical sites. 
Inclusion 
Criteria  
Subjects must meet the following criteria to be eligible to participate: 
1) Clinically-stable adult male or female, and ≥ 65 years of age. Subjects may have 1 or more 
chronic medical diagnoses, but should be clinically stable as assessed by: 
• 
Ambulatory status, living independently in the community or in a residential facility 
providing minimal assistance (eg, meal preparation and transport). 
• 
Absence of changes in medical therapy within 1 month due to treatment failure or toxicity,  
• 
Absence of medical events qualifying as serious adverse events within the prior 2 months; 
and 
• 
Absence of known, current, and life-limiting diagnoses which render survival to 
completion of the protocol unlikely in the opinion of the investigator. 
2) Willing and able to give informed consent prior to trial enrollment, and  
3) Living in the community and able to attend trial visits, comply with trial requirements, and 
provide timely, reliable, and complete reports of adverse events. 
Exclusion 
Criteria  
Subjects will be excluded if they meet any of the following criteria: 
1) Participation in research involving investigational product (drug / biologic / device) within 
45 days before planned date of study vaccination. 
2) Participation in any previous Novavax influenza vaccine clinical trial(s). 
3) History of a serious reaction to prior influenza vaccination, known allergy to constituents of 
Fluzone Quadrivalent or polysorbate 80. 
4) History of Guillain-Barré Syndrome (GBS) within 6 weeks following a previous influenza 
vaccine. 
5) Received any vaccine in the 4 weeks preceding the trial vaccination and any influenza vaccine 
within 6 months preceding the trial vaccination. 
6) Any known or suspected immunosuppressive illness, congenital or acquired, based on medical 
history and/or physical examination. 
7) Chronic administration (defined as more than 14 continuous days) of immunosuppressants or 
other immune-modifying drugs within 6 months prior to the administration of the trial vaccine. 
An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥ 10 mg of 
prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will 
be permitted. 
8) Administration of immunoglobulins and/or any blood products within the 3 months preceding 
the administration of the trial vaccine.  
9) Acute disease at the time of enrollment (defined as the presence of a moderate or severe illness 
with or without fever, or an oral temperature ≥ 38.0°C, on the planned day of vaccine 
administration). 
10) Any condition that in the opinion of the investigator would pose a health risk to the subject if 
enrolled or could interfere with evaluation of the vaccine or interpretation of trial results 

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(including neurologic or psychiatric conditions deemed likely to impair the quality of safety 
reporting). 
11) Known disturbance of coagulation.  
12) Suspicion or recent history (within 1 year of planned vaccination) of alcohol or other substance 
abuse. 
Statistical 
Methods  
General 
Continuous variables will be presented by summary statistics (eg, mean and standard deviation 
[SD] for the non-immunogenicity endpoints; geometric means and their 95% CI for the 
immunogenicity endpoints). Categorical variables will be presented by frequency distributions 
(frequency counts and percentages for the non-immunogenicity endpoints; percentages and their 
95% CIs for the immunogenicity endpoints). 
Analyses Concerning the Primary Immunogenicity Objective 
The per-protocol (PP) population (ie, randomized subjects who received the assigned dose of the 
test article according to the protocol, have HAI serology results at Day 0 and Day 28, and have no 
major protocol deviations) will be the primary population for immunogenicity analysis. A separate 
intent-to-treat (ITT) population analysis will not be produced unless > 5% of at least 1 treatment 
group is excluded from the PP population. No missing data will be imputed. For GMTs and GMRs, 
titers reported below the lower limit of quantitation (LLOQ, ie, below the starting dilution of assay 
reported as “< 10”) will be set to half that limit (ie, 10/2 = 5). 
For purposes of determining non-inferiority (and exploratory superiority) in immunogenicity of 
240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 adjuvant, relative to a US-licensed 
comparator, Fluzone Quadrivalent, for all Quad-NIV homologous influenza strains (2 influenza A 
and 2 influenza B strains) at 28 days post-vaccination, derived/calculated endpoints will include:  
• 
Two-sided 95% CIs for the ratio of Day 28 post-vaccination GMTs between Quad-NIV and 
Fluzone Quadrivalent will be constructed using log normal distribution. The log10 values will 
be used to construct a CI using the analysis of covariance (ANCOVA) with treatment group 
and baseline at Day 0 (adjusted for intergroup variation in baseline [pre-vaccination] titers) as 
the covariates under two-sided type I error rate of 0.05. No type I error rate adjustments will 
be made. The mean difference and the corresponding CI limits will then be exponentiated to 
obtain the ratio of GMT and the corresponding CI. 
• 
Two-sided 95% CIs for the difference of the SCRs between Quad-NIV and Fluzone 
Quadrivalent will be based on the Newcombe hybrid score (METHOD = SCORE 
riskdiff-option for PROC FREQ in SAS).  
Analyses Concerning the Secondary and Exploratory Immunogenicity Objectives  
Immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 adjuvant, relative to 
a US-licensed comparator, Fluzone Quadrivalent, based on HAIs (assayed with both 
egg-propagated virus and wild-type VLP reagents) for all vaccine-homologous influenza A and B 
strains, and at least 1 antigenically-drifted A or B strain at Day 28 post-vaccination, will be 
measured in terms of:   
• 
GMT – defined as the antilog of the mean of the log-transformed HAI titers, on Days 0 and 
28.  
• 
Geometric mean ratio (GMR) – defined as the ratio of post-vaccination to pre-vaccination 
(Day 0) HAI GMTs (GMRPost/Pre) on Day 28.  
• 
Seroconversion rate (SCR) – defined as proportion of subjects in a given treatment group with 
either a baseline reciprocal (Day 0) titer of < 10 and a post-vaccination reciprocal titer ≥ 40, 

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or a baseline reciprocal (Day 0) titer of ≥ 10 and a post-vaccination titer ≥ 4-fold higher on 
Day 28.  
• 
Seroprotection rate (SPR) – defined as the proportion of subjects with a reciprocal HAI titer 
≥ 40 on Day 28.  
• 
Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers). 
An additional time-point at Day 182 may also be tested. 
Microneutralization (MN) responses at Days 0 and 28 post-vaccination will include: 
• 
GMT – defined as the antilog of the mean of the log-transformed neutralizing titer for a given 
treatment group. 
• 
GMR – defined as the ratio of post-vaccination and pre-vaccination neutralizing GMTs within 
the same treatment group (designated as GMRPost/Pre).  
• 
SCR – defined as proportion of subjects in a given treatment group with either a baseline 
reciprocal titer of < lower limit of quantitation (LLOQ) and a post-vaccination reciprocal titer 
4-fold higher than the LLOQ, or a baseline reciprocal titer of ≥ LLOQ and a post-vaccination 
reciprocal titer ≥ 4-fold higher than the baseline titer. 
• 
Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers). 
An additional time-point at Day 182 may also be tested. 
Analysis of exploratory CMI response endpoints will be performed on a subset of approximately 
140 subjects from several pre-designated clinical sites (70 subjects per treatment arm) and results 
may be reported as an addendum to the main clinical study report. 
Analyses Concerning Safety Objectives 
Safety analysis will be descriptive and based on the safety population, defined as all subjects who 
received a dose of trial treatment, analyzed as actually treated. Safety will be summarized overall 
and by individual treatment arms based on solicited short-term reactogenicity post-injection on 
Day 0 - 6, 28-day all AE profile by MedDRA preferred term, and 1-year MAE, SAE, and SNMC 
profiles post-injection on Day 0. All AEs, including MAEs, SAEs, and SNMCs, will be tabulated 
by severity, related (possibly, probably, or definitely vs non-related per investigator assessment), 
and severe and related. The number and percentage (with 95% CI) of subjects in each treatment 
group with a given term will be summarized. A listing and narratives of SAEs will also be 
produced. 
Sample Size 
Considerations 
This study has a single comparison between Quad-NIV and Fluzone Quadrivalent at Day 28 
post-vaccination for the primary immunogenicity objective. No adjustment of the Type I error rate 
for multiple comparisons is warranted since the simultaneous successes of all 8 comparisons 
planned for the 4 strains contained in the vaccines and the two endpoints (GMT and SCR) are 
required for the demonstration of the primary non-inferiority objective of the study.   
Non-inferiority is defined as the lower bound of the 2-sided 95% CI on the ratio of GMTs 
(Quad-NIV vs Fluzone) ≥ 0.67 (ie, unadjusted 1-sided p-value < 0.025 against the null hypothesis 
of H0: Ratio of GMT < 0.67) and the lower bound of the two-sided 95% CI on the difference of 
the SCRs (Quad-NIV - Fluzone) ≥ -10% (ie, unadjusted 1-sided p-value < 0.025 against the null 
hypothesis of H0: Difference of SCRs < -10%).  
For the calculation of sample size estimation, we used assumptions of true differences, ie, the ratio 
of GMTs (Quad-NIV vs Fluzone Quadrivalent) is 1.0 for all 4 homologous strains, and the 
difference of the SCRs is -2% for each of the 4 homologous strains, based on the average 
performance in the previous trial (qNIV-E-201). To achieve an overall 90% power (ie, ~ 97.5% 
power for each of the 4 strains) to demonstrate a non-inferiority margin for SCR difference 
of -10%, the SCR of the reference group (Fluzone Quadrivalent) is assumed to be 0.5 and the SCR 
of treatment group (Quad-NIV) is assumed to be 0.48 under the null hypothesis of inferiority 
(H0: Difference of SCRs < -10%). The significance level of the testing is 0.025. Sample size was 
estimated to be 1195 in each group by assuming equal size in each group. The sample size 
accounted for a 10% attrition rate for the per-protocol population such that the primary analysis 

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population for all immunogenicity endpoints will be 1325 in each group. 
In a previous trial (qNIV-E-201), the observed vaccine-homologous strain-specific standard 
deviations of log10 HAI titers ranged from approximately 0.3 (B/Colorado/06/2017 and 
B/Phuket/3073/2013) 
to 
approximately 
0.4 
(A/Singapore/INFIMH-16-0019/2016 
and 
A/Michigan/45/2015). The calculated power for each strain, unadjusted for multiple comparisons, 
is close to 100% to detect a 1.5-fold difference in GMTs. For 4 strains, this study is designed to 
exclude a GMT ratio of < 0.67 with 100% power. Therefore, for demonstrating non-inferiority for 
4 strains with the true ratio of GMTs of 1.0 and the true SCR differences of -2%, this study provides 
≥ 90% overall power.  
For safety endpoints, the probability of observing at least 1 adverse event among 1325 subjects for 
Quad-NIV is > 90% if the true rate of such events is 0.18%. With 1325 subjects for Quad-NIV, 
observing no adverse events of interest (eg, vaccine-related SAE) would represent an upper bound 
of the 1-sided 95% CI on the percentage of such event is 0.2%. 

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1 
INTRODUCTION 
1.1 
Influenza Virus 
Influenza is an airborne, respiratory pathogen that is generally transmitted by inhalation of 
infectious droplets of respiratory secretions, although transmission via fomites can also occur. 
Infections in humans often lead to annual outbreaks and worldwide epidemics, mainly in the 
winter seasons. The virus infects the upper respiratory epithelium of the nose, throat, bronchi, 
and occasionally the lungs. Clinical characteristics of influenza infection include sudden onset 
of fever, myalgia, headache, severe malaise, dry cough, sore throat, and rhinitis. Although the 
majority of people recover within 1 to 2 weeks without any major medical interventions, 
influenza can be associated with pneumonia and even death, especially in the very young, the 
elderly, and persons with underlying medical conditions such as pulmonary, cardiovascular, 
renal, and liver diseases [Paules 2017]. 
Influenza viruses are enveloped viruses belonging to the family of Orthomyxoviridae and are 
divided into 3 types, designated A, B, and C. Type A and B influenza viruses are responsible 
for yearly epidemic outbreaks of respiratory illness. Type A influenza viruses are further 
subdivided into subtypes based on the antigen structure of the 2 major surface glycoproteins, 
hemagglutinin (HA) and neuraminidase (NA). Among influenza A viruses, 18 HA subtypes and 
11 NA subtypes are known to exist in viruses circulating among wild waterfowl. However, at 
this time, viruses characterized by only 2 combinations of HA and NA subtypes, H1N1 and 
H3N2, are stably established and circulate widely among humans, although H2N2 and H3N8 
viruses have been established in humans in the past [Paules 2017]. Unlike Type A, Type B 
viruses are restricted to humans. Currently, 2 influenza B virus genetic lineages are in 
co-circulation. These lineages, termed Yamagata and Victoria based on their prototype strains, 
have limited antigenic cross-reactivity and often circulate together during the yearly epidemic 
[Paules 2017].  
1.2 
Influenza Disease Burden in Older Adults 
Older adults are at the greatest risk of hospitalization and death due to influenza infection 
[CDC 2019b]. A retrospective study of 3 managed-care organizations during 1996 to 1997 
through 1999 to 2000 estimated that the incidence rate of hospitalization during influenza 
season among people ≥ 65 years of age with underlying high-risk conditions was 
55.6 pneumonia and influenza-associated hospitalizations per 10,000 persons, compared with 
18.7 per 10,000 among lower-risk people of the same age group. Older adults between the ages 
of 50 to 64 with underlying conditions were also at increased risk for hospitalization during 
influenza seasons (12.3 per 10,000), compared with healthy older adults (1.8 per 10,000) 
[Mullooly 2007]. Between the years 1976 to 2007, approximately 21,098 older adults 
(≥ 65 years) were estimated to have died annually due to an influenza-related cause, 
corresponding to 90% of estimated annual average influenza-related mortality across all age 
groups [CDC 2010]. Data from modeling analyses of population-based surveillance covering 
2010 to 2011 through 2012 to 2013 influenza seasons suggests that 71 to 85% of all 
influenza-related deaths occurred in adults ≥ 65 years of age [Reed 2015, Grohskopf 2016].  

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1.3 
Licensed Vaccines Against Influenza Virus for Older Adults 
Vaccination is the cornerstone of influenza control, particularly for high-risk individuals older 
than 65 years, immunocompromised patients, and young children; and offers the most 
cost-effective approach to reduce the morbidity, mortality, and economic burden associated 
with influenza infection [Paules 2017]. To date, 7 quadrivalent inactivated or recombinant 
influenza vaccines, consisting of 2 A virus strains (A/H3N2 and A/H1N1) and strains of both 
B lineages, are licensed for sale in the US and marketed for the 2018-19 influenza season, 
indicated for various populations [FDA 2019, CDC 2019a]. These include the egg-derived 
inactivated virus vaccines Afluria® (Seqirus), Fluarix® (GlaxoSmithKline), FluLaval® 
(ID Biomedical Corp. of Quebec), Fluzone® (Sanofi Pasteur), and Fluzone intradermal 
(Sanofi Pasteur); the cell culture-derived vaccine Flucelvax® (Seqirus), and the recombinant 
DNA technology-derived Flublok® Quadrivalent (Sanofi Pasteur, previously Protein Sciences). 
Three trivalent inactivated or recombinant influenza vaccines are also approved and marketed 
for the 2018-19 influenza season in the US [CDC 2019a]. Only 1 influenza vaccine is approved 
with an adjuvant (FLUAD™ with adjuvant MF59) [CDC 2019a].  
Of all currently-licensed vaccines, 2 are specifically approved for use in older adults, and 
include a high-dose (ie, Fluzone® High-Dose [Fluzone HD] initially approved in the US in 
2009) and an adjuvanted standard-dose inactivated vaccine (ie, FLUAD initially approved in 
the US in 2015); both of these are trivalent [CDC 2019a]. There are currently no data available 
that compare the immunogenicity of FLUAD to Fluzone HD in a randomized clinical trial. 
Although Fluzone HD has reported an increased relative vaccine efficacy of approximately 24% 
in the older adult population compared with standard-dose Fluzone [DiazGranados 2014, Monto 
2017], effectiveness rates reported in older adults have remained quite variable, though 
uniformly suboptimal, from season-to-season since the approval of Fluzone HD in 2009, 
ranging anywhere from -5.8% to 45% from 2009 to 2018 [Griffin 2011, Treanor 2012, Ohmit 
2014, Reed 2014, McLean 2015, Flannery 2018, Zimmerman 2016, CDC 2019a]. During the 
current influenza season (2018 - 19), interim estimates indicate that vaccine efficacy in older 
adults (≥ 50 years of age) remains relatively low at 24% (-15% to 51%) against all influenza 
types [Doyle 2019]. This variability is multifactorial, but is likely, in part, due to antigenic drift 
or mismatch between circulating and vaccine influenza strains leading to reduced effectiveness 
of seasonal influenza vaccines. The most recent example of unanticipated drift occurred in the 
Northern hemisphere 2014-15 influenza season, when A(H3N2) clade 3C.2a viruses replaced 
A/Texas/50/12-like clade 3C.1 viruses represented in the vaccines. This mismatch between 
vaccine and circulating viruses resulted in vaccine effectiveness not different from zero 
[Skowronski 2016]. Emerging data also demonstrate other mechanisms that may account for 
reduction in vaccine effectiveness, specifically the increasingly-recognized problem of 
antigenic changes arising from egg-based influenza vaccine production. It has been shown that 
hemagglutinin proteins produced by viruses replicating in eggs undergo adaptive mutations 
which can critically alter the antigenic structure of key HA head-based epitopes and 
consequently, the immune response in the vaccinee and thereby result in an apparent antigenic 
mismatch between egg-produced vaccine strains and circulating strains [Zost 2017]. This 
mechanism, compounded by a degree of antigenic evolution, may explain the very poor 
effectiveness of 2017 vaccines against A(H3N2) viruses in Australia [Sullivan 2017]. Thus, 
there remains a significant need for influenza vaccines with improved efficacy, and, in 

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particular, the capacity to mitigate the consequences of both naturally-occurring antigenic drift 
between strain selection and circulation of the virus, as well as, potential egg-adaptive mutations 
giving rise to deleterious antigenic changes. The need for improved vaccine performance is the 
greatest in the older adult population, which remains vulnerable to serious complications, 
including death, resulting from influenza infection. Accordingly, a vaccine which induces both 
strong homologous, as well as broadly cross-reactive, hemagglutination inhibition (HAI) 
antibodies, induces potent broadly cross-reactive strain-specific polyfunctional CD4+ T cell 
responses, and is produced in a recombinant wild-type expression system (thereby avoiding the 
problem of egg adaptive mutations), could be of significant added value and could help meet 
the unmet medical need of influenza prevention in older adults.   
1.4 
Novavax’s Nanoparticle Influenza Vaccines 
1.4.1 
Quadrivalent (Quad-NIV) 
Novavax’s Quad-NIV is based on purified, recombinant, full-length HA that self-assemble into 
distinct nanoparticle structures of approximately 20 to 40 nm [Smith 2017]. A 
baculovirus/Spodoptera frugiperda (Sf9) insect cell system is used to clone and express 
recombinant influenza HAs from the 4 influenza strains recommended for the relevant influenza 
season. For the 2019 - 20 Northern Hemisphere influenza season, strains include: 
A/Brisbane/02/2018 (H1N1) pdm09; A/Kansas/14/2017 (H3N2); B/Maryland/15/2016 
(Victoria lineage); and B/Phuket/3073/2013 (Yamagata lineage) [VRBPAC 2019, WHO 2019].  
1.4.2 
Trivalent (Tri-NIV) 
Novavax had previously also developed Tri-NIV, a trivalent precursor to Quad-NIV, which was 
based on purified, recombinant, full-length HA that self-assembles into distinct nanoparticle 
structures of approximately 20 to 40 nm [Smith 2017], and manufactured using the same Sf9 
technology used to manufacture Quad-NIV. Tri-NIV comprised recombinant influenza HAs 
from influenza strains recommended for the 2017-18 Northern Hemisphere influenza season: 
A/Michigan/45/2015 (H1N1); A/HongKong/4801/2014 (H3N2); and B/Brisbane/60/2008 
[WHO 2017].  
Summaries of non-clinical and clinical data for Tri-NIV are available in Section 1.5.1 and in 
the Investigator’s Brochure (IB), respectively. 
1.4.3 
Matrix-M1 Adjuvant 
Adjuvants are compounds which, when combined with a specific vaccine antigen, serve to 
increase the immune response to the vaccine. In general, adjuvants work by engaging one or 
more components of the innate immune system, a system that provides a rapid response to 
infection or tissue damage based on recognition of molecular structures common to large groups 
of microbial pathogens [Coffman 2010]. Thus, adjuvants may both quantitatively increase the 
antibody response and also qualitatively broaden its specificity. In addition, some adjuvants 
may modulate the cellular immune response.   
Matrix-M1 is a saponin-based adjuvant, which can be co-administered with an antigen to induce 
a targeted immune response. Matrix-M1 is manufactured by mixing defined, partially-purified 

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extracts of the bark of the Quillaja saponaria Molina tree with cholesterol and 
phosphatidylcholine in the presence of a detergent. Removal of detergent by diafiltration results 
in the formation of stable cage-like structures of 2 types, designated Matrix-A and Matrix-C, 
dependent on the precise Quillaja extract incorporated. Matrix-A and -C are blended in an 85:15 
ratio, respectively, to yield Matrix-M1. The proposed mode of action of Matrix-M1 does not 
include a depot effect, but rather is through a combination of activities including recruitment 
and activation of innate immune cells, rapid antigen delivery to antigen presenting cells (APCs), 
and enhanced antigen presentation via both Major Histocompatibility Complex (MHC) I and 
MHC II molecules in the draining lymph nodes.   
1.5 
Nonclinical Investigations 
1.5.1 
Matrix-M1-adjuvanted Tri-NIV 
A key animal study of Tri-NIV, a trivalent precursor to Quad-NIV (see Section 1.4.2), was 
conducted in an influenza disease model (ferrets) to evaluate its immunogenicity and protective 
efficacy against both a recent and drifted A/H3N2 challenge strain; and to compare the immune 
response with that of the 2016-17 Fluzone HD and Fluzone Quadrivalent (standard dose) 
vaccines. In ferrets, Tri-NIV administered with Matrix-M1 adjuvant elicited rapid and robust 
immune responses in terms of geometric mean hemagglutinin inhibition (HAI) titers, with 
responses exceeding those induced by Fluzone HD or Fluzone Quadrivalent. Secondly, 
geometric mean 50% microneutralizing (MN) titers against a broad panel of historic H3N2 
strains tested, dating to 1999 and spanning a number of clinically-significant antigenic drift 
events, showed 2 to 214-fold higher titers among animals given Tri-NIV with Matrix-M1 
adjuvant than among animals given Fluzone HD. These data suggest that Tri-NIV may elicit 
antibodies to broadly-neutralizing epitopes capable of providing greater antigenic drift strain 
protection, even against strains such as A/HongKong/4801/2014, which are associated with 
impaired influenza vaccine efficacy in humans. 
Additionally, a good laboratory practices (GLP)-compliant, repeat-dose toxicology study was 
conducted in New Zealand White (NZW) rabbits investigating the safety and immunogenicity 
of a total dose of 60 µg of a nanoparticle influenza vaccine (NIV), a precursor to Tri-NIV 
(containing 30 µg each of A/Switzerland/9715293/2013 and B/Brisbane/60/2008 [in addition 
to A/Anhui/1/2013 neuraminidase alone or in combination with RSV F protein, which are not 
present in the current candidate], and generated using the same baculovirus/Sf9 technology as 
Tri-NIV and Quad-NIV) was administered to animals on Days 1 and 15, alone or with 50 µg 
Matrix-M1 adjuvant. Results showed no adverse effects on mortality, physical examinations, 
cageside observations, dermal Draize observations, body weights, body weight changes, food 
consumption, body temperatures, ophthalmology, clinical chemistry, hematology, gross 
pathology, or histopathology, with robust influenza-specific responses observed among 
actively-immunized animals, when compared to placebo. There were mild inflammatory 
responses at the vaccine injection sites and hyperplasia of the lymph nodes draining the injection 
sites, which were accompanied by elevation of serum inflammatory markers (eg, CRP and 
fibrinogen). These effects were transient and showed rapid resolution and were considered 
normal, non-adverse responses to immunization. A complete description of these nonclinical 
studies is provided in the IB. 

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1.5.2 
Other Matrix-M1-adjuvanted Vaccines 
Additional toxicological studies in NZW rabbits have been performed with two different 
antigens, ie, an influenza virus (H7N9) virus-like particle and an Ebola virus glycoprotein, in 
which up to 100 µg Matrix-M1 alone or with antigen was evaluated. These toxicological 
investigations indicated that Matrix-M1 adjuvant in doses up 100 µg was well-tolerated in the 
animal and antigen system tested with no evidence of toxicity suggestive of any unusual risk or 
target organ for toxicity. Non-adverse findings, including local injection site reactions and 
chemical markers of inflammation, were transient and similar to those reported in the NIV 
toxicology study and were considered consistent with immune system stimulation consequent 
to immunization. Reference the Matrix-M™ Adjuvant Safety Data Supplement for details 
regarding these additional toxicology studies.  
1.6 
Clinical Investigations 
1.6.1 
Summary of Phase 2 Trial (qNIV-E-201) with Quad-NIV  
In a Phase 2, randomized, observer-blinded, active-controlled trial (qNIV-E-201), Novavax 
evaluated the safety and immunogenicity of various formulations (antigen doses) of Quad-NIV, 
based on the four 2018 - 19 Northern Hemisphere influenza season strains: 
A/Michigan/45/2015 
(H1N1); 
A/Singapore/INFIMH-16-0019/2016 
(H3N2); 
B/Colorado/06/2017; and B/Phuket/3073/2013, in adults ≥ 65 years of age (n = 1375 subjects), 
administered alone or with Matrix-M1 adjuvant compared with Fluzone® High-Dose (HD) and 
Flublok® Quadrivalent. Safety and immunogenicity results through Day 28 are available and 
briefly summarized below.  
1.6.1.1 
Safety Through Day 28 
Overall, various formulations (antigen/adjuvant doses) of Quad-NIV administered alone or with 
Matrix-M1 adjuvant showed an acceptable safety profile and were well-tolerated, with no 
significant dose-related toxicities observed. The proportion of subjects with AEs was 
comparable across all adjuvanted Quad-NIV groups (41 - 52%) and the active comparators, 
Fluzone HD (47%) and Flublok (44%); AEs were reported slightly less frequently in the 
unadjuvanted Quad-NIV group (38%). It is notable that the safety profile of Quad-NIV 
remained comparable across groups regardless of increasing the total antigen dose (ie, total HA 
of 180 µg in Phase 1/2 vs 240 or 300 µg HA in Phase 2) or adjuvant dose (ie, 50 or 75 µg 
Matrix-M1). Further, the safety profile of Quad-NIV formulated with the Matrix-M1 adjuvant 
remained comparable to the unadjuvanted active comparators used in this trial. 
Note: The following individual safety summaries regarding solicited and unsolicited AEs, 
MAEs, and SAEs pertain to subjects who received 240 µg of Quad-NIV co-formulated with 
75 µg Matrix-M1, as compared to those who received Fluzone HD or Flublok, as this is the 
dose and formulation selected for evaluation in the present Phase 3 trial.  
Solicited AEs (common vaccine reactogenicity complaints occurring in the first 7 days after 
exposure) occurred with similar frequency in the 240 µg Quad-NIV with 75 µg Matrix-M1 
group (38%) compared with the Fluzone HD and Flublok groups (37 - 38%). These events 
included typical transient vaccine reactogenicity complaints, and all were transient. It is noted 

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that a slightly higher frequency of severe solicited AEs occurred among Quad-NIV recipients 
(3.2%) as compared with Fluzone HD recipients (1.3%) and to a lesser extent Flublok (2.6%); 
however, the 95% confidence intervals were overlapping among all groups. Severe fever was 
not reported in any treatment group.  
Unsolicited AEs were reported by similar proportions of subjects who received 240 µg 
Quad-NIV with 75 µg Matrix-M1 (18%) and Fluzone HD (20%), and slightly less in the 
Flublok group (15%), through Day 28. Reports of severe unsolicited AEs were uncommon and 
reported in 2% of subjects in the Quad-NIV group and 1% of subjects in each of the active 
comparator groups. One severe event each of blood urea increased, anxiety, and nephrolithiasis 
was reported in the Quad-NIV group (3/156 subjects); acute sinusitis, dehydration, and 
hypokalemia in the Fluzone HD group (1/153 subjects); and hypertension in the Flublok group 
(1/151 subjects); none of these events were reported by the investigator as related to study 
treatment.  
MAEs were reported in a similar proportion of subjects across all groups (7% Quad-NIV 
[240 µg HA with 75 µg Matrix-M1]; 9% Fluzone HD; 6% Flublok) with diagnoses spanning 
several SOCs, most commonly infections and infestations, representing common intercurrent 
illnesses with no apparent clustering by treatment group. SNMCs were reported in 2% of 
Quad-NIV subjects and 1% of Fluzone HD and Flublok subjects. Similar to MAEs, the 
diagnoses span several SOCs representing common intercurrent illnesses in this older adult 
population with no apparent clustering by treatment group. 
No serious adverse events (SAEs) leading to death or considered related to study treatment have 
been reported to date. SAEs were reported in one subject each in the 240 µg Quad-NIV with 
75 µg Matrix-M1 group (malignant melanoma) and the Fluzone HD (dehydration) group; no 
SAEs have been reported to date in the Flublok group. Generally, the rate of SAEs is consistent 
with the rate of 1.3% within 30 days post-vaccination reported in the Fluzone HD USPI 
(June 2018). 
Overall, the safety and reactogenicity profiles of various formulations of Quad-NIV were 
generally comparable to both active comparator influenza vaccines based on available data 
through Day 28. 
1.6.1.2 
Immunogenicity Through Day 28 
Overall, immunogenicity results demonstrated that all Matrix-M1 adjuvanted formulations of 
Quad-NIV were immunogenic, inducing robust HAI responses against homologous A and B 
influenza strains, as well as against drifted A/H3N2 strains (A/Switzerland/9715293/2013 and 
A/Wisconsin/19/2017). Moreover, all Matrix-M1 adjuvanted formulations of Quad-NIV were 
generally at least comparable to both Fluzone HD and Flublok using the egg-propagated virus 
or wild-type virus-like particle (VLP) HAI assay formats. Importantly, all Matrix-M1 
adjuvanted formulations of Quad-NIV had significantly greater HAI responses compared with 
Fluzone HD for A/H3N2 strains, both homologous and drifted, as evaluated in the wild-type 
VLP-based HAI assay. These Quad-NIV formulations were comparable or better than Fluzone 
HD (not statistically significant) against these same A/H3N2 strains in the egg-propagated 
assay. Several formulations of Matrix-M1 adjuvanted Quad-NIV were significantly lower for 

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B/Colorado/06/2017 in the egg-propagated HAI assay compared with Fluzone HD, but 
remained comparable (ie, no significant difference) in the VLP-based assay. However, it should 
be 
noted 
that 
both 
Fluzone 
HD 
and 
Flublok 
included 
B/Maryland/15/2016 
(a B/Colorado/06/2017-like virus) for the Victoria lineage B strain in their 2018 - 19 vaccine 
formulations used in this trial, rather than the B/Colorado/06/2017 strain used in the Quad-NIV 
formulations. While both strains were recommended by WHO as acceptable alternative “like” 
strains for the B Victoria lineage, the B/Maryland/15/2016 strain systematically induced 2-fold 
higher HAI antibody responses compared to B/Colorado/06/2017 in ferret studies reported by 
the CDC and WHO [VRBPAC 2018].  
In terms of cell-mediated immunity (CMI), several Matrix-M1 adjuvanted formulations of 
Quad-NIV induced potent strain-specific and cross-reactive polyfunctional CD4+ T cell 
responses. Lastly, as described in further detail in Section 1.7, these safety and immunogenicity 
data support further clinical development of Quad-NIV with Matrix-M1 adjuvant (60 µg per 
HA strain co-formulated with 75 µg of Matrix-M1 adjuvant) in this Phase 3 clinical trial given 
that increasing the Matrix-M1 adjuvant dose from 50 µg to 75 µg appeared to further enhance 
polyfunctional CD4+ T cell responses while maintaining comparable HAI responses and a 
comparable safety profile relative to formulations of Quad-NIV containing 50 µg of Matrix-M1.  
1.6.2 
Matrix-M-adjuvanted Vaccines 
Matrix-M adjuvant, in 1 of 2 formulations (ie, Matrix-M1 and Matrix-M2), has been 
administered with a variety of vaccine antigens to over 2350 human subjects in multiple clinical 
trials in the US, Europe, and Australia. Of this, over 1800 subjects have received vaccines 
containing the Matrix-M1 adjuvant (proposed for use in this trial) and 537 subjects have 
received vaccines containing Matrix-M2 adjuvant (an adjuvant containing the same active 
components as Matrix-M1, but in a slightly different ratio). Among all 15 studies, no reported 
serious adverse events (SAE) have been classified as related to exposure to the Matrix-M 
adjuvant. 
Please refer to the most recent version of the Matrix-M™ Adjuvant Safety Data Supplement for 
detailed summaries of the clinical experience with Matrix-M1-adjuvanted vaccines. 
1.7 
Trial Rationale 
The influenza virus poses a formidable risk of infection resulting in serious illness in older 
adults. Based on estimates by the Centers for Disease Control and Prevention (CDC), in the US 
alone, up to 85% of all influenza-related deaths and 70% of all influenza-related hospitalizations 
occur in people 65 years of age or older [CDC 2017]. During the current influenza season 
(2018 - 19), interim estimates indicate that vaccine efficacy in older adults (≥ 50 years of age) 
remains relatively low at 24% (-15% to 51%) against all influenza types [Doyle 2019]. In light 
of the continued suboptimal effectiveness of seasonal influenza vaccines, particularly in older 
adults. 
Novavax has developed a novel recombinant hemagglutinin (HA) quadrivalent nanoparticle 
influenza vaccine (Quad-NIV) for the prevention of disease due to influenza virus in adults 
≥ 65 years of age, using a recombinant baculovirus and insect cell technology. With a 

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nanoparticle structure, recombinant wild-type sequenced HAs, and use of Matrix-M1 adjuvant, 
Quad-NIV may offer several important advantages over existing licensed egg-derived seasonal 
influenza vaccines, including avoidance of antigenic mismatch due to egg-adaptive mutations; 
induction of both broadly cross-reactive antibody responses against emerging drift variants of 
seasonal influenza viruses [Shinde 2018]; and potent cross-reactive polyfunctional CD4+ T 
cells. 
In a recent Phase 2, dose-finding, formulation-optimizing trial in adults ≥ 65 years of age, 
multiple formulations of Quad-NIV, containing HA-based antigens representing the 4 influenza 
strains recommended for inclusion in the 2018 - 2019 Northern hemisphere seasonal influenza 
vaccine [VRBPAC 2018, WHO 2018] and co-formulated with Matrix-M1 adjuvant, given 
intramuscularly, induced robust hemagglutination inhibition (HAI) antibody responses against 
both homologous A/B and drifted H3N2 strains. Three formulations in particular: formulation 
A (60 µg HA of each strain in-clinic mixed with 50 µg of Matrix-M1); formulation B (60 µg 
HA of each strain co-formulated with 50 µg of Matrix-M1); and formulation C (60 µg HA of 
each strain co-formulated with 75 µg of Matrix-M1), induced comparable HAI antibody 
responses (using both egg-propagated or wild-type VLP agglutinins as reagents) against all 
evaluated homologous and drifted H3N2 strains. In addition, all three formulations 
outperformed Fluzone HD on HAI antibody responses to all evaluated homologous and drifted 
H3N2 strains using the wild-type VLP HAI assays, which assessed the binding of 
vaccine-induced antibodies to HA sequences reflective of circulating viruses not subjected to 
egg adaptation. The short-term reactogenicity and overall safety profiles (through 182 days of 
follow-up) of the three formulations were also comparable. Formulation C (60 µg HA of each 
strain co-formulated with 75 µg of Matrix-M1) induced substantially higher median counts of 
homologous and drifted strain-specific polyfunctional CD4+ T cells at Day 7 following 
immunization. Finally, formulation C elicited significantly higher mean hemagglutination 
inhibition (HAI) titers than unadjuvanted Quad-NIV (formulation E containing only 60 µg HA 
of each strain) for 5 of 6 tested viral hemagglutinins. The totality of safety and immunogenicity 
data to date indicate that formulation C of Quad-NIV is the best candidate to advance in further 
clinical development.  
The Phase 2 data warrant confirmation of the non-inferiority of immunogenicity of 240 µg 
Quad-NIV containing antigens (60 µg HA of each strain) representing the 4 influenza strains 
recommended for inclusion in the 2019 - 2020 Northern hemisphere seasonal influenza vaccine 
[VRBPAC 2019, WHO 2019], co formulated with 75 µg Matrix-M1 adjuvant, as compared to 
a US-licensed quadrivalent seasonal influenza vaccine comparator, Fluzone Quadrivalent, to 
generate data to support licensure of Quad-NIV for the prevention of influenza disease in 
adults ≥ 65 years of age. 
1.8 
Expected Risks from Vaccination with Quad-NIV With or Without 
Matrix-M1 Adjuvant 
The expected risk of vaccination with Quad-NIV in combination with Matrix-M1 adjuvant can 
be directly extrapolated from available safety data through Day 28 from the previous Phase 2 
trial (qNIV-E-201), which tested Quad-NIV alone or adjuvanted with Matrix-M1 in adults 
≥ 65 years of age (n = 1375 subjects) compared with Fluzone HD and Flublok Quadrivalent. 

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To date, there have been a total of 1068 human exposures to Quad-NIV with or without 
Matrix-M1 adjuvant. 
Overall, the safety and reactogenicity profile of all Quad-NIV formulations/groups have been 
generally comparable to the active comparator influenza vaccines (Fluzone HD and Flublok 
Quadrivalent) based on available data reviewed through Day 28. A slightly higher frequency of 
severe solicited AEs occurred among subjects who received 240 µg Quad-NIV with 50 µg 
Matrix-M1 (3.3%) or 240 µg Quad-NIV with 75 µg Matrix-M1 (3.2%) relative to the active 
comparators (delta of < 1%); however, the 95% confidence intervals were overlapping among 
all groups. Injection site pain was the most common local AE (19%) followed by swelling (7%). 
In the group that received 240 µg Quad-NIV with 75 µg Matrix-M1, the most common systemic 
AEs (> 10%) were headache (15%) and muscle pain (10%). Reports of respiratory/facial AEs 
were generally infrequent and occurred in ≤ 5% of subjects, with the exception of cough and 
sore throat, which occurred in 8% of subjects. Severe events occurring in subjects who received 
240 µg Quad-NIV with 75 µg Matrix-M1 included nausea, fatigue, headache, sore throat, 
diarrhea, vomiting, chills, joint pain, muscle pain, difficulty swallowing, and eye redness, 
although these did not occur in significantly greater proportions than in subjects who received 
Fluzone HD or Flublok. Persistence of these signs and symptoms beyond 7 days after injection 
occurs uncommonly and is not expected. Occurrence of these solicited signs and symptoms 
with characteristics consistent with the definition of a SAE (ie, need for an urgent and 
significant medical intervention, and/or hospitalization, and/or residual disability) is also not 
expected. 
Finally, risks identified in human clinical trials with the Matrix-M1 adjuvant have been 
described in detail in the current Matrix-M Adjuvant Safety Data Supplement, which is 
provided for information with the protocol and the Quad-NIV Investigator’s Brochure. 
1.9 
Risks Associated with Fluzone Quadrivalent 
In adults ≥ 65 years of age, the most common (≥ 10%) injection-site reaction was pain (33%) 
and the most common solicited systemic adverse reactions were myalgia (18%), headache 
(13%), and malaise (11%). Unsolicited non-serious adverse events were reported in 12.4% of 
recipients in the Fluzone Quadrivalent group, as compared to 9.8% of recipients in either of the 
comparator trivalent influenza vaccine groups (TIV-1 or TIV-2). The most commonly reported 
adverse events were oropharyngeal pain, rhinorrhea, injection-site induration, and headache. 
Information regarding the post-marketing safety data for Fluzone Quadrivalent is available in 
the Package Insert, which will be supplied to Investigators. Of note, subjects with a history of 
Guillain-Barré syndrome within 6 weeks of any influenza vaccine should not receive Fluzone 
Quadrivalent or be enrolled in this trial (see trial exclusion criteria in Section 5.2). 

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2 
TRIAL OBJECTIVES 
2.1 
Primary Objectives 
• To demonstrate the non-inferior immunogenicity of 240 µg Quad-NIV co-formulated with 
75 µg Matrix-M1 adjuvant, relative to a US-licensed comparator, Fluzone Quadrivalent, in 
clinically stable adults ≥ 65 years of age, in terms of hemagglutination inhibition (HAI) 
(assayed with egg-propagated virus) antibody responses to all Quad-NIV homologous 
influenza strains (ie, 2 influenza A and 2 influenza B strains) at Day 28 post-vaccination. 
• To describe the safety profile of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and the comparator in clinically stable adults ≥ 65 years of age. The safety profile 
will include solicited short-term reactogenicity; 28-day all adverse event (AE) profile; 
1-year post-injection medically-attended adverse event (MAE), serious adverse event 
(SAE), 
and 
significant 
new 
medical 
condition 
(SNMC), 
including 
immunologically-mediated adverse events of special interest (AESIs). 
2.2 
Secondary Objectives 
• To describe the immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and of a US-licensed comparator, Fluzone Quadrivalent, in clinically stable adults 
≥ 65 years of age, in terms of HAI (assayed with both egg-propagated virus and wild-type 
VLP reagents) antibody responses to all Quad-NIV homologous influenza strains 
(2 influenza A and 2 influenza B strains) and at least 1 antigenically drifted A or B strain in 
terms of geometric mean titers (GMTs), geometric mean ratio (GMR), seroconversion rate 
(SCR), seroprotection rate (SPR), and the baseline adjusted ratio of GMTs between 
treatment arms at Day 28. An additional time-point at Day 182 may be tested by HAI for 
these outcomes in a subset of subjects in each treatment group. 
2.3 
Exploratory Objectives 
• To evaluate the superior immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg 
Matrix-M1 adjuvant, relative to Fluzone Quadrivalent, in clinically stable adults ≥ 65 years 
of age, in terms of HAI (assayed with both egg-propagated virus and wild-type VLP 
reagents) antibody responses against all 4 vaccine homologous influenza strains 
(ie, 2 influenza A and 2 influenza B strains) and 1-2 antigenically-drifted A and/or B strains 
at Days 0 and 28 post-vaccination. 
• To describe the immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 
adjuvant, and of a US-licensed comparator, Fluzone Quadrivalent, in clinically stable 
adults ≥ 65 years of age, in terms of microneutralization (MN) responses to 
vaccine-homologous and/or antigenically-drifted influenza strains at Days 0 and 28 
post-vaccination, in terms of GMTs, GMR, SCR, and the baseline adjusted ratio of GMTs 
between treatment arms at Days 28 post-vaccination. Note: Due to the time-consuming 
nature of MN testing, this exploratory objective may be completed in a subset of participants 
in each study treatment group and/or a subset of strains after the initial study HAI data are 
complete and reported in an addendum. Laboratory staff will remain blinded as to treatment 
assignments until all projected MN tests are complete. Similarly, an additional time-point 
at Day 182 may also be tested.  

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• To describe the quality and amplitude of cell-mediated immune (CMI) responses in healthy 
adults ≥ 65 years of age to vaccination with 240 µg Quad-NIV co-formulated with 75 µg 
Matrix-M1 adjuvant, as measured by functional T cell responses based on intracellular 
cytokine analysis. Additional markers of CMI (eg, memory B cells and/or other T cell 
subsets) may be evaluated depending on availability/recovery of cell volume. Due to the 
laborious nature of the cellular assays, they will be performed on subjects from a limited 
number of participating sites and results may be reported as an addendum to the main 
clinical study report. 

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3 
TRIAL OVERVIEW 
3.1 
Design 
This is a Phase 3, randomized, observer-blinded, active-controlled trial to evaluate the 
immunogenicity and safety of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 adjuvant 
against a licensed comparator in clinically stable adults ≥ 65 years of age to be conducted in the 
United States. Approximately 2650 eligible subjects will be enrolled and randomized at a 1:1 
ratio into 1 of 2 treatment groups, as shown in Table 1 below. The active group (Group A) and 
the comparator group (Group B) will each consist of approximately 1325 subjects. Both groups 
will be stratified by site, age (65 to < 75 and ≥ 75 years), and history of prior year receipt of the 
2018 - 19 influenza vaccine. On Day 0, all subjects will receive a study treatment as indicated 
in Table 1 by intramuscular (IM) injection. Total injection volumes for Quad-NIV will be 
0.5 mL. Trial follow-up for each subject will span approximately 1 year from the Day 0 
injection. It is anticipated that a percentage of the randomized trial subjects will not complete 
the trial. Subjects who withdraw or are discontinued will not be replaced. 
Table 1: Trial Design for qNIV-E-301 
 
Day 0 Trial Treatment Injection 
 
Subjects Per 
Group 
Treatment 
Group 
Vaccine HA Dose per Strain, μg 
(H1N1/H3N2/BV/BY) 
Matrix-M1 
Adjuvant Dose 
Injection 
Volume 
Treatment 
Arm 
A 
Quad-NIV 
60, 60, 60, 60 
75 µg 
0.5 mL 
Non-dominant 
1325 
B 
2019-20 Fluzone Quadrivalent[1] 
1325 
Total Trial Subjects 
2650 
Abbreviations: Bv = B Victoria lineage; BY = B Yamagata lineage; HA = Hemagglutinin  
Note: All subjects will receive a single vaccination by IM injection on Day 0. If the non-dominant arm is not available for 
injection, then the dominant arm will be used. 
[1] Fluzone Quadrivalent will be administered at the manufacturer’s recommended dose and volume.   
3.2 
Trial Endpoints 
3.2.1 
Primary Endpoints 
• Comparative HAI antibody responses (assayed with egg-propagated virus) on Day 28, 
summarized in terms of the ratio of geometric mean titers (GMTs) AND seroconversion 
rate (SCR) difference, between subjects receiving Quad-NIV or Fluzone Quadrivalent for 
all 4 vaccine homologous influenza strains (ie, 2 influenza A and 2 influenza B strains).  
Non-inferiority for each homologous strain will be demonstrated if: 
o 
The lower bound of the two-sided 95% CI on the ratio of the GMTs 
(GMTQuadNIV/GMTFluzone) is ≥ 0.67,  
AND 
o 
The lower bound of the two-sided 95% CI on the difference between the SCRs 
(SCRQuadNIV-SCRFluzone) is ≥ -10%.  

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• Number and percentage (95% CI) of subjects with solicited local and systemic adverse 
events over the 7 days post-injection (ie, Day 0 through Day 6, inclusive); all adverse events 
through 28 days post-injection (ie, Day 0 through Day 27, inclusive); and MAEs, SAEs, 
and SNMCs – including AESIs – through 1 year post-injection.  
3.2.2 
Secondary Endpoints 
• HAI antibody titers (assayed with both egg-propagated virus and wild-type VLP reagents) 
at Days 0 and 28 specific for vaccine-homologous A and B strain(s), and 
antigenically-drifted influenza strains. An additional time-point at Day 182 may also be 
tested with a subset of subjects. Derived/calculated endpoints based on these data will 
include:  
o GMT – defined as the antilog of the mean of the log-transformed HAI titers, on Days 0 
and 28.  
o Geometric mean ratio (GMR) – defined as the ratio of post-vaccination to 
pre-vaccination (Day 0) HAI GMTs (GMRPost/Pre) on Day 28.  
o Seroconversion rate (SCR) – defined as proportion of subjects in a given treatment 
group with either a baseline reciprocal (Day 0) titer of < 10 and a post-vaccination 
reciprocal titer ≥ 40, or a baseline reciprocal (Day 0) titer of ≥ 10 and a post-vaccination 
titer ≥ 4-fold higher on Day 28.  
o Seroprotection rate (SPR) – defined as the proportion of subjects with a reciprocal HAI 
titer ≥ 40 on Day 28.  
o Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for 
intergroup variation in baseline [pre-vaccination] titers). 
3.2.3 
Exploratory Endpoints  
• Comparative HAI antibody responses (assayed with both egg-propagated virus and 
wild-type VLP reagents) on Day 28, summarized in terms of the ratio of geometric mean 
titers (GMTs) AND seroconversion rate (SCR) difference, between subjects receiving 
Quad-NIV or Fluzone Quadrivalent for all 4 vaccine homologous influenza strains 
(ie, 2 influenza A and 2 influenza B strains) and 1 - 2 antigenically-drifted A and/or B 
strains. 
Superior immunogenicity for each strain will be demonstrated if: 
o The lower bound of the two-sided 95% CI on the ratio of the GMTs 
(GMTQuadNIV/GMTFluzone) is greater than 1.5,  
AND 
o The lower bound of the two-sided 95% CI on the difference between the seroconversion 
rates (SCRQuadNIV-SCRFluzone) is greater than 10%. 
• Microneutralization 
(MN) 
responses: 
Neutralizing 
antibody 
titers 
specific 
to 
vaccine-homologous A and B strain(s) and/or antigenically-drifted influenza strains, at 
Days 0 and 28 post-vaccination, as measured by a microneutralization assay. An additional 
time-point at Day 182 may also be tested. Derived/calculated endpoints based on these data 
will include: 

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o GMT – defined as the antilog of the mean of the log-transformed neutralizing titer for a 
given treatment group. 
o GMR – defined as the ratio of post-vaccination and pre-vaccination neutralizing GMTs 
within the same treatment group (designated as GMRPost/Pre).  
o SCR – defined as proportion of subjects in a given treatment group with either a baseline 
reciprocal titer of < lower limit of quantitation (LLOQ) and a post-vaccination 
reciprocal titer 4-fold higher than the LLOQ, or a baseline reciprocal titer of ≥ LLOQ 
and a post-vaccination reciprocal titer ≥ 4-fold higher than the baseline titer. 
o Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for 
intergroup variation in baseline [pre-vaccination] titers). 
• Counts and/or proportions of Days 0, 7, 28, and 182 peripheral blood effector memory T cell 
populations that secrete one or more of IL-2, CD40L, IFN-γ, and TNF-α cytokines 
following in vitro restimulation with HA in subjects selected for cellular immune response 
monitoring. Counts and/or proportions of additional markers of CMI, as appropriate. 
3.3 
Randomization and Blinding Procedure 
Subject randomization will be conducted using an Interactive Web Randomization System 
(IWRS). Stratification will be by site, age, and history of receipt of the 2018-19 influenza 
vaccine. Proportions of subjects in the various strata will not be pre-specified; rather, the goal 
will be to achieve an approximately equal distribution of subjects with these characteristics 
across the two treatment groups.  
Preparation and administration of each test article dose will be performed by unblinded vaccine 
pharmacists/administrators. These persons, identified prior to trial dosing, will not perform any 
trial assessments post-dosing.  
3.4 
Maintaining the Blinded Randomization Scheme 
Randomization procedures will be performed using IWRS, with treatment assignments known 
only to the responsible unblinded vaccine administrators at the trial center. Subjects and the 
main trial team clinical staff will remain blinded for the duration of the trial unless emergency 
unblinding is necessary. Refer to Section 3.5 for information regarding the process for 
emergency unblinding.   
All treatment assignments, vaccine storage and accountability, and/or dosing-related matters 
will be monitored by a designated “unblinded monitor.” Any deviations will be discussed, 
documented, and resolved by the unblinded monitor and the unblinded site personnel. Reports 
provided by the unblinded monitor will be reviewed by designated unblinded personnel at either 
Novavax or the clinical research organization (CRO), not involved with the main trial team. No 
reports from the unblinded monitor will be released to the Trial Master File (TMF) until 
database lock for Day 364.   
3.5 
Procedure for Unblinding Individual Subjects During the Trial 
In the event of a medical emergency, when knowledge of one or more subject’s treatment 
assignment may influence his/her clinical care or the conduct of the trial, the sponsor’s Chief 

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Medical Officer (CMO) or an investigator or designee may request that the blind be broken for 
the subject(s) experiencing the emergency. Prior to unblinding for individual subjects at site 
investigator’s request, however, the requesting party must use all reasonable efforts to contact 
the Medical Monitor or designee to discuss the decision to break the blind. In the case of such 
individual subjects, the investigator will be expected to provide a rationale for the necessity of 
unblinding based on a meaningful change to the subject’s immediate and short-term medical 
care which will result from knowledge of treatment assignment.  
Novavax retains the right to unblind the treatment allocation for SAEs that are unexpected and 
are suspected to be causally related to the test article, and that potentially require expedited 
reporting to regulatory authorities.  
If unblinding of an individual subject is deemed necessary, the unblinded staff member shall 
obtain subject dose details from the randomization system. The date and time of breaking the 
blind as well as the reason must be recorded and placed in the Pharmacy Binder by unblinded 
staff. The individual subject dose details should be revealed only in case of an emergency where 
further treatment of the subject is dependent on knowing the investigational product he/she has 
received. The investigator should not otherwise divulge the subject’s treatment assignment to 
site staff, and should provide the information only to those individuals involved in the direct 
care of the subject. The date and reasons for breaking the blind must be submitted to the Medical 
Monitor within 24 hours. 
3.6 
Trial Duration 
The maximum duration of an individual subject’s participation in the trial conduct is 
approximately 1 year. 

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4 
TRIAL TEST ARTICLES 
The investigational product (IP) under evaluation in this trial is Quad-NIV adjuvanted with 
Matrix-M1 adjuvant. Discussions on the IP are presented in this section. 
4.1 
Overview of Product and Manufacturing Process for Clinical Trial 
Material 
Novavax’s Quad-NIV is based on purified, recombinant full-length HA that self-assembles into 
distinct nanoparticle structures of approximately 20 to 40 nm [Smith 2017]. The 
baculovirus/Spodoptera frugiperda (Sf9) insect cell system is used to clone and express 
recombinant influenza HAs from the influenza strains recommended for the 2019-20 Northern 
Hemisphere 
influenza 
season: 
A/Brisbane/02/2018 
(H1N1) 
pdm09; 
A/Kansas/14/2017 (H3N2); B/Maryland/15/2016 (Victoria lineage); B/Phuket/3073/2013 
(Yamagata lineage) [VRBPAC 2019, WHO 2019].  
Matrix-M1 is a saponin-based adjuvant, which is co-administered with an antigen to induce an 
enhanced immune response. Matrix-M1 is manufactured by mixing defined, partially-purified 
extracts of the bark of the Quillaja saponaria Molina tree, termed Fraction-A and Fraction-C, 
with cholesterol and phosphatidylcholine in the presence of a detergent.  
4.2 
Manufacture of Bulk Antigen 
4.2.1 
Recombinant Baculovirus 
The recombinant influenza HA genes are cloned into E. coli flashBAC GOLD baculovirus 
transfer vectors (Oxford Expression Technologies, Oxford, UK). The HA genes are under the 
transcriptional control of the baculovirus AcMNPV polyhedrin promoter at the 5' end and 
includes a poly (A) sequence at the 3' end. For each influenza strain, recombinant baculovirus 
expressing a HA gene are identified, plaque-purified, and amplified for use in the manufacture 
of recombinant influenza HA antigens.  
4.2.2 
Production and Purification of Quad-NIV 
Manufacture of each HA protein antigen is initiated by infecting Sf9 cells in exponential growth 
with baculovirus containing the strain-specific HA gene. After infection, cells are collected by 
centrifugation, washed with a detergent-free buffer, and then lysed in the presence of detergent 
to release membrane-bound HA protein. Leupeptin hemi-sulfate salt is added to the lysis buffer 
to protect the HA protein from cellular proteases released during the lysis step. The supernatant 
containing the HA protein is separated from cell debris through the use of depth filtration before 
it is purified on an ion exchange trimethylaminoethyl (TMAE) column. The flow-through 
fraction is then loaded onto a Capto Blue mixed-mode chromatography to capture and remove 
additional baculovirus and Sf9 host cell proteins, while HA is recovered in the flow-through 
fraction. Nanofiltration is then performed to remove viruses from the HA product stream. The 
HA protein is then loaded onto a lentil lectin column, which selectively binds the glycosylated 
protein. After washing, the HA protein is eluted from the column with buffer containing 
methyl-α-D-mannopyranoside (MMP) and polysorbate 80 (PS80). Eluted fractions are 
processed by tangential flow filtration, to concentrate the HA product and exchange it into the 

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final formulation buffer. The product is then diluted to a final formulation containing sodium 
phosphate and PS80, and then filtered (0.22 μm) to produce bulk drug substance that is clear 
and colorless, and contains no preservatives. Each HA bulk drug substance is stored at ≤ -60°C 
until the 4 strains are mixed and diluted to the target concentration with buffer, and filled as 
drug product. The final composition of the drug product formulation is 25 mM sodium 
phosphate, 150 mM sodium chloride, 100 mM arginine hydrochloride, 5% w/v trehalose, and 
0.03% PS80, pH 7.5. 
4.2.3 
Manufacture of Matrix-M1 Adjuvant 
Matrix-M1 is manufactured by mixing defined, partially-purified extracts of the bark of the 
Quillaja saponaria Molina tree, termed Fraction-A and Fraction-C, with cholesterol and 
phosphatidylcholine in the presence of a detergent. Detergent removal by diafiltration results 
in the formation of stable cage-like structures of 2 types, designated Matrix-A and Matrix-C, 
based on the precise Quillaja fraction incorporated. The designation, Matrix-M, refers 
generically to a blend of Matrix-A and Matrix-C particles together at any ratio. An 85:15 ratio 
(by weight) of Matrix-A and Matrix-C particles, respectively, yields Matrix-M1. For a more 
detailed description of the manufacturing process of Matrix-M1 adjuvant, refer to the current 
Matrix-M Adjuvant Safety Data Supplement.  
4.3 
Description of Clinical Trial Dosage Formulation 
Quad-NIV drug product co-formulated with Matrix-M1 adjuvant is filled directly into vials at 
appropriate concentrations. The buffer composition is the same as bulk antigen concentration 
alone, ie, 25 mM sodium phosphate, 150 mM sodium chloride, 100 mM arginine hydrochloride, 
5% w/v trehalose, and 0.03% PS80, pH 7.5. The co-formulated drug product will be filled into 
2R single-use glass vials.  
4.4 
Fluzone Quadrivalent – Active Comparator 
Fluzone Quadrivalent® (Sanofi Pasteur) will be administered based on manufacturer’s 
instructions, which will be provided in the Pharmacy Manual. 
4.5 
Investigational Product Packaging, Storage, and Handling 
All IPs will be packaged in validated shipping containers for distribution to the investigational 
sites under refrigerated conditions. The vials and cartons will be labeled with the following 
information: manufacturer’s name and address, product name, manufacture date, storage 
requirements (2 - 8°C), directions for use, and any other investigational product labeling 
appropriate to the jurisdiction in which the trial is conducted. Fluzone Quadrivalent will be 
packaged, shipped, and stored based on manufacturer’s instructions. All IP and comparator 
materials should be stored at 2 - 8°C in a temperature-monitored refrigerator. Access to this 
refrigerator should be limited to designated site personnel.   
4.6 
Compliance and Drug Accountability 
All quantities of the test articles must be reconciled at the completion of enrollment and a 
written explanation provided for any discrepancies. Unless specific written instructions to the 
contrary are provided by Novavax, all unused test articles are to be inventoried, and either 

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destroyed or returned to Novavax (or designee) by the clinical site upon notice by Novavax or 
the site monitor. All used vials will be accounted for on the clinical site’s IP Dispensation Log 
by applying the tear-off portion of the vial/syringe label. 

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5 
SELECTION OF TRIAL SUBJECTS 
5.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible to participate: 
1) Clinically-stable adult male or female, ≥ 65 years of age. Subjects may have 1 or more 
chronic medical diagnoses, but should be clinically stable as assessed by: 
• Ambulatory status, living independently in the community or in a residential facility 
providing minimal assistance (eg, meal preparation and transport), 
• Absence of changes in medical therapy within 1 month due to treatment failure or 
toxicity,  
• Absence of medical events qualifying as serious adverse events within the prior 
2 months, and 
• Absence of known, current, and life-limiting diagnoses which render survival to 
completion of the protocol unlikely in the opinion of the investigator. 
2) Willing and able to give informed consent prior to trial enrollment, and  
3) Living in the community and able to attend trial visits, comply with trial requirements, and 
provide timely, reliable, and complete reports of adverse events. 
5.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria: 
1) Participation in research involving investigational product (drug / biologic / device) within 
45 days before planned date of study vaccination. 
2) Participation in any previous Novavax’s influenza vaccine clinical trial(s). 
3) History of a serious reaction to prior influenza vaccination, known allergy to constituents 
of Fluzone Quadrivalent or polysorbate 80. 
4) History of Guillain-Barré Syndrome (GBS) within 6 weeks following a previous influenza 
vaccine. 
5) Received any vaccine in the 4 weeks preceding the trial vaccination and any influenza 
vaccine within 6 months preceding the trial vaccination. 
6) Any known or suspected immunosuppressive illness, congenital or acquired, based on 
medical history and/or physical examination. 
7) Chronic administration (defined as more than 14 continuous days) of immunosuppressants 
or other immune-modifying drugs within 6 months prior to the administration of the trial 
vaccine. An immunosuppressant dose of glucocorticoid will be defined as a systemic 
dose ≥ 10 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal 
glucocorticoids will be permitted. 

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8) Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the administration of the trial vaccine.  
9) Acute disease at the time of enrollment (defined as the presence of a moderate or severe 
illness with or without fever, or an oral temperature ≥ 38.0°C, on the planned day of vaccine 
administration). 
10) Any condition that in the opinion of the investigator would pose a health risk to the subject 
if enrolled or could interfere with evaluation of the vaccine or interpretation of trial results 
(including neurologic or psychiatric conditions deemed likely to impair the quality of safety 
reporting). 
11) Known disturbance of coagulation.  
12) Suspicion or recent history (within 1 year of planned vaccination) of alcohol or other 
substance abuse. 

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6 
TRIAL ASSESSMENTS AND PROCEDURES 
A trial schematic flowchart is provided in Appendix 1. A detailed description of procedures 
performed at each visit is provided in Section 6.1.  
6.1 
Trial Visit Procedures 
6.1.1 
Day 0 – Screening Visit 
The following procedures will be performed on the day of the planned vaccination: 
• Written informed consent will be obtained in conformance with Section 11.3 of this 
protocol. 
• Inclusion and exclusion criteria review consistent with Section 5. 
• Review of medical history, including influenza vaccination history in the previous 3 years 
(with emphasis on 2018-19 vaccine) and history of adverse reactions to prior influenza 
vaccines and allergies. 
• Medication history, including concomitant medications and vaccines within the last year. 
• Physical examination including the head, eyes, ears, nose, and throat (HEENT), abdomen, 
extremities, and at least inguinal, cervical, and axillary nodes, gross motor function, and 
skin; vital signs (heart rate, blood pressure, respiratory rate, and oral temperature); height 
and weight.  
Note that further procedures may be performed at the investigator’s discretion in order to 
adequately screen subjects against eligibility criteria and/or to confirm medical history. 
Potential subjects who meet all of the inclusion criteria and none of the exclusion criteria may 
be enrolled. Note: Subjects should be free of acute illness (defined as the presence of a moderate 
or severe illness with or without fever, or an oral temperature ≥ 38.0°C) in order to receive the 
test article injection. Subjects presenting with an acute illness on Day 0 may return to the trial 
site within the next 7 days, as the enrollment timelines allow, to receive their injection provided 
symptoms have resolved. 
6.1.2 
Day 0 – Injection Visit 
All subjects with confirmed eligibility will have the following procedures performed: 
• Blood draw for baseline immunogenicity testing (20 mL, see Section 7.1). 
• A subset of approximately 140 subjects from several pre-designated clinical sites (to target 
approximately 70 evaluable subjects per treatment group) will provide additional blood 
samples (27 mL per visit) at 4 time points (ie, Days 0, 7, 28, and 182) to support testing of 
cell-mediated immune responses (CMI). Note: All subjects at several pre-designated CMI 
testing sites will participate in CMI blood sampling and the Informed Consent document at 
those sites will be adjusted accordingly.  
• Randomization to a treatment group. 
• Alcohol swab cleansing of the injection site followed by IM injection of the assigned trial 
treatment into the deltoid muscle of the non-dominant arm. Note: If the non-dominant arm 

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is not available for the injection due to post-surgical changes, skin changes, or prior injury, 
the dominant arm may be used.  
• Monitoring for any AEs for approximately 30 - 60 minutes following vaccination. 
• Post-injection vital sign collection (heart rate, blood pressure, respiratory rate, and oral 
temperature) at 30 - 60 minutes following vaccination. 
• Distribution of the subject diary, thermometer, and a measuring tool to facilitate 
documentation of any AEs (solicited and unsolicited), concomitant medications, physicians 
visits, or hospitalizations, occurring from the time of discharge from the trial clinic on Day 0 
through Day 6 (inclusive). Subjects will also be instructed to call the trial clinic for any 
Grade 3 (severe) solicited or unsolicited health events, and/or health status changes of 
concern to the subject.  
• Schedule the Day 7 or 28 visit before subjects may be dismissed from the clinic.  
6.1.3 
Day 3 (± 1 day) – Safety Telephone Contact 
• Using an IRB-approved script, the trial staff will contact the subjects using a telephone call 
to query for any Grade 3 solicited or unsolicited event and/or SAE experienced, and any 
concomitant medications taken for these events since the last visit. Subjects may be asked 
to return to the clinic for an unscheduled visit to evaluate the event(s) at the trial 
investigator’s discretion. 
6.1.4 
Day 7 (± 1 day) – Follow-up Visit 
A subset of approximately 140 subjects who were enrolled at several pre-designated clinical 
sites, and who provided blood for CMI responses at Day 0, will return to the clinic on Day 7 
for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Interval history to query for any unsolicited AEs, including MAEs, SNMCs, or SAEs, 
occurring since the last trial visit, and any concomitant medications taken. A directed 
physical examination may be performed at the investigator’s discretion to evaluate any AEs.  
• Blood draw to assess CMI responses (27 mL). 
• Schedule the Day 28 visit. 
6.1.5 
Day 28 (± 4 days) – Follow-up Visit 
All subjects will return to the clinic on approximately Day 28 for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Review and collection of subject diary. 
• Blood draw for immunogenicity assessments (20 mL) for all subjects. 
• Blood draw to assess CMI responses (27 mL) for a subset of approximately 140 subjects 
who were enrolled at several pre-designated clinical sites. 

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• Interval history to query for any unsolicited AEs, including MAEs, SNMCs, or SAEs, 
occurring since the last trial visit, and any concomitant medications taken. A directed 
physical examination may be performed at the investigator’s discretion to evaluate any AEs. 
• Schedule the Day 90 telephone contact and the Day 182 in-clinic visit. 
6.1.6 
Day 90 (± 7 days) – Safety Telephone Contact 
• Using an IRB-approved script, the trial staff will contact the subjects using a telephone call 
to query for any MAEs, SAEs, and SNMCs since their last visit, and any concomitant 
medications taken for these events.  
6.1.7 
Day 182 (± 7 days) – Follow-up Visit 
At Day 182, all subjects will return to the clinic for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Blood draw for immunogenicity assessments (20 mL) for all subjects. 
• Blood draw to assess CMI responses (27 mL) for a subset of approximately 140 subjects 
who were enrolled at several pre-designated clinical sites. 
• Interval history to query for any MAEs, SNMCs, or SAEs occurring since the last telephone 
contact, and any concomitant medications taken for these events. A directed physical 
examination may be performed at the investigator’s discretion to evaluate any AEs.  
• Schedule the end of the trial (Day 364) telephone contact.   
6.1.8 
Day 364 (± 14 days) – Safety Telephone Contact 
• Using an IRB-approved script, the trial staff will contact the subjects using a telephone call 
to query for any MAEs, SAEs, and SNMCs since their last visit, and any concomitant 
medications taken for these events.  
• This visit will mark the end of the trial for the subjects. 
6.2 
Unscheduled Visits 
Unscheduled visits are defined as any visits performed to the site outside of the regular visit 
schedule and can occur at the investigator’s discretion for any other trial procedures deemed 
necessary. Subjects will be encouraged to notify the investigator if any severe (Grade 3) local 
or systemic solicited AEs occur within the 7-day post-dosing period (eg, from Day 0 through 
Day 6), or if any severe, serious, or otherwise concerning AEs occur at any time following 
dosing. If symptoms are presented that would require a physical exam to adequately assess 
potential AEs, the exam should be performed and vital signs collected.  
6.3 
Concomitant Therapy 
Subjects may receive all concomitant medications and procedures deemed necessary to provide 
adequate healthcare during the trial, with the exception of those specified in the exclusion 
criteria. Routine medical standards of care are permitted, including vaccines needed for 
emergent indications (eg, tetanus booster in response to a penetrating injury). Routine 
(ie, non-emergent) vaccinations, except the seasonal influenza vaccine, are permitted for all 

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subjects after completion of the Day 28 trial visit. Subjects who receive a seasonal influenza 
vaccine outside of the study before Day 364 will be considered protocol deviations.  
Concomitant medications, procedures, and hospitalizations will be recorded throughout the trial 
including the period from the day informed consent is obtained through the end of trial 
follow-up. All new or changed concomitant medications taken through Day 28 will be recorded; 
thereafter, only concomitant medications taken for MAEs, SNMCs, or SAEs will be recorded. 
The investigator will document the reason for use of the concomitant medication. 
6.4 
Declining Trial Treatments or Procedures 
Subjects have the right to decline trial treatment or other trial procedures for any reason at any 
time during the trial. This trial contemplates one injection of either Quad-NIV with Matrix-M1 
adjuvant or Fluzone Quadrivalent. Refusal of the investigational test article on Day 0 constitutes 
trial withdrawal without exposure, and no further follow-up is required. If a subject declines 
trial procedures subsequent to receipt of the investigational product, it should be recorded as a 
protocol deviation and the reason should be clearly documented in the source document. The 
subject will be asked to complete all other trial procedures as applicable. If the subject does not 
wish to remain in the trial, the subject can choose to withdraw consent and discontinue at any 
time as outlined in Section 6.5. 
The investigator may, at his/her discretion, restrict a subject from receiving trial treatment or 
other trial procedures if he/she considers it to be in the subject's best interest to do so, but can 
suggest that the subject remain in the trial to be followed for safety if the subject has received 
a test article. In this situation, the reason for not performing the trial treatment and/or procedure 
should also be recorded as a protocol deviation and clearly documented in the source document. 
6.5 
Premature Discontinuation from Trial 
Subjects who provide consent but are found to be ineligible on screening will be informed of 
the reason for ineligibility and may be provided with local medical referral by the investigator 
as appropriate, but will receive no further trial follow-up. 
Subject participation in the trial is strictly voluntary. Subjects have the right to withdraw from 
the trial at any time and for any reason, without penalty. The investigator may also, at his/her 
discretion, discontinue subjects from the trial if he/she considers it to be in the participant's best 
interest to do so, or if the subject is not willing or able to comply with the trial requirements. 
Novavax will be notified immediately by the investigator if a subject prematurely ends trial 
participation. The reason for early discontinuation will be clearly documented in the electronic 
case report form (eCRF). A withdrawal due to an AE will initiate additional reporting 
requirements as outlined in Section 8.3.  
In the event of early termination, investigators will make every reasonable effort to perform 
trial completion procedures. Trial completion procedures will include a query for any MAEs, 
SNMCs, or SAEs occurring since the last trial visit, and any concomitant medications taken to 
treat these events. If the subject discontinues from the trial prior to the Day 28 visit, sites will 

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request the subjects to provide blood samples for serology testing (20 mL). Subjects that 
terminate from the trial early will not be replaced.   
6.6 
Protocol Deviations 
A protocol deviation (PD) will be defined as a failure to comply with the requirements set forth 
in the protocol. PDs may be determined programmatically through the course of the trial. 
Examples of programmatically-determined PDs are provided in Table 2. 
Table 2:  Programmatically-Determined Protocol Deviations  
Missed Visit 
Out of Window Visit 
Trial Procedure Not Done 
Randomization Error 
6.7 
Trial Termination 
Novavax reserves the right to terminate the trial at any time for any reason. If and when the trial 
is terminated (either prematurely or as scheduled), the investigator will notify the IRB for the 
trial and other authorities, as required by local regulatory requirements.  
The scheduled end of the trial will be the completion of the last Day 364 follow-up visit with 
the last trial subject. 

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7 
TRIAL LABORATORY REQUIREMENTS 
Appendix 3 specifies the maximum amount of blood (up to 168 mL) to be drawn for 
immunogenicity laboratory assessments to be completed throughout the trial.  
7.1 
Serological Assessments of Immunogenicity 
Immunogenicity assessments will be made on subject sera collected on Days 0, 28, and 182. 
The primary measure of immunogenicity for the trial is serum Day 28 HAI antibody titer 
specific for the HA receptor binding domains of each of the virus strains included in Quad-NIV 
using egg-propagated virus as the agglutinin in the HAI assay. The secondary measure of 
immunogenicity includes HAI titers specific for the HA receptor binding domains of 
vaccine-homologous and antigenically-drifted strains on Days 0 and 28 using both 
egg-propagated virus and VLP as the agglutinin in the HAI assay; an additional time-point at 
Day 182 may also be tested. In addition, neutralizing antibody titers specific for the virus strains 
included in Quad-NIV, as well as selected antigenically-drifted strains, may be evaluated.  
7.1.1 
Hemagglutination Inhibition (HAI) Assay 
7.1.1.1 
Egg-Propagated HAI 
Briefly, sera will be treated with receptor-destroying enzyme (RDE) to remove non-specific 
inhibitors of hemagglutination, followed by heat-inactivation, and then plated into microtiter 
wells, starting with an initial dilution of 1:10 and followed by a series of 2-fold dilutions. The 
HA antigen (ie, egg-propagated whole virus) and human erythrocyte suspension will be added 
to designated wells in 2 steps, with mixing and incubation at each step. The titration endpoint 
will be taken as the highest dilution that demonstrates complete inhibition of hemagglutination. 
The serum HAI titer will be calculated from the GMT of duplicate test results. The HAI assay, 
as described in P_SOP_02076, will be validated for this Phase 3 trial in Novavax Clinical 
Immunology Laboratory under the supervision of Dr. Joyce Plested, Senior Director of Clinical 
Immunology. 
7.1.1.2 
VLP-based HAI 
Due to the documented inability of recent A(H3N2) strains to agglutinate avian or small 
mammal red blood cell reagents in hemagglutination inhibition (HAI) assays and, in addition, 
the presence of immunologically-significant mutations induced by egg passage in the HA of 
these strains [Zost 2017], vaccine immunogenicity will be assessed by the classical HAI method 
adapted with 140 - 190 nm recombinant wild-type hemagglutinin virus-like particles 
(HA-VLPs), reflecting the amino acid sequence of circulating virus, as the agglutinating agent 
and human type-O red blood cells (RBCs) as the agglutination target in order to restore 
assessment of HAI antibody activity. Briefly, sera will be first treated with RDE to remove 
non-specific inhibitors of hemagglutination, followed by heat-inactivation, and then plated into 
microtiter wells, starting with an initial dilution of 1:10 and followed by a series of 2-fold 
dilutions. The HA-VLPs and human erythrocyte suspension will be added to designated wells 
in 2 steps, with mixing and incubation at each step. The titration endpoint will be taken as the 
highest dilution that demonstrates complete inhibition of hemagglutination. The serum HAI 
titer will be calculated from the GMT of duplicate test results. The HAI assay will be validated 

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for this Phase 3 trial and performed as described in P_SOP_02041 in Novavax Clinical 
Immunology Laboratory under the supervision of Dr. Joyce Plested, Senior Director of Clinical 
Immunology.    
7.1.2 
Microneutralization Assay 
The influenza virus microneutralization assay will be based on the WHO manual for the 
laboratory diagnosis and virological surveillance of influenza, with minor modifications 
[WHO 2011]. Briefly, subject test sera will be heat-inactivated at 56°C for 30 minutes. Sera will 
be prepared in 3-fold serial dilutions (starting from 1:10) in duplicate, in 96-well plates. Positive 
and negative serum controls will also be included. An approximate tissue culture infective dose 
of 100 (TCID50) wild-type cell-derived virus will be added and incubated for 120 minutes at 
37°C ± 2°C in 5.0% ± 1% carbon dioxide (CO2) for influenza A virus and at 32°C ± 2°C in 
5.0% ± 1% carbon dioxide (CO2) for influenza B virus. After incubation, 100 µL of trypsinized 
Madin Darby Canine Kidney (MDCK) cells at a concentration of 1.5 x 105/mL will be added 
to each well and incubated for 18 to 22 hours at 37°C ± 2°C in 5.0% ± 1% CO2 for influenza A 
virus and at 32°C ± 2°C in 5.0% ± 1% carbon dioxide (CO2) for influenza B virus. On Day 2, 
plates will be fixed, blocked, and incubated with mouse anti-influenza A nucleoprotein (NP) 
monoclonal antibody blend (MAB8251 for influenza A viruses or MAB8661 for influenza B 
viruses, EMD Millipore, Temecula, CA), followed by washing and incubation with a 
peroxidase-conjugated goat anti-mouse immunoglobulin G (IgG, Kirkegaard and Perry 
Laboratories, Gaithersburg, MD). Finally, plates will be washed and incubated with 
3,3',5,5'-tetramethylbenzidine substrate (Sigma) and the optical density (OD) will be read after 
adding the stop solution. A sample titration curve is plotted OD against dilution using a 
4-parameter curve fit. The sample neutralizing titer is interpolated on the titration curve as 
reciprocal of dilution at the OD that 50% of MDCK cells are infected. A 4-parameter fit 
(SoftMax Pro software) will use the following equation to determine the OD value at which 
50% of the MDCK cells are infected:  
X = [(average OD of virus control wells) + (average OD of cell control wells)] / 2 
The microneutralization assay (Novavax P_SOP_02069) will be qualified before use and will 
be performed in the Novavax Clinical Immunology Laboratory under the supervision of Dr. 
Joyce Plested, Senior Director of Clinical Immunology. 
7.2 
Assessments of Cell-Mediated Immunity 
7.2.1 
Assessment of T Cell Responses Based on Intracellular Cytokine 
Staining 
Human PBMCs are cultured in 96-well U-bottom plates at a density of 1 x 106 cells/well and 
treated with anti-CD28 and anti-CD49d antibodies. At the same time, the samples will be treated 
with HA protein from the tested strains or a heterologous strain, a positive control for T cell 
activation, or medium only (negative control). After incubation at 37°C for 6 hours in the 
presence of BD GolgiPlug™ and BD GolgiStop™ (BD Biosciences) for the last 4 hours, cells 
are labelled for surface markers (CD3, CD4, CD8, CD45RA, and CCR7 [BD Biosciences, San 
Jose, CA]) and the LIVE/DEAD indicator dye (Life Technologies, NY) is added. The 

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intracellular cytokines are detected by antibodies specific for IFN-γ, TNF-α, and IL-2. 
Expression of CD40L will also be tested. The samples are processed using a LSR-Fortessa flow 
cytometer (Becton Dickinson, San Jose, CA). Data are analyzed using Flowjo software version 
10 (Tree Star Inc., Ashland, OR). A limited qualification of this assay will be performed prior 
to its use in clinical testing. 
7.2.2 Assessment of Memory B Cell Response Based on Elispot Analysis. 
HA-specific memory B cells are tested using Elispot analysis. PBMCs are cultured in the 
presence of R848 and human IL-2 for 5 days, and then added into plates that were pre-coated 
with Flu HA proteins of the tested strains. Flu HA-specific antibody-secreting cells are detected 
and counted by HRP conjugated anti-human IgG antibody. 
7.3 
Retention and Use of Archived Specimens 
Subject serum samples may be archived by Novavax or its contractors for a period not to exceed 
25 years. Archived samples may be used for repetition of the assays listed in Section 7.1 using 
different influenza antigens, or for other exploratory assays of influenza virus immunity or 
vaccine response in development. Archived sera may also be used for clinical laboratory testing 
for safety if needed to evaluate an adverse event, provided that a) sample storage falls within 
conditions previously validated by the clinical laboratory to yield interpretable results (or an 
appropriate control strategy can be used to evaluate potential storage impacts), and b) such 
testing will not include either assays to detect human immunodeficiency virus (HIV) infection, 
or any human genetic testing. Archived serum samples may also be used to create positive or 
negative panels for quality control or for assay development related to influenza virus or other 
infectious diseases (excluding HIV), in which case they will be anonymized.  

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8 
TRIAL ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events (AEs) are defined as any unfavorable or unintended change in the physical, 
psychological, or biochemical condition of the subject. An AE temporally related to 
participation in the trial or due to a procedure performed in the trial, will be documented whether 
or not considered related to the test article. This definition includes intercurrent illnesses and 
injuries, and exacerbations of pre-existing conditions. Stable pre-existing conditions which do 
not change in nature or severity during the trial are not considered AEs; however, these should 
be collected as part of the medical history. AEs will be considered treatment emergent from the 
date and time of the first administration of the investigational product.   
Data concerning all classes of adverse events will be collected at scheduled visits from the time 
informed consent is obtained on Day 0 through Day 28, inclusive. After these specified days, 
data concerning MAEs, SNMCs, and SAEs will be collected (see Sections 8.1.4 and 8.2 for 
details of these AEs), as well as additional information regarding outcomes/resolutions of AEs 
reported prior that had no stop date recorded. In addition to the scheduled visits, subjects will 
be instructed to notify the investigator and/or return to the clinic if any severe AE (solicited or 
otherwise) or event fulfilling the definition of an SAE occurs at any time following vaccination. 
If at a scheduled or unscheduled visit, symptoms are presented that would require a physical 
exam to adequately assess potential AEs, the exam should be performed and vital signs 
collected. Adverse events will be recorded as observed by the investigator, designated 
personnel, or as provided by the subject on the diary card or during the in-person visit. Full 
details of the AE (ie, nature, date of onset, and recovery, as well as an assessment of severity, 
relationship to trial treatment [unsolicited events only], seriousness, treatment, and outcome) 
will be recorded in the source documentation and captured in the eCRF, and will generally 
require the investigator(s) causality assessment, except as discussed below. 
8.1.1 
Solicited Adverse Events/Subject Diary 
Subjects will be provided with a diary for the documentation of any AEs, daily recording of 
their body temperature and certain common post-vaccination symptoms, and concomitant 
medications and procedures starting on vaccination day and for 6 days following the Day 0 
vaccination (ie, from Day 0 through Day 6, inclusive). A series of local injection site and 
systemic reactions that are reasonably likely to occur in vaccine programs (Table 3) will be 
solicited daily in the diary and standardized severity grades offered to the subject. Subjects will 
report injection site events occurring on the deltoid where the test article was administered. A 
standard tool for the measurement of visible local reactions will be provided (see example 
provided in Appendix 1) as will a digital oral thermometer. Subjects will also be asked to record 
any physician visits or hospitalizations, and any unsolicited AEs experienced during Day 0 
through Day 6. In addition to reporting Grade 3 solicited adverse events in the diary card, 
subjects should be encouraged to contact the investigator by telephone if these occur. The 
investigator may request an ad hoc clinic visit at his/her judgment, and should enter any Grade 
3 solicited adverse events reported by telephone in the eCRF promptly, even if the balance of 
diary data is not yet available. 

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Table 3: Listing of Diary Solicited Events 
Injection Site 
(Local) Events: 
Systemic Events 
General  
Gastrointestinal 
Respiratory/Facial  
Pain 
Oral temperature 
Nausea 
Eye redness 
Bruising  
Chills 
Vomiting 
Facial swelling 
Redness  
Muscle pain  
Diarrhea 
Eyelid swelling 
Swelling  
Joint pain  
 
Hoarseness 
 
Headache 
 
Sore throat  
 
Fatigue 
 
Cough  
 
 
 
Difficulty breathing   
 
 
 
Wheezing 
 
 
 
Chest tightness 
 
 
 
Difficulty swallowing 
Note: All events listed will be solicited by diary for 7 days post-dosing. Subjects will report injection site events 
occurring on the arm where the test article was administered. Events reported outside the solicitation window 
will be categorized and reported as unsolicited AEs. 
Standard severity grading definitions will be provided in the diary. Grading of visible, 
measurable injection site reactions will be based on the Food and Drug Administration (FDA) 
Guidance for Industry, Toxicity Grading Scale (TGS) for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). Definitions are 
summarized in Table 5. Oral temperatures will be collected as a continuous variable and graded 
by the investigator based on ranges provided in the TGS as shown in Table 6.   
Investigators will not be required to assess causality of solicited adverse events specifically 
named in the diary if onset is during the solicitation period (these will be presumed to be 
treatment-related). Adverse events consistent with the solicited adverse events listed in the 
diary, but with onset after the solicitation period (ie, Day 7 thereafter), will be captured as 
unsolicited AEs and are subject to all procedures for unsolicited AE data. 
Solicited AEs, collected from the subject diary, which continue after the collection period 
(ie, on or after Day 7 for vaccination-emergent events) will be followed to resolution. 
The continuing, solicited AE will be captured by verbatim term on an “AE eCRF” page. 
The investigators will be required to assess severity of the continuing solicited adverse event(s) 
starting from the time after the last diary entry until resolution. 
8.1.2 
Unsolicited Adverse Events 
Any AEs reported spontaneously by subjects will be categorized as unsolicited events and 
Medical Dictionary for Regulatory Activities (MedDRA) coded by system organ class (SOC) 
and preferred term (PT). Solicited events with an onset after the solicitation period will also be 
classified as unsolicited AEs. Unsolicited events that occur within 7 days following vaccination 
should also be recorded in the subject diary. If any Grade 3 unsolicited event is reported during 
this period, subjects should be encouraged to contact the investigator by telephone. The 
investigator may request an ad hoc clinic visit at his/her judgment, and should enter any Grade 3 
unsolicited adverse event reported by telephone in the unsolicited AE eCRF promptly, even if 
the balance of diary data is not yet available. All unsolicited AEs will be assessed for severity 

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(as defined in Section 8.1.2) and for causality (as discussed in Section 8.5), and will be 
documented in the source documents and captured in the eCRF. 
8.1.3 
Vital Sign Abnormalities as Adverse Events 
For purposes of reporting vital sign abnormalities as AEs, those values that show an increase in 
the toxicity grade relative to the baseline values (in the same subject) and attain at least a 
Grade 2 (eg, normal or Grade 1 to Grade 2, or Grade 2 to Grade 3) should be reported as an AE, 
at the investigator’s judgement. Investigators may report lesser abnormalities as AEs if 
indicated based on clinical judgment. Abnormal vital signs may be repeated at the investigator’s 
discretion, and because these measures are highly labile, should only be reported as AEs when 
the investigator believes there is a persistent and meaningful and clinically-significant 
physiologic change. If multiple assessments of vital signs are made, then only the most recent 
measurement will be reported. Vital sign abnormalities which are the logical consequence of 
another diagnosis (eg, irregular tachycardia in a subject with atrial fibrillation or fever in a 
subject with pneumonia) need not be reported separately. 
8.1.4 
Medically-attended Events and Significant New Medical Conditions 
These classes of events will be collected at all trial visits, and if offered spontaneously by the 
subject at any time.   
Medically-attended events (MAEs) are adverse events which result in an unscheduled visit to a 
healthcare provider due to symptomatic illness or injury. These may include office visits, clinic 
visits, home consultations, or emergency room evaluations for non-life-threatening events that 
do not result in hospitalization (life-threatening events or hospitalizations are SAEs, see 
Section 8.2).   
Significant new medical conditions (SNMCs) are adverse events that are new (that is, not 
present at baseline), clinically significant (meaning that they imply an important change in the 
subject’s long-term health status), and typically chronic (requiring an ongoing change in the 
subject’s medical management). This category is not meant to include minor or transient 
diagnoses or age-related changes. For example, while new diagnoses of presbyopia or tinea 
versicolor are chronic conditions, they are not SNMCs because no significant change in health 
status is implied. Similarly, adverse events which are isolated, treatable events that resolve and 
do not require chronic therapy are also not SNMCs (examples could include an uncomplicated 
acute urinary tract infection or a simple fracture resolved with conservative treatment and with 
no residual disability). In contrast, new diagnoses of rheumatoid arthritis or coronary artery 
disease are SNMCs because they imply a long-term change in health status and require ongoing 
medical management. Additionally, because it has been hypothesized that immunizations with 
or without adjuvant may be associated with autoimmunity, regulatory authorities have 
requested that Novavax instruct investigators to be especially vigilant regarding the AESIs 
listed in Table 4. Note that this regulatory request is not specific to Novavax’s Quad-NIV or 
Matrix-M1 adjuvant; and there is no current evidence to suggest that the trial drugs in this 
protocol are, or are not, associated with these illnesses. The list is not intended to be exhaustive, 
nor does it exclude the possibility that other diagnoses may be AESIs.     

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Table 4: Adverse Events of Special Interest   
Categories 
Diagnoses (as MedDRA® Preferred Terms) 
Neuroinflammatory Disorders: 
Acute disseminated encephalomyelitis (including site specific 
variants: eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
myeloradiculomyelitis), 
cranial 
nerve 
disorders 
including 
paralyses/paresis (eg, Bell’s palsy), Guillain-Barre syndrome 
(including 
Miller 
Fisher 
syndrome 
and 
other 
variants), 
immune-mediated 
peripheral 
neuropathies 
and 
plexopathies 
(including chronic inflammatory demyelinating polyneuropathy, 
multifocal motor neuropathy and polyneuropathies associated with 
monoclonal gammopathy), myasthenia gravis, multiple sclerosis, 
narcolepsy, optic neuritis, transverse myelitis, uveitis 
Musculoskeletal and Connective 
Tissue Disorders: 
Antisynthetase syndrome, dermatomyositis, juvenile chronic arthritis 
(including Still’s disease), mixed connective tissue disorder, 
polymyalgia rheumatic, polymyositis, psoriatic arthropathy, relapsing 
polychondritis, rheumatoid arthritis, scleroderma (including diffuse 
systemic form and CREST syndrome), spondyloarthritis (including 
ankylosing spondylitis, reactive arthritis [Reiter's Syndrome] and 
undifferentiated spondyloarthritis), systemic lupus erythematosus, 
systemic sclerosis, Sjogren’s syndrome  
Vasculidities: 
Large vessels vasculitis (including giant cell arteritis such as 
Takayasu's arteritis and temporal arteritis), medium sized and/or small 
vessels vasculitis (including polyarteritis nodosa, Kawasaki's disease, 
microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss 
syndrome [allergic granulomatous angiitis], Buerger’s disease 
[thromboangiitis obliterans], necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody [ANCA] positive vasculitis [type unspecified], 
Henoch-Schonlein purpura, Behcet's syndrome, leukocytoclastic 
vasculitis)  
Gastrointestinal Disorders: 
Crohn’s disease, celiac disease, ulcerative colitis, ulcerative proctitis 
Hepatic Disorders:  
Autoimmune hepatitis, autoimmune cholangitis, primary sclerosing 
cholangitis, primary biliary cirrhosis 
Renal Disorders: 
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis 
rapidly 
progressive, 
membranous 
glomerulonephritis, membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis 
Cardiac Disorders: 
Autoimmune myocarditis/cardiomyopathy 
Skin Disorders: 
Alopecia areata, psoriasis, vitiligo, Raynaud’s phenomenon, erythema 
nodosum, autoimmune bullous skin diseases (including pemphigus, 
pemphigoid 
and 
dermatitis 
herpetiformis), 
cutaneous 
lupus 
erythematosus, morphoea, lichen planus, Stevens-Johnson syndrome, 
Sweet’s syndrome  
Hematologic Disorders: 
Autoimmune hemolytic anemia, autoimmune thrombocytopenia, 
antiphospholipid syndrome 
Metabolic Disorders: 
Autoimmune thyroiditis, Grave’s or Basedow’s disease, Hashimoto 
thyroiditis, diabetes mellitus type 1, Addison’s disease 

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Table 4: Adverse Events of Special Interest   
Categories 
Diagnoses (as MedDRA® Preferred Terms) 
Other Disorders: 
Goodpasture syndrome, idiopathic pulmonary fibrosis, sarcoidosis, 
pernicious anemia  
The eCRF will provide a field in which the investigator may designate AEs as MAEs, SNMCs, 
or both. Because of the significance of the designation for the subject’s health, long-term 
medical management, and for evaluation of vaccine safety, SNMCs are expected to be 
substantiated diagnoses, not isolated symptoms which might or might not be a SNMC, and the 
investigator should record sufficient data in the eCRF to support the diagnosis. 
8.2 
Serious Adverse Events 
A SAE is defined as an AE that results in any of the following outcomes:  
• Death, 
• An immediate threat to life,  
• In-patient hospitalization or prolongation of an existing hospitalization. (Hospitalization is 
defined as an actual admission, not a 24-hour stay or emergency room visit; note that 
elective surgeries, undertaken for conditions present prior to receipt of trial drug and 
without complication, should not be considered SAEs),  
• A persistent or significant disability/incapacity (substantial disruption of an ability to 
conduct normal life functions), or  
• A congenital anomaly or birth defect (not relevant to this protocol).  
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in in-patient hospitalization. Events which could 
have led to the above outcomes had they occurred with greater severity are not SAEs, but should 
be reported as AEs, MAEs, or SNMCs, as appropriate.  
The eCRF will provide a field for designating an AE as an SAE. SAEs are associated with 
enhanced reporting requirements (see Section 8.3). 
8.3 
Safety Reporting Requirements and Timelines for SAEs and 
Certain Other Events 
Any SAE must be reported (using the SAE Report Form) to Novavax Product Safety within 24 
hours of the investigator’s first knowledge of the event, regardless of the presumed relationship 
to the investigational product. The investigator or qualified designee must complete the SAE 
Report Form, sign, and transmit the completed form to Novavax Product Safety.  

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Initial reports of SAEs may be reported via fax or e-mail. Initial reports must be signed 
(physically or electronically) by the investigator or a qualified sub-investigator and transmitted 
to Novavax Product Safety within 24 hours of site awareness. When additional follow-up 
information becomes available, a written follow-up SAE Report Form must be completed, 
signed by the investigator or a qualified sub-investigator, and transmitted as soon as possible. 
The investigator is responsible for obtaining detailed information to support all SAE reports, 
including records of inpatient and outpatient care, laboratory reports, and autopsy or medical 
examiner reports.    
The following events must also be reported to the Medical Monitor within 24 hours of the 
investigator’s first knowledge of the event: 
• Any withdrawal of consent after dosing due to an AE. 
• Overdose (of a test article as specified in the protocol with or without an AE). 
• Inadvertent or accidental exposure to the test article with or without an AE. 
• Medication error (includes the administration of an incorrect treatment, an expired test 
article, a test article that has deviated from its required storage or refrigeration requirements, 
or any test article prior to documentation of informed consent). 
Novavax will be responsible for notifications of SAEs to the relevant regulatory authorities; 
investigators will be responsible for IRB notification.  
8.4 
Severity 
All AEs will be assigned severity by the subject and/or investigator (as applicable) according 
to the TGS. Subjects will also be able to indicate severity for any AEs experienced and record 
this in their diary according to the same scale. For quick reference, an abbreviated grading scale 
is provided in Table 5 for visible and non-visible local AEs and for systemic AEs for which 
severity is based on interference with daily activities and not numeric ranges, and in Table 6 for 
fever and gastrointestinal adverse events of nausea, vomiting, and diarrhea.   
The severity of visually-evaluated local AEs will be a function of size. During the diary period, 
subjects will monitor the size of visible local AEs at the injection site using the Subject 
Measurement Tool (Appendix 4) which has concentric circles that correspond to the diameters 
specified in Table 5. For the purposes of reporting during the solicitation period (ie, Day 0 
through 6) the subjects’ observations will form the primary data. During clinic visits, 
investigators may measure any persisting local AEs with a ruler, documenting the size of the 
reaction at its widest diameter, using the numeric scale provided in Table 5 to assess for severity. 
Non-visible local AEs (eg, pain) will be assigned a severity based primarily on interference 
with daily activities.  
Systemic solicited AEs and unsolicited AEs will be assigned a severity grade based primarily 
on disruption of normal daily activities, with the exception of fever and select solicited 
gastrointestinal AEs that have their own distinct toxicity grades (Table 6). Medical care-seeking 
is typically absent for Grade 1 (mild) and often present for Grade 3 (severe) events, but is not 
the primary determinant of severity, since individuals behave differently in this regard. 

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Severity of vital sign abnormalities (including oral temperature, which is captured as a 
continuous variable) will be graded based on established ranges provided in the TGS and 
reported as an AE using the criteria outlined in Section 8.1.3. 
Table 5: Definition of Severity Grading for Adverse Events 
 
Definitions for Local Adverse Events 
Definitions for Systemic Adverse 
Events 
Severity 
Grade 
Visual Local AE Size 
Grading 
Description 
Non-Visual Local AE 
Grading Description 
Systemic AE  
Grading Description 
0 – Normal 
Reaction size 
 (greatest single diameter) 
< 2.5 cm 
No noticeable symptom 
No noticeable symptom or finding 
1 – Mild 
Reaction size 
(greatest single diameter) 
2.5 to 5.0 cm 
Discomfort or tenderness 
noticeable, but does not 
interfere with normal 
daily activities 
Mild symptoms or diagnostic 
observations; intervention not 
indicated; no interference with 
normal activity 
2 – Moderate 
Reaction size  
(greatest single diameter) 
> 5.0 to 10.0 cm 
Moderate discomfort or 
tenderness on firm 
pressure; causes some 
limitation of normal daily 
activities 
Moderate symptoms or diagnostic 
observations; some interference with 
normal activity, not requiring 
medical intervention 
3 – Severe 
Reaction size 
(greatest single diameter) 
> 10.0 cm 
Severe pain at rest, pain 
or tenderness 
immobilizes the injected 
limb and prevents normal 
daily activities 
Severe symptoms, significantly 
disrupts or prevents normal daily 
activities, generally requires medical 
attention/intervention 
  
Table 6:  Severity Grade Definitions for Solicited Gastrointestinal Adverse Events and Fever  
 
Gastrointestinal Adverse Event 
 
Severity Grade 
Nausea 
Vomiting 
Diarrhea 
Fever 
0 – Normal 
No noticeable 
symptom 
No noticeable 
symptom 
No noticeable 
symptom 
< 38.0 
1 – Mild 
No interference 
with activity, or 1 
to 2 episodes/ 
24-hour period 
No interference 
with activity, or 1 
to 2 episodes/ 
24-hour period 
1 to 3 unformed 
(loose) 
stools/24-hour 
period 
38.0 to 38.4 
2 – Moderate 
Some interference 
with activity, or > 
2 episodes/ 
24-hour period 
Some interference 
with activity, or 
> 2 episodes/ 
24-hour period 
4 to 5 unformed 
(loose) 
stools/24-hour 
period 
38.5 to 38.9 
3 – Severe 
Prevents daily 
activity, or requires 
intravenous 
hydration 
Prevents daily 
activity, or requires 
intravenous 
hydration 
≥ 6 loose 
stools/24-hour 
period, or requires 
> 38.9 

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Table 6:  Severity Grade Definitions for Solicited Gastrointestinal Adverse Events and Fever  
 
Gastrointestinal Adverse Event 
 
Severity Grade 
Nausea 
Vomiting 
Diarrhea 
Fever 
intravenous 
hydration 
8.5 
Relationship (Causality) 
The relationship of an AE to the test article must be assessed and documented by the 
investigator or a qualified sub-investigator. Based on the criteria described below, the 
investigator must classify the AE according to the following categories shown in Table 7. 
Table 7: Definition of Relationship for Adverse Events 
Relationship 
Relationship Description 
Unrelated / Unlikely  
• 
May or may not follow a reasonable temporal sequence from administration of 
the test article; 
• 
No plausible mechanism based on known or suspected actions of the test article 
or product class; 
• 
Readily explained by known characteristics of the subject’s clinical state, 
common intercurrent illnesses, or other treatments administered to the subject. 
Possibly 
• 
Follows a reasonable temporal sequence from administration of the test article; 
• 
Based on known or suspected actions of the test article or product class, a 
plausible mechanism could exist; 
• 
May be reasonably explained by known characteristics of the subject’s clinical 
state, common intercurrent illnesses, or other treatments administered to the 
subject; but the investigator deems this less likely than test article effect. 
Probably 
• 
Follows a reasonable temporal sequence from administration of the test article; 
• 
Based on known or suspected actions of the test article or product class, a 
plausible mechanism could exist; 
• 
Cannot be reasonably explained by known characteristics of the subject’s 
clinical state, common intercurrent illnesses, or other treatments administered 
to the subject. 
Definitely 
• 
Follows a reasonable temporal sequence from administration of the test article; 
• 
Consistent with known actions of the test article or product class; 
• 
Cannot be reasonably explained by known characteristics of the subject’s 
clinical state, common intercurrent illnesses, or other treatments administered 
to the subject. 
• 
May be confirmed by re-challenge (if applicable). 
 

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9 
TRIAL DATA MANAGEMENT 
9.1 
Recording and Collection of Data 
Novavax will provide sites with source document templates for the recording and collection of 
subject data. Data will be entered into an electronic data capture (EDC) system by site staff. All 
EDC entries will be completed as soon as possible after the subject's visit. Corrections to data 
in the EDC system will be documented in the electronic audit trail that is compliant to US FDA 
regulations (21 Code of Federal Regulations Part 11). The investigator will review data resident 
in the EDC and indicate by electronic signature that, to his/her knowledge, the data are complete 
and accurate. If further changes are made after this, the investigator will need to again sign the 
Investigator Signature Page electronically. Designated source documents will be signed and 
dated by the appropriate trial personnel. The investigator must agree to ensure completion and 
maintenance of source documents for each subject participating in the trial. 
9.2 
Data Quality Assurance 
All trial data will be entered by clinical trial site staff with trial-specific EDC training into a 
computerized data management system via EDC. Statistical analyses of data will only be 
performed after all clinical monitoring and data queries have been resolved.  
9.3 
Monitoring 
Novavax, as the Sponsor of this trial, is responsible for ensuring the proper conduct of the trial, 
in accordance with the Declaration of Helsinki (Amended Fortaleza, Brazil, 2013) and Good 
Clinical Practices (GCP) including, but not limited to, protocol adherence and the validity of 
the data recorded in the database. For the purposes of this trial, Novavax may transfer 
responsibility for the clinical monitoring to a CRO who may monitor on-site or remotely. 
Novavax and/or CRO are responsible for ensuring that the site(s) prepare complete, accurate, 
legible, and well-organized clinical trial data. On-site monitoring inspections will be routinely 
performed in order to review data entry of source documentation directly captured on paper and 
transcribed into the system, to ensure protocol adherence, to assess site operational capabilities, 
and to perform other monitoring activities that cannot be performed remotely. In addition, 
clinical monitors will provide ongoing support to ensure the investigator’s continued 
understanding of all applicable regulations concerning the clinical evaluation of the 
investigational vaccine, and the proper execution of the protocol, as well as the investigator’s 
reporting responsibilities. 
The clinical trial sites will be monitored periodically for database accuracy and completeness, 
adherence to the protocol, regulatory compliance, safety reporting, clinical trial material 
accountability, and the maintenance of comprehensive source documents. When data entry has 
been completed by the appropriate trial staff, source documents verified and monitored by 
Novavax and/or CRO representatives, and reviewed by the investigator, the investigator should 
sign and date the Investigator Signature Page. 

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9.4 
Audit and Inspection 
Novavax CQA reserves the option to develop a Quality Assurance plan to ensure the integrity 
of the conduct of the clinical trial. CQA visits may be performed during the trial and post-trial 
by Novavax CQA or other personnel authorized by Novavax. Regulatory authorities reserve 
the right to audit trial sites following submission of data in regulatory applications. By signing 
this protocol, the investigator acknowledges that these inspection procedures may take place 
and agrees to provide access to the required subject records and other trial documentation. 
Further, the investigator agrees to inform Novavax and the IRB immediately of any scheduled 
or unscheduled inspection by regulatory authorities. 
9.5 
Adherence to and Changes to the Protocol 
Any change or addition to this protocol will only be made when a protocol amendment has been 
written, approved, and signed by Novavax and the investigator before the change or addition 
can be considered effective, unless immediate implementation of a change is necessary to 
ensure the safety of subjects. This amendment must also be submitted to the IRB for approval 
and, when necessary, regulatory authority approval before implementation. Protocol 
amendments may affect consent forms of current and future subjects. Novavax will clearly 
specify when a protocol amendment includes safety, procedural, and/or efficacy information 
that will require specific informed consent form (ICF) text changes. 
9.6 
Retention of Records 
It is the responsibility of the investigator and trial staff to maintain a comprehensive and 
centralized filing system of all trial-related documentation, which is suitable for inspection at 
any time by Novavax, its designees, and regulatory agencies. These should minimally include: 
 Subject files including the completed eCRF (based on output from clinical database) on 
compact disc (CD), supporting source documentation, and the informed consent and any 
other subject information. 
 Trial files (essential documents and regulatory files) including the protocol with all 
amendments, the IB, safety and protocol deviations meeting IRB reportable criteria, copies 
of all regulatory documentation, and all correspondence with the IRB, regulatory authority, 
and Novavax. 
 Pharmacy files including all investigational vaccine shipment, receipt, storage, dispensing, 
and accountability records, and pharmacy-related correspondence. 
In addition to the eCRF, the investigator will maintain adequate records that fully document the 
progress of the trial. Copies of these trial records and related documents must be kept on file by 
the investigator for a period of no less than 15 years (or longer if mandated by relevant local 
regulations). ALL DOCUMENTATION AND MATERIAL PROVIDED BY NOVAVAX OR 
A NOVAVAX REPRESENTATIVE FOR THIS TRIAL (CASE REPORT FORMS, 
PROTOCOL, ETC) ARE TO BE RETAINED IN A SECURE PLACE AND 
TREATED AS CONFIDENTIAL MATERIAL. 

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10 
TRIAL STATISTICAL CONSIDERATIONS 
This section includes a brief description of the statistical analyses that will be performed in this 
trial.  
10.1 Subject Populations 
The following subject populations will be used in all analyses: 
• Safety Population - Includes all trial subjects that provide consent, are randomized, and 
receive the test article. The Safety Population will be used for all safety analyses; and will 
be analyzed as actually treated.  
• Per-Protocol Population (PP) - Includes all subjects in the Safety Population that received 
the assigned dose of the test article according to protocol, have HAI serology results for 
Day 0 and Day 28, and have no major protocol deviations affecting the primary 
immunogenicity outcomes as determined by Novavax prior to database lock and 
unblinding. The PP Population will be the primary population used for immunogenicity 
analyses.  
• Intent-to-Treat (ITT) Population - Includes all subjects in the Safety Population that provide 
any HAI serology data. The ITT Population will be the secondary population used for any 
immunogenicity analyses and will be analyzed according to treatment as randomized. 
Analysis using the ITT population will not be performed if it differs from the PP population 
by ≤ 5% of the subjects for each of the 2 treatment groups. 
10.2 General 
Continuous variables will be presented by summary statistics (eg, mean and standard deviation 
[SD] for the non-immunogenicity endpoints; geometric means and their 95% CI for the 
immunogenicity endpoints). Categorical variables will be presented by frequency distributions 
(frequency counts and percentages for the non-immunogenicity endpoints; percentages and 
their 95% CIs for the immunogenicity endpoints). 
10.3 Demographics and Protocol Compliance 
Demographic parameters and other baseline characteristics (eg, age, sex, race, and ethnicity) 
will be summarized by treatment group for all subjects in the safety population. The number 
and description of protocol deviations will be summarized for all enrolled subjects who signed 
the ICF and were randomized in to the study. 
10.4 Analyses Addressing Protocol Objectives 
10.4.1 Analyses of Primary Objectives 
10.4.1.1 
Immunogenicity 
The Per-Protocol (PP) population (ie, randomized subjects who received the assigned dose of 
the test article according to the protocol, have HAI serology results at Day 0 and Day 28, and 
have no major protocol deviations) will be the primary population for immunogenicity analysis. 
A separate intent-to-treat (ITT) population analysis will not be produced unless > 5% of at least 

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1 treatment group is excluded from the PP population. No missing data will be imputed. For 
GMTs and GMRs, titers reported below the lower limit of quantitation (LLOQ, ie, below the 
starting dilution of assay reported as “< 10”) will be set to half that limit (ie, 10/2 = 5). 
For purposes of determining non-inferiority (and exploratory superiority) in immunogenicity of 
240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 adjuvant, relative to a US-licensed 
comparator, Fluzone Quadrivalent, for all Quad-NIV homologous influenza strains (2 influenza 
A and 2 influenza B strains) at 28 days post-vaccination, derived/calculated endpoints will 
include:  
• Two-sided 95% CIs for the ratio of Day 28 post-vaccination GMTs between Quad-NIV and 
Fluzone Quadrivalent will be constructed using log normal distribution. The log10 values 
will be used to construct a CI using the analysis of covariance (ANCOVA) with treatment 
group and baseline at Day 0 (adjusted for intergroup variation in baseline [pre-vaccination] 
titers) as the covariates under two-sided type I error rate of 0.05. No type I error rate 
adjustments will be made. The mean difference and the corresponding CI limits will then 
be exponentiated to obtain the ratio of GMT and the corresponding CI. 
• Two-sided 95% CIs for the difference of the SCRs between Quad-NIV and Fluzone 
Quadrivalent will be based on the Newcombe hybrid score (METHOD = SCORE 
riskdiff-option for PROC FREQ in SAS). 
10.4.2 Analysis of Secondary and Exploratory Immunogenicity Objectives 
Immunogenicity of 240 µg Quad-NIV co-formulated with 75 µg Matrix-M1 adjuvant, relative 
to a US-licensed comparator, Fluzone Quadrivalent, based on HAIs (assayed with both 
egg-propagated virus and wild-type VLP reagents) for all vaccine-homologous influenza A and 
B strains, and at least 1 antigenically-drifted A or B strain at Day 28 post-vaccination, will be 
measured in terms of: 
• Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed 
HAI titers, on Days 0 and 28. 
• Geometric mean ratio (GMR) – defined as the ratio of post-vaccination to pre-vaccination 
(Day 0) HAI GMTs (GMRPost/Pre) on Day 28. 
• Seroconversion rate (SCR) – defined as proportion of subjects in a given treatment group 
with either a baseline reciprocal (Day 0) titer of < 10 and a post-vaccination reciprocal titer 
≥ 40, or a baseline reciprocal (Day 0) titer of ≥ 10 and a post-vaccination titer ≥ 4-fold higher 
on Day 28.  
• Seroprotection rate (SPR) – defined as the proportion of subjects with a reciprocal HAI titer 
≥ 40 on Day 28. 
• Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers). 
An additional time-point at Day 182 may also be tested. 

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Microneutralization (MN) responses at Days 0 and 28 post-vaccination will include:  
• GMT – defined as the antilog of the mean of the log-transformed neutralizing titer for a 
given treatment group. 
• GMR – defined as the ratio of post-vaccination and pre-vaccination neutralizing GMTs 
within the same treatment group (designated as GMRPost/Pre).  
• SCR – defined as proportion of subjects in a given treatment group with either a baseline 
reciprocal titer of < lower limit of quantitation (LLOQ) and a post-vaccination reciprocal 
titer 4-fold higher than the LLOQ, or a baseline reciprocal titer of ≥ LLOQ and a 
post-vaccination reciprocal titer ≥ 4-fold higher than the baseline titer. 
• Ratio of GMTs between treatment arms at Day 28 post-vaccination (adjusted for intergroup 
variation in baseline [pre-vaccination] titers).  
An additional time-point at Day 182 may also be tested. 
Analysis of exploratory CMI response endpoints will be performed on a subset of approximately 
140 subjects from several pre-designated clinical sites (70 subjects per treatment arm) and 
results may be reported as an addendum to the main clinical study report. 
10.4.3 Analyses Concerning Safety Objectives 
Safety analysis will be descriptive and based on the safety population, defined as all subjects 
who received a dose of trial treatment. Safety will be summarized overall and by individual 
treatment arms based on solicited short-term reactogenicity post-injection on Day 0 - 6, 28-day 
all AE profile by MedDRA preferred term, and 1-year MAE, SAE, and SNMC profiles 
post-injection on Day 0. All AEs, including MAEs, SAEs, and SNMCs will be tabulated by 
severity, related (possibly, probably, or definitely vs non-related per investigator assessment), 
and severe and related. The number and percentage (with 95% CI) of subjects in each treatment 
group with a given term will be summarized. A listing and narratives of SAEs will also be 
produced.  
10.5 Sample Size Considerations 
This study has a single comparison between Quad-NIV and Fluzone Quadrivalent at Day 28 
post-vaccination for the primary immunogenicity objective. No adjustment of the Type I error 
rate for multiple comparisons is warranted since the simultaneous successes of all 
8 comparisons planned for the 4 strains contained in the vaccines and the two endpoints 
(GMT and SCR) are required for the demonstration of the primary non-inferiority objective of 
the study.   
Non-inferiority is defined as the lower bound of the 2-sided 95% CI on the ratio of GMTs 
(Quad-NIV vs Fluzone) ≥ 0.67 (ie, unadjusted 1-sided p-value < 0.025 against the null 
hypothesis of H0: Ratio of GMT < 0.67) and the lower bound of the two-sided 95% CI on the 
difference of the SCRs (Quad-NIV - Fluzone) ≥ -10% (ie, unadjusted 1-sided p-value < 0.025 
against the null hypothesis of H0: Difference of SCRs < -10%).  
For the calculation of sample size estimation, we used assumptions of true differences, ie, the 
ratio of GMTs (Quad-NIV vs Fluzone Quadrivalent) is 1.0 for all 4 homologous strains, and 

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the difference of the SCRs is -2% for each of the 4 homologous strains, based on the average 
performance in the previous trial (qNIV-E-201). To achieve an overall 90% power 
(ie, ~ 97.5% power for each of the 4 strains) to demonstrate a non-inferiority margin for SCR 
difference of -10%, the SCR of reference group (Fluzone Quadrivalent) is assumed to be 0.5 
and the SCR of treatment group (Quad-NIV) is assumed to be 0.48 under the null hypothesis 
of inferiority (H0: Difference of SCRs < -10%). The significance level of the testing is 0.025. 
Sample size was estimated to be 1195 in each group by assuming equal size in each group. The 
sample size accounted for a 10% attrition rate for the per-protocol population such that the 
primary analysis population for all immunogenicity endpoints will be 1325 in each group. 
In a previous trial (qNIV-E-201), the observed vaccine-homologous strain-specific standard 
deviations of log10 HAI titers ranged from approximately 0.3 (B/Colorado/06/2017 and 
B/Phuket/3073/2013) to approximately 0.4 (A/Singapore/INFIMH-16-0019/2016 and 
A/Michigan/45/2015). The calculated power for each strain, unadjusted for multiple 
comparisons, is close to 100% to detect a 1.5-fold difference in GMTs. For 4 strains, this study 
is designed to exclude a GMT ratio of < 0.67 with 100% power. Therefore, for demonstrating 
non-inferiority for 4 strains with the true ratio of GMTs of 1.0 and the true SCR differences of 
-2%, this study provides ≥ 90% overall power. 
For safety endpoints, the probability of observing at least 1 adverse event among 1325 subjects 
for Quad-NIV is > 90% if the true rate of such events is 0.18%. With 1325 subjects for 
Quad-NIV, observing no adverse events of interest (eg, vaccine-related SAE) would represent 
an upper bound of the 1-sided 95% CI on the percentage of such event is 0.2%. 
10.6 Plan for Statistical Summaries and Analyses 
10.6.1 Day 28 Unblinded Data Review 
An unblinded data review will be conducted upon completion of Day 28 visits, which will 
include all primary endpoints (HAI antibody responses assayed with egg-propagated virus) 
testing of associated Day 28 serum samples for all 4 vaccine homologous influenza strains 
(ie, 2 influenza A and 2 influenza B strains) and safety data through Day 28. Data concerning 
secondary and exploratory endpoints will be included in the unblinded review of Days 0 and 28 
as they become available. For the review, treatment codes will only be unblinded after the data 
are deemed ready for the analysis after all subjects have completed the Day 28 visit and the data 
are monitored. The determination of the readiness will be based on the blinded review of 
outstanding queries of critical data points. Given the time-consuming nature of the 
microneutralization, these data may be presented only in the final CSR or an addendum (see 
Section 10.6.2). 
In order to execute this review, a select group of trial staff will be unblinded at the CRO and at 
Novavax. All personnel unblinded to the trial data will be documented. No individual unblinded 
at a subject treatment level will be involved in follow-up safety monitoring. Specifically, 
personnel at the clinical trial site including, investigators and trial staff, research site, 
immunology laboratory, and trial subjects will remain blinded to treatment assignments until 
the end of trial (ie, Day 364).  

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Since trial procedures and monitoring practices will not change following the review and the 
trial will not be terminated prematurely on the basis of these data, no decision cut points or 
stopping rules will be stipulated. Immunogenicity and safety analyses from the unblinded 
review may be presented in an abbreviated unblinded clinical study report (CSR) drafted by the 
Sponsor that may be submitted to regulatory authorities as needed. 
10.6.2 Final Clinical Study Report 
The final CSR will present the balance of all safety and immunogenicity (if any) data through 
Day 364 (the scheduled end of trial). The database will be locked and the final CSR prepared, 
when all of the above data have been entered, reviewed, and all queries related to the data have 
been addressed. Any decisions to deviate from the planned analyses will be described in detail 
in the final CSR. 
10.7 Computer Methods 
Statistical analyses will be performed using SAS® version 9.3 or greater under a Windows 
operating system. 

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11 
TRIAL LEGAL AND ETHICAL REQUIREMENTS 
11.1 Compliance with Regulatory Requirements 
This trial will be conducted in accordance with the protocol, the Declaration of Helsinki 
(amended Fortaleza, Brazil, 2013), International Conference on Harmonisation (ICH) GCP 
Guidelines, and the US FDA regulatory requirements. 
11.2 Ethics Committee 
This trial will be conducted under the auspices of a properly-constituted IRB, as defined by US 
regulatory requirements, and in accordance with the Declaration of Helsinki (amended 
Fortaleza, Brazil, 2013). This committee will review and approve all aspects of the trial, 
including the protocol and ICF to be used, any and all advertising or informational materials, 
and any modifications made to the protocol and ICF, prior to, or during the trial. Prior to 
initiation of clinical activity, investigators will provide Novavax with a copy of the 
communication from the IRB indicating approval of the protocol and ICF. In the event that a 
central IRB is used, Novavax will provide copies of correspondence to the investigators. All 
changes to the protocol or ICF must be reviewed and approved prior to implementation, except 
where necessary to eliminate apparent immediate hazards to human subjects.  
If applicable, the investigators will be responsible for obtaining annual IRB renewal throughout 
the duration of the trial. Copies of the investigators’ annual report to the IRB and copies of the 
IRB continuance of approval must be furnished to Novavax. 
11.3 Informed Consent 
The investigators or designated site trial staff members will be responsible for obtaining written 
informed consent (and any applicable local or state regulatory documentation), signed and dated 
by each subject, prior to his/her participation in the trial. Informed consent will be obtained 
from a subject after a full explanation of the purpose of the trial, the risks and discomforts 
involved, potential benefits, etc, have been provided by the investigators, both verbally and in 
writing. The original signed copy of the ICF must be maintained in the institution's records and 
will be subject to inspection by a representative of Novavax and/or regulatory agencies. The 
subject will also be given a copy of the signed consent form. 
11.4 Required Site Documentation 
The following documents must be provided to Novavax or its designee prior to the start of the 
trial: 
• Current Curriculum Vitae and medical licenses (as applicable) for the principal investigator 
and all sub-investigators, 
• Financial Disclosure Forms from the principal investigator and all sub-investigators, 
• Signed protocol and amendments (if any), 

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• Copy of correspondence from the IRB indicating approval of the protocol, ICF, and any 
site-specific trial advertisements, signed by the IRB chairperson or designee, and containing 
the name and address of the IRB, 
• Membership roster of the IRB, listing names and occupations. If an investigator 
participating in this trial is an IRB member, documentation should be provided of his/her 
abstention from voting on this protocol, 
• ICF reviewed and approved by the IRB, or a revised document if changes were requested 
by the committee with the IRB stamp and date, and 
• Reference ranges for all safety tests required in the protocol and documentation of 
laboratory licensure if the trial site’s local clinical laboratory will be used.  
11.5 Subject Confidentiality 
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties, other than those cited below, is prohibited. Subject 
confidentiality will be further ensured by utilizing a subject identification code and subject 
initials. Relevant US national and local jurisdictions governing privacy rules and protection of 
human subjects will be followed in this trial. 
In compliance with regulatory guidelines regarding the monitoring of clinical studies, and in 
fulfillment of the investigator's obligations to Novavax, it is required that data generated as a 
result of the trial be available for inspection, on request, by personnel from Novavax, CRO 
monitors representing Novavax, and/or regulatory agencies. These shall include all trial 
relevant documentation, including medical histories to verify eligibility, laboratory test results 
to verify transcription accuracy, treatment and diagnostic reports, and admission/discharge 
summaries for hospital admissions occurring while the subject is on-trial. 
As part of the required content of the informed consent, subjects must be informed that their 
records will be reviewed by Novavax and/or regulatory agencies. Should access to the medical 
record require a separate waiver or authorization, it is the investigator's responsibility to obtain 
such permission from the subject in writing before the subject is entered into the trial. 
11.6 Disclosure of Information 
Information concerning the investigational Quad-NIV and patent application processes, 
scientific data, or other pertinent information is confidential and remains the property of 
Novavax. The investigator may use this information for the purposes of the trial only. It is 
understood by the investigator that Novavax will use information developed in this clinical trial 
in connection with the development of the investigational vaccine and therefore may disclose 
it as required to other clinical investigators and to regulatory agencies. In order to allow the use 
of the information derived from this clinical trial, the investigator understands that he/she has 
an obligation to provide complete test results and all data developed during this trial to 
Novavax. Authorization to publish or otherwise publically disclose the results of this trial is 
strictly governed by the terms set forth in the clinical trial agreement. 

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12 
REFERENCES 
CDC. Estimates of Deaths Associated with Seasonal Influenza - United States, 1976-2007. 
MMWR Morb Mortal Wkly Rep (2010); 59(33): 1057-62. 
CDC. (2017). Seasonal Influenza Vaccine Effectiveness, 2005-2017. Retrieved 19 April 2018 
from https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html. 
CDC. (2019 -a). Influenza Vaccine - United States, 2018-19 Influenza Season. Retrieved 27 
March 2019 from https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html. 
CDC. (2019 -b). What You Should Know and Do This Flu Season If You Are 65 Years and 
Older. Retrieved 27 March 2019, from https://www.cdc.gov/flu/highrisk/index.htm. 
Coffman RL, Sher A, Seder RA. Vaccine Adjuvants: Putting Innate Immunity to Work. 
Immunity (2010); 33(4): 492-503. 
DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of High-Dose Versus 
Standard-Dose Influenza Vaccine in Older Adults. N Engl J Med (2014); 371(7): 635-45. 
Doyle JD, Chung JR, Kim SS, et al. Interim Estimates of 2018-2019 Seasonal Influenza Vaccine 
Effectiveness - United States, February 2019. MMWR Morb Mortal Wkly Rep (2019); 68(6): 
135-9. 
FDA. (2019). Vaccines Licensed for Use in the United States. Retrieved 27 March 2019, from 
https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833. 
Flannery B, Chung J, Belongia EA, et al. (2018). Interim Estimates of 2017-18 Seasonal 
Influenza Vaccine Effectiveness - United States, February 2018. MMWR Morb Mortal Wkly 
Rep (2018); 67(6): 180-5. 
Griffin MR, Monto AS, Belongia EA, et al. Effectiveness of Non-Adjuvanted Pandemic 
Influenza A Vaccines for Preventing Pandemic Influenza Acute Respiratory Illness Visits in 
4 U.S. Communities. PLoS One (2011); 6(8): e23085. 
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza 
with Vaccines. MMWR Recomm Rep (2016); 65(5): 1-54. 
McLean HQ, Thompson MG, Sundaram ME, et al. Influenza Vaccine Effectiveness in the 
United States During 2012-2013: Variable Protection by Age and Virus Type. J Infect Dis 
(2015); 211(10): 1529-40. 
Monto AS. Moving Toward Improved Influenza Vaccines. J Infect Dis (2017); 215(4): 500-2. 
Mullooly JP, Bridges CB, Thompson WW, et al. Influenza- and RSV-Associated 
Hospitalizations Among Adults. Vaccine (2007); 25(5): 846-55. 

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Ohmit SE, Thompson MG, Petrie JG, et al. Influenza Vaccine Effectiveness in the 2011-2012 
Season: Protection Against Each Circulating Virus and the Effect of Prior Vaccination on 
Estimates. Clin Infect Dis (2014); 58(3): 319-27. 
Paules C and Subbarao K. Influenza. Lancet (2017); 390(10095): 697-708. 
Reed C, Kim IK, Singleton JA, et al. Estimated Influenza Illnesses and Hospitalizations Averted 
by Vaccination - United States, 2013-14 Influenza Season. MMWR Morb Mortal Wkly Rep 
(2014); 63(49): 1151-4. 
Reed C, Chaves SS, Daily Kirley P, et al. Estimating Influenza Disease Burden from 
Population-Based Surveillance Data in the United States. PLoS One (2015); 10(3): e0118369. 
Shinde V, Fries L, Wu Y, et al. Improved Titers Against Influenza Drift Variants with a 
Nanoparticle Vaccine. N Engl J Med (2018); 378(24): 2346-8. 
Skowronski DM, Chamber C, Sabaiduc S, et al. A Perfect Storm: Impact of Genomic Variation 
and Serial Vaccination on Low Influenza Vaccine Effectiveness During the 2014-2015 Season. 
Clin Infect Dis 2016; 63(1): 21–32. 
Smith G, Liu Y, Flyer D, et al. Novel Hemagglutinin Nanoparticle Influenza Vaccine with 
Matrix-M™ Adjuvant Induces Hemagglutination Inhibition, Neutralizing, and Protective 
Responses in Ferrets Against Homologous and Drifted A(H3N2) Subtypes. Vaccine 2017; 
35(40): 5366-72. 
Sullivan SG, Chilver MB, Carville KS, et al. Low Interim Influenza Effectiveness, Australia, 1 
May to 24 September 2017. Euro Surveill (2017); 22(43): 10.2807/1560-7917. 
Treanor JJ, Talbot HK, Ohmit SE, et al. Effectiveness of Seasonal Influenza Vaccines in the 
United States During a Season with Circulation of All Three Vaccine Strains. Clin Infect Dis 
(2012); 55(7): 951-9. 
VRBPAC. (2018). Summary Minutes: 151st Vaccines and Related Biological Products 
Advisory 
Committee. 
Retrieved 
29 
March 
2018. 
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVa
ccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM6
02610.pdf. 
VRBPAC. (2019). Summary Minutes: 152nd Vaccines and Related Biological Products 
Advisory 
Committee. 
Retrieved 
27 
March 
2019. 
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVa
ccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM6
33766.pdf. 
WHO (2011). Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza. 
WHO Global Influenza Surveillance Network. Retrieved 18 October 2017, from 
http://whqlibdoc.who.int/publications/2011/9789241548090_eng.pdf.  

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WHO. (2017). Recommended Composition of Influenza Virus Vaccines for Use in the 
2017-2018 Northern Hemisphere Influenza Season. Retrieved 18 October 2017, from 
https://www.who.int/influenza/vaccines/virus/recommendations/2017_18_north/en/. 
WHO. (2018). Recommended Composition of Influenza Virus Vaccines for Use in the 
2018-2019 Northern Hemisphere Influenza Season. Retrieved 29 March 2018, from 
https://www.who.int/influenza/vaccines/virus/recommendations/2018_19_north/en/. 
WHO. (2019). Recommended Composition of Influenza Virus Vaccines for Use in the 
2019-2020 Northern Hemisphere Influenza Season. Retrieved 27 March 2019, from 
https://www.who.int/influenza/vaccines/virus/recommendations/2019_20_north/en/. 
Zimmerman RK, Nowalk MP, Chung J, et al. 2014-2015 Influenza Vaccine Effectiveness in 
the United States by Vaccine Type. Clin Infect Dis (2016); 63(12): 1564-73. 
Zost SJ, Parkhouse K, Gumina ME, et al. Contemporary H3N2 Influenza Viruses Have a 
Glycosylation Site that Alters Binding of Antibodies Elicited by Egg-Adapted Vaccine Strains. 
Proc Natl Acad Sci U S A (2017); 114(47): 12578-83. 
 
 

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APPENDIX 1 – QNIV-E-301 TRIAL PROCEDURES SCHEDULE 
Trial Day:  
0 
3 
7 
28 
90 
182 
364 
Window (days): 
± 1 
± 1 
± 4 
± 7 
± 7 
± 14 
Trial Procedures 
Trial Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
Physical Exam 
X 
 
X [4] 
X [4] 
 
X [4] 
 
Vital Signs 
X [1] 
 
X 
X 
 
X 
Serology  
X 
 
 
X 
 
X 
PMBC for CMI 
X[5] 
 
X[5] 
X[5] 
 
X[5] 
 
Trial Treatment Injection  
X 
 
 
 
 
 
Adverse Event Review [2] 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Review [2] 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Review 
 
 
 
X [3] 
 
 
End of Trial 
 
 
 
 
 
 
X 
Note: Procedures shaded in grey are performed via scripted telephone call. 
[1] Vital signs to be captured pre-vaccination and between 30 to 60 minutes post-vaccination. 
[2] All adverse events and concomitant medications taken will be collected through Day 28; thereafter, only MAEs, SAEs, 
and SNMCs and medications taken for these events will be collected.  
[3] The subject diary will be reviewed by the investigator and collected at the Day 28 visit. 
[4] If needed, a physical examination may be performed, based on the investigator’s discretion. 
[5] To be collected from a subset of approximately 140 subjects from several pre-designated clinical sites. 

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APPENDIX 2 – QNIV-E-301 SUBJECT DIARY CARD (DRAFT) 
 
*A subject diary will be provided to all subjects to record solicited and unsolicited adverse events experienced, concomitant medications used, and any medical 
visits/procedures sought, within the first 7 days following the Day 0 vaccination. The above is a sample excerpt from such a diary. It is provided for informational 
purposes only and may differ from the actual diary issued to subjects. 

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APPENDIX 3 – QNIV-E-301 BLOOD DRAW SCHEDULE 
Trial Visit Day 
Amount of Blood Drawn for 
Immunogenicity Assessment (mL) 
Amount of Blood Drawn for 
CMI Assessment (mL) 
Day 0 (pre-vaccination) 
20  
27[1] 
Day 7 (± 1 day) 
-- 
27[1] 
Day 28 (± 4 days) 
20  
27[1] 
Day 182 (± 7 days) 
20 
27[1] 
TOTAL FOR ENTIRE 
TRIAL (mL) 
60 – 168 [2] 
[1] To be collected from a subset of approximately 140 subjects from several pre-designated clinical sites.  
[2] Most subjects will provide up to 60 mL of blood in the trial. A subset of approximately 140 subjects from several 
pre-designated clinical sites will provide up to 168 mL.   

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APPENDIX 4 – QNIV-E-301 SUBJECT MEASUREMENT TOOL 
(Do not use this page in clinic, as it may not be to exact scale) 
 
 
The Subject Measurement Tool consists of a transparent set of concentric circles with diameters 
that correspond to the ranges in the toxicity grading scale (2.5, 5, and 10 cm, in diameter). 
Subjects are instructed to overlay the template over the injection site for any reaction that can 
be visually observed (eg, redness, swelling, bruising). An assessment of severity is then made 
by determining the circle that best describes the size of the reaction: reactions that are smaller 
than Circle A (2.5 cm) are considered Grade 0; reactions larger than Circle A but equal to or 
smaller than Circle B (5 cm) are considered Grade 1; reactions larger than Circle B but equal 
to or smaller than Circle C (10 cm) are considered Grade 2; reactions larger than Circle C are 
considered Grade 3. The table below summarizes the severity grading for visible injection site 
reactions based on size.  
Definition of Severity Grading for Visible Local Adverse Events 
Severity Grade 
Injection Site Grading Description 
0 - Normal 
Reaction size fits inside Circle A 
1 - Mild 
Reaction size larger than Circle A, but fits inside Circle B 
2 - Moderate 
Reaction size larger than Circle B, but fits inside Circle C 
3 - Severe 
Reaction size larger than Circle C 
 
A
B
C
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