A Phase 1/2, Randomized, Observer-Blinded, Active-Controlled Trials to Evaluate the Safety and Immunogenicity of a Recombinant Trivalent Nanoparticle Influenza Vaccine With Matrix-M1 Adjuvant (NanoFlu) in Healthy Older Adults
Phase: PHASE1
Conditions: Influenza
Sponsor: Novavax

 
 
A PHASE 1/2, RANDOMIZED, OBSERVER-BLINDED, ACTIVE-CONTROLLED TRIAL TO 
EVALUATE THE SAFETY AND IMMUNOGENICITY OF A RECOMBINANT TRIVALENT 
NANOPARTICLE INFLUENZA VACCINE (TRI-NIV) WITH MATRIX-M1™ ADJUVANT IN 
HEALTHY OLDER ADULTS ≥ 60 YEARS OF AGE 
 
Investigational Materials: 
Hemagglutinin Nanoparticle Influenza Vaccine, 
Trivalent (Tri-NIV), representing 
A/Michigan/45/2015 (H1N1); 
A/HongKong/4801/2014 (H3N2); and 
B/Brisbane/60/2008, administered with Matrix-M1 
Adjuvant 
Protocol Number: 
tNIV-E-101 
Sponsor: 
Novavax, Inc. (Novavax) 
20 Firstfield Road 
Gaithersburg, MD 20878 USA 
Responsible Clinical Operations 
Manager: 
Michelle Spindler 
Associate Director, Clinical Operations 
Novavax, Inc. 
Gaithersburg, MD 20878 
Office: 240.401.0972 
Email: mspindler@novavax.com 
Version & Date: 
Version 5.0 – 13 November 2017  
Prior Version(s): 
Version 4.0 – 18 October 2017 
Version 3.0 – 24 August 2017 
 
Version 2.0 – 21 July 2017 
 
Version 1.0 – 14 July 2017 
 
 
 
 
 
 
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 

Nanoparticle Influenza Vaccine, Trivalent  
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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, 
Trivalent 
(Tri-NIV), 
representing 
A/Michigan/45/2015 
(H1N1); 
A/HongKong/4801/2014 
(H3N2); 
and 
B/Brisbane/60/2008; 
administered with Matrix-M1 Adjuvant 
Protocol: 
tNIV-E-101  
Date of Issue: 
13 November 2017   
 
I have read and approve the protocol specified above and agree on its content: 
Novavax, Inc. 
 
 
James F. Cummings, MD  
Vice President, Clinical Development  
Novavax, Inc. 
 Date 
 
D. Nigel Thomas, PhD 
Vice President, Clinical Operations 
Novavax, Inc.  
 
 Date 
Clinical Trial Site 
 
 
 
Print Name – Principal Investigator 
 Date 
 
 
Signature 
 

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PROTOCOL CHANGE HISTORY 
 
Protocol Version 5.0, 13 November 2017 (revised from 4.0, 18 October 2017) 
The following is a summary of changes made to this version.  
Location of Change  
Change/Modification in Version 5.0 
Section 7.2.1 
The description of the hemagglutination inhibition (HAI) assay has been 
updated to include the following text:  
Based on new findings in a recent investigation concerning egg passage-
induced point mutations in contemporary A(H3N2) strains [Zost 2017], 
testing (for at least H3N2 strains) will also be performed in a qualified 
assay using hemagglutinating antigens produced by recombinant 
methods capable of generating HA with and without specific egg-induced 
mutations.  
Section 12  
The following reference has been added:  
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. 
PNAS 
2017. 
www.pnas.org/cg/doi/10.1073/pnas.1712377114.  
 
 
Protocol Version 4.0, 18 October 2017 (revised from 3.0, 24 August 2017) 
The following is a summary of changes made to this version.  
Location of Change  
Change/Modification in Version 4.0 
Section 2.2, 3.2.2, 
Synopsis  
The secondary objective and endpoint have been updated to indicate that 
hemagglutination inhibition (HAI) and microneutralization responses 
will not only be assessed against historic A strains, but may also assess 
a drifted A strain.  
Section 3.2.1, Synopsis  
The 21 days post vaccination all adverse event (AE) profile period has 
been further defined by the addition of the following:  
Note: The 21 day post vaccination all adverse event profile will include 
all unsolicited AEs reported from test article receipt until the day 
preceding the rescue dose, ie, events with onset dates between days 0 to 
20 for subjects who receive the rescue dose as scheduled on day 
21. Rules for defining the dataset in subjects who receive the rescue dose 

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Location of Change  
Change/Modification in Version 4.0 
before or after day 21, or no rescue dose, are detailed in the statistical 
analysis plan. 
Primary endpoint “Seroconversion rate difference – defined as the 
difference of seroconversion rates between each of the Tri-NIV vaccine 
groups and Fluzone HD group and its two-sided 95% CI” has been 
deleted to avoid redundancy. 
Section 8.1 
It has been clarified that the 21 day post vaccination all adverse event 
profile will include all unsolicited AEs reported from test article receipt 
until the day preceding the rescue dose, ie, events with onset dates 
between days 0 to 20 for subjects who receive the rescue dose as 
scheduled on day 21. Rules for defining the dataset in subjects who 
receive the rescue dose before or after day 21, or no rescue dose, are 
detailed in the statistical analysis plan. 
Section 8.1.1 
In the event of a Grade 3 solicited adverse event reported by telephone 
during the solicitation period, it has been clarified that investigator 
should enter the AEs in the subject diary, instead of in the adverse event 
electronic case report form, as was originally written.  
Table 4  
The list of adverse events of special interest has been updated to include 
2 additional AEs, ie, Eaton-Lambert syndrome and rosacea.   
Section 6.6  
Table of protocol deviations has been updated to include “diary 
compliance” under programmatically-determined protocol deviations 
and “others” under self-reported protocol deviations. These will be any 
protocol deviations that do not belong under any pre-specified category. 
Section 10.4.1.2, 
Synopsis  
Text has been corrected to indicate that within-group geometric mean 
ratio (GMRpost/pre) will be conducted using paired t-test, and not analysis 
of covariance.  
Section 10.5, Synopsis  
The following text has been deleted because non-inferiority assessment 
is not an objective of this trial:   
Tri-NIV is expected to be comparable (statistically non-inferior) to the 
currently licensed Fluzone HD in terms of SCR. If the underlying SRRs 
is 70% for both the Tri-NIV and active control groups for a given strain, 
with 100 subjects in each group, the trial has a 46% power to detect -0.10 
non-inferiority (NI) margin. If the underlying SRR is 50%, the power 
will be 41%. 
General  
Minor changes have been made to improve the readability and 
consistency of the document.  
 
Protocol Version 3.0, 24 August 2017 (revised from 2.0, 21 July 2017) 

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The following is a summary of changes made to this version.  
Location of Change  
Change/Modification in Version 3.0 
Section 3.1, 3.1.1, Table 
1, Synopsis  
To ensure safety of trial participants, enrollment has been divided into 2 
stages. Stage 1 will enroll a group of approximately 60 subjects 
(approximately 20 subjects per treatment group) and Stage 2 will enroll 
the remainder of the subjects per treatment group. The only difference in 
the 2 stages will be a safety review in-clinic visit for Stage 1 subjects on 
Day 7 (+1 day) of the trial, whereat subjects will be asked to present their 
subject diaries. In Stage 2, a safety review telephone call on Day 7 (±1 
day) of the trial will replace the clinic visit. Progression from Stage 1 to 
Stage 2 will require favorable review of cumulative Stage 1 safety 
against vaccination holding rules that have been specified in a new 
Section 3.1.1.1.  
Section 3.1.1.1, Synopsis 
Section has been added to specify vaccination holding rules, which are:  
1) The occurrence of at least 1 serious adverse event among any Stage 
1 subject assessed by the sponsor as definitely related to the trial 
treatment.  
2) The occurrence of any severe (grade 3) solicited (local or systemic) 
adverse event term in   > 10% of all Stage 1 subjects. 
Section 3.1.1.2, Synopsis   Section has been added to indicate that subjects will continue to be 
evaluated for safety even after Stage 1 enrollment.  
Section 3.5  
It has been specified that subject trial treatment may be unblinded also in 
the event a vaccination holding rule is met.  
Section 6.1.4, Synopsis  
All Stage 1 subjects will be required to complete an in-clinic visit on Day 
7 (+1 day) of the trial and present their subject diaries. Stage 2 subjects 
will be required to complete a safety telephone call on Day 7 (± 1 day). 
These subjects will present their subject diaries on their Day 21 visit.  
Section 10.4.1.2, Synopsis It has been specified that the within-group geometric mean ratio 
(GMRpost/pre) will be conducted using the analysis of covariance 
(ANCOVA) adjusted by the baseline value based on log-transformed 
values, when evaluating neutralizing antibody titers.  
Appendix 1, Synopsis  
The distinction between an onsite visit for Stage 1 subjects and a safety 
telephone call for Stage 2 subjects has been specified in the table.  
General  
Minor changes have been made to improve the readability and 
consistency of the document.  
 
 

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Protocol Version 2.0, 21 July 2017 (revised from 1.0, 14 July 2017) 
The following is a summary of changes made to this version.  
Location of Change  
Change/Modification in Version 2.0 
Section 1.6  
Minor modifications have been made to text describing RSV-E-205 data.  
Synopsis, Section 6.1.5, 
Appendix 1  
Criteria specifying whether subjects can receive Day 21 injection have 
been added. Specifically, 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 second vaccination. 
Subjects presenting with an acute illness on Day 21 may return to the 
study site within the next 7 days to receive their 2nd vaccination. If a 
subject has experienced any adverse event/serious adverse event between 
study Days 0 and 21, then Day 21 vaccination may be administered or 
delayed for up to 7 days based on the Investigator’s discretion. 
Section 1.4, 4.1 
The size of the HA nanoparticle has been specified to approximately 
20 to 40 nm.  
Section 4.2.2 
The manufacturing process of Tri-NIV has been updated to indicate that 
an additional purification step is required for the B/strain nanoparticle 
(ie, Capto Blue Chromatography) and that nanoparticles from both 
strains are nanofiltered prior to being loaded onto the lentil lectin 
column.  
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 ......................................................................................................... 7 
LIST OF TABLES.................................................................................................................. 10 
GLOSSARY OF ABBREVIATIONS ................................................................................... 11 
CLINICAL PROTOCOL SYNOPSIS ................................................................................. 14 
1 
INTRODUCTION ........................................................................................................... 24 
1.1 Influenza Virus ............................................................................................................. 24 
1.2 Influenza Disease Burden in Older Adults ................................................................... 24 
1.3 Licensed Vaccines Against Influenza Virus for Older Adults ..................................... 25 
1.4 Nanoparticle Influenza Vaccine, Trivalent (Tri-NIV) ................................................. 25 
1.5 Matrix-M1 Adjuvant .................................................................................................... 26 
1.6 Nonclinical Investigations ............................................................................................ 26 
1.6.1 
Matrix-M1-adjuvanted Tri-NIV ........................................................................... 26 
1.6.2 
Other Matrix-M1-adjuvanted Vaccines ................................................................ 27 
1.7 Clinical Investigations .................................................................................................. 27 
1.7.1 
Matrix-M1-adjuvanted Vaccines .......................................................................... 27 
1.8 Trial Rationale .............................................................................................................. 27 
1.9 Expected Risks from Tri-NIV with Matrix-M1 Adjuvant ........................................... 29 
1.10 Risks Associated with Fluzone HD .............................................................................. 31 
2 
TRIAL OBJECTIVES .................................................................................................... 32 
2.1 Primary Objectives ....................................................................................................... 32 
2.2 Secondary Objectives ................................................................................................... 32 
2.3 Exploratory Objectives ................................................................................................. 32 
3 
TRIAL OVERVIEW ...................................................................................................... 33 
3.1 Design ........................................................................................................................... 33 
3.1.1 
Safety Monitoring of Enrollment and Vaccinations ............................................. 33 
3.1.1.1 
Vaccination Holding Rules ......................................................................... 34 
3.2 Trial Endpoints ............................................................................................................. 36 
3.2.1 
Primary Endpoints ................................................................................................ 36 
3.2.2 
Secondary Endpoints ............................................................................................ 36 
3.2.3 
Exploratory Endpoints .......................................................................................... 37 
3.3 Randomization and Blinding Procedure....................................................................... 37 
3.4 Maintaining the Blinded Randomization Scheme ........................................................ 37 
3.5 Procedure for Unblinding Individual Subjects During the Trial .................................. 38 

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3.6 Trial Duration ............................................................................................................... 38 
4 
TRIAL TEST ARTICLES ............................................................................................. 39 
4.1 Overview of Product and Manufacturing Process for Clinical Trial Material ............. 39 
4.2 Manufacture of Bulk Antigen....................................................................................... 39 
4.2.1 
Recombinant Baculovirus ..................................................................................... 39 
4.2.2 
Production and Purification of Tri-NIV ................................................................ 39 
4.2.3 
Manufacture of Matrix-M1 Adjuvant ................................................................... 40 
4.3 Description of Clinical Trial Dosage Formulation ....................................................... 40 
4.4 Placebo ......................................................................................................................... 40 
4.5 Fluzone HD – Active Comparator................................................................................ 41 
4.6 Investigational Product Packaging, Storage, and Handling ......................................... 41 
4.7 Compliance and Drug Accountability .......................................................................... 41 
5 
SELECTION OF TRIAL SUBJECTS .......................................................................... 42 
5.1 Inclusion Criteria .......................................................................................................... 42 
5.2 Exclusion Criteria ......................................................................................................... 42 
6 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................... 44 
6.1 Trial Visit Procedures ................................................................................................... 44 
6.1.1 
Day 0 – Screening Visit ........................................................................................ 44 
6.1.2 
Day 0 – Injection 1 Visit ....................................................................................... 44 
6.1.3 
Day 3 (± 1 day) – Safety Telephone Contact ........................................................ 45 
6.1.4 
Day 7 (+1 day) – Safety Follow-up Visit for (Stage 1 Subjects ONLY).............. 45 
6.1.5 
Day 7 (± 1 day) – Safety Telephone Contact (Stage 2 Subjects ONLY) ............. 45 
6.1.6 
Day 21 (± 2 days) – Injection 2 Visit .................................................................... 45 
6.1.7 
Day 56 (± 2 days) – Follow-up Visit .................................................................... 46 
6.1.8 
Day 90 (± 7 days) – Safety Telephone Contact .................................................... 46 
6.1.9 
Day 182 (± 7 days) – Follow-up Visit .................................................................. 46 
6.1.10 Day 273 (± 7 days) – Safety Telephone Contact .................................................. 46 
6.1.11 Day 364 (± 14 days) – Follow-up Visit ................................................................ 47 
6.2 Unscheduled Visits ....................................................................................................... 47 
6.3 Concomitant Therapy ................................................................................................... 47 
6.4 Declining Trial Treatments or Procedures ................................................................... 47 
6.5 Premature Discontinuation from Trial ......................................................................... 48 
6.6 Protocol Deviations ...................................................................................................... 48 
6.7 Trial Termination ......................................................................................................... 49 
7 
TRIAL LABORATORY REQUIREMENTS .............................................................. 50 
7.1 Clinical Laboratory Testing.......................................................................................... 50 
7.2 Serological Assessments of Immunogenicity............................................................... 50 

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7.2.1 
Hemagglutination Inhibition (HAI) Assay (Q2 Solutions) ................................... 50 
7.2.2 
Microneutralization Assay (Novavax) .................................................................. 50 
7.2.3 
Biosensor Competitive-binding Assay (Novavax) ............................................... 51 
7.3 Retention and Use of Archived Specimens .................................................................. 51 
8 
TRIAL ASSESSMENT OF SAFETY ........................................................................... 52 
8.1 Adverse Events ............................................................................................................. 52 
8.1.1 
Solicited Adverse Events/Subject Diary ............................................................... 52 
8.1.2 
Unsolicited Adverse Events .................................................................................. 53 
8.1.3 
Vital Sign Abnormalities as Adverse Events ........................................................ 54 
8.1.4 
Clinical Laboratory Findings as AEs .................................................................... 54 
8.1.5 
Medically-attended Events and Significant New Medical Conditions ................. 55 
8.2 Serious Adverse Events ................................................................................................ 57 
8.3 Safety Reporting Requirements and Timelines for SAEs and Certain Other Events .. 58 
8.4 Severity ......................................................................................................................... 58 
8.5 Relationship (Causality) ............................................................................................... 60 
9 
TRIAL DATA MANAGEMENT .................................................................................. 62 
9.1 Recording and Collection of Data ................................................................................ 62 
9.2 Data Quality Assurance ................................................................................................ 62 
9.3 Monitoring .................................................................................................................... 62 
9.4 Audit and Inspection .................................................................................................... 63 
9.5 Adherence to and Changes to the Protocol .................................................................. 63 
9.6 Retention of Records .................................................................................................... 63 
10 TRIAL STATISTICAL CONSIDERATIONS ............................................................. 65 
10.1 Subject Populations ...................................................................................................... 65 
10.2 General ......................................................................................................................... 65 
10.3 Demographics and Protocol Compliance ..................................................................... 65 
10.4 Analyses Addressing Protocol Objectives ................................................................... 66 
10.4.1 Analyses of Primary Objectives ........................................................................... 66 
10.4.1.1 
Safety .......................................................................................................... 66 
10.4.1.2 
Immunogenicity .......................................................................................... 66 
10.5 Sample Size Considerations ......................................................................................... 67 
10.6 Plan for Statistical Summaries and Analyses ............................................................... 67 
10.6.1 Day 21 Unblinded Data Review ........................................................................... 67 
10.6.2 Final Clinical Study Report .................................................................................. 68 
10.7 Computer Methods ....................................................................................................... 68 
11 TRIAL LEGAL AND ETHICAL REQUIREMENTS ................................................ 69 
11.1 Compliance with Regulatory Requirements................................................................. 69 

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11.2 Institutional Review Board ........................................................................................... 69 
11.3 Informed Consent ......................................................................................................... 69 
11.4 Required Site Documentation ...................................................................................... 69 
11.5 Subject Confidentiality ................................................................................................. 70 
11.6 Disclosure of Information ............................................................................................ 70 
12 REFERENCES ................................................................................................................ 71 
Appendix 1 – tNIV-E-101 TRIAL PROCEDURES SCHEDULE ..................................... 73 
Appendix 2 – tNIV-E-101 SUBJECT DIARY CARD (DRAFT) ....................................... 75 
Appendix 3 – tNIV-E-101 BLOOD DRAW SCHEDULE .................................................. 76 
Appendix 4 – tNIV-E-101 SUBJECT MEASUREMENT TOOL ...................................... 77 
 
LIST OF TABLES 
Table 1: 
Trial Design ............................................................................................................ 35 
Table 2:  Protocol Deviations ................................................................................................ 48 
Table 3: 
Listing of Diary Solicited Events ........................................................................... 53 
Table 4: 
Adverse Events of Special Interest ......................................................................... 56 
Table 5: 
Definition of Severity Grading for Adverse Events ............................................... 59 
Table 6:  Severity Grade Definitions for Solicited Gastrointestinal Adverse Events and 
Fever ....................................................................................................................... 59 
Table 7: 
Definition of Relationship for Adverse Events ...................................................... 60 
 

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GLOSSARY OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
APC 
Antigen Presenting Cells  
AST 
Aspartate Aminotransferase  
BUN 
Blood Urea Nitrogen  
C 
Celsius  
CBC 
Complete Blood Count  
CBER 
Center for Biologics Evaluation and Research 
CD 
Compact Disc 
CDC 
Centers for Disease Control and Prevention  
CI 
Confidence Interval 
cm 
Centimeter  
CMO 
Chief Medical Officer  
CQA 
Clinical Quality Assurance  
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
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 
HAI 
Hemagglutination Inhibition  
HD 
High Dose  
HEENT 
Head, Eyes, Ears, Nose, Throat  
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 

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Abbreviation or Term 
Definition 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IM 
Intramuscular(ly) 
IP 
Investigational Product  
IRB 
Institutional Review Board  
ITT 
Intent-to-treat 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Liter 
LLOQ 
Lower Limit of Quantitation  
M 
Molar Concentration 
MAE 
Medically-attended Event 
MDCK 
Madin Darby Canine Kidney (cells line)  
MedDRA 
Medical Dictionary for Regulatory Activities  
μg 
Microgram 
MHC 
Major Histocompatibility Complex  
μL 
Microliter 
μM 
Micromolar 
MMP 
Methyl-α-D-mannopyranoside 
mg 
Milligram 
mL 
Milliliter 
mM 
Millimolar 
MN 
Microneutralization 
NA 
Neuraminidase 
NaCl 
Sodium Chloride 
ng 
Nanogram 
NI 
Non-inferiority  
NP 
Nucleoprotein  
NZW 
New Zealand White (rabbits) 
OD 
Optical Density  

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Abbreviation or Term 
Definition 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Protocol Deviation  
PP 
Per Protocol 
PS 
Polysorbate  
PT 
Preferred Term 
RBC 
Red Blood Cell 
RDE 
Receptor Destroying Enzyme  
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 
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  
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
w/v 
Weight to Volume  

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CLINICAL PROTOCOL SYNOPSIS 
NAME OF COMPANY 
Novavax, Inc. 
INDIVIDUAL 
TRIAL TABLE 
SYNOPSIS 
(FOR NATIONAL 
AUTHORITY USE 
ONLY) 
NAME OF ACTIVE INGREDIENT 
Nanoparticle Influenza Vaccine, Trivalent:  
A/Michigan/45/2015 (H1N1);  
A/HongKong/4801/2014 (H3N2); and 
B/Brisbane/60/2008;  
Matrix-M1™ Adjuvant 
Protocol Number:  tNIV-E-101 
Protocol Title: A Phase 1/2, Randomized, Observer-Blinded, Active-Controlled Trial to Evaluate the Safety and 
Immunogenicity of a Recombinant Trivalent Nanoparticle Influenza Vaccine (Tri-NIV) with Matrix-M1™ 
Adjuvant in Healthy Older Adults ≥ 60 Years of Age 
Sponsor:  Novavax, Inc., 20 Firstfield Road, Gaithersburg, MD 20878  
Investigational Material: Hemagglutinin Nanoparticle Influenza Vaccine, Trivalent (Tri-NIV), representing 
A/Michigan/45/2015 (H1N1); A/HongKong/4801/2014 (H3N2); and B/Brisbane/60/2008; administered with 
Matrix-M1 Adjuvant 
Reference Materials:  Fluzone® High-Dose (HD), a United States (US)-licensed, egg-derived and 
formaldehyde-inactivated, seasonal trivalent influenza vaccine manufactured for the 2017-2018 Northern 
Hemisphere season  
Regimen and Dosing:  All subjects will receive an intramuscular (IM) injection on Day 0 of the assigned test 
article. Injections will contain either 15 µg hemagglutinin (HA) antigen from each of 3 strains (Tri-NIV) with 
50 µg Matrix-M1 adjuvant (Group A); 60 µg HA antigen from each of 3 strains (Tri-NIV) with 50 µg Matrix-M1 
adjuvant (Group B); or the recommended dose of Fluzone HD (Group C). All Group A and B subjects will be 
administered a rescue injection on Day 21 with a licensed seasonal influenza vaccine while all Group C subjects 
will be administered a sterile saline placebo injection on Day 21 to maintain the trial blind.    
Phase of Development:  Phase 1/2 
Trial Rationale:  
The influenza virus poses a formidable risk of infection to 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 2017b]. Novavax, Inc. has 
developed an insect cell-derived, egg-free, influenza vaccine (Tri-NIV) based on recombinant HA nanoparticle 
antigens, which represent the 3 major influenza types/subtypes, recommended for inclusion in the 2017-2018 
seasonal influenza vaccine by the World Health Organization (WHO) and the Center for Biologics Evaluation and 
Research (CBER).  
Currently, the Advisory Committee on Immunization Practices (ACIP) and CDC recommend that older adults 
receive an annual vaccination with any seasonal influenza vaccine approved for use in this age group; inactivated 
influenza (standard or high dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or recombinant influenza 
(trivalent) vaccines are considered acceptable options [Grohskopf 2016, CDC 2017b]. There are 2 vaccines 
specifically approved for use in older adults, including high-dose (ie, Fluzone® High-Dose initially approved in 
the US in 2009) and adjuvanted (ie, FLUAD™ initially approved in the US in 2015) trivalent inactivated influenza 
vaccines [CDC 2017b]. 
While the efficacy of Fluzone HD and existing adjuvanted influenza vaccines is improved in older adults relative 
to standard-dose, egg-derived inactivated influenza vaccines, it remains suboptimal and also vulnerable to 
antigenic drift in circulating strains between strain selection in the first quarter of a given year and virus circulation 

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in the following winter season. The latter phenomenon has been particularly troublesome for A(H3N2) strains over 
the past 10 to 15 years. Accordingly, a vaccine with both strong homologous hemagglutination inhibiting (HAI) 
and broadly-neutralizing antibody responses, which might address drifted strains, could be of added value in older 
adults. 
Several features of Tri-NIV warrant clinical investigation of its safety and immunogenicity among older adults. In 
ferrets, Tri-NIV administered with Matrix-M1 adjuvant elicited rapid and robust immune responses in terms of 
geometric mean HAI titers with responses exceeding those induced by Fluzone HD. 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 drift strain protection, 
even against strains such as A/HongKong/4801/2014, which are associated with impaired influenza vaccine 
efficacy in humans. While cross-lineage B virus antibody responses were not seen in naïve animals, the possibility 
of such responses should be considered, and will be evaluated, in immunologically-experienced humans. 
Because Tri-NIV is produced at high yields in insect cells, it potentially presents a more cost-effective method of 
producing large quantities of an annual seasonal influenza vaccine when compared to the traditional egg-based 
manufacturing processes, and if successful, may also offer a flexible and rapidly-responsive platform for 
production of novel influenza hemagglutinins from strains with pandemic potential. Initial development, however, 
will focus on potential superior benefits of a seasonal trivalent or quadrivalent formulation in the vulnerable older 
adult population. 
Two Tri-NIV treatment groups evaluating either 15 or 60 µg of HA antigen per strain have been proposed to 
1) allow comparison with immunogenicity and safety profile of Fluzone HD and 2) evaluate the antigen dose 
response to inform further clinical development of the vaccine. The Matrix-M1 adjuvant, shown to remarkably 
enhance immunological responses of several vaccine antigens, with an overall acceptable safety profile in over 
1400 humans exposed to date, is proposed as the adjuvant of choice.  
Trial Objectives: 
Primary:  
• 
To describe the safety and tolerability of Tri-NIV at 2 different doses, and the licensed comparator Fluzone 
HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age. The safety profile will include solicited short-
term reactogenicity; 21-day all adverse event (AE) profile; 1-year post-dosing medically-attended adverse 
event (MAE), serious adverse event (SAE), and significant new medical condition (SNMC) profile; and 
selected pre- and post-immunization clinical laboratory parameters. 
• 
To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD 
(Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based on hemagglutination inhibition (HAI) 
responses to vaccine-homologous influenza A and B strains, as recommend for the 2017-18 Northern 
hemisphere vaccine, at Day 21 post-dosing. 
Secondary:  
• 
To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD 
(Sanofi Pasteur), based on hemagglutination inhibition (HAI) responses to at least 2 historic and/or drifted A 
virus strains (one H1N1 and one H3N2). 
• 
To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD 
(Sanofi Pasteur), based on microneutralization (MN) responses to vaccine-homologous and historic and/or 
drifted influenza A strains, and the vaccine-homologous B/Victoria lineage strain, at Day 21 post-dosing.  
Exploratory:  
• 
To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD 
(Sanofi Pasteur), based on HAI and MN responses to a contemporary B/Yamagata lineage strain Day 21 
post-dosing.  
• 
To describe the immune response to Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD 
(Sanofi Pasteur), as measured by competitive-binding assays using purified HA and broadly-neutralizing HA 
monoclonal antibodies of varying specificities on Days 0 and 21. 
 

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Trial Endpoints: 
Primary Endpoints: 
• 
Number and percentage (95% confidence interval [CI]) of subjects with solicited local and systemic adverse 
events over the 7 days post-injection (ie, Day 0 through Day 6 post-dosing); all adverse events (including 
adverse changes in clinical laboratory parameters) through 21 days post-injection; and MAEs, SAEs, and 
SNMCs through 1 year post-Day 0 dosing. Note: The 21 day post vaccination all adverse event profile will 
include all unsolicited AEs reported from test article receipt until the day preceding the rescue dose, ie, events 
with onset dates between days 0 to 20 for subjects who receive the rescue dose as scheduled on day 21. Rules 
for defining the dataset in subjects who receive the rescue dose before or after day 21, or no rescue dose, are 
detailed in the statistical analysis plan. 
• 
Antibody titers specific for the HA receptor binding domains of each of the virus strains included in Tri-NIV 
as measured by the HAI assay at Day 0 pre-dosing and Day 21 post-dosing. Derived/calculated endpoints 
based on these data will include: 
o 
Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed HAI titers for a 
given treatment group. 
o 
Geometric mean ratio (GMR) – defined as the ratio of Day 21 post-vaccination and pre-vaccination HAI 
GMTs within the same treatment group (designated as GMRPost/Pre). 
o 
Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline HAI titer < 1:10 
and a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and a 4-fold increase in post-vaccination 
HAI titer relative to baseline. 
o 
Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer ≥ 1:40. 
Secondary Endpoints: 
• 
Antibody titers specific for the HA receptor binding domains of at least 2 historic and/or drifted A virus 
strains (one H1N1 and one H3N2) as measured by the HAI assay at Day 0 pre-dosing and Day 21 post-dosing. 
Derived/calculated endpoints based on these data will include: 
o 
Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed HAI titers for a 
given treatment group. 
o 
Geometric mean ratio (GMR) – defined as the ratio of post-vaccination and pre-vaccination HAI GMTs 
within the same treatment group (designated as GMRPost/Pre). 
o 
Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline HAI titer < 1:10 
and a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and a 4-fold increase in post-vaccination 
HAI titer relative to baseline. 
o 
Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer ≥ 1:40. 
• 
Neutralizing antibody titers specific for the virus strains included in Tri-NIV and the Fluzone HD comparator, 
as well as selected historical A strains, as measured by a microneutralization assay at Day 0 pre-dosing and 
Day 21 post-dosing. In view of the time-consuming nature of neutralization assays, these may be performed 
on an informative subset of subjects who are selected for this purpose at randomization. Derived/calculated 
endpoints based on these data will include: 
o 
Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed neutralizing titer 
for a given treatment group. 
o 
Geometric mean ratio (GMR) – defined as the ratio of Day 21 post-vaccination and pre-vaccination 
neutralizing GMTs within the same treatment group (designated as GMRPost/Pre). 
o 
Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline neutralizing titer 
< 1:10 and a post-vaccination titer ≥ 1:40, or a baseline titer ≥ 1:10 and a 4-fold increase in post-
vaccination titer relative to baseline. 
Exploratory Endpoints: 
• 
HAI and neutralizing antibody titers specific for a contemporary B/Yamagata virus strain. Derived/calculated 
endpoints based on these data will be as described above.  

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• 
Levels of antibodies competitive with broadly-neutralizing monoclonal antibodies to HA of varying 
specificities, as measured by competitive-binding in a biosensor assay. 
Trial Design:   
This is a Phase 1/2, randomized, observer-blinded, active-controlled trial. Approximately 330 eligible subjects will 
be enrolled and randomized into 1 of 3 treatment groups as shown in the Trial Design table below. Each group 
will consist of approximately 110 subjects total, stratified by age (60 to < 75 and ≥ 75 years), gender, and history 
of receipt of 2016 - 17 influenza vaccine. On Day 0, subjects in Groups A and B will be administered an IM 
injection of 15 or 60 µg HA per strain of Tri-NIV in a 0.3 or 0.8 mL volume, respectively; subjects in Group C 
will receive the preconfigured comparator (Fluzone HD) at the manufacturer’s recommended dose and volume. 
On Day 21, all Group A and B subjects will be administered a rescue injection with a licensed seasonal influenza 
vaccine, while all Group C subjects will be administered an injection with sterile saline placebo (in a total volume 
of 0.5 mL) to maintain trial blind. Trial follow-up for each subject will span approximately 1 year from the Day 0 
injection Schedule of Events. 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. The maximum duration of the trial will 
be approximately 1 year for each subject.  
Enrollment will be divided into 2 stages. Stage 1 will enroll a group of approximately 60 subjects (approximately 
20 subjects per treatment group) and Stage 2 will enroll the remainder of the subjects per treatment group. The 
only difference in the 2 stages will be a safety review in-clinic visit for Stage 1 subjects on Day 7 (+1 day) of the 
trial, whereat subjects will be asked to present their subject diaries. In Stage 2, a safety review telephone call on 
Day 7 (±1 day) of the trial will replace the clinic visit. Progression from Stage 1 to Stage 2 will require favorable 
review of cumulative Stage 1 safety against vaccination holding rules as defined in Safety Monitoring of 
Enrollment and Vaccinations Section below.  
Safety Monitoring of Enrollment and Vaccinations: 
This will be a first-in-human trial with Tri-NIV formulated with Matrix-M1 adjuvant. Thus, vaccination holding 
rules will be used to govern progression from the Stage 1 group to full enrollment in Stage 2. Solicited and 
unsolicited AEs reported from all Stage 1 subjects within 7 days of Day 0 vaccination will be evaluated against 
vaccination holding rules (See Vaccination Holding Rules below). These AE data will be summarized by the 
sponsor statistician, reviewed, and provided to an independent medical monitor in aggregate form (without 
unblinding or subdivision by treatment group). If vaccination holding rules are not met, the independent medical 
monitor will notify the sponsor Chief Medical Officer (CMO) to proceed with enrollment of subjects. If 
vaccination holding rules are met, the independent medical monitor will notify the sponsor CMO who will pause 
enrollment pending further review and request unblinding of the data. The independent medical monitor and the 
sponsor will review the unblinded data and develop a report and recommendation to either: a) resume enrollment, 
b) amend the protocol and resume enrollment, or c) terminate the protocol. The report, the recommendation, and 
the amended protocol and ICF (if relevant), will be provided to the IRB and CBER, and enrollment will not 
recommence until IRB approval is obtained. 
Vaccination Holding Rules:  
Adverse event reports meeting any one of the following 2 criteria will result in a hold being placed on subsequent 
enrollment and vaccinations, pending further review by the independent medical monitor and sponsor:  
1) The occurrence of at least 1 serious adverse event among any Stage 1 subject assessed by the sponsor as 
definitely related to the trial treatment.  
2) The occurrence of any severe (grade 3) solicited (local or systemic) adverse event term in   > 10% of all Stage 
1 subjects.  
If vaccination holding rules are met at any review point, the independent medical monitor will: 
1) Review a summary of all individual data of the relevant subject(s), including the unblinded treatment 
assignment, and summary safety data relative to all treatment groups; and  
2) If there exists any imbalance that is higher in one of the two Tri-NIV treatment groups compared to the Fluzone 
HD group, review a detailed accounting from the investigator(s) as to the exact nature of the clinical symptoms or 
physical findings in the subject(s) triggering the holding rule, including any potential causation and evidence of 

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resolution with or without treatment.  
Ongoing Evaluation: 
In addition to the above vaccination holding rules after Stage 1, solicited adverse events enrollment and vaccination 
will be suspended pending discussion with CBER and the IRB in the event of:  
1) Any tabulation of solicited adverse events (to be repeated approximately weekly during active enrollment) 
which demonstrates the occurrence of any severe (grade 3) solicited (local or systemic) adverse event term in   
> 10% of all subjects (note that unmonitored data will perforce be used for this tabulation), or 
2) The occurrence of at least 1 serious adverse event in any subject assessed by the sponsor as definitely related 
to the trial treatment.  
Trial Design 
Group 
Day 0 Trial Treatment Injection (non-dominant deltoid) 
Day 21 
Rescue 
Injection[2] 
(dominant 
deltoid) 
Stage 1 
Subjects 
[3] 
Stage 2 
Subjects 
[3] 
Subjects 
per 
Group 
Vaccine 
Name 
HA Dose per 
Strain, μg 
(H1N1/H3N2/BV) 
Total 
HA 
Dose,  
μg 
Matrix-
M1 
Adjuvant 
Dose, µg[1] 
Injection 
Volume, 
mL 
A 
Tri-NIV 
15 / 15 / 15  
45 
50 
0.3 
Licensed 
seasonal 
influenza 
vaccine 
 
20 
90 
110 
B 
Tri-NIV 
60 / 60 / 60 
180 
0.8 
20 
90 
110 
C 
Fluzone 
HD 
60 / 60 / 60  
180 
None  
0.5 
Placebo  
20 
90 
110 
Total Trial Target Subjects  
60 
270 
330 
Note: All subjects will receive 2 vaccinations by IM injection on Day 0 and Day 21. 
[1] Matrix-M1 adjuvant will be formulated with the vaccine at the time of vaccination by the unblinded pharmacist in 
accordance with the Trial Pharmacy Manual.  
[2] All subjects who received Tri-NIV will receive a rescue injection with a licensed seasonal influenza vaccine on Day 21. 
Subjects who receive Fluzone HD on Day 0 will receive an injection with sterile saline placebo (0.5 mL) to maintain 
trial blind. 
[3] Enrollment will be divided into 2 stages. Stage 1 will consist of approximately 20 subjects per treatment group. Stage 2 
will consist of the remainder of targeted subjects for enrollment per treatment group.  
Trial Visit Procedures: 
All subjects will undergo procedures summarized in the Schedule of Events Table and described in detail below.  
Day 0 – Screening Visit 
Healthy male and female volunteers, ≥ 60 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 2016 - 17 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 Eligibility Criteria) may be enrolled.  
Day 0 – Trial Treatment Injection Visit 
All subjects who have eligibility confirmed will be randomized to 1 of 3 treatment groups and will have blood 
drawn for baseline immunogenicity testing (eg, HAI/MN titers; 20 mL) and clinical laboratory safety parameters 
assessments (ie, serum chemistry and hematology; 10 mL). Subjects will then receive a single IM injection of 
Tri-NIV or Fluzone HD in their non-dominant deltoid, according to treatment assignment. Note: if only the 
dominant deltoid is available for injection, it is acceptable to administer the trial treatment in the dominant deltoid. 

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Subjects will be monitored in the clinic for 30 to 60 minutes following injection with the trial treatment for the 
occurrence of any AEs and for the evaluation of post-vaccination 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 offered. 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 Contact/In-clinic Visits  
Safety follow-up visits will be performed by scripted telephone contact on Day 3 to query for any grade 3 solicited 
or unsolicited event and/or SAE experienced since the last visit or telephone contact, and any concomitant 
medications taken for these events. 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. Subjects in Stage 1 of the trial will complete a Day 
7 (+1 day) in-clinic visit to return their diaries, provide vital signs, report any AEs they experienced since their last 
visit, and schedule their next Day 21 (± 2 days) in-clinic visit. Subjects will Stage 2 will complete a Day 7 (±1 
day) telephone call with the trial staff and will return their diaries on their next Day 21 (± 2 days) in-clinic visit. 
On their Day 21 visit, all subjects will be queried for any AEs, MAEs, SNMCs, and SAEs occurring since the last 
trial visit, and any concomitant medications taken. In addition, the following procedures will be performed on 
Day 21 for all subjects: vital sign collection and collection of blood samples for immunogenicity testing (eg, 
HAI/MN titers; 20 mL) and clinical laboratory safety assessments of hematology and serum chemistry parameters 
(10 mL). A rescue injection with a licensed seasonal influenza vaccine will be administered to all subjects that 
received Tri-NIV on Day 0, according to the manufacturer’s instruction, whereas all subjects who received Fluzone 
HD on Day 0 will be given an injection of sterile saline placebo to maintain trial blind. Administration should be 
performed on the dominant deltoid. Note: if only the non-dominant deltoid is available for injection, it is acceptable 
to administer the trial treatment in the non-dominant deltoid. 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 second vaccination. Subjects presenting with an acute illness on Day 21 may return to the study site 
within the next 7 days to receive their 2nd vaccination. If a subject has experienced any AEs/SAE between study 
Days 0 and 21, then Day 21 vaccination may be administered or delayed for up to 7 days based on the 
Investigator’s discretion. Subjects will be monitored in the clinic for 30 to 60 minutes following injection with the 
trial treatment for the occurrence of any AEs and for the evaluation of post-vaccination vital signs.  
Additional safety follow-up will include an in-clinic visit on Day 56 (± 2 days), a telephone contact visit on Day 90 
(± 7 days) and Day 273 (± 7 days), and an in-clinic visit on Day 182 (± 7 days) and Day 364 (± 14 days) to query 
for any MAEs, SNMCs, and SAEs occurring since the last trial visit or telephone contact, and any concomitant 
medications taken for these events.  
Schedule of Events: 
Trial Day:  
0 
3 
7 
(Stage 1 
ONLY) [8] 
7  
(Stage 2 
ONLY)[8] 
21 
56 
90 
182 
273 
364 
Window (days): 
 
± 1 
+1 
± 1 
± 2 
± 2 
± 7 
± 7 
± 7 
± 14 
Trial Procedures 
Trial Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/Medication 
History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X[7] 
 
X [7] 
X [7] 
 
X [7] 
 
X [7] 

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Schedule of Events (Continued): 
Trial Day:  
0 
3 
7 
(Stage 1 
ONLY) 
[8] 
 
7  
(Stage 2 
ONLY)[8] 
 
21 
56 
90 
182 
273 
364 
Window (days): 
 
± 1 
+1 
± 1 
± 2 
± 2 
± 7 
± 7 
± 7 
± 14 
Trial Procedures 
Vital Signs 
X [1] 
 
X 
 
X [1] 
X 
 
X 
 
X 
Clinical Safety 
Laboratory [2] 
X 
 
 
 
X 
 
 
 
 
 
Serology  
X 
 
 
 
X 
 
 
 
 
 
Trial Treatment 
Injection  
X 
 
 
 
 
 
 
 
 
 
Rescue Injection 
with a licensed 
seasonal influenza 
vaccine [6] 
 
 
 
 
X 
 
 
 
 
 
Adverse Event 
Review [4] 
X 
X [3] 
X 
X[3]  
X 
X 
X 
X 
X 
X 
Concomitant 
Medications Review 
[4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary 
Review 
 
X [3] 
X [5] 
X [3] 
X 
[5] 
 
 
 
 
 
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] Includes assessments for hematology (complete blood count [CBC] with hemoglobin, hematocrit, red blood cell [RBC] 
count, platelet count, and white blood cell [WBC] count with differential) and serum chemistry (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase, creatinine, and blood 
urea nitrogen [BUN]).  
[3] Subjects will be asked to report any grade 3 solicited or unsolicited adverse event or SAE experienced since the last visit 
and may be asked to return to the clinic for an unscheduled visit to evaluate the event(s) at the Investigator’s discretion.  
[4] All adverse events and concomitant medications taken will be collected through Day 21; thereafter only MAEs, SAEs, 
and SNMCs and medications taken for these events will be collected.  
[5] The subject diary will be reviewed by the investigator and collected at the Day 7 visit (Stage 1 subjects ONLY) or Day 21 
visit (Stage 2 subjects ONLY). 
[6] On Day 21, all Group A and B subjects will be administered a rescue injection with a licensed influenza vaccine, and all 
Group C subjects will be administered an injection of saline placebo to maintain trial blind. 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 second vaccination. Subjects presenting with an acute illness 
on Day 21 may return to the study site within the next 7 days to receive their 2nd vaccination. If a subject 
has experienced any AEs/SAE between study Days 0 and 21, then Day 21 vaccination may be administered 
or delayed for up to 7 days based on the Investigator’s discretion. 
[7] If needed, a physical examination may be performed, based on the investigator’s discretion. 
[8] All Stage 1 subjects will be required to complete a Day 7 in-clinic visit to present their subject diaries, whereas Stage 2 
subjects will be required to complete a safety telephone call. 
 
 

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Eligibility Criteria:  
Inclusion: 
Subjects must meet the following criteria to be eligible to participate: 
1) Healthy adult male or female, ≥ 60 years of age, 
2) Willing and able to give informed consent prior to trial enrollment, and  
3) Able to attend trial visits, comply with trial requirements, and provide reliable and complete reports of adverse 
events. 
Exclusion: 
Subjects will be excluded if they meet any of the following criteria: 
1) Any ongoing, symptomatic acute or chronic illness requiring medical or surgical care.  
• 
Asymptomatic chronic conditions or findings (eg, mild hypertension, dyslipidemia) that are not 
associated with evidence of end-organ damage are not exclusionary provided that they are being 
appropriately managed and are clinically stable (ie, unlikely to result in symptomatic illness within the 
time-course of this trial) in the opinion of the investigator. 
• 
Acute or chronic illnesses or conditions which may be reasonably predicted to become symptomatic if 
treatment were withdrawn or interrupted are exclusionary, even if stable. 
• 
Acute or chronic illnesses reasonably expected to be associated with increased risks in the event of  
influenza infection (eg, cardio-pulmonary diseases, diabetes mellitus, renal or hepatic dysfunction, 
hemoglobinopathies) are exclusionary, even if stable.  
• 
Note that illnesses or conditions may be exclusionary, even if otherwise stable, due to therapies used to 
treat them (see exclusion criteria 2, 5, 8, 9). 
2) Participation in research involving investigational product (drug / biologic / device) within 45 days before 
planned date of first injection. 
3) History of a serious reaction to prior influenza vaccination, or known allergy to constituents of influenza 
vaccines - including egg proteins - or polysorbate 80. 
4) History of Guillain-Barré Syndrome (GBS) within 6 weeks following a previous influenza vaccine. 
5) Receipt of 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 or during the trial.  
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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Statistical Methods:   
General 
All analysis populations will be defined and full descriptions of each population will be provided. Demographic 
parameters and other baseline characteristics (age, sex, race, ethnicity, as well as influenza vaccine exposure within 
the 2016-17 influenza season) will be summarized by treatment group for all subjects in the safety population, as 
well as the number and description of protocol deviations.  
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 Safety Objective 
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, 21-day all AE profile by MedDRA preferred term, and 1-year MAE, 
SAE, and SNMC profiles post-injection on Day 0. Note: The 21 day post vaccination all adverse event profile will 
include all unsolicited AEs reported from test article receipt until the day preceding the rescue dose, ie, events with 
onset dates between days 0 to 20 for subjects who receive the rescue dose as scheduled on day 21. Rules for 
defining the dataset in subjects who receive the rescue dose before or after day 21, or no rescue dose, are detailed 
in the statistical analysis plan. All AEs, 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. Clinical 
laboratory data will be summarized by means and 95% confidence interval, minima and maxima, at Day 0 and 
Day 21 in each treatment group, as well as means and 95% confidence interval of change from baseline at Day 21. 
Changes from baseline will also be summarized at Day 21 for each treatment group in terms of the proportion of 
subjects with no change in toxicity grade versus proportions with one, two, or three grade changes. A listing and 
narratives of SAEs will also be produced.  
Analyses Concerning Immunogenicity Objectives  
The immunogenicity analysis will be based on the per-protocol (PP) population. A separate intent-to-treat (ITT) 
population analysis will not be produced unless > 10% of at least 1 treatment group is excluded from the PP 
population. HAI antibody titers specific for each of the vaccine-homologous, historical and/or drifted, and cross-
lineage virus strains tested will be summarized by treatment group based on the following parameters (with 95% 
CIs): 
1) Geometric mean titer (GMT) at baseline (screening) and post-vaccination on Day 21. Samples with no 
detectable HAI activity at the lowest dilution (1:10) will be assigned a value of 5 for calculation. 
2) GMR – the ratio of the post-vaccination GMT on Day 21 to the baseline (Day 0) value. 
3) Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline HAI titer < 1:10 and 
a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and a 4-fold increase on Day 21 in post-
vaccination HAI titer relative to baseline. 
4) Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer ≥ 1:40 at a given time 
point. 
Neutralizing antibody titers specific for each of the virus strains will be summarized by treatment group for each 
virus stain tested based on the following parameters (with 95% CIs): 
1) GMT at baseline (screening) and post-vaccination on Day 21. Samples with no detectable neutralizing activity 
at the lowest dilution (1:10) will be assigned a value of 5 for calculation. 
2) GMR – the ratio of the post-vaccination GMT on Day 21 to the baseline (Day 0) value. 

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3) SCR defined as the percentage of subjects with either a baseline neutralizing titer < 1:10 and a post-vaccination 
titer ≥ 1:40, or a baseline titer ≥ 1:10 and a 4-fold increase on Day 21 in post-vaccination titer relative to 
baseline. 
Percentages of subjects with immune response will be calculated along the corresponding two-sided exact 
(Clopper-Pearson) binomial CIs. GMTs will be summarized by treatment group and visit day along with the 
corresponding two-sided 95% CIs, by exponentiating the corresponding log-transformed means and their 95% 
CIs. Two-sided 95% CIs for the difference in proportions of participants demonstrating SCR and SPR between a 
Tri-NIV group and the Fluzone HD group will be based on the Newcombe hybrid score (METHOD = SCORE 
riskdiff-option for PROC FREQ in SAS). The within-group geometric mean ratio (GMRpost/pre) will be 
conducted using paired t-test based on log transformed value. Then, the mean difference and the corresponding 
95% CI limits will be exponentiated to obtain the GMT ratio and the corresponding CI.   
Reverse cumulative distribution displays of HAI and MN titers for each virus strain will be produced in which 
Day 0 and Day 21 distributions will be displayed separately by treatment group. Titers reported below the lowest 
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).  
Sample Size Considerations  
The sample size is chosen as adequate for an initial description of safety and immunogenicity to direct future 
development and dosing. No hypothesis tests are specified and the sample size is not intended to support any 
statistical contrast of Tri-NIV with Fluzone HD. For safety endpoints, the probability of observing at least one 
adverse event among 110 subjects for each of the two Tri-NIV groups or 220 for the two Tri-NIV groups combined, 
are > 90% if the true rate of such events is 2.1% and 1.1%, respectively. With 110 for each of the two Tri-NIV 
group or 220 for the two Tri-NIV groups combined, observing no adverse events of interest (eg, vaccine-related 
SAE) would represent an upper bound of the one-sided 95% CI on the percentage of such events of 2.7% and 
1.4%, respectively.  

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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 two 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, two 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 2017 -b]. 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, 6 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 U.S. [FDA 2017, CDC 2017a]. Nine (9) trivalent 
inactivated or recombinant influenza vaccines are also approved in the US, including 1 vaccine 
available in 3 trivalent formulations (high-dose, standard trivalent, and intradermal). Live 
attenuated vaccines have been excluded from the preceding counts as they are not approved for 
persons over 49 years of age.  
Of all currently-licensed vaccines, 2 are specifically approved for use in older adults, and 
include a high-dose (ie, Fluzone® High-Dose initially approved in the US in 2009) and an 
adjuvanted (ie, FLUAD™ initially approved in the US in 2015) trivalent inactivated influenza 
vaccine [CDC 2017a]. Although Fluzone High-Dose (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], efficacy rates reported in older 
adults have remained quite variable season-to-season since the approval of Fluzone HD in 2009 
ranging anywhere from -5.8% to 45% from 2009 to 2016 [Griffin 2011, Treanor 2012, 
Ohmit 2014, Reed 2014, McLean 2015, Flannery 2016, Zimmerman 2016, CDC 2017]. This 
variability is likely, in part, due to antigenic drift or mismatch between circulating and vaccine 
influenza strains leading to reduced effectiveness of seasonal influenza vaccines. For example, 
Fluzone HD was ~36% more effective in reducing mortality in 2012-13 compared with ~2.5% 
in 2013-14 due to the increase in the circulation of A(H3N2) strains known to be associated 
with higher mortality in the elderly [Shay 2017]. There are currently no randomized studies 
comparing FLUAD with Fluzone HD [CDC 2017b]. Thus, there remains a significant need for 
influenza vaccines with improved efficacy, and, in particular, the capacity to buffer the 
consequences of antigenic drift occurring between strain selection and circulation of the virus. 
This is particularly true in the older adult population, which remains vulnerable to serious 
complications, including death, resulting from influenza infection. Accordingly, a vaccine with 
both strong homologous hemagglutination inhibiting (HAI) and broadly neutralizing antibody 
responses, which might address drifted strains, could be of added value and could help meet the 
unmet medical need in older adults. Generally, for all influenza vaccines, a hemagglutination 
inhibition (HAI) titer ≥ 1: 40 has been associated with protection from influenza illness 
[Hobson 1972].  
1.4 Nanoparticle Influenza Vaccine, Trivalent (Tri-NIV) 
Novavax’s Tri-NIV is based on purified, recombinant, full-length HA that self-assembles into 
distinct nanoparticle structures of approximately 20 to 40 nm. A baculovirus/Spodoptera 
frugiperda (Sf9) insect cell system is used to clone and express 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].  Sf9 insect cells produce recombinant, uncleaved, glycosylated HAs that 

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assemble into homo-oligomers as trimers. When purified, HA trimers form higher order 
structures composed of 2 to 9 or more trimers per nanoparticle.  
1.5 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 
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 two 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.   
1.6 Nonclinical Investigations  
1.6.1 Matrix-M1-adjuvanted Tri-NIV  
A pivotal animal study of Tri-NIV 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 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. 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-signficant 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 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 Tri-NIV (30 µg each of A/Switzerland/9715293/2013 and 

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B/Brisbane/60/2008 [in addition to A/Anhui/1/2013 neuraminidase and RSV F protein, which 
are not present in the current candidate]). Tri-NIV was administered to animals on Days 1 and 
15, alone or with 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. A complete 
description of the non-clinical development and datasets for Tri-NIV may be found in the 
Investigators’ Brochure. 
1.6.2 Other Matrix-M1-adjuvanted Vaccines 
The totality of the GLP-compliant toxicology data obtained in animal studies to evaluate 
Matrix-M1 alone, or when co-administered with multiple different antigens (including 
egg-derived influenza antigens, recombinant-produced influenza hemagglutinin and 
neuraminidase, recombinant HSV-2 proteins, Plasmodium falciparum circumsporozoite protein 
sequences, RSV F antigen, and Ebolavirus glycoprotein) has failed to demonstrate overt 
systemic or organ-specific toxicities; and treatments overall, were generally well-tolerated. 
Transient and inconsistent reductions in body weight and red cell mass parameters, as well as 
temperature elevations, were noted in adjuvanted vaccine recipients in some studies, but these 
findings either resolved completely or tended to resolution following the recovery period. Local 
injection site inflammation and regional lymph node hyperplasia consistent with active 
immunization were present in acute necropsies, but again showed resolution at recovery 
time-points. Vaccines adjuvanted with Matrix-M1 demonstrated immune responses to vaccine 
antigens, substantiating active treatment and responsiveness to the test articles. A summary of 
the non-clinical experience with Matrix-M1 is available in the Matrix-M Adjuvant Safety Data 
Supplement (Version 3.0). 
1.7 Clinical Investigations  
1.7.1 Matrix-M1-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 1,433 human subjects in a total of 14 clinical 
trials in the US, Europe, and Australia; 9 are completed and 5 are ongoing, and may or may not 
have unblinded data available. A total of 896 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. Among all 14 studies, no reported serious adverse events 
(SAE) have been classified as related to exposure to the Matrix-M adjuvant. 
Please refer to the Matrix-M Adjuvant Safety Data Supplement (Version 3.0) for detailed 
summaries of the clinical experience with Matrix-M1-adjuvanted vaccines. 
1.8 Trial Rationale 
The influenza virus poses a formidable risk of infection to older adults. Based on estimates by 
the Centers for Disease Control and Prevention (CDC), in the US alone, up to 85% of all 

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influenza-related deaths and 70% of all influenza-related hospitalizations occur in people 
65 years of age or older [CDC 2017b]. Novavax, Inc. has developed an insect cell-derived, 
egg-free, influenza vaccine (Tri-NIV) based on recombinant hemagglutinin (HA) nanoparticle 
antigens, which represent the 3 major influenza types/subtypes, recommended for inclusion in 
the 2017 - 2018 seasonal influenza vaccine by the World Health Organization (WHO) and the 
Center for Biologics Evaluation and Research (CBER).  
Currently, the Advisory Committee on Immunization Practices (ACIP) and CDC recommend 
that older adults receive an annual vaccination with any seasonal influenza vaccine approved 
for use in this age group; inactivated influenza (standard or high dose, trivalent or quadrivalent, 
unadjuvanted or adjuvanted) or recombinant influenza (trivalent) vaccines are considered 
acceptable options [Grohskopf 2016, CDC 2017b]. There are 2 vaccines specifically approved 
for use in older adults, including high-dose (ie, Fluzone® High-Dose initially approved in the 
US in 2009) and adjuvanted (ie, FLUAD™ initially approved in the US in 2015) trivalent 
inactivated influenza vaccines [CDC 2017b]. 
While the efficacy of Fluzone HD, and existing adjuvanted influenza vaccines, is improved in 
older adults relative to standard-dose, egg-derived inactivated influenza vaccines, it remains 
suboptimal - and also vulnerable to antigenic drift in circulating strains between strain selection 
in the first quarter of a given year and virus circulation in the following winter season. The latter 
phenomenon has been particularly troublesome for A(H3N2) strains over the past 10 to 
15 years. Accordingly, a vaccine with both strong homologous hemagglutination inhibiting 
(HAI) and broadly neutralizing antibody responses – which might address drifted strains – could 
be of added value in older adults. 
Several features of Tri-NIV warrant clinical investigation of its safety and immunogenicity 
among older adults. In ferrets, the trivalent nanoparticle candidate 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. 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-signficant 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 drift strain protection, 
even against strains such as A/HongKong/4801/2014, which are associated with impaired 
influenza vaccine efficacy in humans. While cross-lineage B virus antibody responses were not 
seen in naïve animals, the possibility of such responses should be considered, and will be 
evaluated, in immunologically-experienced humans. 
Because Tri-NIV is produced at high yields in insect cells, it potentially presents a more 
cost-effective method of producing large quantities of an annual seasonal influenza vaccine 
when compared to the traditional egg-based manufacturing processes, and, if successful, may 
also offer a flexible and rapidly-responsive platform for production of novel influenza 
hemagglutinins from strains with pandemic potential. Initial development, however, will focus 

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on potential superior benefits of a seasonal trivalent or quadrivalent formulation in the 
vulnerable older adult population. 
Two Tri-NIV treatment groups evaluating either 15 or 60 µg of HA antigen per strain in Tri-NIV 
have been proposed to 1) allow comparison with immunogenicity and safety profile of Fluzone 
HD and 2) evaluate the antigen dose response to inform further clinical development of the 
vaccine. The Matrix-M1 adjuvant, shown to remarkably enhance immunological responses of 
several vaccine antigens, with an overall acceptable safety profile in over 1400 humans exposed 
to date, is proposed as the adjuvant of choice.  
1.9 Expected Risks from Tri-NIV with Matrix-M1 Adjuvant  
This proposed trial will be the first human exposure to Tri-NIV with Matrix-M1 adjuvant. 
Expected risks of vaccination with Tri-NIV in combination with Matrix-M1 adjuvant can be 
extrapolated from older adult studies of Novavax’s respiratory syncytial virus fusion protein 
(RSV F) nanoparticle vaccine, which is manufactured using the same baculovirus/Sf9 insect 
cell system technology used to produce Tri-NIV.  
The first of these studies was a Phase 3 trial of a high dose of an unadjuvanted RSV F 
nanoparticle antigen (135 µg) given to a total of 5,921 older adult subjects, conducted from 
07 November 2015 to 23 November 2016. An additional 5,935 older adult subjects received 
placebo. The safety profile of active vaccinees was not remarkably different from that of 
placebo subjects. Similar proportions of active and placebo subjects reported an adverse event 
(AE) relating to short-term reactogenicity of trial treatment (ie, 25 and 22%, respectively). 
About 1 to 2% of subjects from each group described these events as severe, which included 
injection site pain, bruising, redness, and swelling, as well as severe headache, fatigue, muscle 
pain, diarrhea, joint pain, chills, nausea, vomiting, and fever. Only 2 (out of 5,921 total) active 
subjects reported severe fever (ie, oral temperature of > 38.9°C). Similar proportions of active 
and placebo subjects also reported unsolicited adverse events (ie, 58 and 57%, respectively). 
Among these, 6 and 7% of placebo and active subjects, respectively, experienced an AE 
considered related to trial treatment. Commonly-reported (> 5 subjects per group) related AEs 
included upper respiratory tract infection, bronchitis, sinusitis, arthralgia, pain in extremity, 
myalgia, blood pressure systolic increased, blood pressure increased, blood pressure diastolic 
increased, cough, rhinorrhea, oropharyngeal pain, nasal congestion, sneezing, sinus congestion, 
diarrhea, nausea, headache, dizziness, fatigue, pyrexia, chills, pain, injection site bruising, 
injection site pruritus, injection site pain, injection site erythema, hypertension, rash, and 
pruritus.  
While most AEs were mild to moderate in nature, about 0.4% placebo and 0.7% active subjects 
reported a severe AE considered related to the treatment. Severe and related AEs reported by 
more than 1 trial subject included increase in blood pressure (13 active subjects and 8 placebo), 
including systolic (13 active subjects and 9 placebo) and diastolic (3 active subjects and 
3 placebo); and headache (2 active subjects and 0 placebo). About 9% of subjects in each group 
reported a serious adverse event (SAE). SAEs considered by the investigator to be related to 
treatment included acute myocardial infarction (1 active subject), cardiac failure congestive 
(1 active subject), transient ischemic attack (1 active subject), and large intestine stenosis and 

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diverticulitis (1 placebo subject). Novavax accepted the trial investigator’s assessment of these 
SAEs with caution, given that all SAEs could readily be explained by the subject’s medical 
history and/or natural disease progression in the general older adult population. No differences 
were noted in active or placebo subjects’ tendency to seek medical care.   
The second trial is an ongoing Phase 2 older adult trial of low and high doses of the RSV F 
nanoparticle antigen (ie, 35, 65, 95, 120, and 135 µg), given with or without 50 µg Matrix-M1 
adjuvant or an aluminum adjuvant, either as a 1-dose or 2-dose regimen on Days 0 and 21, with 
the goal of identifying a vaccine formulation and regimen that would maximize the 
immunogenicity of the antigen. A total of 149 subjects received the RSV F antigen with 
Matrix-M1 adjuvant; 99 subjects received RSV F antigen with aluminum; 25 subjects received 
placebo; and 26 subjects received 135 µg of unadjuvanted RSV F antigen.  
Safety data from an interim unblinding at 3 months into the trial revealed that all formulations 
of the RSV F nanoparticle antigen, with or without Matrix-M1 adjuvant or the aluminum 
adjuvant, were well-tolerated among subjects. More subjects reported an AE among 
Matrix-M1-adjuvanted vaccinees (65 to 100%), than among aluminum-adjuvanted vaccinees 
(50 to 76%), unadjuvanted vaccinees (77%), or placebo recipients (56%). As was expected, 
short-term reactogenicty among 2-dose Matrix-M1-adjuvanted vaccinees was increased when 
compared to reactogenicity among 1-dose Matrix-M1-adjuvanted vaccinees (70 to 80% vs. 
40 to 60% of vaccines, respectively), and was consistently higher than subjects that received 
the unadjuvanted RSV F antigen (27%) and those that received placebo (36%). The proportions 
of subjects with severe solicited AEs among 2-dose Matrix-M1-adjuvanted vaccinees was 
higher (0 to 13% of subjects [ie, 6 subjects]), when compared to 1-dose Matrix-M1-adjuvanted 
vaccinees (0 to 4% [ie, 1 subject]), and placebo recipients (0%). An antigen-dose response in 
terms of severe solicited AEs was present among Matrix-M1-adjuvanted vaccinees, where 
subjects that received 65 or 135 µg RSV F antigen appeared to experience more severe AEs 
than subjects that received 35 µg, regardless of whether they received 1 or 2 doses of trial 
treatment. Notably, all the described short-term reactogenicity events were transient. 
The reported incidence of unsolicited AEs was similar across treatment groups, ie, 46 to 68% 
of aluminum-adjuvanted vaccinees, 46 to 88% of Matrix-M1-adjuvanted vaccinees, 65% 
unadjuvanted vaccinees, compared to 48% placebo. AEs considered related to treatment were 
reported by 8 to 40% of Matrix-M1-adjuvanted vaccinees, 8 to 36% of aluminum-adjuvanted 
vaccinees, 27% unadjuvanted vaccinees, and 12% placebo subjects. Related AEs reported by 
>1 Matrix-M1-adjuvanted vaccinee included upper respiratory tract infection, injection site 
pain, fatigue, injection site reaction, injection site erythema, muscle spasms, blood urea 
increased, and oropharyngeal pain.   
Severe and treatment-related unsolicited AEs were reported in only 3 subjects (none received 
Matrix-M1), and included pyrexia, lower respiratory tract infection, and skin lesion, and no 
antigen-dose or Matrix-M1 adjuvant relationship was noted. A total of 8 subjects reported 
SAEs. These included 4 aluminum-adjuvanted vaccinees and 4 Matrix-M1-adjuvanted 
vaccinees. None of these SAEs were considered by the investigator as related to the treatment. 
No relationship between the incidence of significant new medical conditions (SNMCs) or 

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medically-attended adverse events (MAEs), and receipt of the RSV F antigen with or without 
Matrix-M1 adjuvant was noted.  
1.10 Risks Associated with Fluzone HD  
Fluzone HD has been the subject of several large clinical trials including over 18,500 recipients 
of Fluzone HD contrasted to over 17,200 subjects concurrently treated with Fluzone, a standard-
dose (15µg of each HA) trivalent inactivated influenza vaccine. In these studies, local injection 
site solicited adverse events typical of intramuscular vaccine reactogenicity and occurring in 
the first 7 days after dosing occurred between 1.3- and 1.6-fold more commonly in the Fluzone 
HD recipients than Fluzone recipients, including a 35.6% incidence of local injection site pain, 
14.9% erythema, and 8.9% swelling. Systemic complaints such as myalgia, malaise, and 
headache were only modestly more common in high-dose Fluzone recipients, occurring in 
approximately 17 to 21%. Fever occurred in 3.6% of Fluzone HD vaccinees. The majority of 
all these events were mild in severity. Considering the longer term adverse event profile, 
Fluzone HD was not distinguishable from standard dose influenza vaccine.  
A variety of events have been reported in the post-marketing experience with Fluzone and 
Fluzone HD, but a causal relationship has not been established. Information regarding the 
post-marketing safety data for Fluzone products is available in the Package Insert, which will 
be supplied to Investigators. Of note, Fluzone HD is produced in eggs, in common with the 
majority of inactivated vaccines.  Therefore, subjects with known history of severe allergic 
reaction to any influenza vaccine, or allergy to egg proteins, should not receive Fluzone HD. 
Additionally, subjects with a history of Guillain-Barré syndrome within 6 weeks of any 
influenza vaccine should not receive Fluzone HD 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 describe the safety and tolerability of Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age. The 
safety profile will include solicited short-term reactogenicity; 21-day all adverse event (AE) 
profile; 1-year post-dosing medically-attended adverse event (MAE), serious adverse event 
(SAE), and significant new medical condition (SNMC) profile; and selected pre- and 
post-immunization clinical laboratory parameters. 
• To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based 
on hemagglutination inhibition (HAI) responses to vaccine-homologous influenza A and B 
strains, as recommend for the 2017 - 18 Northern hemisphere vaccine, at Day 21 
post-dosing. 
2.2 Secondary Objectives  
• To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur) based on hemagglutination inhibition (HAI) 
responses to at least 2 historic and/or drifted A virus strains (one H1N1 and one H3N2). 
• To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur), based on microneutralization (MN) responses to 
vaccine-homologous and historic and/or drifted influenza A strains, and the vaccine-
homologous B/Victoria lineage strain, at Day 21 post-dosing.  
 
2.3 Exploratory Objectives  
• To describe the immunogenicity of Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur), based on HAI and MN responses to a 
contemporary B/Yamagata lineage strain Day 21 post-dosing.  
• To describe the immune response to Tri-NIV at 2 different doses, and the licensed 
comparator Fluzone HD (Sanofi Pasteur), as measured by competitive-binding assays using 
purified HA and broadly-neutralizing HA monoclonal antibodies of varying specificities on 
Days 0 and 21. 
 
 

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3 TRIAL OVERVIEW 
3.1 Design 
This is a Phase 1/2, randomized, observer-blinded, active-controlled clinical trial. 
Approximately 330 eligible subjects will be enrolled and randomized into 1 of 3 treatment 
groups, as shown in Table 1. Each group will consist of approximately 110 subjects total, 
stratified by age (60 to < 75 and ≥ 75 years), gender, and history of receipt of 2016 - 17 influenza 
vaccine.  
On Day 0, subjects in Groups A and B will be administered an IM injection of 15 or 60 µg HA 
per strain of Tri-NIV in a 0.3 or 0.8 mL volume, respectively; subjects in Group C will receive 
the preconfigured comparator (Fluzone HD) at the manufacturer’s recommended dose and 
volume. On Day 21, all Group A and B subjects will be administered a rescue injection with a 
licensed seasonal influenza vaccine, while all Group C subjects will be administered an 
injection with sterile saline placebo (in a total volume of 0.5 mL) to maintain trial blind. 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. The maximum duration of the trial will 
be approximately 1 year for each subject.  
Enrollment will be divided into 2 stages. Stage 1 will enroll a group of approximately 60 
subjects (approximately 20 subjects per treatment group) and Stage 2 will enroll the remainder 
of the subjects per treatment group. The only difference in the 2 stages will be a safety review 
in-clinic visit for Stage 1 subjects on Day 7 (+1 day) of the trial, whereat subjects will be asked 
to present their subject diaries. In Stage 2, a safety review telephone call on Day 7 (±1 day) of 
the trial will replace the clinic visit. Progression from Stage 1 to Stage 2 will require favorable 
review of cumulative Stage 1 safety against vaccination holding rules as defined in Section 
3.1.1.1.  
3.1.1 Safety Monitoring of Enrollment and Vaccinations 
This will be a first-in-human trial with Tri-NIV formulated with Matrix-M1 adjuvant. Thus, 
vaccination holding rules will be used to govern progression from the Stage 1 group to full 
enrollment in Stage 2. Solicited and unsolicited AEs reported from all Stage 1 subjects within 
7 days of Day 0 vaccination will be evaluated against vaccination holding rules (3.1.1.1). These 
AE data will be summarized by the sponsor statistician, reviewed, and provided to an 
independent medical monitor in aggregate form (without unblinding or subdivision by treatment 
group). If vaccination holding rules are not met, the independent medical monitor will notify 
the sponsor Chief Medical Officer (CMO) to proceed with enrollment of subjects. If vaccination 
holding rules are met, the independent medical monitor will notify the sponsor CMO who will 
pause enrollment pending further review and request unblinding of the data. The independent 
medical monitor and the sponsor will review the unblinded data and develop a report and 
recommendation to either: a) resume enrollment, b) amend the protocol and resume enrollment, 
or c) terminate the protocol. The report, the recommendation, and the amended protocol and 

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ICF (if relevant), will be provided to the IRB and CBER, and enrollment will not recommence 
until IRB approval is obtained. 
3.1.1.1 
Vaccination Holding Rules  
Adverse event reports meeting any one of the following 2 criteria will result in a hold being 
placed on subsequent enrollment and vaccinations, pending further review by the independent 
medical monitor and sponsor:  
1) The occurrence of at least 1 serious adverse event among any Stage 1 subject assessed by 
the sponsor as definitely related to the trial treatment.  
2) The occurrence of any severe (grade 3) solicited (local or systemic) adverse event term in   
> 10% of all Stage 1 subjects.  
If vaccination holding rules are met at any review point, the independent medical monitor will: 
1) Review a summary of all individual data of the relevant subject(s), including the unblinded 
treatment assignment, and summary safety data relative to all treatment groups; and  
2) If there exists any imbalance that is higher in one of the two Tri-NIV treatment groups 
compared to the Fluzone HD group, review a detailed accounting from the investigator(s) 
as to the exact nature of the clinical symptoms or physical findings in the subject(s) 
triggering the holding rule, including any potential causation and evidence of resolution 
with or without treatment.  
3.1.1.2 
Ongoing Evaluation 
In addition to the above vaccination holding rules after Stage 1, enrollment and vaccination will 
be suspended pending discussion with CBER and the IRB in the event of:  
1) Any tabulation of solicited adverse events (to be repeated approximately weekly during 
active enrollment) which demonstrates the occurrence of any severe (grade 3) solicited 
(local or systemic) adverse event term in  > 10% of all subjects (note that unmonitored data 
will perforce be used for this tabulation), or 
2) The occurrence of at least 1 serious adverse event in any subject assessed by the sponsor as 
definitely related to the trial treatment.  

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Table 1: Trial Design 
Group 
Day 0 Trial Treatment Injection 
 (non-dominant deltoid)  
Day 21 Rescue 
Injection[2] 
(dominant 
deltoid) 
Stage 1 
Subjects[3] 
Stage 2 
Subjects[3] 
Total 
Subjects 
per Group  
Vaccine Name 
HA Dose per 
Strain, μg 
(H1N1/H3N2/B
V) 
Total HA 
Dose,  μg 
Matrix-M1 
Adjuvant 
Dose, µg[1] 
Injection 
Volume, 
mL 
Vaccine  
A 
Tri-NIV 
15 / 15 / 15  
45 
50 
0.3 
Licensed seasonal 
influenza vaccine 
 
20 
90 
110 
B 
Tri-NIV 
60 / 60 / 60 
180 
0.8 
20 
90 
110 
C 
Fluzone HD 
60 / 60 / 60  
180 
None  
0.5 
Placebo  
20 
90 
110 
Total Trial Target Subjects  
60 
270 
330 
Note: All subjects will receive 2  vaccinations by IM injection on Day 0 and Day 21. 
[1] Matrix-M1 adjuvant will be formulated with the vaccine at the time of vaccination by the unblinded pharmacist in accordance with the Trial Pharmacy Manual.  
[2] All subjects who received Tri-NIV will receive a rescue injection with a licensed seasonal influenza vaccine. Subjects who received Fluzone HD on Day 0 will receive an injection 
with sterile saline placebo (0.5 mL) to maintain trial blind.  
[3] Enrollment will be divided into 2 stages. Stage 1 will consistent of approximately 20 subjects per treatment group. Stage 2 will consist of the remainder of targeted subjects for 
enrollment per treatment group.  

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3.2 Trial Endpoints 
3.2.1 Primary Endpoints 
• Number and percentage (95% confidence intervals [CI]) of subjects with solicited local and 
systemic adverse events over the 7 days post-injection (ie, Day 0 through Day 6 
post-dosing); all adverse events (including adverse changes in clinical laboratory 
parameters) through 21 days post-injection; and MAEs, SAEs, and SNMCs through 1 year 
post-Day 0 dosing. Note: The 21 day post vaccination all adverse event profile will include 
all unsolicited AEs reported from test article receipt until the day preceding the rescue dose, 
ie, events with onset dates between days 0 to 20 for subjects who receive the rescue dose as 
scheduled on day 21.  Rules for defining the dataset in subjects who receive the rescue dose 
before or after day 21, or no rescue dose, are detailed in the statistical analysis plan. 
• Antibody titers specific for the HA receptor binding domains of each of the virus strains 
included in Tri-NIV as measured by the HAI assay at Day 0 pre-dosing and Day 21 post-
dosing . Derived/calculated endpoints based on these data will include: 
o Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed 
HAI titers for a given treatment group. 
o Geometric mean ratio (GMR) – defined as the ratio of post-vaccination and 
pre-vaccination HAI GMTs within the same treatment group (designated as 
GMRPost/Pre). 
o Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline 
HAI titer < 1:10 and a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and 
a 4-fold increase in post-vaccination HAI titer relative to baseline. 
o Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer 
≥ 1:40. 
3.2.2 Secondary Endpoints 
• Antibody titers specific for the HA receptor binding domains of at least 2 historic and/or 
drifted A virus strains (one H1N1 and one H3N2) as measured by the HAI assay at Day 0 
pre-dosing and Day 21 post-dosing. Derived/calculated endpoints based on these data will 
include: 
o Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed 
HAI titers for a given treatment group. 
o Geometric mean ratio (GMR) – defined as the ratio of post-vaccination and 
pre-vaccination HAI GMTs within the same treatment group (designated as 
GMRPost/Pre). 
o Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline 
HAI titer < 1:10 and a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and 
a 4-fold increase in post-vaccination HAI titer relative to baseline. 
o Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer 
≥ 1:40. 

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• Neutralizing antibody titers specific for the virus strains included in Tri-NIV and the 
Fluzone HD comparator, as well as selected historical A virus strains, as measured by a 
microneutralization assay at Day 0 pre-dosing and Day 21 post-dosing. In view of the time-
consuming nature of neutralization assays, these may be performed on an informative subset 
of subjects who are selected for this purpose at randomization.  Derived/calculated 
endpoints based on these data will include: 
o Geometric mean titer (GMT) – defined as the antilog of the mean of the log-transformed 
neutralizing titer for a given treatment group. 
o Geometric mean ratio (GMR) – defined as the ratio of post-vaccination and 
pre-vaccination neutralizing GMTs within the same treatment group (designated as 
GMRPost/Pre). 
o Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline 
neutralizing titer < 1:10 and a post-vaccination titer ≥ 1:40, or a baseline titer ≥ 1:10 and 
a 4-fold increase in post-vaccination titer relative to baseline. 
3.2.3 Exploratory Endpoints  
• HAI and neutralizing antibody titers specific for a contemporary B/Yamagata virus strain. 
Derived/calculated endpoints based on these data will be as described above. 
• Levels of antibodies competitive with broadly-neutralizing monoclonal antibodies to HA of 
varying specificities, as measured by competitive-binding in a biosensor assay. 
3.3 Randomization and Blinding Procedure 
Subject randomization will be conducted using an Interactive Web Randomization System 
(IWRS). Stratification will be by age (60 to < 75 and ≥ 75 years), gender, and history of receipt 
of 2016 - 17 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 various 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 by 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 

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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 and official declaration of unblinding is given by Novavax.   
3.5 Procedure for Unblinding Individual Subjects During the Trial 
In the event of a medical emergency, or in the event of a triggering of vaccination holding rules, 
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 CMO or an investigator or designee may request 
that the blind be broken for the subject(s) experiencing the emergency or contributing to holding 
rule activation. Prior to unblinding for individual subjects, 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.  In addition, the Chief Medical Officer will have the right to 
request unblinding of Stage 1 subjects when vaccination holding rules are met (Section 3.1.1.1). 
If unblinding of an individual subject is deemed necessary, the unblinded staff member shall 
obtain subject dose details from the IWRS. 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 Tri-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  
Tri-NIV is based on purified, recombinant full-length HA that self-assembles into distinct 
nanoparticle structures of approximately 20 to 40 nm. The baculovirus/Sf9 insect cell system 
was used to clone and express recombinant influenza HAs from the 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]. In Sf9 insect 
cells, recombinant, uncleaved HAs are produced that are glycosylated and assemble into 
homo-oligomers as trimers. Purified, HA trimers form higher order structures composed of 2 to 
9 or more trimers per nanoparticle. 
Matrix-M1 is a saponin-based adjuvant, which is co-administered with an antigen to induce an 
enhanced immune response. Matrix-M 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 Tri-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 (TMAE) column. The B/Strain requires an additional 
chromatography step following TMAE to further remove host cell proteins. The B/strain flow-
through fraction is loaded onto a Capto Blue mixed-mode chromatography to capture and 
remove additional BV and Sf9 host cell proteins, while B/strain HA is recovered in the flow-
through fraction. Nanofiltration is then performed to remove viruses from the HA product 
stream of both A and B-strains. The HA protein is then loaded onto a lentil lectin column, which 

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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 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 3 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% w/v 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  
The HA protein content in each purified bulk drug substance is measured and the 3 HA drug 
substances are mixed and diluted to the target concentration specified in the protocol in 25 mM 
sodium phosphate, 150 mM sodium chloride, 100 mM arginine hydrochloride, 5% w/v 
trehalose, and 0.03% w/v PS80, pH 7.5. The formulated drug product for Tri-NIV is then filled 
into 2R single-use glass vials. 
Matrix-M1 adjuvant is formulated in phosphate buffer, 150 mM sodium chloride, pH 7.2, and 
filled into 2.0 mL single-use glass vials.  
A simple in-clinic mixing strategy will be developed which allows administration of the target 
doses by the addition of Matrix-M1 in integral multiples of 0.1 mL to the Tri-NIV antigen, 
followed by mixing, then withdrawal and injection of 0.3 or 0.8 mL volumes intramuscularly 
into subjects. The Pharmacy Manual will provide detailed mixing instructions for the unblinded 
pharmacist.  
4.4 Placebo  
Sterile saline will be used as placebo for subjects in Group C for their Day 21 injection (supplied 
in a single-dose vial at a concentration of 9 mg/mL in a 2 mL volume by VWR International).  

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4.5 Fluzone HD – Active Comparator  
Fluzone® High-Dose (Sanofi Pasteur) will be administered based on manufacturer’s 
instructions, which will be provided in the Pharmacy Manual.  
4.6 Investigational Product Packaging, Storage, and Handling 
All IP (ie, Tri-NIV and Matrix-M1 adjuvant) will be packaged in validated shipping containers 
for distribution to the investigational sites under refrigerated conditions. The Tri-NIV 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 HD and placebo 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.   
4.7 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 
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 
and verified prior to destruction. 

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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) Healthy adult male or female, ≥ 60 years of age, 
2) Willing and able to give informed consent prior to trial enrollment, and  
3) Able to attend trial visits, comply with trial requirements, and provide reliable and complete 
reports of adverse events. 
5.2 Exclusion Criteria 
Subjects will be excluded if they fulfill any of the following criteria: 
1) Any ongoing, symptomatic acute or chronic illness requiring medical or surgical care.  
o Asymptomatic chronic conditions or findings (eg, mild hypertension, dyslipidemia) that 
are not associated with evidence of end-organ damage are not exclusionary provided 
that they are being appropriately managed and are clinically stable (ie, unlikely to result 
in symptomatic illness within the time-course of this trial) in the opinion of the 
investigator. 
o Acute or chronic illnesses or conditions which may be reasonably predicted to become 
symptomatic if treatment were withdrawn or interrupted are exclusionary, even if stable. 
o Acute or chronic illnesses reasonably expected to be associated with increased risks in 
the event of  influenza infection (eg, cardio-pulmonary diseases, diabetes mellitus, renal 
or hepatic dysfunction, hemoglobinopathies) are exclusionary, even if stable.  
o Note that illnesses or conditions may be exclusionary, even if otherwise stable, due to 
therapies used to treat them (see exclusion criteria 2, 5, 8, 9). 
2) Participation in research involving investigational product (drug / biologic / device) within 
45 days before planned date of first injection. 
3) History of a serious reaction to prior influenza vaccination, or known allergy to constituents 
of influenza vaccines - including egg proteins - or polysorbate 80. 
4) History of Guillain-Barré Syndrome (GBS) within 6 weeks following a previous influenza 
vaccine. 
5) Receipt of 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 

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≥ 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 or during the trial.  
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 one 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 2016 - 17 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. 
6.1.2 Day 0 – Injection 1 Visit     
All subjects with confirmed eligibility will have the following procedures performed: 
• Blood draw for baseline immunogenicity testing (20 mL, see Section 7.2) and clinical safety 
assessments (10 mL). 
• Randomization to a treatment group. 
• Alcohol swab cleansing of the injection site followed by IM injection into the non-dominant 
deltoid of the assigned trial treatment. Note that if only the dominant deltoid is available for 
the injection, it is acceptable to inject the assigned trial treatment into the dominant deltoid. 
• Monitoring for any AEs for 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 

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grade 3 (severe) solicited or unsolicited health events, and/or health status changes of 
concern to the subject.  
• Schedule the Days 3 telephone contact, Day 7 follow-up visit (Stage 1 ONLY) or Day 7 
telephone contact (Stage 2 ONLY), and Day 21 in-clinic visit before subjects may be 
dismissed from the clinic. 
6.1.3 Day 3 (± 1 day) – Safety Telephone Contact  
• Using an Institutional Review Board (IRB)-approved script, the trial staff will contact the 
subjects using a telephone call to query for any grade 3 solicited or unsolicited adverse event 
or SAE experienced since their last visit, and any concomitant medications taken for these 
events. 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) – Safety Follow-up Visit for (Stage 1 Subjects ONLY)   
All Stage 1 subjects will return to the clinic on approximately Day 7 for the following 
procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Review and collection of subject diary. 
• 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 21 visit. 
6.1.5 Day 7 (± 1 day) – Safety Telephone Contact (Stage 2 Subjects ONLY) 
• 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 adverse event or SAE experienced since 
their last telephone contact, and any concomitant medications taken for these events. 
Subjects may be asked to return to the clinic for an unscheduled visit to evaluate the event(s) 
at the trial investigator’s discretion. 
6.1.6 Day 21 (± 2 days) – Injection 2 Visit  
All subjects will return to the clinic on approximately Day 21 for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Review and collection of subject diary (Stage 2 subjects ONLY). 
• 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 for immunogenicity assessments (20 mL) and clinical safety assessments 
(10 mL). 

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• Alcohol swab cleansing of the injection site followed by IM injection into the dominant 
deltoid of a licensed seasonal influenza vaccine (using the manufacturer’s instructions) for 
Group A and B subjects only, and of saline placebo for Group C subjects only. Note that if 
only the non-dominant deltoid is available for the injection, it is acceptable to inject the 
assigned trial treatment into the non-dominant deltoid. 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 second vaccination. Subjects presenting 
with an acute illness on Day 21 may return to the study site within the next 7 days to receive 
their 2nd vaccination. If a subject has experienced any AEs/SAE between study Days 0 and 
21, then Day 21 vaccination may be administered or delayed for up to 7 days based on the 
Investigator’s discretion. 
• Monitoring for any AEs for 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. 
• Schedule the Day 56 visit. 
6.1.7 Day 56 (± 2 days) – Follow-up Visit 
At Day 56, all subjects will return to the clinic for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• Interval history to query for any MAEs, SNMCs, or SAEs occurring since the last trial visit, 
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 Day 90 telephone contact and the Day 182 in-clinic visit.  
6.1.8 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.  
6.1.9 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). 
• 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 Day 273 telephone contact and the end of the trial visit (Day 364) in-clinic 
visit.   
6.1.10 Day 273 (± 7 days) – Safety Telephone Contact  

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• 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.  
6.1.11 Day 364 (± 14 days) – Follow-up Visit 
At Day 364, all subjects will return to the clinic for the following procedures: 
• Vital sign collection (heart rate, blood pressure, respiratory rate, and oral temperature). 
• 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.  
• 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 are permitted for all subjects after completion of the Day 21 trial 
visit.  
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 21 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 2 injections containing either Tri-NIV with 
Matrix-M1 adjuvant, Fluzone HD, or saline placebo. 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 

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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, as well as a blood draw for serology testing (20 mL) and clinical safety 
laboratory testing (10 mL) if prior to the Day 21 trial visit. 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. While the majority of PDs will be self-reported by the clinical sites in the 
electronic case report form (eCRF), in certain instances PDs may also be determined 
programmatically through the course of the trial. Examples of both types of PDs are provided 
in Table 2. 
Table 2:  Protocol Deviations  
Self-reported PDs 
Programmatically-determined PDs 
Excluded Concomitant Medication or Procedure 
Missed Visit 
Inclusion / Exclusion Criteria 
Out of Window Visit 
Informed Consent 
Trial Procedure Not Done 
Vaccination Error 
Randomization Error 

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Table 2:  Protocol Deviations  
Self-reported PDs 
Programmatically-determined PDs 
Other[1] 
Diary Compliance  
[1] PDs that do not belong under any pre-specified category will be categorized as “Other” using an open-text field. 
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 60 mL) to be drawn for safety 
laboratory assessments and immunogenicity laboratory assessments to be completed 
throughout the trial.  
7.1 Clinical Laboratory Testing 
The following laboratory tests will be performed by a qualified central laboratory designated 
by Novavax on blood samples collected from subjects on Days 0 and 21. 
• Serum chemistry – alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, alkaline phosphatase (ALP), creatinine, and blood urea nitrogen (BUN).  
Hematology – complete blood count (CBC) with hemoglobin, hematocrit, red blood cell 
(RBC) count, platelet count, and white blood cell (WBC) count with differential.  
7.2 Serological Assessments of Immunogenicity   
Immunogenicity assessments will be made on subject sera collected on Days 0 and 21. The 
primary measure of immunogenicity for the trial is HAI titers specific for the HA receptor 
binding domains of each of the virus strains included in Tri-NIV. The secondary and 
/exploratory variables of immunogenicity include HAI titers specific for the HA receptor 
binding domains of at least 2 historic A virus strains (one H1N1 and one H3N2), and a 
representative of the B/Yamagata lineage; and neutralizing antibody titers specific for the virus 
strains included in Tri-NIV and the Fluzone HD comparator, as well as selected historical strains 
and a B/Yamagata strain. In addition, exploratory measures of immunogenicity also include 
antibodies competitive with broadly-neutralizing monoclonal antibodies to HA of varying 
specificities, as measured by competitive-binding in a biosensor assay.  
7.2.1 Hemagglutination Inhibition (HAI) Assay (Q2 Solutions and Other HAI 
Laboratories)  
Hemagglutination inhibition testing will be conducted by Q2 Solutions using thawed frozen 
subject serum samples in a standardized and validated method with virus antigens produced in 
embryonated chicken eggs. Sera will be first treated to remove non-specific inhibitors of 
hemagglutination and then plated onto a microtiter well, starting with an initial dilution of 1:10 
and followed by a series of 2-fold dilutions. The appropriate virus antigen and indicator 
erythrocyte suspension will be added to designated wells in 2 steps, with mixing and incubation 
at each step. The titration end-point will be taken as the highest dilution that demonstrates 
complete inhibition (100%) of hemagglutination. The serum HAI titer will be the geometric 
mean of triplicate test results. Based on new findings in a recent investigation concerning egg 
passage-induced point mutations in contemporary A(H3N2) strains [Zost 2017], testing (for at 
least H3N2 strains) will also be performed in a qualified assay using hemagglutinating antigens 
produced by recombinant methods capable of generating HA with and without specific egg-
induced mutations.   
7.2.2 Microneutralization Assay (Novavax) 

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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 treated with receptor-destroying enzyme (RDE) 
and heat-inactivated at 56°C for 30 minutes. Sera will be prepared in 2-fold serial dilutions 
(starting from 1:10) in duplicates, in 96-well plates. Positive and negative virus controls and 
anti-influenza serum standards will also be included. An approximate tissue culture infective 
dose of 100 TCID50 will be added and incubated for 60 minutes at 37°C ± 2°C in 5.0% ± 1% 
CO2. After incubation, 100 µL of trypsinized 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. 
On Day 2, plates will be fixed, blocked, and incubated with anti-influenza A nucleoprotein (NP) 
monoclonal antibody pool (1:1 of MAB8257 and MAB8258, Millipore Billerica, MA), 
followed by washing and incubation with a peroxidase-conjugated goat anti-mouse 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 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 
All values ≤ X will be deemed positive for neutralization activity. 
7.2.3 Biosensor Competitive-binding Assay (Novavax)  
A surface plasmon resonance (SPR) assay to evaluate subject serum antibodies competitive 
with known broadly-neutralizing monoclonal antibodies is under development by Novavax, Inc. 
Biosensor surfaces will be loaded with the different HA nanoparticles  Subject serum samples 
(diluted to sub-saturating antibody concentrations) for Day 0 and 21 will be reacted with the 
immobilized HA to capture anti-HA antibody. Broadly-neutralizing monoclonal antibodies 
(mAb) will then be reacted with the immobilized HA:anti-HA antibody sensors. The presence 
of broadly-neutralizing antibodies in subject sera will be determined by quantitating the amount 
of mAb competition.  
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 7.2 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 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 through 21 days post-injection. Note: The 21 day post vaccination 
all adverse event profile will include all unsolicited AEs reported from test article receipt until 
the day preceding the rescue dose, ie, events with onset dates between days 0 to 20 for subjects 
who receive the rescue dose as scheduled on day 21.  Rules for defining the dataset in subjects 
who receive the rescue dose before or after day 21, or no rescue dose, are detailed in the 
statistical analysis plan.. After these specified days, data concerning MAEs, SNMCs, and SAEs 
will be collected (see Sections 8.1.5 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 six 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 4) 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 

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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 solicited AE subject diary promptly, 
even if the balance of diary data is not yet available. 
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 seven 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) 

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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 
(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) may be reported as an AE. 
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 Clinical Laboratory Findings as AEs  
Clinical laboratory parameters will be tabulated in trial reports by grades using the TGS 
provided in the Trial Operations Manual, which is based on the FDA Guidance for Industry, 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (September 2007). Minor adaptations have been made to the grade 
ranges for some parameters in consideration of the normal, high, and low reference ranges 
established at the central laboratory.  
Laboratory values that show an increase in the toxicity grade relative to baseline values in the 
same subject, and attain at least Grade 2 (eg, normal or Grade 1 to Grade 2 or higher) will be 
reported as AEs. Repeat testing will be conducted as defined below until the laboratory 
parameter returns to baseline, becomes stable, or an explanatory diagnosis is available:  
• Grade 2 events - weekly, from the time the investigator becomes aware of the abnormal 
laboratory parameter. 
• Grade 3 events - every 72 hours, from the time the investigator becomes aware of the 
abnormal laboratory parameter.  
The investigator may also elect to report less severe abnormalities as AEs, at his/her discretion, 
if the abnormality is of sufficient concern to trigger, or should have triggered, a diagnostic 
evaluation (including repeat testing). 

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8.1.5 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 adverse 
events of special interest (AESI) listed in Table 4. Note that this regulatory request is not 
specific to Novavax’s Tri-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 
(including 
Eaton-Lambert 
syndrome), 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 glomerulo-
nephritis, membranoproliferative glomerulonephritis, and mesangio-
proliferative 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, rosacea  
Hematologic Disorders: 
Autoimmune hemolytic anemia, autoimmune thrombocytopenia, 
antiphospholipid syndrome 

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Table 4: Adverse Events of Special Interest   
Categories 
Diagnoses (as MedDRA® Preferred Terms) 
Metabolic Disorders: 
Autoimmune thyroiditis, Grave’s or Basedow’s disease, Hashimoto 
thyroiditis, diabetes mellitus type 1, Addison’s disease 
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. 
Full details of MAEs and SNMCs  (ie, nature, date of onset, and recovery (if applicable) as well 
as an assessment of severity, relationship to trial agent, seriousness, treatment, and outcome) 
will be recorded in the source documentation and captured in the eCRF, and will require the 
investigator(s) causality assessment. 
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 one 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). 

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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.  
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 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, inclusive) 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. 

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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. 
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 
No interference 
with activity, or 1 
1 to 3 unformed 
(loose) 
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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 
to 2 episodes/ 
24-hour period 
to 2 episodes/ 
24-hour period 
stools/24-hour 
period 
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 
intravenous 
hydration 
> 38.9 
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; 

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Table 7: Definition of Relationship for Adverse Events 
Relationship 
Relationship Description 
• 
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 rechallenge (if applicable). 

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9 TRIAL DATA MANAGEMENT 
9.1 Recording and Collection of Data 
Novavax will provide sites with source documents for the recording and collection of subject 
data. Data will be entered into an electronic data capture (EDC) system by site staff. All source 
documents and 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. A quality audit 
may be performed to assure the quality and integrity of the clinical data generated and the 
accuracy of its reporting following Novavax clinical quality assurance (CQA) processes.  
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 independent clinical monitors or a CRO who may 
monitor on-site or remotely. Novavax and/or independent clinical monitors 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. Where applicable, 
the database will be checked against applicable source documents to verify completeness and 
accuracy. When data entry has been completed by the appropriate trial staff, source documents 

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verified and monitored by Novavax and/or CRO representatives, and reviewed by the 
investigator, the investigator should sign and date the Investigator Signature Page. 
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 Investigator’s Brochure, 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, 

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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 21, 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. 
10.2 General 
All analysis populations will be defined and full descriptions of each population will be 
provided. Demographic parameters and other baseline characteristics (age, sex, race, ethnicity, 
as well as influenza vaccine exposure within the 2016 influenza season) will be summarized by 
treatment group for all subjects in the safety population, as well as the number and description 
of protocol deviations.  
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, as well as the 
number and description of protocol deviations. 

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10.4 Analyses Addressing Protocol Objectives 
10.4.1 Analyses of Primary Objectives  
10.4.1.1 
Safety  
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, 21-day all 
AE profile by MedDRA preferred term, and 1-year MAE, SAE, and SNMC profiles 
post-injection on Day 0. Note: The 21 day post vaccination all adverse event profile will include 
all unsolicited AEs reported from test article receipt until the day preceding the rescue dose, ie, 
events with onset dates between days 0 to 20 for subjects who receive the rescue dose as 
scheduled on day 21.  Rules for defining the dataset in subjects who receive the rescue dose 
before or after day 21, or no rescue dose, are detailed in the statistical analysis plan. All AEs, 
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. Clinical laboratory data will be summarized by means and 95% confidence 
interval, minima and maxima, at Day 0 and Day 21 in each treatment group, as well as means 
and 95% confidence interval of change from baseline at Day 21.  Changes from baseline will 
also be summarized at Day 21 for each treatment group in terms of the proportion of subjects 
with no change in toxicity grade versus proportions with one, two, or three grade changes. A 
listing and narratives of SAEs will also be produced.  
10.4.1.2 
Immunogenicity  
The immunogenicity analysis will be based on the PP population. A separate ITT population 
analysis will not be produced unless > 10% of at least 1 treatment group is excluded from the 
PP population. HAI antibody titers specific for each of the vaccine-homologous, historical 
and/or drifted, and cross-lineage virus strains tested, will be summarized by treatment group 
based on the following parameters (with 95% CIs): 
1) Geometric mean titer (GMT) at baseline (screening) and post-vaccination on Day 21. 
Samples with no detectable HAI activity at the lowest dilution (1:10) will be assigned a 
value of 5 for calculation. 
2) GMR – the ratio of the post-vaccination GMT on Day 21 to the baseline (Day 0) value. 
3) Seroconversion rate (SCR) – defined as the percentage of subjects with either a baseline 
HAI titer < 1:10 and a post-vaccination titer ≥ 1:40, or a baseline HAI titer ≥ 1:10 and a 
4-fold increase on Day 21 in post-vaccination HAI titer relative to baseline. 
4) Seroprotection rate (SPR) – defined as the percentage of subjects with an HAI titer ≥ 1:40 
at a given time-point. 

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Neutralizing antibody titers specific for each of the virus strains will be summarized by 
treatment group for each virus stain tested based on the following parameters (with 95% CIs): 
1) GMT at baseline (screening) and post-vaccination on Day 21. Samples with no detectable 
neutralizing activity at the lowest dilution (1:10) will be assigned a value of 5 for 
calculation. 
2) GMR – the ratio of the post-vaccination GMT on Day 21 to the baseline (Day 0) value. 
3) SCR defined as the percentage of subjects with either a baseline neutralizing titer < 1:10 
and a post-vaccination titer ≥ 1:40, or a baseline titer ≥ 1:10 and a 4-fold increase on Day 
21 in post-vaccination titer relative to baseline. 
Percentages of subjects with immune response will be calculated along the corresponding two-
sided exact (Clopper-Pearson) binomial CIs. GMTs will be summarized by treatment group and 
visit day along with the corresponding two-sided 95% CIs, by exponentiating the corresponding 
log-transformed means and their 95% CIs. Two-sided 95% CIs for the difference in proportions 
of participants demonstrating SCR and SPR between a Tri-NIV group and the Fluzone HD 
group will be based on the Newcombe hybrid score (METHOD = SCORE riskdiff-option for 
PROC FREQ in SAS). The within-group geometric mean ratio (GMRpost/pre) will be 
conducted using paired t-test based on log-transformed values. Then, the mean difference and 
the corresponding 95% CI limits will be exponentiated to obtain the GMT ratio and the 
corresponding CI.  
Reverse cumulative distribution displays of HAI and MN titers for each virus strain will be 
produced in which Day 0 and Day 21 distributions will be displayed separately by treatment 
group. Titers reported below the lowest 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). 
10.5 Sample Size Considerations  
The sample size is chosen as adequate for an initial description of safety and immunogenicity 
to direct future development and dosing. No hypothesis tests are specified and the sample size 
is not intended to support any statistical contrast of Tri-NIV with Fluzone HD. For safety 
endpoints, the probability of observing at least one adverse event among 110 subjects for each 
of the two Tri-NIV groups or 220 for the two Tri-NIV groups combined, are > 90% if the true 
rate of such events is 2.1% and 1.1%, respectively. With 110 for each of the two Tri-NIV group 
or 220 for the two Tri-NIV groups combined, observing no adverse events of interest (eg, 
vaccine-related SAE) would represent an upper bound of the one-sided 95% CI on the 
percentage of such events of 2.7% and 1.4%, respectively.  
10.6 Plan for Statistical Summaries and Analyses 
10.6.1 Day 21 Unblinded Data Review  
An unblinded review will be conducted of all available immunogenicity and safety data 
(inclusive of clinical laboratory safety assessments) upon completion of Day 21 visits for all 
subjects. For the review, treatment codes will only be unblinded after the data are deemed ready 

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for the analysis after all subjects have completed the Day 21 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. 
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 trialsubjects will remain blinded to treatment assignments until 
the end of trial (ie, Day 364).  
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 Institutional Review Board  
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’s 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 Tri-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 14 July 2017 
from https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm. 
CDC. (2017 -a). Influenza vaccine - United States, 2016-17 influenza season Retrieved June 27 
2017 from https://www.cdc.gov/flu/protect/vaccine/vaccines.htm. 
CDC. (2017 -b). What you should know and do this Flu season if you are 65 years and older 
Retrieved June 27 2017 from https://www.cdc.gov/flu/about/disease/65over.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. 
FDA. (2017). Vaccines Licensed for Use in the United States.   Retrieved July 13 2017, from 
https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833. 
Flannery B, Chung J. (2016). Influenza vaccine effectiveness, including LAIV vs IIV in 
children and adolescents, US Flu VE Network, 2015-16. Retrieved 14 July 2017 from 
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2016-06/influenza-05-
flannery.pdf. 
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. 
Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody 
in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond) 1972;  
70(4): 767-77. 
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): 500-02. 
Mullooly JP, Bridges CB, Thompson WW, et al. Influenza- and RSV-associated 
hospitalizations among adults. Vaccine 2007;  25(5): 846-55. 

Nanoparticle Influenza Vaccine, Trivalent  
Confidential 
tNIV-E-101 Protocol  
Novavax, Inc. 
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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. 
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. 
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. 
Shay DK, Chillarige Y, Kelman J, et al. Comparative Effectiveness of High-Dose Versus 
Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries in Preventing 
Postinfluenza Deaths During 2012-2013 and 2013-2014. J Infect Dis 2017;  215(4): 510-17. 
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. 
WHO (2011). Manual for the laboratory diagnosis and virological surveillace of influenza 
WHO global influenza surveillance network  
WHO. (2017). Recommended composition of influenza virus vaccines for use in the 2017-2018 
northern hemisphere influenza season. 2 March 2017. 
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. 
PNAS 2017. www.pnas.org/cg/doi/10.1073/pnas.1712377114.  
 

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APPENDIX 1 – TNIV-E-101 TRIAL PROCEDURES SCHEDULE 
Trial Day:  
0 
3 
7 (Stage 1 
ONLY) [8] 
7 (Stage 2 
ONLY)[8] 
21 
56 
90 
182 
273 
364 
Window (days): 
 
± 1 
+1 
± 1 
± 2 
± 2 
± 7 
± 7 
± 7 
± 14 
Trial Procedures 
Trial Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/Medicatio
n History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X[7] 
 
X [7] 
X [7] 
 
X [7] 
 
X [7] 
Vital Signs 
X [1] 
 
X 
 
X [1] 
X 
 
X 
 
X 
Clinical Safety 
Laboratory [2] 
X 
 
 
 
X 
 
 
 
 
 
Serology  
X 
 
 
 
X 
 
 
 
 
 
Trial Treatment 
Injection  
X 
 
 
 
 
 
 
 
 
 
Rescue Injection 
with a licensed 
seasonal influenza 
vaccine [6] 
 
 
 
 
X 
 
 
 
 
 
Adverse Event 
Review [4] 
X 
X [3] 
X 
X[3]  
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
Review [4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary 
Review 
 
X [3] 
X [5] 
X [3] 
X [5] 
 
 
 
 
 
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] Includes assessments for hematology (complete blood count [CBC] with hemoglobin, hematocrit, red blood cell [RBC] 
count, platelet count, and white blood cell [WBC] count with differential) and serum chemistry (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase, creatinine, and blood urea nitrogen [BUN]).  
[3] Subjects will be asked to report any grade 3 solicited or unsolicited adverse event or SAE experienced since the last visit and 
may be asked to return to the clinic for an unscheduled visit to evaluate the event(s) at the Investigator’s discretion.  
[4] All adverse events and concomitant medications taken will be collected through Day 21; thereafter only MAEs, SAEs, and 
SNMCs and medications taken for these events will be collected.  
[5] The subject diary will be reviewed by the investigator and collected at the Day 7 visit (Stage 1 subjects ONLY) or Day 21 
visit (Stage 2 subjects ONLY). 
[6] On Day 21, all Group A and B subjects will be administered a rescue injection with a licensed influenza vaccine, and all 
Group C subjects will be administered an injection of saline placebo to maintain trial blind. 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 second vaccination. Subjects presenting with an acute illness on 
Day 21 may return to the study site within the next 7 days to receive their 2nd vaccination. If a subject has 
experienced any AEs/SAE between study Days 0 and 21, then Day 21 vaccination may be administered or 
delayed for up to 7 days based on the Investigator’s discretion. 
[7] If needed, a physical examination may be performed, based on the investigator’s discretion. 

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Trial Day:  
0 
3 
7 (Stage 1 
ONLY) [8] 
7 (Stage 2 
ONLY)[8] 
21 
56 
90 
182 
273 
364 
Window (days): 
 
± 1 
+1 
± 1 
± 2 
± 2 
± 7 
± 7 
± 7 
± 14 
Trial Procedures 
[8] All Stage 1 subjects will be required to complete a Day 7 in-clinic visit to present their subject diaries, whereas Stage 2 
subjects will be required to complete a safety telephone call. 
 

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APPENDIX 2 – TNIV-E-101 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 seven days following 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 – TNIV-E-101 BLOOD DRAW SCHEDULE  
Trial Visit Day 
Amount of Blood Drawn for 
Immunogenicity Assessment 
(mL) 
Amount of Blood Drawn for 
Clinical Safety Assessment 
(mL) 
Day 0 (pre-vaccination) 
20  
10  
Day 21 (± 2 days) 
20  
10  
TOTAL FOR ENTIRE TRIAL (mL) 
60 
 
 

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APPENDIX 4 – TNIV-E-101 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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