Randomized, Double-Blinded, Phase 2 Study to Assess Safety and Immunogenicity of Homologous and Heterologous Prime-Boost Vaccination Strategies With Stockpiled Inactivated Monovalent Influenza A(H5) Vaccines Administered Intramuscularly With Either AS03 or MF59® as Adjuvant
Phase: PHASE2
Conditions: Influenza A Virus, H5N1 Subtype
Sponsor: Biomedical Advanced Research and Development Authority

CLINICAL STUDY PROTOCOL 
Randomized, Double-Blinded, Phase 2 Study to Assess Safety and 
Immunogenicity of Homologous and Heterologous Prime-Boost 
Vaccination Strategies With Stockpiled Inactivated Monovalent Influenza 
A(H5) Vaccines Administered Intramuscularly 
With Either AS03 or MF59® as Adjuvant 
BP-I-16-005 
Sponsor: 
Biomedical Advanced Research and Development 
Authority (BARDA) 
200 Independence Avenue, S.W. 
Room 640-G 
Washington, DC 20201 
 
 
 
 
 
 
 
 
 
 
IND Number: 
 
Version of Protocol:  
2.0 
Date of Protocol:  
Amendment 1: 26 February 2018 
Previous Versions and Dates: 
Version 1.0, 19 October 2017 
Version 1.1, 17 November 2017 
Version 1.2, 26 January 2018 
 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by BARDA. The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of BARDA. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 

BARDACSN 
Protocol: BP-I-16-005 Version 2.0 
H5 Influenza Vaccine With Either AS03 or MF59 
26 February 2018 
Protocol Approval - Sponsor Signatory 
Study Title 
Randomized, Double-Blinded, Phase 2 Study to Assess Safety and 
Immunogenicity of Homologous and Heterologous Prime-Boost 
Vaccination Strategies With Stockpiled Inactivated Monovalent 
Influenza A(HS) Vaccines Administered Intramuscularly With Either 
AS03 or MFS9® as Adjuvant 
Protocol Number 
BP-I-16-005 
Protocol Date 
26 February 2018 
Protocol accepted and approved by: 
Senior Medical Officer, Division of Clinical Development 
 
 
 
 
 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “Randomized, 
Double-Blinded, Phase 2 Study to Assess Safety and Immunogenicity of Homologous and 
Heterologous Prime-Boost Vaccination Strategies With Stockpiled Inactivated Monovalent 
Influenza A(H5) Vaccines Administered Intramuscularly With Either AS03 or MF59® as 
Adjuvant.” 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 2.0, dated 26 February 2018, the International 
Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with BARDA or implement protocol changes without institutional review board 
approval except to eliminate an immediate risk to subjects. I agree to administer study 
treatment only to subjects under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the investigational product to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from BARDA. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 4 
Table of Contents 
Table of Contents ....................................................................................................................... 4 
List of Tables .............................................................................................................................. 8 
List of Figures ............................................................................................................................ 8 
Protocol Synopsis....................................................................................................................... 9 
List of Abbreviations................................................................................................................ 19 
1 
Introduction ...................................................................................................................... 21 
2 
Study Objectives ............................................................................................................... 26 
2.1 
Primary Objectives.................................................................................................. 26 
2.1.1 
Primary Safety Objective ......................................................................... 26 
2.1.2 
Primary Immunogenicity Objective......................................................... 26 
2.2 
Secondary Objectives.............................................................................................. 27 
2.2.1 
Secondary Safety Objectives ................................................................... 27 
2.2.2 
Secondary Immunogenicity Objectives ................................................... 27 
2.3 
Exploratory Immunogenicity Objectives ................................................................ 27 
3 
Investigational Plan .......................................................................................................... 28 
3.1 
Study Design ........................................................................................................... 28 
3.1.1 
Rationale of Study Design ....................................................................... 30 
3.1.2 
Study Groups ........................................................................................... 31 
3.1.3 
Study Pausing Rules ................................................................................ 31 
3.1.4 
Future Investigations ............................................................................... 32 
4 
Subject Selection and Withdrawal Criteria ...................................................................... 33 
4.1 
Selection of Study Population ................................................................................. 33 
4.1.1 
Inclusion Criteria ..................................................................................... 33 
4.1.2 
Exclusion Criteria .................................................................................... 34 
4.2 
Withdrawal of Subjects From the Study ................................................................. 36 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................ 36 
4.2.2 
Handling of Withdrawals ......................................................................... 37 
4.2.3 
Replacements ........................................................................................... 38 
4.3 
Revaccination Eligibility ........................................................................................ 38 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 5 
5 
Study Groups .................................................................................................................... 40 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 40 
5.2 
Investigational Product Administered ..................................................................... 40 
5.3 
Management of Clinical Supplies ........................................................................... 40 
5.3.1 
Investigational Product Packaging and Storage ....................................... 40 
5.3.2 
Investigational Product Accountability .................................................... 41 
5.3.3 
Other Supplies ......................................................................................... 41 
5.4 
Overdose Management ........................................................................................... 41 
5.4.1 
Treatment of Overdose ............................................................................ 41 
5.5 
Blinding .................................................................................................................. 42 
5.5.1 
Breaking the Blind ................................................................................... 42 
5.6 
Treatment Compliance ............................................................................................ 43 
5.7 
Prior Vaccinations and Concomitant Medications .................................................. 43 
5.7.1 
Prohibited Prior and Concomitant Medications....................................... 43 
5.7.2 
Permitted Prior and Concomitant Medication ......................................... 44 
6 
Study Assessments and Procedures .................................................................................. 45 
6.1 
Demographics and Medical History ....................................................................... 45 
6.2 
Safety Assessments ................................................................................................. 45 
6.2.1 
Vital Sign Measurements ......................................................................... 45 
6.2.2 
Postvaccination Evaluation ...................................................................... 45 
6.2.3 
Complete Physical Examination .............................................................. 46 
6.2.4 
Clinical Safety Laboratory Tests .............................................................. 46 
6.2.5 
Adverse Events ........................................................................................ 47 
6.2.5.1 
Definitions of Adverse Events ................................................................. 47 
6.2.5.2 
Solicited Local and Systemic Reactogenicity Symptoms........................ 48 
6.2.5.3 
Assessing and Documenting Adverse Events .......................................... 48 
6.2.5.4 
Reporting Adverse Events ....................................................................... 50 
6.2.5.5 
Assessment of Severity ............................................................................ 53 
6.2.5.6 
Assessment of Causality .......................................................................... 53 
6.2.5.7 
Assessing Expectedness ........................................................................... 54 
6.2.5.8 
Follow-Up of Subjects Reporting Adverse Events .................................. 54 
6.3 
Immunogenicity Assessments ................................................................................. 55 
6.4 
Pregnancy ................................................................................................................ 55 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 6 
6.5 
Sample Collections ................................................................................................. 56 
7 
Statistical and Analytical Plan .......................................................................................... 57 
7.1 
Primary Endpoints .................................................................................................. 57 
7.2 
Secondary Endpoints .............................................................................................. 57 
7.3 
Exploratory Endpoints ............................................................................................ 58 
7.4 
Sample Size Calculations ........................................................................................ 58 
7.5 
Analysis Sets ........................................................................................................... 59 
7.6 
Description of Subgroups to be Analyzed .............................................................. 60 
7.7 
Statistical Analysis Methodology ........................................................................... 60 
7.7.1 
Subject Disposition .................................................................................. 60 
7.7.2 
Analyses of Demographic and Baseline Characteristics ......................... 61 
7.7.3 
Analysis of Primary Endpoints ................................................................ 61 
7.7.3.1 
Analysis of Primary Safety Endpoint ...................................................... 61 
7.7.3.2 
Analysis of Primary Immunogenicity Endpoint ...................................... 61 
7.7.4 
Analysis of Secondary Endpoint ............................................................. 61 
7.7.4.1 
Analysis of Secondary Safety Endpoint .................................................. 61 
7.7.4.2 
Analysis of Secondary Immunogenicity Endpoint .................................. 61 
7.7.5 
Analyses of Exploratory Immunogenicity Endpoint ............................... 62 
7.7.6 
Other Analyses ......................................................................................... 62 
7.7.7 
Interim Analyses ...................................................................................... 62 
7.8 
Data Quality Assurance........................................................................................... 62 
7.8.1 
Data Management .................................................................................... 63 
8 
Ethics ................................................................................................................................ 64 
8.1 
Institutional Review Board ..................................................................................... 64 
8.2 
Ethical Conduct of the Study .................................................................................. 64 
8.3 
Subject Information and Consent ........................................................................... 64 
9 
Investigator’s Obligations ................................................................................................ 66 
9.1 
Confidentiality ........................................................................................................ 66 
9.2 
Financial Disclosure................................................................................................ 66 
9.3 
Investigator Documentation .................................................................................... 66 
9.4 
Study Conduct ......................................................................................................... 67 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 7 
9.5 
Adherence to Protocol ............................................................................................ 68 
9.6 
Adverse Events and Study Report Requirements ................................................... 68 
9.7 
Investigator’s Final Report ..................................................................................... 68 
9.8 
Records Retention ................................................................................................... 68 
9.9 
Publications ............................................................................................................. 68 
10 Study Management ........................................................................................................... 69 
10.1 Monitoring .............................................................................................................. 69 
10.1.1 
Safety Monitoring: Responsibilities for Ensuring the Safety of Study 
Subjects .................................................................................................... 69 
10.1.2 
Principal Investigator ............................................................................... 69 
10.1.3 
Study Sponsor .......................................................................................... 69 
10.1.4 
Medical Monitor ...................................................................................... 69 
10.1.5 
Independent Data Monitoring Committee ............................................... 70 
10.1.6 
Institutional Review Board ...................................................................... 70 
10.1.7 
Regulatory Authority ............................................................................... 70 
10.1.8 
Inspection of Records .............................................................................. 70 
10.2 Management of Protocol Amendments and Deviations.......................................... 71 
10.2.1 
Modification of the Protocol .................................................................... 71 
10.2.2 
Protocol Deviations ................................................................................. 71 
10.3 Study Termination ................................................................................................... 72 
10.4 Final Report ............................................................................................................ 72 
11 Reference List................................................................................................................... 73 
12 Appendices ....................................................................................................................... 76 
12.1 Appendix 1: Schedule of Events ............................................................................. 76 
12.2 Appendix 2: Potentially Immune-Mediated Medical Conditions ........................... 84 
12.3 Appendix 3: US FDA Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (a partial list) ......................................................................................... 88 
12.4 Appendix 4: Protocol Amendments and Version Updates ...................................... 93 
12.4.1 
Protocol Version 1.1 (Typographical Error Correction) .......................... 93 
12.4.2 
Protocol Version 1.2 ................................................................................. 94 
12.4.3 
Protocol Amendment 1, Version 2.0 ...................................................... 112 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 8 
List of Tables 
Table 3–1 
Treatment Arms ............................................................................................... 29 
Table 6–1 
Schedule of Diary Cards and Safety Data Reporting Period .......................... 50 
Table 7–1 
Safety – Power for Detecting at Least 1 SAE, MAAE, or a Grade 3 Solicited 
AE ................................................................................................................... 59 
Table 7–2 
Immunogenicity – Power for Meeting Success Criteria of SPR..................... 59 
Table 12–1 
Schedule of Events, Groups A to D, G to J ..................................................... 77 
Table 12–2 
Schedule of Events, Groups E, F, K, L ........................................................... 80 
List of Figures 
Figure 6-1 
Safety Event Reporting Period, Groups A to D, G to J ................................... 52 
Figure 6-2 
Safety Event Reporting Period, Groups E, F, K, L ......................................... 52 
 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 9 
Protocol Synopsis 
Protocol Number: 
BP-I-16-005 
Title: 
Randomized, Double-Blinded, Phase 2 Study to Assess Safety and 
Immunogenicity of Homologous and Heterologous Prime-Boost 
Vaccination Strategies With Stockpiled Inactivated Monovalent 
Influenza A(H5) Vaccines Administered Intramuscularly With Either 
AS03 or MF59® as Adjuvant 
Sponsor: 
Biomedical Advanced Research and Development Authority 
(BARDA) 
200 Independence Avenue, S.W. 
Room 640-G 
Washington, DC 20201 
Study Phase: 
2 
Study Sites: 
Multiple sites in the United States  
Study Population: 
Approximately 720 healthy adult male or nonpregnant female 
subjects, 18 to 49 years old who meet all eligibility criteria 
Rationale: 
The main purpose of this study is to assess the ability of H5 influenza 
virus vaccines and adjuvants present in the National Pre-Pandemic 
Influenza Vaccine Stockpile (NPIVS) to generate an immune response 
to homologous and to antigenically distant heterologous H5 influenza 
virus strains.  
The study is designed to evaluate the safety and immunogenicity of 
vaccination strategies with homologous or antigenically distant 
heterologous H5 influenza virus vaccines administered with AS03 or 
MF59 adjuvant. 
Objectives: 
Primary:  
Safety: 
• To assess the safety and reactogenicity for 8 days postvaccination, 
inclusive of the vaccination day (Day 1 through Day 8 and Day 22 
through Day 29), of a 2-dose vaccination series using homologous 
monovalent inactivated H5 influenza virus vaccine or 
antigenically distant heterologous H5 influenza virus vaccines 
administered intramuscularly (IM) with AS03 or MF59 adjuvant 
on Days 1 and 22 (henceforth referred to as “prime-boost”), as 
determined by solicited local and systemic reactogenicity 
symptoms. 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 10 
 
Safety: 
• To assess the safety and reactogenicity for 8 days postvaccination, 
inclusive of the vaccination day (Day 1 through Day 8, Day 22 
through Day 29, and Day 142 through Day 149), of a 3-dose 
vaccination series using homologous monovalent inactivated H5 
influenza virus vaccine administered IM with AS03 or MF59 
adjuvant on Days 1 and 22, and a third dose 120 days after the 
second dose with an antigenically heterologous H5 influenza virus 
vaccine administered IM with AS03 or MF59 adjuvant on Day 142 
(henceforth referred to as “prime-prime-boost”), as determined by 
solicited local and systemic reactogenicity symptoms. 
Immunogenicity: 
• To assess the serum hemagglutination inhibition (HAI) antibody 
seroprotection rate (SPR) against strains contained in the study 
vaccines on Day 43 of the prime-boost vaccination series 
administered IM with AS03 or MF59 adjuvant on Days 1 and 22. 
• To assess the serum HAI antibody SPR against strains contained in 
the study vaccines on Day 163 of the prime-prime-boost 
vaccination series administered IM with AS03 or MF59 adjuvant 
on Days 1, 22, and 142. 
 
Secondary: 
Safety:  
• To assess the occurrence of serious adverse events, medically 
attended adverse events (MAAEs), and potentially 
immune-mediated medical conditions (PIMMCs; see Appendix 2, 
Section 12.2) in the 12 treatment groups through 12 months after 
the last dose of study vaccine.  
• To assess the occurrence of unsolicited adverse events for 21 days 
after each dose of study vaccine. 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 11 
 
Immunogenicity: 
• To assess the serum HAI antibody titers, SPRs, and seroconversion 
rates (SCRs) against each vaccine strain in the study through 
Day 142 of the prime-boost vaccination series.  
• To assess the serum HAI antibody titers, SPRs, and SCRs against 
each vaccine strain in the study through Day 262 of the 
prime-prime-boost vaccination series.  
• To assess the serum microneutralization (MN) antibody titers and 
SCRs against each vaccine strain in the study through Day 142 of 
the prime-boost vaccination series. 
• To assess the serum MN antibody titers and SCRs against each 
vaccine strain in the study through Day 262 of the 
prime-prime-boost vaccination series. 
 
Exploratory: 
Immunogenicity: 
• To assess peripheral antibody responses to epitopes within the 
influenza virus surface proteins hemagglutinin or neuraminidase 
induced by prime-boost or prime-prime-boost vaccination series. 
• To examine cell-mediated (eg, B cell, CD4+ T cell, CD8+ T cell) 
responses in a subset composed of approximately half of enrolled 
subjects using peripheral blood mononuclear cells collected at 
Day 1, Day 22, Day 43, and Day 142 (Groups A-D, G-J) or Day 1, 
Day 22, Day 43, Day 142, Day 163, and Day 262 (Groups E, F, K, 
L). 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 12 
Subject Population 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in 
this study: 
1. 
Is a male or nonpregnant female 18 to 49 years of age, inclusive, 
on Day 1 (first vaccination). 
2. 
Will avoid nonstudy vaccinations until 21 days after the last 
vaccination. 
3. 
Provides written informed consent prior to the initiation of any 
study-related procedures. 
4. 
Has a stable health status, as established by physical 
examination, vital sign measurements, and medical history. 
5. 
Has access to a consistent and reliable means of telephone 
contact, which may be in the home, workplace, or by personal 
mobile electronic device. 
6. 
Is able to understand and comply with planned study procedures. 
7. 
Lives a reasonable distance from the site to be able to travel to 
and from the site for follow-up visits and agrees to go to the site 
for evaluation in the case of an adverse event.  
8. 
Agrees to stay in contact with the site for the duration of the 
study, has no current plans to move from the study area, and 
provides updated contact information as necessary. 
 
Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from 
the study: 
1. 
Has a known allergy to eggs or other components of the vaccine 
(including gelatin, formaldehyde, octoxinol-9, thimerosal, or 
chicken protein), or allergy to squalene-based adjuvants or has 
had severe reactions following previous immunizations with 
contemporary influenza virus vaccines. 
2. 
A woman who has a positive urine pregnancy test prior to 
vaccination in this study or a woman who is breastfeeding. 
3. 
A female of childbearing potentiala who refuses to use an 
acceptable method of birth controlb from Day 1 (first 
vaccination) to end-of-study visit and, if sexually active, who has 
not used a reliable birth control method for at least 2 months 
prior to Day 1 (first vaccination). 
a 
Female of childbearing potential is defined as post-onset menarche and 
premenopausal female capable of becoming pregnant. This does not include 
females who meet any of the following conditions: menopausal >1 year, tubal 
ligation >1 year, bilateral salpingo-oophorectomy, or hysterectomy. 
b 
Adequate contraception is defined as a contraceptive method with failure rate 
 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 13 
of less than 1% per year when used consistently and correctly and, when 
applicable, in accordance with the product label, for example: abstinence from 
penile-vaginal intercourse; oral contraceptives, either combined or 
progestogen alone; injectable progestogen; implants of etonogestrel or 
levonorgestrel; estrogenic vaginal ring; percutaneous contraceptive patches; 
intrauterine device or intrauterine system; male partner sterilization at least 
6 months prior to the female Day 1 (first vaccination), and this male is the sole 
partner for that subject (The information on the male sterility can come from 
the site personnel’s review of the subject’s medical records or interview with 
the subject on her medical history); male condom combined with a vaginal 
spermicide (foam, gel, film, cream, or suppository); male condom combined 
with a female diaphragm, either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
4. 
Is immunosuppressed as a result of an underlying illness or 
treatment, or anticancer chemotherapy or radiation therapy 
(cytotoxic) within the preceding 36 months prior to Day 1 (first 
vaccination). 
5. 
Has an active neoplastic disease or a history of any hematologic 
malignancy. A subject with superficial skin cancer who does not 
require intervention other than local excision is not excluded. 
6. 
Has long-term use (≥14 consecutive days) of glucocorticoids 
including oral or parenteral prednisone or equivalent (>20 mg 
total dose per day) or high-dose inhaled steroids (>800 mcg/day 
of beclomethasone dipropionate or equivalent) within 1 month 
prior to screening. (Low-dose [≤800 mcg/day of beclomethasone 
dipropionate or equivalent] inhaled and topical steroids are 
allowed). 
7. 
Has a diagnosis of schizophrenia, bipolar disease, or other major 
psychiatric diagnosis. 
8. 
Has been hospitalized for psychiatric illness, history of suicide 
attempt, or confinement for danger to self or others, within the 
past 10 years. 
9. 
Has a neurological or psychiatric diagnosis, which, although 
stable, is judged by the investigator to render the potential subject 
unable or unlikely to comply with the protocol or to provide 
accurate safety reports. 
10. Has received immunoglobulin or other blood product (with the 
exception of Rho[D] immune globulin) within the 3 months prior 
to Day 1 (first vaccination). 
11. Has received any live vaccine within 4 weeks or inactivated 
vaccines within 2 weeks prior to Day 1 (first vaccination). This 
includes seasonal influenza vaccines. 
12. Has an acute or chronic medical condition that, in the opinion of 
the investigator, would render vaccination unsafe or would 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 14 
interfere with the evaluation of responses. This includes 
PIMMCs such as Guillain-Barré syndrome, narcolepsy, current 
or history of autoimmune or chronic inflammatory disease (listed 
in Appendix 2, Section 12.2). 
13. Has a first-degree relative with narcolepsy. 
14. Has an acute illness, including body temperature greater than 
100.4°F, at screening, immediately prior to each vaccination or, 
per subject report, within 3 days prior to each vaccination. 
Subjects with an acute illness can be rescheduled for a 
vaccination as long as the vaccination visit is within the visit 
window. Note that subjects may return for randomization 
following resolution of the acute illness as long as recruitment 
remains open and subjects are within 14 days of signing consent. 
15. Has a Grade 2 or greater (by US Food and Drug Administration 
toxicity grade) safety laboratory value at screening.  
16. Has received an experimental agent (vaccine, biologic, device, 
blood product, or medication) within 1 month prior to Day 1 
(first vaccination) in this study or plans receipt of an 
experimental agent during the study period. 
17. Is participating or plans to participate in another interventional 
clinical study (either active or follow-up phase) during the study 
period. 
18. Has received an influenza H5 vaccine in the past or has a history 
of H5 influenza infection prior to enrollment. 
19. Has known human immunodeficiency virus, hepatitis B, or 
hepatitis C infection. 
20. Has a history of alcohol or drug abuse within 5 years prior to 
Day 1 (first vaccination). 
21. Has a body mass index >35 kg/m2. 
22. Has any condition that would, in the opinion of the investigator, 
place him or her at an unacceptable risk of injury or render him 
or her unable to meet the requirements of the protocol (including 
site of injection reactogenicity assessments). 
23. Is a first-degree relative of any person working on this study: site 
or sponsor. 
 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 15 
Study Design: 
This is a randomized, double-blinded, Phase 2 study to assess the 
safety and immunogenicity of a homologous or heterologous 
prime-boost or prime-prime-boost series with inactivated monovalent 
influenza H5 vaccines stored in the NPIVS, administered IM with 
either AS03 or MF59 adjuvant in healthy males and nonpregnant 
females, aged 18 to 49 years, inclusive. 
Screening will occur within a 14-day period before randomization. 
Approximately 720 subjects will be equally and randomly assigned to 
one of 12 study groups within each site and will receive either 2 doses 
of adjuvanted vaccine separated by 21 days (Groups A-D, G-J) or 
2 doses of adjuvanted vaccine separated by 21 days followed by a 
third dose of adjuvanted vaccine 120 days following the second dose 
(Groups E, F, K, L). Approximately half of enrolled subjects per study 
group will be selected to provide a blood sample for peripheral blood 
mononuclear cell collection. Study staff not involved in IP preparation 
and administration will be blinded to unique group assignment until 
clinical study report (CSR) database freeze.  
Treatment Arms 
Study 
Group 
Dose #1 (Day 1) Strain 
Details  
Dose #2 (Day 22) Strain 
Details  
Dose #3 (Day 142) Strain 
Details  
Adjuvant
A 
VN 
gf/WA 
N/A 
AS03 
B 
IN 
C 
dk/BANG 
D 
gf/WA  
IN 
E 
dk/BANG 
dk/BANG 
bhg/QL 
F 
gf/WA 
gf/WA 
bhg/QL 
G 
VN 
gf/WA 
N/A 
MF59 
H 
IN 
I 
dk/BANG 
J 
gf/WA 
IN 
K 
dk/BANG 
dk/BANG 
bhg/QL 
L 
gf/WA 
gf/WA 
bhg/QL 
Note: Investigational products are abbreviated according to the following: 
• 
VN = A/Vietnam/1203/2004 (H5N1) 
• 
IN = A/Indonesia/05/2005 (H5N1) 
• 
dk/BANG = A/duck/Bangladesh/19097/2013 (H5N1) 
• 
gf/WA = A/gyrfalcon/Washington/41088-6/2014 (H5N8) 
• 
bhg/QL = A/barheaded goose/Qinghai Lake/1A/2005 (H5N1) 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 16 
 
All investigational products will be prepared and administered by an 
unblinded staff member. The study staff observing the subject after 
vaccination and the subject will be blinded to the group assigned. 
Subjects who participate in this study will be asked to consent to be 
contacted with a request to participate in future clinical studies of 
subjects who have been vaccinated against influenza H5, such as 
longer interval prime-boost studies. 
Estimated Study 
Duration: 
Up to 13 months per subject for Groups A-D and G-J and up to 
17 months per subject for Groups E, F, K, and L. 
Safety Assessments: Safety assessments will include the following: 
• Vital sign measurements (oral temperature, pulse rate, and blood 
pressure) 
• Physical examination 
• Clinical safety laboratory tests (hematology, coagulation, 
chemistry/metabolic panel, urine pregnancy in women of 
childbearing potential)  
• Solicited local and systemic reactogenicity symptoms during the 
8 days after each vaccination  
• Adverse events through 21 days following each vaccination 
• Serious adverse events, MAAEs, and PIMMCs from the time of 
the first vaccination through approximately 12 months after the last 
vaccination 

BARDA CSN 
H5 Influenza Vaccine With Either AS03 or MF59 
Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
Page 17 
Immunogenicity 
Assessments: 
Immunogenicity assessments will include the following assessments 
at Day 1, Day 22, Day 43, and Day 142 (Groups A-D, G-J) and at 
Day 1, Day 22, Day 43, Day 142, Day 163, and Day 262 (Groups E, 
F, K, L). 
• Serum HAI antibody titers 
• Seroprotection based on serum HAI antibody titers, defined as an 
HAI antibody titer ≥1:40 
• Seroconversion based on serum HAI antibody titers, defined as 
either a prevaccination HAI titer <1:10 and a postvaccination HAI 
titer ≥1:40, or a prevaccination HAI titer ≥1:10 and a minimum 
4-fold rise in postvaccination HAI titer 
• Serum MN antibody titers 
• Seroconversion based on serum MN antibody titers, defined as 
either a prevaccination MN titer <1:10 and a postvaccination MN 
titer ≥1:40, or a prevaccination MN titer ≥1:10 and a minimum 
4-fold rise in postvaccination MN titer 
Investigational 
Product, Dosage, 
and Route of 
Administration: 
Investigational product consists of H5 influenza virus vaccine 
aseptically prepared with adjuvant at the site and administered IM as 
either 2 doses of adjuvanted vaccine 21 days apart (Groups A-D, G-J) 
or 2 doses of adjuvanted vaccine separated by 21 days followed by a 
third dose of adjuvanted vaccine 120 days following the second dose 
(Groups E, F, K, L).  
The study vaccines will be prepared by mixing H5 influenza virus 
vaccine antigen with either AS03 or MF59 adjuvant prior to 
administration. The study vaccine (0.5 mL) should be administered by 
IM injection in the deltoid muscle of the arm within 30 minutes of 
mixing. Each vaccination will be given in alternating arms whenever 
possible. If a subject has a scar or tattoo that interferes with injection 
site assessment, the vaccine can be given in the same arm as the 
previous injection. 
Sample Size: 
Approximately 720 subjects with 60 subjects per study group will be 
enrolled in the study.  

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Statistical Methods: Data will be summarized with descriptive statistics for quantitative 
parameters, and by incidence rates and the corresponding 
95% confidence intervals for categorical findings, as appropriate.  
No formal significance testing will be performed. Details of the 
statistical analyses, methods, and data conventions are described in the 
statistical analysis plan. 
No formal independent data monitoring committee meetings are 
planned for this study. The independent data monitoring committee 
will meet only if a pausing rule is met. 
Two interim analyses are planned based on cumulative 
immunogenicity and safety data after all subjects complete Day 43 
and all subjects complete Day 163. At each time point, the study 
database will be monitored, cleaned, and frozen through the data cut 
time point. Safety and immunogenicity data will be summarized by 
study group. Interim analysis results will be unblinded at the group 
level, and each group will be assigned a fake name. Results will be 
provided to the sponsor with groups identified only by their fake 
names. A single CSR will be written with unblinded data at the subject 
level after Groups E, F, K, L have completed Day 262. Additional 
safety results from the time of CSR database freeze until the 
end-of-study visit for all groups will be included in an addendum to 
the final CSR. 
Date of Protocol: 
26 February 2018 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BARDA 
Biomedical Advanced Research and Development Authority 
CDROM 
Compact Disc Read-Only Memory 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CSR 
clinical study report 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
hemagglutinin 
HAI 
hemagglutination inhibition  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IFAS 
immunogenicity-full analysis set 
IM 
intramuscularly 
IP 
investigational product 
IPPS 
immunogenicity per-protocol set 
IRB 
institutional review board 
IRT 
interactive response technology  
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
microneutralization 
NPIVS 
National Pre-Pandemic Influenza Vaccine Stockpile 
PBMC 
peripheral blood mononuclear cell 
PIMMC 
potentially immune-mediated medical condition 
PT 
preferred term 
SAE 
serious adverse event 

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Abbreviation 
Definition 
SCR 
seroconversion rate 
SOC 
system organ class 
SPR 
seroprotection rate 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 

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1 
Introduction 
Avian influenza H5N1 virus infections were first detected in humans in 1997 during a poultry 
outbreak in Hong Kong SAR, China. Since its re-emergence in 2003, influenza H5N1 virus 
has spread from Asia to Europe, Africa, and North America, becoming endemic in poultry in 
some countries in Asia and Africa. Reports of sporadic transmission from birds to humans 
continue, and as of July 2017, 859 individuals have been diagnosed with H5N1 virus 
infection, including 453 deaths. Antigenic drift has resulted in over 40 distinct H5 
hemagglutinin (HA) clades since 1997, and live-bird market surveillance identified novel 
clade 2.3.4.4 reassortant viruses of different subtypes in Asia since 2009, including H5N2, 
H5N3, H5N5, H5N6, and H5N8 strains (Gu et al 2011; Zhao et al 2012; Zhao et al 2013; Hill 
et al 2015; Wong et al 2015;World Health Organization 2017a). Some of these clade 2.3.4.4 
viruses have begun to spread internationally to Asia (H5N6), Europe, Africa, and North 
America (H5N8). After the first detection of the Eurasian H5N8 in the Pacific Northwest of 
the United States in December 2014, the resulting reassortant H5N2 viruses spread to 
21 states by June 2015 affecting 48 million poultry (United States Department of Agriculture 
2016). No human cases of H5N8 were detected; however, there have been 
16 laboratory-confirmed cases of human infection with H5N6 (clade 2.3.4.4) reported in 
China since 2014, including 9 fatalities (World Health Organization 2017b).  
While the risk of human infection with H5 influenza viruses is low, the Department of Health 
and Human Services continuously monitors the risk and prepares to respond to the threat of 
novel influenza virus outbreaks in the United States. In order to prepare and respond 
effectively to future influenza pandemic threats, the Biomedical Advanced Research and 
Development Authority (BARDA) within the Office of the Assistant Secretary for 
Preparedness and Response, has established and maintains the National Pre-Pandemic 
Influenza Vaccine Stockpile (NPIVS) that comprises bulk adjuvants, pre-pandemic antigens, 
and final containers of vaccines that were manufactured from candidate vaccine viruses from 
representative clades of H5 influenza viruses (eg, clades 1, 2.1, 2.2, 2.3). These candidate 
vaccine viruses are carefully chosen based on ongoing surveillance of influenza A viruses 
circulating in animals and assessment of associated potential pandemic risk. 
In the case of a declared pandemic emergency, the vaccine exactly matching the antigenic 
properties of the pandemic virus will not be available until several months later. Production 
issues, such as virus and purification yields that vary depending on the virus characteristics, 

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make it difficult to estimate how long it would take during a pandemic emergency to produce 
enough doses of any vaccine to protect the US population. Therefore, it is important to 
develop potential strategies for immediate deployment of stockpiled H5 influenza virus 
vaccines as an interim intervention in response to a pandemic emergency. Previous studies 
suggest that heterologous prime and boost vaccination regimens (ie, different HA antigens 
used for prime and boost vaccinations) may be superior to homologous prime and boost 
vaccination regimens (ie, the same HA antigens used for prime and boost vaccinations) in 
generating cross-reactive immune responses to antigenically divergent influenza viruses 
(Belshe et al 2011, Belshe et al 2014, Gillard et al 2013, Gillard et al 2014, Leroux-Roels et 
al 2010, Levine et al 2017). Furthermore, there is some evidence suggesting that when 
compared to a homologous prime-boost vaccination regimen, a heterologous prime-boost 
vaccination regimen including adjuvant may broaden and enhance cross-reactive 
hemagglutination inhibition (HAI) antibody responses to a panel of antigenically divergent 
H5 influenza viruses (Levine et al 2017, unpublished data). 
Influenza virus vaccines induce antibodies against the viral HA antigen in the vaccine, 
thereby blocking viral attachment to human respiratory epithelial cells. In some human 
challenge studies of other influenza viruses, antibody titers of at least 1:40 have been 
associated with protection from influenza infection in up to 50% of subjects.  
Sanofi Pasteur Influenza A/Vietnam/1203/2004 (H5N1), A/Indonesia/05/2005 (H5N1), and 
A/bar-headed goose/Qinghai Lake/1A/2005 (H5N1) vaccines contain 30 mcg/mL HA from 
SJRG-161052, Indo5/PR8-RG2, and SJRG-163222 candidate vaccine viruses respectively, in 
sodium phosphate buffered isotonic saline. These monovalent vaccines also contain gelatin 
(0.05%), trace amounts of formaldehyde (≤200 mcg/mL), polyethylene glycol 
p-isooctylphenyl ether (≤0.05%), and sucrose (≤2.0%). In addition, thimerosal at a 
concentration of approximately 0.01% was added as a preservative (Fluzone Quadrivalent 
[Influenza Vaccine] 2016). 
Seqirus (formerly Novartis) A/duck/Bangladesh/19097/2013 H5N1 vaccine contains 
30 mcg/mL HA from SJ007 candidate vaccine virus in sodium phosphate buffered isotonic 
saline. Each 0.5 mL vial of monovalent vaccine may also contain residual amounts of Madin 
Darby canine kidney cell protein (≤8.4 mcg), protein other than HA (≤160 mcg), Madin 
Darby canine kidney cell DNA (≤10 ng), polysorbate 80 (≤1500 mcg), 

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cetyltrimethylammonium bromide (≤18 mcg), and β–propiolactone (≤0.5 mg) (Flucelvax 
Quadrivalent [Influenza Vaccine] 2016).  
Seqirus (formerly bioCSL) A/gyrfalcon/Washington/41088-6/2014 (H5N8) vaccine contains 
30 mcg/mL HA from IDCDC-RG43A candidate vaccine virus in isotonic phosphate buffer. 
Each 0.5 mL vial of monovalent vaccine may also contain trace amounts of sodium 
taurodeoxycholate (≤10 ppm), ovalbumin (<1 mcg), neomycin sulfate (≤0.2 pg), polymyxin 
B (≤0.03 pg), and beta-propiolactone (≤25 ng) (Afluria 2010). 
The adjuvant MF59® is an oil-in-water emulsion composed of squalene and a buffer; the 
emulsion is stabilized by the addition of 2 emulsifiers (a water-soluble surfactant 
[polysorbate 80, also known as Tween® 80] and an oil-soluble surfactant [sorbitan trioleate, 
also known as Span® 85]). Biodegradable squalene oil is a natural metabolite of cholesterol 
and a normal component of cell membranes. MF59 enhances immune responses to antigen 
by targeting 3 different cell types, including monocytes, macrophages, and granulocytes. 
MF59 has a range of effects on these cells, including increased antigen uptake, release of 
chemoattractants, and induction of cell differentiation (FLUAD [Influenza Vaccine, 
Adjuvanted] 2016).  
MF59 has been developed to enhance the immunogenicity of purified subunit antigens, has 
been tested in several animal models in combination with different antigens, and has been 
evaluated in humans (Schultze et al 2008). MF59 was the first adjuvant for human use to be 
licensed after alum and, as part of an enhanced seasonal trivalent inactivated subunit 
influenza vaccine (FLUAD®) for the elderly, is now licensed in more than 30 countries 
worldwide. MF59 is also the adjuvant of European Union-licensed monovalent A(H1N1) 
swine influenza subunit egg-derived vaccine (FOCETRIA®), a cell-derived pandemic 
vaccine (CELTURA®), and licensed pre-pandemic vaccine (AFLUNOV®). 
Warnings and precautions for the influenza virus vaccines include history of a 
hypersensitivity reaction to chicken or egg proteins or life-threatening reactions to previous 
influenza vaccinations. Immunocompromised persons may have a reduced immune response 
to influenza virus vaccines. The most common (≥10%) adverse reactions observed with the 
vaccines used in this study are pain at injection site, tenderness, headache, malaise, 
induration/swelling, redness, itching, myalgia, arthralgia, shivering, and sweating.  

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Extensive safety data have been gathered on the use of glycoprotein antigens or recombinant 
proteins combined with MF59. These data indicate that such vaccine antigens, when 
administered with MF59, are safe, and generally well tolerated. Additionally, these vaccines 
have frequently elicited a strong antibody response against the particular antigens. As of 
30 April 2015, approximately 43 600 subjects had received at least 1 dose of influenza virus 
vaccines combined with MF59 adjuvant in completed clinical studies. The completed studies 
showed that the MF59 adjuvant significantly improved the immunogenicity of inactivated 
subunit influenza virus vaccines, with a clinically acceptable increase in the incidence of 
injection site reactions (Schultze et al 2008). According to an integrated safety analysis, filed 
in the BB-Master File for MF59, there was an increased risk of solicited local and systemic 
reactions in subjects exposed to MF59, while there was a similar or decreased risk of all 
unsolicited adverse events (AEs), autoimmune diseases, new onset chronic diseases, 
cardiovascular disease, serious adverse events (SAEs), hospitalizations, and deaths when 
compared with non-MF59-adjvuanted vaccines (Pellegrini et al 2009).  
The AS03 adjuvant is composed of squalene, DL-α-tocopherol, and polysorbate 80. AS03 is 
approved for human use as the adjuvant component of the Influenza H5N1 Virus Monovalent 
Vaccine, Adjuvanted (Influenza A (H5N1) Virus Monovalent Vaccine 2013).  
Other influenza vaccines containing AS03 adjuvant were administered outside the United 
States during the Influenza A 2009 (H1N1) pandemic. The following AEs were identified: 
anaphylaxis, allergic reactions, febrile convulsions, Guillain-Barre syndrome, narcolepsy, 
somnolence, paresthesia, angioedema, generalized skin reactions, urticaria, and injection site 
reactions (including inflammation, mass, necrosis, and ulcer) (Influenza A (H5N1) Virus 
Monovalent Vaccine 2013).  
Both the AS03 and MF59-adjuvanted vaccines have been licensed in the United States (eg, 
AS03 in the Influenza A [H5N1] Virus Monovalent Vaccine, Adjuvanted [Influenza A 
(H5N1) Virus Monovalent Vaccine 2013] and MF59 in the FLUAD vaccine [FLUAD 
(Influenza Vaccine, Adjuvanted) 2016]). There are no major safety concerns associated with 
the use of these adjuvants; however, there is epidemiological evidence of an association 
between influenza vaccine adjuvanted with AS03 and narcolepsy. In studies of influenza 
A(H1N1) vaccine adjuvanted with AS03, there was a small increased risk of narcolepsy in 
subjects who received adjuvanted vaccine; however, narcolepsy developed almost 
exclusively in the pediatric population vaccinated with influenza A(H1N1) adjuvanted with 

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AS03 (Pandemrix®, GlaxoSmithKline, Wavre, Belgium, produced in Dresden, Germany) and 
primarily in Scandinavian countries (Lind et al 2014, Nohynek et al 2012). A small study to 
assess the risk of narcolepsy following administration of a similar vaccine adjuvanted with 
AS03 (Arepanrix®, GlaxoSmithKline, Wavre, Belgium, produced in Quebec City, Canada) 
was performed in Quebec, Canada (Montplaisir et al 2014). The Canadian study showed a 
small risk of developing narcolepsy after receiving the AS03-adjuvanted A(H1N1)pdm09 
vaccine manufactured in Quebec. This risk occurred primarily in people less than 20 years of 
age and was much less than that seen in some European countries. An additional study was 
conducted in the United States, which found that influenza vaccines containing the 
A(H1N1)pdm09 virus strain were not associated with an increased risk of narcolepsy (Duffy 
et al 2014). Finally, the “SOMNIA study” conducted by the US Centers for Disease Control 
and Prevention assessed the risk of narcolepsy following administration of adjuvanted 
A(H1N1)pdm09 vaccines. Comparison of incidence rates of narcolepsy before, during, and 
after the use of adjuvanted A(H1N1)pdm09 influenza vaccines provided no evidence outside 
of the signaling country Sweden (Shimabukuro et al 2017). 
This is a randomized, double-blinded, Phase 2 study to assess the safety and immunogenicity 
of a homologous or heterologous vaccination series with inactivated monovalent influenza 
H5 vaccines stored in the NPIVS, administered intramuscularly (IM) with either AS03 or 
MF59 adjuvant in healthy males and nonpregnant females, aged 18 to 49 years, inclusive. 
Two doses of adjuvanted vaccine separated by 21 days or 2 doses of adjuvanted vaccine 
separated by 21 days followed by a third dose of adjuvanted vaccine 120 days following the 
second dose will utilize HA antigens from the NPIVS.  
The study is designed to further inform options for strategic deployment of pre-pandemic 
influenza vaccines stockpiled in the NPIVS. In particular, we will determine whether 1) the 
antigenic characteristics of 2 antigens used for prime and boost and 2) the sequence in which 
the priming and boosting antigens are administered are important for optimal elicitation of 
immune responses to the vaccine. The antigens included in this study were carefully chosen 
based on the relative antigenic distance between the HAs of pre-pandemic vaccine strains 
and relative to the currently circulating H5 influenza viruses. Furthermore, this study will 
address serologic responses to the vaccination regimens when administered with each of the 
adjuvants (AS03 or MF59) held in the NPIVS and whether boosting can be observed with 
heterologously distinct strains when using either adjuvant (AS03 or MF59) in a single-dose 
or a 2-dose priming series. 

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2 
Study Objectives 
2.1 
Primary Objectives 
2.1.1 
Primary Safety Objective 
• To assess the safety and reactogenicity for 8 days postvaccination, inclusive of the 
vaccination day (Day 1 through Day 8 and Day 22 through Day 29), of a 2-dose 
vaccination series using homologous monovalent inactivated H5 influenza virus vaccine 
or antigenically distant heterologous H5 influenza virus vaccines administered IM with 
AS03 or MF59 adjuvant on Days 1 and 22 (henceforth referred to as “prime-boost”), as 
determined by solicited local and systemic reactogenicity symptoms. 
• To assess the safety and reactogenicity for 8 days postvaccination, inclusive of the 
vaccination day (Day 1 through Day 8, Day 22 through Day 29, and Day 142 through 
Day 149), of a 3-dose vaccination series using homologous monovalent inactivated H5 
influenza virus vaccine administered IM with AS03 or MF59 adjuvant on Days 1 and 22, 
and a third dose 120 days after the second dose with an antigenically heterologous H5 
influenza virus vaccine administered IM with AS03 or MF59 adjuvant on Day 142 
(henceforth referred to as “prime-prime-boost”), as determined by solicited local and 
systemic reactogenicity symptoms. 
2.1.2 
Primary Immunogenicity Objective 
• To assess the serum HAI antibody seroprotection rate (SPR) against strains contained in 
the study vaccines on Day 43 of the prime-boost vaccination series administered IM with 
AS03 or MF59 adjuvant on Days 1 and 22.  
• To assess the serum HAI antibody SPR against strains contained in the study vaccines on 
Day 163 of the prime-prime-boost vaccination series administered IM with AS03 or 
MF59 adjuvant on Days 1, 22, and 142.  

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2.2 
Secondary Objectives 
2.2.1 
Secondary Safety Objectives 
• To assess the occurrence of SAEs, medically attended adverse events (MAAEs), and 
potentially immune-mediated medical conditions (PIMMCs; see Appendix 2, 
Section 12.2) in the 12 treatment groups through 12 months after the last dose of study 
vaccine.  
• To assess the occurrence of unsolicited AEs for 21 days after each dose of study vaccine.  
2.2.2 
Secondary Immunogenicity Objectives 
• To assess the serum HAI antibody titers, SPRs, and seroconversion rates (SCRs) against 
each vaccine strain in the study through Day 142 of the prime-boost vaccination series.  
• To assess the serum HAI antibody titers, SPRs, and SCRs against each vaccine strain in 
the study through Day 262 of the prime-prime-boost vaccination series.  
• To assess the serum microneutralization (MN) antibody titers and SCRs against each 
vaccine strain in the study through Day 142 of the prime-boost vaccination series. 
• To assess the serum MN antibody titers and SCRs against each vaccine strain in the study 
through Day 262 of the prime-prime-boost vaccination series. 
2.3 
Exploratory Immunogenicity Objectives 
• To assess peripheral antibody responses to epitopes within the influenza virus surface 
proteins HA or neuraminidase induced by prime-boost or prime-prime-boost vaccination 
series. 
• To examine cell-mediated (eg, B cell, CD4+ T cell, CD8+ T cell) responses in a subset 
composed of approximately half of enrolled subjects using peripheral blood mononuclear 
cells (PBMCs) collected at Day 1, Day 22, Day 43, and Day 142 (Groups A-D, G-J) or 
Day 1, Day 22, Day 43, Day 142, Day 163, and Day 262 (Groups E, F, K, L). 

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3 
Investigational Plan 
3.1 
Study Design 
This is a randomized, double-blinded, Phase 2 study to assess the safety and immunogenicity 
of a homologous or heterologous prime-boost or prime-prime-boost series with inactivated 
monovalent influenza H5 vaccines stored in the NPIVS, administered IM with either AS03 or 
MF59 adjuvant in healthy males and nonpregnant females, aged 18 to 49 years, inclusive. 
Screening will occur within a 14-day period before randomization. Approximately 
720 subjects will be equally and randomly assigned to one of 12 study groups within each 
site. Study staff not involved in investigational product (IP) preparation and administration 
will be blinded to unique group assignment. Two doses of adjuvanted vaccine separated by 
21 days (Groups A-D, G-J) or 2 doses of adjuvanted vaccine separated by 21 days followed 
by a third dose of adjuvanted vaccine 120 days following the second dose (Groups E, F, K, 
L) will include HA antigen from the NPIVS.  
Investigational product treatment arms are detailed in Table 3–1. 
 

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Table 3–1 
Treatment Arms 
Study 
Group 
Dose #1 (Day 1) Strain Details 
(Manufacturer) 
Dose #2 (Day 22) Strain Details 
(Manufacturer) 
Dose #3 (Day 142) Strain Details 
(Manufacturer) 
Adjuvant
A 
A/Vietnam/1203/2004 H5N1 (Sanofi Pasteur)
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
N/A 
AS03 
B 
A/Indonesia/05/2005 H5N1 (Sanofi Pasteur) 
C 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
D 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/Indonesia/05/2005 H5N1 (Sanofi Pasteur) 
E 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
A/barheaded goose/Qinghai Lake/1A/2005 
(H5N1) (Sanofi Pasteur) 
F 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/barheaded goose/Qinghai Lake/1A/2005 
(H5N1) (Sanofi Pasteur) 
G 
A/Vietnam/1203/2004 H5N1 (Sanofi Pasteur)
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
N/A 
MF59 
H 
A/Indonesia/05/2005 H5N1 (Sanofi Pasteur) 
I 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
J 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/Indonesia/05/2005 H5N1 (Sanofi Pasteur) 
K 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
A/duck/Bangladesh/19097/2013 H5N1 
(Seqirus) 
A/barheaded goose/Qinghai Lake/1A/2005 
(H5N1) (Sanofi Pasteur) 
L 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/gyrfalcon/Washington/41088-6/2014 H5N8 
(Seqirus) 
A/barheaded goose/Qinghai Lake/1A/2005 
(H5N1) (Sanofi Pasteur) 
Abbreviation: N/A, not applicable. 

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All IP will be prepared and administered by an unblinded staff member. The study staff 
observing the subject after vaccination and the subject will be blinded to group assigned. 
Subject completion is defined as completing all study visits through Visit 9 (end-of-study 
visit) for Groups A-D and G-J (Table 12–1) or Visit 14 (end-of-study visit) for Groups E, F, 
K, L (Table 12–2). Approximately half of enrolled subjects per study group will be selected 
to provide a blood sample for PBMC collection. A select number of sites will have capability 
for PBMC collections, and only subjects enrolled at those sites will contribute to the PBMC 
subset. Subjects who participate in this study will be asked to consent to be contacted with a 
request to participate in future clinical studies of subjects who have been vaccinated against 
influenza H5, such as longer interval prime-boost studies. 
No formal independent data monitoring committee (IDMC) meetings are planned for this 
study. The IDMC will meet only if a pausing rule is met.  
Two interim analyses are planned based on cumulative immunogenicity and safety data after 
all subjects complete Day 43 and all subjects complete Day 163. At each time point, the 
study database will be monitored, cleaned, and frozen through the data cut time point. Safety 
and immunogenicity data will be summarized by study group. Interim analysis results will be 
unblinded at the group level, and each group will be assigned a fake name. Results will be 
provided to the sponsor with groups identified only by their fake names.  
A single clinical study report (CSR) will be written with unblinded data at the subject level 
after Groups E, F, K, L have completed Day 262. Additional safety results from the time of 
CSR database freeze until the end-of-study visit for all groups will be included in an 
addendum to the final CSR. 
3.1.1 
Rationale of Study Design  
The main purpose of this study is to assess the ability of H5 influenza vaccines and adjuvants 
present in the NPIVS to generate an immune response to homologous and to antigenically 
distant heterologous H5 influenza virus strains.  
The study is designed to evaluate the safety and immunogenicity of vaccination strategies 
with homologous or antigenically distant heterologous H5 influenza virus vaccines 
administered with AS03 or MF59 adjuvant. 

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3.1.2 
Study Groups 
There will be a total of 12 study groups. For a complete list of study groups and 
corresponding vaccination and adjuvants schemes refer to Table 3–1. 
3.1.3 
Study Pausing Rules 
Study pausing rules will be monitored throughout the study by the medical monitor. The 
sponsor will pause study enrollment and study vaccine administration and the IDMC will 
review unblinded safety data if any of the following are met: 
• Occurrence of one or more SAE(s), MAAE(s), or PIMMC(s) judged to be related to IP; 
OR 
• Any potentially life-threatening AE judged to be related to IP (An AE or suspected 
adverse reaction is considered “life threatening” if, in the view of either the investigator 
or sponsor, its occurrence places the patient or subject at immediate risk of death. It does 
not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death); OR 
• A death, if judged to be related to IP; OR 
• Anaphylaxis or bronchospasm within 4 hours of injection judged to be related to IP; OR 
• 10% of vaccinated subjects at a given vaccination time point when at least 50% of 
subjects in that group have been vaccinated experience the same or similar systemic or 
local Grade 3 (toxicity scoring) or higher event; OR 
• A pattern of significant symptoms, physical findings, or laboratory abnormalities that, 
although individually minor, collectively represent a safety concern in the opinion of the 
investigator or the medical monitor. 

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3.1.4 
Future Investigations 
Using the informed consent form (ICF), subjects who participate in this study will also be 
asked the following questions: 
1. Permission to be contacted with a request to participate in future clinical studies of 
subjects who have been vaccinated against influenza H5, such as longer interval 
prime-boost studies.  
2. Permission to obtain and store an additional aliquot of serum and to obtain and store 
any leftover serum from research laboratories for future investigations, such as testing 
for immune response to heterologous influenza H5 or other strains or subtypes of 
influenza viruses. 

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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
Approximately 720 subjects will be enrolled at multiple sites in the United States. Subjects 
will be assigned to study treatment only if they meet all of the inclusion criteria and none of 
the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed. Adherence to the 
criteria as specified in the protocol is essential. Subjects must satisfy all of the following 
criteria at study entry and eligibility must be reviewed just prior to each vaccination. 
4.1.1 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is a male or nonpregnant female 18 to 49 years of age, inclusive, on Day 1 (first 
vaccination). 
2. Will avoid nonstudy vaccinations until 21 days after the last vaccination. 
3. Provides written informed consent prior to the initiation of any study-related 
procedures. 
4. Has a stable health status, as established by physical examination, vital sign 
measurements, and medical history. 
5. Has access to a consistent and reliable means of telephone contact, which may be in 
the home, workplace, or by personal mobile electronic device. 
6. Is able to understand and comply with planned study procedures. 
7. Lives a reasonable distance from the site to be able to travel to and from the site for 
follow-up visits and agrees to go to the site for evaluation in the case of an AE.  
8. Agrees to stay in contact with the site for the duration of the study, has no current 
plans to move from the study area, and provides updated contact information as 
necessary. 

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4.1.2 
Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from the study: 
1. Has a known allergy to eggs or other components of the vaccine (including gelatin, 
formaldehyde, octoxinol-9, thimerosal, or chicken protein), or allergy to 
squalene-based adjuvants or has had severe reactions following previous 
immunizations with contemporary influenza virus vaccines. 
2. A woman who has a positive urine pregnancy test prior to vaccination in this study or 
a woman who is breastfeeding. 
3. A female of childbearing potentiala who refuses to use an acceptable method of birth 
controlb from Day 1 (first vaccination) to end-of-study visit and, if sexually active, 
who has not used a reliable birth control method for at least 2 months prior to Day 1 
(first vaccination). 
a 
Female of childbearing potential is defined as post-onset menarche and premenopausal female capable 
of becoming pregnant. This does not include females who meet any of the following conditions: 
menopausal >1 year, tubal ligation >1 year, bilateral salpingo-oophorectomy, or hysterectomy. 
b 
Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per year 
when used consistently and correctly and, when applicable, in accordance with the product label, for 
example: abstinence from penile-vaginal intercourse; oral contraceptives, either combined or 
progestogen alone; injectable progestogen; implants of etonogestrel or levonorgestrel; estrogenic 
vaginal ring; percutaneous contraceptive patches; intrauterine device or intrauterine system; male 
partner sterilization at least 6 months prior to the female Day 1 (first vaccination), and this male is the 
sole partner for that subject (The information on the male sterility can come from the site personnel’s 
review of the subject’s medical records or interview with the subject on her medical history); male 
condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository); male condom 
combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, 
or suppository). 
4. Is immunosuppressed as a result of an underlying illness or treatment, or anticancer 
chemotherapy or radiation therapy (cytotoxic) within the preceding 36 months prior to 
Day 1 (first vaccination). 
5. Has an active neoplastic disease or a history of any hematologic malignancy. A subject 
with superficial skin cancer who does not require intervention other than local 
excision is not excluded. 

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6. Has long-term use (≥14 consecutive days) of glucocorticoids including oral or 
parenteral prednisone or equivalent (>20 mg total dose per day) or high-dose inhaled 
steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within 1 month 
prior to screening. (Low-dose [≤800 mcg/day of beclomethasone dipropionate or 
equivalent] inhaled and topical steroids are allowed). 
7. Has a diagnosis of schizophrenia, bipolar disease, or other major psychiatric diagnosis. 
8. Has been hospitalized for psychiatric illness, history of suicide attempt, or 
confinement for danger to self or others, within the past 10 years. 
9. Has a neurological or psychiatric diagnosis, which, although stable, is judged by the 
investigator to render the potential subject unable or unlikely to comply with the 
protocol or to provide accurate safety reports. 
10. Has received immunoglobulin or other blood product (with the exception of Rho[D] 
immune globulin) within the 3 months prior to Day 1 (first vaccination). 
11. Has received any live vaccine within 4 weeks or inactivated vaccines within 2 weeks 
prior to Day 1 (first vaccination). This includes seasonal influenza vaccines. 
12. Has an acute or chronic medical condition that, in the opinion of the investigator, 
would render vaccination unsafe or would interfere with the evaluation of responses. 
This includes PIMMCs such as Guillain-Barré syndrome, narcolepsy, current or 
history of autoimmune or chronic inflammatory disease (listed in Appendix 2, 
Section 12.2).  
13. Has a first-degree relative with narcolepsy. 
14. Has an acute illness, including body temperature greater than 100.4°F, at screening, 
immediately prior to each vaccination or, per subject report, within 3 days prior to 
each vaccination. Subjects with an acute illness can be rescheduled for vaccination as 
long as the vaccination visit is within the visit window. Note that subjects may return 
for randomization following resolution of the acute illness as long as recruitment 
remains open and subjects are within 14 days of signing consent. 
15. Has a Grade 2 or greater (by US Food and Drug Administration [FDA] toxicity grade) 
safety laboratory value at screening. 

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16. Has received an experimental agent (vaccine, biologic, device, blood product, or 
medication) within 1 month prior to Day 1 (first vaccination) in this study or plans 
receipt of an experimental agent during the study period. 
17. Is participating or plans to participate in another interventional clinical study (either 
active or follow-up phase) during the study period. 
18. Has received an influenza H5 vaccine in the past or has a history of H5 influenza 
infection prior to enrollment. 
19. Has known human immunodeficiency virus, hepatitis B, or hepatitis C infection. 
20. Has a history of alcohol or drug abuse within 5 years prior to Day 1 (first vaccination). 
21. Has a body mass index >35 kg/m2. 
22. Has any condition that would, in the opinion of the investigator, place him or her at an 
unacceptable risk of injury or render him or her unable to meet the requirements of the 
protocol (including site of injection reactogenicity assessments). 
23. Is a first-degree relative of any person working on this study: site or sponsor. 
4.2 
Withdrawal of Subjects From the Study 
The duration of the study is defined for each subject as beginning on the date signed written 
informed consent is provided through the last follow-up visit (Visit 9 [end-of-study visit] for 
Groups A-D and G-J [Table 12–1] and Visit 14 [end-of-study visit] for Groups E, F, K, L 
[Table 12–2]).  
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study or study treatment (ie, no longer receive IP) at any 
time and for any reason without prejudice to their future medical care by the investigator or 
at the site. Every effort should be made to keep subjects in the study. Refer to Section 4.2.2 
for handling of withdrawals. The reasons for subjects not completing the study will be 
recorded. A subject may be withdrawn from the study or study treatment (ie, no longer 
receive IP) for any of the following reasons: 
1. Does not meet the protocol inclusion or exclusion criteria at the time of the second or, 
if applicable, third vaccination. 

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2. Noncompliance with the protocol. 
3. Serious or intolerable AE(s) that in the investigator’s opinion requires withdrawal 
from the study.  
4. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
elevation that is Grade 2 (moderate) or greater based on FDA toxicity grading (ie, 
≥2.6 × upper limit of normal [ULN]; see Appendix 3, Section 12.3) that does not 
resolve on repeat testing to the screening baseline value (eg, baseline toxicity score). 
(Note, subjects with elevated ALT and/or AST values cannot be revaccinated until 
resolution occurs [see Section 4.3].) 
5. Other laboratory safety assessments that reveal Grade ≥3 hematological or 
biochemical values. 
6. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justifies withdrawal. 
7. Lost to follow-up. 
8. Other (eg, pregnancy, development of contraindications to use of IP). 
9. The subject withdraws consent or the investigator or BARDA decides to discontinue 
the subject’s participation in the study. 
In addition, Study Pausing Rules (Section 3.1.3) will be monitored throughout the study by 
the medical monitor.  
The investigator will also withdraw all subjects if BARDA terminates the study. Upon 
occurrence of a serious or intolerable AE, the investigator will confer with BARDA. If a 
subject is discontinued from the study or study treatment because of an AE, the event will be 
followed until it is resolved or becomes stable. Any subject may withdraw his or her consent 
at any time. 
4.2.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. 
Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at BARDA’s request. 

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Subjects who discontinue study treatment or active participation in the study will no longer 
receive IP. When a subject withdraws from the study, the reason(s) for withdrawal shall be 
recorded by the investigator on the relevant page of the electronic case report form (eCRF).  
Whenever possible, all subjects who discontinue from the study prematurely will undergo all 
early termination assessments (Table 12–1 and Table 12–2). Subjects who discontinue study 
treatment prematurely will be encouraged to attend subsequent visits according to the 
protocol. Subjects who fail to return for final assessments will be contacted by the site in an 
attempt to have them comply with the protocol. A subject will not be considered lost to 
follow-up until every attempt to contact the subject has been made, at minimum 
2 (documented) phone calls, followed by a registered letter. Every effort should be made to 
collect safety data on subjects through the end-of-study visit. 
It is vital to obtain follow-up data on any subject withdrawn from the study or study 
treatment (ie, no longer receiving IP) because of an AE or SAE. In every case, efforts must 
be made to undertake protocol-specified safety follow-up procedures. 
4.2.3 
Replacements 
If a subject is randomly assigned to a study group but not administered the first dose of IP, 
then a replacement subject will be randomly assigned to treatment via interactive response 
technology (IRT). A unique randomization number will be assigned to the replacement 
subject. If a subject is withdrawn from the study after receipt of the first dose of IP, this 
subject will not be replaced. 
4.3 
Revaccination Eligibility 
Subjects are free to withdraw from further study vaccination at any time upon request. A 
subject may not be eligible to receive further study vaccination for any of the following 
reasons: 
1. Does not meet the protocol inclusion or exclusion criteria at the time of the second 
or, if applicable, third vaccination. 
2. Noncompliance with the protocol. 
3. Serious or intolerable AE(s) that in the investigator’s opinion precludes further study 
vaccination.  

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4. A serum ALT or AST elevation that is Grade 2 (moderate) or greater based on FDA 
toxicity grading (ie, ≥2.6 × ULN; see Appendix 3, Section 12.3) regardless of 
investigator-assessed clinical significance. Note, such an elevated ALT and/or AST 
value must be resolved on repeat testing to the screening baseline value (eg, baseline 
toxicity score) before revaccination can occur. Only those subjects who have 
resolution of the ALT and/or AST elevations within the visit window are eligible for 
revaccination. 
5. Other laboratory safety assessments that remain clinically significant prior to 
planned vaccination.  
6. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justifies no further study vaccination. 
7. Other (eg, pregnancy, development of contraindications precluding further study 
vaccination). 
All subjects who discontinue from study treatment prematurely will follow the same visit 
schedule as other subjects.  

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5 
Study Groups 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to 1 of 12 study groups stratified by site. An IRT will be 
used to administer the randomization schedule centrally. Biostatistics will generate the 
randomization schedule using SAS® software Version 9.3 or later (SAS Institute Inc, Cary, 
North Carolina) for IRT, which will link sequential subject randomization numbers to 
treatment codes. The randomization schedule will be created by the dedicated randomization 
team, stored in a separate project area, and will be blinded to the project team. 
5.2 
Investigational Product Administered 
All IP will be aseptically prepared and administered by an unblinded staff member, according 
to the details outlined in the Study Procedures Manual. The study staff observing the subject 
after vaccination and the subject will be blinded. Two doses of adjuvanted vaccine separated 
by 21 days (Groups A-D, G-J) or 2 doses of adjuvanted vaccine separated by 21 days 
followed by a third dose of adjuvanted vaccine 120 days following the second dose 
(Groups E, F, K, L), which include HA antigen from the NPIVS, will be administered IM 
according to Table 3–1.  
The study vaccines will be prepared by mixing H5 influenza virus vaccine antigen with either 
AS03 or MF59 adjuvant prior to administration. The study vaccine (0.5 mL) should be 
administered by IM injection in the deltoid muscle of the arm within 30 minutes of mixing. 
Each vaccination will be given in alternating arms whenever possible. If a subject has a scar 
or tattoo that interferes with injection site assessment, the vaccine can be given in the same 
arm as the previous injection.   
5.3 
Management of Clinical Supplies 
5.3.1 
Investigational Product Packaging and Storage 
Investigational product will be packaged and labelled according to applicable local and 
regulatory requirements. Each kit will contain a (randomized) dosage for 1 subject and will 
contain a sufficient quantity for dispensing for 1-time usage. Single-use vials will be labelled 
with a single panel label. Each kit will also be labelled with a single panel label.  

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Vaccine and adjuvant must be stored in a secure area (eg, a locked room or locked 
refrigerator), protected from light and moisture, and kept at a controlled standard 
refrigeration temperature between 2°C to 8°C (35°F-46°F). 
5.3.2 
Investigational Product Accountability 
The investigator will maintain accurate records of receipt of all IP, including dates of receipt. 
In addition, accurate records will be kept regarding when and how much IP is dispensed and 
administered to each subject in the study. Reasons for departure from the expected dispensing 
regimen must also be recorded. At the completion of the study, to satisfy regulatory 
requirements regarding accountability, all IP will be reconciled and retained or destroyed 
according to applicable regulations. No IP will be destroyed until authorized in writing by the 
sponsor.  
5.3.3 
Other Supplies 
Other clinical supplies that will be provided to the sites for distribution to subjects include 
diary cards, a measuring tool for measuring injection site erythema and swelling, and a 
thermometer for measuring body temperature. 
5.4 
Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the SAE hotline (Section 6.2.5.4). In case of any AEs 
associated with the overdose, these should be reported on relevant AE/SAE sections in the 
eCRF. Any overdose should be recorded as a protocol violation and promptly reported to the 
sponsor. No overdoses are expected as the vaccine and adjuvant will be administered by 
study staff. 
5.4.1 
Treatment of Overdose 
Treatment of overdose would include supportive and symptomatic care, according to the 
standards of care at the site. The investigator should promptly notify the medical monitor 
about the overdose and seek his/her input on the medical management, as needed. 

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5.5 
Blinding 
This is a double-blind study. All IP will be prepared and administered by an unblinded study 
staff member. Investigational product accountability will be monitored by a separate 
unblinded monitor. All other persons involved in the study will be blinded to study group 
assignment, including the study staff observing the subject after vaccination and the subject. 
Until the final database lock and unblinding, all unblinded data analyses will be handled by 
the unblinded team of statisticians and programmers. A strict firewall between the blinded 
and unblinded teams will be maintained. 
For the 2 planned interim analyses, BARDA, site personnel, and subjects will be unblinded 
for all interim data at Day 43 and Day 163 only at the study group level (ie, data will be 
provided with each group having a fake designation). For the final analysis, all parties will be 
unblinded to all data at the subject level at Day 142 (Groups A-D, G-J) and Day 262 
(Groups E, F, K, L).  
With the exception of the unblinded study staff who administer the IP and a separate 
unblinded monitor who will monitor IP accountability, all other study staff are to remain 
blinded until CSR database freeze and a formal unblinding is scheduled. The members of the 
IDMC will review subject level unblinded safety data on an ad hoc basis for any immediate 
concerns that are observed. A separate unblinded team will handle any ad hoc production of 
unblinded tables, listings, and figures for ad hoc IDMC meetings. Blinded individuals will 
not be made aware of any unblinded data provided to the IDMC. 
5.5.1 
Breaking the Blind 
The blind should not be broken. As needed to meet regulatory reporting requirements, 
designated pharmacovigilance personnel may be unblinded to treatment status of individual 
subjects. In this circumstance, and if there are no other concerns, neither BARDA nor the 
study staff (except the unblinded study staff member who prepares and administers the 
vaccine) will be unblinded to treatment status. In all cases where the blind is broken, the date, 
reason for code breaking, and the name and signature of the investigator who broke the blind 
will be recorded. Subjects whose study group assignment is unblinded will not receive any 
subsequent IP. 

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5.6 
Treatment Compliance 
The IP will be administered by an unblinded study staff member, and date, time, and location 
(left or right arm) of administration will be recorded in the subjects’ eCRF. Subject 
compliance will be determined by the number and percentage of subjects who receive IP at 
each vaccination by study group. Any deviations from the dosing schedule outside the 
defined visit windows (Table 12–1 and Table 12–2) will be flagged in the clinical database. 
5.7 
Prior Vaccinations and Concomitant Medications 
Use of all concomitant medications that the subject is taking at the time of Visit 1 (Day 1), 
medications taken up to 14 days prior to Visit 1 (Day 1), and vaccines received 12 months 
prior to Visit 1 (Day 1) will be recorded in the subject’s eCRF. The minimum requirement is 
that drug name, dose, frequency, route of administration, and the dates of administration are 
to be recorded. This will include all prescription drugs, herbal products, vitamins, minerals, 
and over-the-counter medications. Any changes, additions, and/or deletions in concomitant 
medications and vaccinations also will be recorded in the subject’s eCRF throughout the 
course of the subject’s participation in the study. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
Sites may contact the medical monitor regarding use of concomitant medications prior to 
enrollment for guidance as necessary. If it is discovered that a subject is using a prohibited 
concomitant medication after he or she is enrolled in the study, the site should contact the 
medical monitor to resolve the situation. All instances of use of prohibited concomitant 
medications must be documented in the eCRF. All vaccinations obtained outside of the study 
itself will be recorded while the subject is enrolled. 
5.7.1 
Prohibited Prior and Concomitant Medications 
Immunosuppression as a result of an underlying illness or treatment or the use of anticancer 
chemotherapy or radiation therapy (cytotoxic) within the preceding 36 months prior to Day 1 
(first vaccination) is prohibited. Long-term use (≥14 consecutive days) of glucocorticoids 
including oral or parenteral prednisone or equivalent (>20 mg total dose per day) or 

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high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) 
within the preceding 1 month prior to screening is prohibited. Prior treatment with 
immunoglobulin or other blood product (with the exception of Rho[D] immune globulin) 
within 3 months prior to vaccination in this study is prohibited.  
Receipt of any live vaccines within 4 weeks or inactivated vaccines within 2 weeks prior to 
Day 1 (first vaccination) until 21 days after the last vaccination is prohibited. This includes 
seasonal influenza vaccines. Receipt of an experimental agent (eg, vaccine, biologic, device, 
blood product, or medication) within 1 month prior to Day 1 (first vaccination) in this study 
or receipt of any experimental agent during the study period is prohibited. 
5.7.2 
Permitted Prior and Concomitant Medication 
Low-dose (≤800 mcg/day of beclomethasone dipropionate or equivalent) inhaled and topical 
steroids are allowed. 
Prohibited concomitant medication during the study may be given at the discretion of the 
investigator if deemed in the best interest of the subject’s health. It is the responsibility of the 
investigator to ensure that details regarding the medication will be recorded in full in the 
eCRF.  

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6 
Study Assessments and Procedures 
Before performing any study-related procedures, the investigator will explain the study to 
potential subjects and all potential subjects will be given an ICF to read and sign. Subjects 
will have the opportunity to have any questions answered before signing the ICF. The 
investigator must address all questions raised by the subject. The investigator will also sign 
the ICF. The schedule of events is shown in Table 12–1 and Table 12–2. 
6.1 
Demographics and Medical History 
Demographic data and a complete medical history (including prior and concomitant medical 
conditions/procedures, drug, alcohol, and tobacco use, as well as current use of herbal 
supplements and multivitamins) will be collected at screening and updated at Visit 1. 
6.2 
Safety Assessments 
Safety assessments will include the following: vital sign measurements, physical 
examination, clinical safety laboratory tests, and solicited local and systemic reactogenicity 
symptoms, and occurrence of AEs, MAAEs, PIMMCs (see Appendix 2, Section 12.2), and 
SAEs. These assessments are detailed in Sections 6.2.1 through 6.2.5. 
6.2.1 
Vital Sign Measurements 
Vital sign measurements will include oral temperature, pulse rate, and diastolic and systolic 
blood pressure (after subject is seated for at least 5 minutes).  
6.2.2 
Postvaccination Evaluation 
At Visits 1 and 4 (Groups A-D, G-J) and at Visits 1, 4, and 8 (Groups E, F, K, L), subjects 
will be monitored for solicited (Section 6.2.5.2) and unsolicited AEs, SAEs, MAAEs, 
PIMMCs, and serious and suspected unexpected adverse reactions (SUSARs) for at least 
30 minutes after vaccination. Details regarding collecting and reporting solicited local and 
systemic reactogenicity symptoms are presented in Section 6.2.5.2. Diary cards will be 
distributed according to Table 6–1 and will be used to record solicited local and systemic 
reactions. Solicited local and systemic reactogenicity will be toxicity graded. 

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After the subject has been monitored for 30 minutes after vaccination, the following 
evaluations will be performed: 
1. Obtain 30±5-minute postvaccination vital sign measurements (oral temperature, pulse 
rate, and diastolic and systolic blood pressure) and toxicity grade. 
2. Complete a 30±5-minute postvaccination injection site examination for solicited 
reactogenicity (local and systemic) and toxicity grade (see Section 6.2.5.2). If a visible 
injection-site abnormality is observed, document with a photographa. 
a  Photographs will be taken by study staff only in the event of abnormal findings (not expected with usual 
vaccine administration) for accurate description and evaluation of the findings and safety reviews. There 
are no digital format requirements; the photographs will not be stored in the study database and will not 
be used as part of the safety analysis. Photographs will be shared with the medical monitor, sponsor, and 
IDMC in a secure and blinded manner without exposing personal identification information (including 
tattoos). Subjects will be asked to provide informed consent requesting their permission to take a 
photograph of the finding for the purpose of medical management and safety evaluations. 
6.2.3 
Complete Physical Examination 
A complete physical examination at screening will include the following: height (inches) and 
weight (pounds) and an assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, 
lungs, heart, abdomen, lymph nodes, musculoskeletal system/extremities, and neurological 
system. 
A targeted physical examination will be performed as mentioned in the schedule of events 
(Table 12–1 and Table 12–2) and at the discretion of the investigator, if necessary, to evaluate 
AEs or clinical laboratory abnormalities. 
6.2.4 
Clinical Safety Laboratory Tests 
Clinical safety laboratory tests will include the following according to Table 12–1 and Table 
12–2: 
• hematology: complete blood count with differential and platelet count.  
• coagulation: partial thromboplastin time and prothrombin time (international normalized 
ratio). 
• chemistry/metabolic panel: ALT, AST, total bilirubin, creatinine, and blood urea nitrogen. 

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• urine pregnancy test: for female subjects of childbearing potential, a urine pregnancy test 
will be performed at screening, prior to vaccination on Days 1 and 22, and at any 
unscheduled visit (if clinically indicated) for all groups. In addition, the test will be 
performed prior to vaccination on Day 142 for Groups E, F, K, and L. 
6.2.5 
Adverse Events 
6.2.5.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all treatment-emergent AEs that are observed or 
reported during the study, regardless of their relationship to IP or their clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to IP. Subjects will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
An SAE is defined as any event that results in any of the following: 
• Death, 
• Is immediately life threatening,  
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
• Results in persistent or significant disability/incapacity, or  
• Is a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or 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, a 
blood dyscrasia or convulsion that does not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
Medically attended AEs are defined as AEs with medically attended visits, including hospital, 
emergency room, urgent care clinic, or other visits to or from medical personnel (medical 
doctor, physician assistant, nurse practitioner) for any reason. 

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Potentially immune-mediated medical conditions are considered adverse events of special 
interest. The PIMMCs of concern for this study are detailed in Appendix 2, Section 12.2. 
6.2.5.2 
Solicited Local and Systemic Reactogenicity Symptoms 
All subjects will record solicited local and systemic reactions and other unsolicited 
symptoms/complaints, including start and stop dates, on an 8-day diary card following each 
vaccination. The investigator or his/her designee will review the information from the diary 
card or from memory with the subject at each visit and grade reactogenicity using a standard 
toxicity grade (Appendix 3, Section 12.3). The diary card will be collected from the subjects 
and stored as a source document.  
• Solicited local reactions at the injection site will include erythema/redness, 
induration/swelling, and pain. 
• Solicited systemic reactions will include fever, myalgia, arthralgia, fatigue, headache, 
nausea, vomiting, diarrhea, and chills. 
The above solicited local and systemic reactions will be recorded including start and stop 
dates, worst daily grade, any treatment required, and action taken. The investigator will 
assess if solicited local and systemic reactions will be considered as related to IP according to 
Section 6.2.5.6. The severity of local and systemic reactions will be graded using the FDA 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (Appendix 3, Section 12.3). 
6.2.5.3 
Assessing and Documenting Adverse Events 
Adverse events will be assessed from the time the subject receives the first vaccination 
through Day 43 for Groups A-D and G-J and through Day 163 for Groups E, F, K, L. 
Medically attended adverse events, PIMMCs (Appendix 2, Section 12.2), and SAEs will be 
assessed from the time the subject receives the first vaccination until exit from the study. 
Additional details regarding eliciting and documenting local and systemic reactions are 
provided in Section 6.2.5.2. 
At every study visit (except Visit 1), subjects will be asked a standard nonleading question to 
elicit any medically related changes in their well-being. They will also be asked if they have 
been hospitalized, had any accidents, used any new medications, received any vaccinations, 

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or changed concomitant medication regimens (both prescription and over-the-counter 
medications). 
Subjects will be provided with diary cards to assist them in recording and reporting both 
unsolicited AEs and solicited local and systemic reactions (Section 6.2.5.2), according to 
Table 6–1. 
Laboratory findings that qualify as AEs and nonqualifying laboratory abnormalities outside 
the laboratory’s reference range will be toxicity graded according to the FDA Toxicity 
Grading Scale (Appendix 3, Section 12.3). Similarly, vital signs outside the clinic reference 
range will be graded according to the same scale. The toxicity grade for each identified 
laboratory finding and out-of-reference range vital sign will be documented in the study 
dataset.  
The investigator will assess each Toxicity Scale Grade 1-4 finding and determine whether the 
finding is clinically significant. Grade 1-3 clinically significant findings will be categorized 
as AEs. An FDA toxicity Grade 2 (moderate) or greater (ie, ≥2.6 × ULN; see Appendix 3, 
Section 12.3) ALT and/or AST elevation (regardless of investigator-assessed clinical 
significance) will be entered into the AE reporting page. All Grade 4 findings (regardless of 
investigator-assessed clinical significance) will be graded as AEs. Other safety assessments 
(eg, vital sign measurements), or those identified from review of other documents (eg, diary 
card), including those that worsen from baseline, or are felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. 
For a laboratory finding assessed as an AE (see above), the investigator should report a 
medical condition rather than the name of the laboratory test abnormality whenever possible. 
For example, if the subject has a clinically significant Grade 1, 2, or 3 increased white blood 
cell count due to bronchitis, then the investigator should report the medical condition of 
“bronchitis” rather than “high white blood cell count.” Similarly, a clinically significant 
decreased hemoglobin should be reported as “anemia” rather than “low hemoglobin,” and a 
clinically significant decreased platelet count should be reported as “thrombocytopenia” 
rather than “low platelets.”  
Any clinically significant safety assessment that is associated with an underlying disease 
(unless explicitly identified above), unless judged by the investigator to be more severe than 
expected for the subject’s condition, should not be reported as an AE. 

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Table 6–1 provides the safety data reporting periods used in this study. 
Table 6–1 
Schedule of Diary Cards and Safety Data Reporting Period 
Diary 
Card 
Number 
Type of Event 
Vaccination 
Dose 
Collection Period 
Days After 
Dosing (7 days 
After Each 
Vaccination) 
Collection 
Period: 
Study Days 
Study Groups 
I 
Solicited AEs 
Unsolicited AEsa 
Dose 1 
Postvaccination 
Days 1-8 
Days 1-8 
All 
II 
Unsolicited AEsa 
Dose 1 
Postvaccination 
Days 9-21 
Days 9-21 
All 
III 
Solicited AEs 
Unsolicited AEsa 
Dose 2 
Postvaccination 
Days 1-8 
Days 22-29 
All 
IV 
Unsolicited AEsa 
Dose 2 
Postvaccination 
Days 9-21 
Days 30-43 
All 
V 
Solicited AEs 
Unsolicited AEsa 
Dose 3 
Postvaccination 
Days 1-8 
Days 142-149 
Groups E, F, K, L 
VI 
Unsolicited AEsa 
Dose 3 
Postvaccination 
Days 9-21 
Days 150-163 
Groups E, F, K, L 
NA 
SAEs, MAAEs, 
and PIMMCs 
Entire study periodb 
All 
NA 
Pregnancies 
Entire study periodc 
All 
Abbreviations: AE, adverse event; MAAE, medically attended adverse event; PIMMC, potentially immune-mediated 
medical condition; SAE, serious adverse event.  
a 
Unsolicited AEs will be collected through the end of the study visit window for each AE collection period (ie, 21 days 
after each vaccination ±3-day window = 21 ±3 days).  
b 
The entire study period is from the time a subject receives the first study injection through the end-of-study visit. If the 
investigator becomes aware of any related SAE or related MAAE after exit from or completion of the study, he or she 
is obligated to report this event.  
c 
Pregnancies that occur during a subject’s participation in the study will be followed until resolution and 2 weeks after 
live birth even if the pregnancy ends after the end-of-study visit.  
6.2.5.4 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes event term, time of onset, investigator-specified 
assessment of severity and relationship to IP, time of resolution of the event, seriousness, any 
required treatment or evaluations, and outcome. Adverse events resulting from concurrent 
illnesses, reactions to concurrent illnesses (unless judged by the investigator to be expected 
for the subject’s underlying condition), reactions to concurrent medications, or progression of 
disease states must also be reported. All AEs will be followed to adequate resolution or 
stabilization. The latest version of the Medical Dictionary for Regulatory Activities 

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(MedDRA) at the time of study startup will be used to code all AEs. Additional details 
regarding reporting of local and systemic reactions are provided in Section 6.2.5.2. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates beyond what is 
expected for that condition at any time during the study, it should be recorded as an AE. 
Any AE that meets SAE or PIMMC criteria (Section 6.2.5.1 and Appendix 2, Section 12.2) 
must be reported to PPD immediately (ie, within 24 hours) after the time site personnel first 
learn about the event. The following contact information is to be used for SAE reporting: 
 
SAE Hotline:
 
 
SAE Fax line:
 
The safety event reporting periods are shown in Figure 6-1 for Groups A to D and G to J and 
Figure 6-2 for Groups E, F, K, and L. Solicited AEs will be collected for 7 days after each 
vaccination. Unsolicited AEs will be collected for 21 days after each of 2 vaccine doses 
(Groups A-D and G-J) and for 21 days after each of 3 vaccine doses (Groups E, F, K, and L). 
Serious adverse events and PIMMCs will be collected for approximately 13 months after the 
first study vaccine dose (Groups A-D and G-J) and for approximately 17 months after the 
first study vaccine dose (Groups E, F, K, and L).  

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Figure 6-1 
Safety Event Reporting Period, Groups A to D, G to J 
 
Abbreviations: AE, adverse event; MAAE, medically attended adverse event; PIMMC, potentially immune-mediated 
medical condition; SAE, serious adverse event; Sol, solicited; Unsol, unsolicited. 
Figure 6-2 
Safety Event Reporting Period, Groups E, F, K, L 
 
Abbreviations: AE, adverse event; MAAE, medically attended adverse event; PIMMC, potentially immune-mediated 
medical condition; SAE, serious adverse event; Sol, solicited; Unsol, unsolicited. 
Days 1 to 21 
Dose 1
Day 1
Dose 2
Day 22
End-of-
Study 
(Day 387)
Sol AEs 
Sol AEs
Unsol AEs 
Unsol AEs
SAE, MAAE, PIMMC, Pregnancies
Days 1 to 8 
Entire study duration 
Days 22 to 29
Days 22 to 43
Dose 1
Day 1 
UnsolAEs 
Days 1 to 21 
Dose 2
Day 22 
End-of-
Study 
(Day 507)
Sol AEs 
Sol AEs
Unsol AEs 
UnsolAEs
SAE, MAAE, PIMMC, Pregnancies
Days 1 to 8 
Entire study duration 
Days 22 to 29
Days 22 to 43
<>Dose 3
Day 142
Sol AEs 
Days 142 to 149
Days 142 to 163

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6.2.5.5 
Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the subject’s daily activities. 
All solicited AEs will be graded according to the FDA Toxicity Grading Scale (Appendix 3, 
Section 12.3) and entered into the AE reporting page. Grade 1-3 hematology or serum 
chemistry values determined by the investigator to be clinically significant will be entered 
into the AE reporting page. An FDA toxicity Grade 2 (moderate) or greater (ie, ≥2.6 × ULN; 
see Appendix 3, Section 12.3) ALT and/or AST elevation (regardless of investigator-assessed 
clinical significance) will be entered into the AE reporting page, and the grading will be 
consistent with the FDA toxicity score. All Grade 4 laboratory findings are considered AEs 
regardless of the investigator’s determination of clinical significance and should also be 
entered using the FDA toxicity score for severity. In all other cases, the severity of each AE 
will be rated as mild, moderate, or severe using the following criteria: 
Mild: 
An event usually transient in nature and generally not interfering with 
normal activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal 
activities. 
Severe: 
An AE that is incapacitating and/or prevents normal activities. 
 
Changes in the intensity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. The 
severity of solicited AEs will be classified. 
6.2.5.6 
Assessment of Causality 
The investigator’s assessment of the relationship between an AE and study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 

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The relationship or association of the IP in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is not a reasonable possibilitya that the AE 
is related to the IP. 
Related: 
This relationship suggests that there is a reasonable possibilitya that the AE is 
related to the IP. 
Note: The investigator should consider the package inserts of all products administered in this study when 
determining causality.  
a 
Reasonable possibility means there is evidence to suggest a causal relationship between the IP and the AE.  
6.2.5.7 
Assessing Expectedness 
Expected AEs are AEs consistent with the applicable product information provided by the 
sponsor (the investigator brochures for IP). The sponsor, in consultation with the medical 
monitor, determines expectedness of SAEs and MAAEs. The sponsor and medical monitor 
should consider the package inserts of all products administered in this study when 
determining expectedness. If the assessment is that the SAE or MAAE is expected, no further 
reporting is required. If the medical monitor’s assessment is that the SAE or MAAE is 
unexpected, then the event may represent a SUSAR or expedited SAE for reporting purposes. 
6.2.5.8 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. In the case of an abnormal 
laboratory value that is entered as an AE due to toxicity grade parameters (ie, clinically 
significant Grade 1 to 3, Grade 4 [regardless of clinical significance], and ALT and/or AST 
elevations ≥2.6 × ULN), the subject will be required to have a repeat laboratory test with 
results assessed by the investigator and continued monitoring until the results return to the 
screening baseline value (ie, baseline toxicity score) or are considered stable with a new 
baseline. Subjects may not receive revaccination if ALT and/or AST elevations reach ≥2 by 
FDA toxicity score and do not return to the screening baseline value (ie, baseline toxicity 
score) by the time of revaccination.  

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6.3 
Immunogenicity Assessments 
Immunogenicity assessments will include the following assessments at Day 1, Day 22, 
Day 43, and Day 142 (Groups A-D, G-J) and at Day 1, Day 22, Day 43, Day 142, Day 163, 
and Day 262 (Groups E, F, K, L). 
• Serum HAI antibody titers 
• Seroprotection based on serum HAI antibody titers, defined as an HAI antibody titer 
≥1:40 
• Seroconversion based on serum HAI antibody titers, defined as either a prevaccination 
HAI titer <1:10 and a postvaccination HAI titer ≥1:40, or a prevaccination HAI titer 
≥1:10 and a minimum 4-fold rise in postvaccination HAI titer 
• Serum MN antibody titers 
• Seroconversion based on serum MN antibody titers, defined as either a prevaccination 
MN titer <1:10 and a postvaccination MN titer ≥1:40, or a prevaccination MN titer ≥1:10 
and a minimum 4-fold rise in postvaccination MN titer 
The details on the handling, processing, and shipping will be provided in the Laboratory 
Manual.  
6.4 
Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an IP may have interfered 
with the effectiveness of a contraceptive medication. Any pregnancy that occurs during study 
participation must be reported using a clinical study pregnancy form. If a subject becomes 
pregnant, she will not have any invasive procedures performed and will not receive any 
further vaccinations, as normally mandated by the protocol. The subject will undergo all 
other evaluations according to the schedule of events (Table 12–1 and Table 12–2). To ensure 
subject safety, each pregnancy must be reported to the sponsor, BARDA, within 2 weeks of 
learning of its occurrence. The pregnancy must be followed up to resolution and 2 weeks 
after live birth to determine outcome (including spontaneous miscarriage, elective 
termination, normal birth, or congenital abnormality) and status of mother and child, even if 
the subject was discontinued from the study or if the pregnancy ends after the end-of-study 
visit (Visit 9 [Groups A-D, G-J] and Visit 14 [Groups E, F, K, L]). Pregnancy complications 

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and elective terminations for medical reasons must be reported as an AE or SAE. 
Spontaneous miscarriages must be reported as an SAE. 
6.5 
Sample Collections 
Procedures for the handling and processing of biological samples are provided in the 
Laboratory Manual.  
The hematology, coagulation, and chemistry/metabolic panel laboratory analyses will be 
performed at a central laboratory. Reference ranges will be used by the investigator to assess 
the laboratory data for clinical significance and pathological changes and will be graded 
according to the FDA Toxicity Grading Scale (Appendix 3, Section 12.3). 
The samples collected for immunogenicity testing and cell-mediated assays will be stored in 
appropriate conditions as specified in the Laboratory Manual until shipped for testing at a 
facility designated by the sponsor.  

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7 
Statistical and Analytical Plan 
This is a descriptive study and no formal hypotheses for the primary endpoints are being 
tested. The main purpose of this study is to assess the ability of H5 influenza vaccines and 
adjuvants present in the NPIVS to generate an immune response to homologous and to 
antigenically distant heterologous H5 influenza virus strains. The primary outcomes will be 
descriptive in terms of whether the study vaccines are safe and immunogenic. 
7.1 
Primary Endpoints 
• Safety: Occurrence of mild, moderate, or severe solicited local and systemic 
reactogenicity symptoms during the 8 days postvaccination, inclusive of the vaccination 
day 
• Immunogenicity: SPR (defined as the proportion of subjects achieving a serum HAI titer 
of at least 1:40 against influenza antigen) against strains contained in the vaccines on 
Day 43 for Groups A-D and G-J and on Day 163 for Groups E, F, K, L  
7.2 
Secondary Endpoints 
Secondary Safety Endpoints: 
• Occurrence of SAEs, MAAEs, and PIMMCs in 12 treatment groups through 12 months 
after the last dose of study vaccine  
• Occurrence of any AEs leading to study withdrawal 
• Frequency and severity of unsolicited AEs for 21 days following each vaccination  
• Occurrence of clinical safety laboratory abnormalities at all collected time points  
• Occurrence of vital sign abnormalities at all collected time points 
Secondary Immunogenicity Endpoints: 
• Serum HAI and MN antibody responses at all collected time points 
• SPR of serum HAI antibody at collected time points 

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• Seroconversion rate (defined as proportion of subjects achieving either a prevaccination 
antibody titer of <1:10 and a postvaccination titer of at least 1:40 or a prevaccination 
antibody titer of at least 1:10 and a 4-fold or greater increase of postvaccination antibody 
titer; if antibody titer is undetectable, it will be assigned a value of half the lower limit of 
detection) at all collected postvaccination time points 
7.3 
Exploratory Endpoints 
Exploratory Immunogenicity Endpoints: 
• Peripheral antibody responses to epitopes within the influenza virus surface proteins HA 
or neuraminidase at all collected time points 
• Cell-mediated (eg, B cell, CD4+ T cell, CD8+ T cell) responses in a subset composed of 
approximately half of enrolled subjects using PBMCs at all collected time points 
7.4 
Sample Size Calculations 
Approximately 720 subjects with 60 subjects per study group will be enrolled in the study. 
Approximately half of enrolled subjects will be selected to provide a blood sample for PBMC 
collection. 
The number of subjects proposed to be enrolled in this protocol is based upon previous 
experience with similar studies such as the Mix and Match Studies (NCT 01317745 and 
NCT 01217758) performed by Division of Microbiology and Infectious Diseases/National 
Institute of Allergy and Infectious Diseases. These prior studies had study groups of similar 
size that proved to be sufficient to allow the collection of meaningful data, especially with 
respect to acute solicited AEs and antibody results. While the current study is not designed to 
test specific hypotheses, Table 7–1 and Table 7–2 indicate the power of the proposed sample 
size to detect a range of common, immediate postvaccination elicited safety events as well as 
to meet the success criteria for SPR. 

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Table 7–1 
Safety – Power for Detecting at Least 1 SAE, MAAE, or a Grade 3 
Solicited AE 
True Event Rate (%) 
Power (%) 
N = 60 
Power (%) 
N = 120 
0.1 
5.8 
11.3 
0.5 
26.0 
45.2 
1 
45.3 
70.1 
2 
70.2 
91.2 
3 
83.9 
97.4 
4 
91.4 
99.3 
5 
95.4 
99.8 
Abbreviations: AE, adverse event; MAAE, medically attended adverse event; SAE, serious adverse event.  
Note: The exact method was used for the calculations in this table. 
Note: Serious adverse events and MAAEs will be collected for approximately 12 months after the last study vaccine dose.  
Note: Solicited AEs will be collected for 7 days after each of the vaccine doses. 
Table 7–2 
Immunogenicity – Power for Meeting Success Criteria of SPR 
Success Criteria (%) 
Proportion of Subjects Achieving a 
Serum HAI Antibody Titer of at Least 
1:40 for the Testing Vaccine (%) 
Power (%) 
N = 60 
Power (%) 
N = 120 
70 
90 
98.5 
>99.9 
85 
81.9 
99.0 
80 
44.9 
79.0 
Abbreviations: HAI, hemagglutination inhibition; SPR, seroprotection rate. 
7.5 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Full analysis set (FAS): The FAS will consist of all subjects who are randomly assigned to 
receive IP. All analyses using the FAS will group subjects according to randomized 
treatment.  
Safety set: The safety set will consist of all subjects who are randomly assigned and receive 
at least 1 dose of IP. Safety endpoint summaries and listings will be performed on the safety 
set using study group treatment actually received. 
Immunogenicity-full analysis set (IFAS): The IFAS will consist of all subjects who are 
randomly assigned, receive at least 1 dose of IP, and have at least 1 valid postvaccination and 

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determinate assay result. As supportive analysis, all the immunogenicity endpoint summaries 
will be performed on the IFAS by actual treatments received. 
Immunogenicity per-protocol set (IPPS): The IPPS is a subset of the IFAS, where all subjects 
meet the IFAS criteria and must meet the following criteria: 
• have received all the doses of IP to which they were randomly assigned  
• have valid and determinate assay result for HAI at Day 43 for Groups A-D and G-J, and 
Day 163 for Groups E, F, K, L 
• have no significant protocol deviations that are determined to potentially interfere with 
the immunogenicity assessment of IP.  
All the immunogenicity endpoint summaries will be performed primarily on the IPPS using 
treatment actually received. 
7.6 
Description of Subgroups to be Analyzed 
No subgroup analyses are planned. 
7.7 
Statistical Analysis Methodology 
Study data will be summarized with descriptive statistics (mean, standard deviation, median, 
minimum, maximum, and number of observations) for quantitative parameters and by 
incidence rates and the corresponding 95% confidence intervals (CIs) for categorical findings 
as appropriate.  
No formal significance testing will be performed. Details of the statistical analyses, methods, 
and data conventions are described in the statistical analysis plan. 
7.7.1 
Subject Disposition 
Subject disposition will be summarized by study group and will include subjects who are 
enrolled, randomly assigned, discontinue, and complete the study. For discontinued subjects, 
reasons for discontinuation will be summarized. 

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7.7.2 
Analyses of Demographic and Baseline Characteristics 
Demographic and baseline characteristics, such as age, gender, race, body weight, height, and 
medical history will be summarized by study group using descriptive statistics. 
7.7.3 
Analysis of Primary Endpoints 
7.7.3.1 
Analysis of Primary Safety Endpoint 
Solicited local and systemic reactions (recorded as AEs, Section 6.2.5.2) during the 8 days 
after each vaccination, inclusive of the vaccination day, will be summarized as a frequency 
table that includes 95% exact CIs by study group and by the degree of severity (mild, 
moderate, or severe).  
7.7.3.2 
Analysis of Primary Immunogenicity Endpoint 
The SPR and corresponding 95% CIs of HAI antibody responses against strains contained in 
the vaccine at Day 43 for Groups A-D and G-J, and Day 163 for Groups E, F, K, L will be 
summarized for each study group. 
7.7.4 
Analysis of Secondary Endpoint 
7.7.4.1 
Analysis of Secondary Safety Endpoint 
Serious adverse events, MAAEs, PIMMCs, and AEs leading to study withdrawal will be 
summarized by study group and system organ class (SOC)/preferred term (PT). 
Unsolicited AEs (including clinically significant laboratory and vital sign abnormalities) for 
21 days following each vaccination will be summarized by study group, SOC/PT, and further 
summarized by severity and relatedness. 
Clinical safety laboratory abnormalities will be summarized at prevaccination and 7 days 
after each vaccination by study group.  
7.7.4.2 
Analysis of Secondary Immunogenicity Endpoint 
Geometric mean titers and the corresponding 95% CIs of serum HAI and MN antibody 
responses will be summarized at all collected time points. 

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The SPR and corresponding 95% CIs for HAI antibodies will be summarized by study group 
at all collected time points.  
The SCR and the corresponding 95% CIs for both HAI and MN antibodies will be 
summarized by study group at all collected postvaccination time points. 
7.7.5 
Analyses of Exploratory Immunogenicity Endpoint 
The exploratory analyses will be described in the statistical analysis plan.  
7.7.6 
Other Analyses 
Prior and posttreatment physical examination findings, the number and percentage of 
subjects who receive 1, 2, and 3 total doses of IP will be summarized by study group. 
7.7.7 
Interim Analyses 
Interim analyses will be performed based on cumulative immunogenicity and safety data at 
Day 43 and Day 163 for all study groups. At each time point the study database will be 
monitored, cleaned, and frozen through the data cut time point. The study team, except the 
unblinded team members, should remain blind until final database lock and unblinding. 
Interim analysis results will be unblinded at the group level, and each group will be assigned 
a fake name. Results will be provided to the sponsor with groups identified only by their fake 
names. 
7.8 
Data Quality Assurance 
The sponsor will perform quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any subjects in this study, sponsor personnel and the investigator 
will review the protocol, the package inserts, investigator brochures, the eCRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs. A qualified representative of the sponsor will monitor 
the conduct of the study by visiting the site and by contacting the site by telephone and 
e-mail. During these site visits, information recorded in the eCRFs will be verified against 
source documents. 

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7.8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports. 
Study site staff will enter subject data into Medidata RAVE. The analysis data populations 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD and/or 
BARDA standards and data cleaning procedures to ensure the integrity of the data, eg, 
removing errors and inconsistencies in the data. Adverse events (including SAEs, MAAEs, 
and PIMMCs) and concomitant medication terms will be coded using the MedDRA and 
WHODrug dictionaries, respectively. 
After database lock, each site will receive a Compact Disc Read-Only Memory (CDROM) 
containing all of their site-specific eCRF data as entered into Medidata RAVE for the study, 
including full discrepancy and audit history. Additionally, a CDROM copy of all of the site’s 
data from the study will be created and sent to the sponsor for storage. PPD will maintain a 
duplicate CDROM copy for their records. In all cases, subject names or initials will not be 
collected by or transmitted to the sponsor. 

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8 
Ethics 
8.1 
Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an institutional review board (IRB) before participation of 
human subjects in research studies. Before study onset, the protocol, informed consent, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB. Documentation of all IRB approvals and of the IRB 
compliance with ICH harmonised tripartite guideline E6(R1): Good Clinical Practice (GCP) 
will be maintained by the site and will be available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB. The 
investigator must promptly supply the sponsor or its designee, the IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
8.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
8.3 
Subject Information and Consent 
A written informed consent in compliance with regulatory authority regulations and US 
Title 21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each subject 
before entering the study or performing any unusual or nonroutine procedure that involves 
risk to the subject. An informed consent template may be provided by the sponsor to sites. If 
any institution-specific modifications to study-related procedures are proposed or made by 
the site, the consent should be reviewed by the sponsor or its designee or both before IRB 
submission. Once reviewed, the consent will be submitted by the investigator to his or her 

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IRB for review and approval before the start of the study. If the ICF is revised during the 
course of the study, all active participating subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
Using the ICF, subjects who participate in this study will also be asked 3 questions (included 
in Section 3.1.4). The investigator shall retain the signed original ICF(s) and give a copy of 
the signed original form to the subject or legal guardian. 

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9 
Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 
Financial Disclosure 
Investigators and subinvestigators are required to provide financial disclosure information to 
allow the sponsor to submit the complete and accurate certification or disclosure statements 
required under 21 CFR 54. In addition, the investigators and subinvestigators must provide to 
the sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study. 
9.3 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• IRB approval 
• Original investigator-signed investigator agreement page of the protocol 

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• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
• Current (within 2 years) curriculum vitae for the investigator and each subinvestigator 
listed on Form FDA 1572 
• Medical licenses for all investigators 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators and subinvestigators must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
• Executed clinical study agreement 
• Documentation of Federal Wide Assurance number and expiration date 
• IRB-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to the 
subject or legal guardian 
• Site delegation log 
• Documentation of human subjects protection training by all staff listed on the site 
delegation log 
• Laboratory certifications and normal ranges for central laboratory, in accordance with 
42 CFR 493 
• Centers for Laboratory Improvement Amendments Waiver for pregnancy tests performed 
onsite 
9.4 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R1) and 21 CFR 312. The investigator will conduct all aspects of this study in accordance 
with all national, state, and local laws or regulations. Study information from this protocol 
will be posted on publicly available clinical study registers before enrollment of subjects 
begins. 

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9.5 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and 21 CFR 312 and all applicable guidelines and regulations. 
9.6 
Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the site IRB as appropriate. 
9.7 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any reports required. 
9.8 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP, as described in 21 CFR 312.62. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to 
be retained. 
9.9 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will determine how the manuscript is written and edited, 
the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 

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10 Study Management 
10.1 Monitoring 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. Investigational product accountability will be monitored by a 
separate unblinded monitor. 
10.1.1 
Safety Monitoring: Responsibilities for Ensuring the Safety of 
Study Subjects 
The regulatory authority, BARDA, the institution where the research is performed, and all 
members of the investigator’s clinical team share responsibility for ensuring that participants 
in this study are exposed to the least possible risk of AEs that may result from participation in 
this protocol. 
10.1.2 
Principal Investigator 
The principal investigator has a personal responsibility to closely monitor study subjects and 
an inherent authority to take whatever measures necessary to ensure their safety. The 
principal investigator has the authority to terminate, suspend, or require changes to a clinical 
study for safety concerns and may delay an individual’s study IP administration if the 
principal investigator has some suspicion that the study vaccine might place a subject at 
significant risk. Where specified, responsibilities of the principal investigator may be 
delegated to a medically qualified team member (designee). The principal investigator or 
designee determines severity and causality with respect to the study IP for each AE.  
10.1.3 
Study Sponsor 
The sponsor also has an institutional responsibility to ensure subject safety. This 
responsibility is vested in a medical monitor and an IDMC.  
10.1.4 
Medical Monitor 
The medical monitor is the sponsor’s representative and is a physician or surgeon in the 
United States. The medical monitor will maintain current personal knowledge of the study 
through observation, review of study records and source documentation, monitor for study 

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pausing rules, and discuss the conduct of the study with the investigator and personnel. The 
medical monitor reviews the safety of the IP for protocols in a specific region and, in 
conjunction with the sponsor, determines expectedness of the AE. The medical monitor, in 
consultation with the sponsor, will review causality for SAEs/MAAEs/PIMMCs and may 
discuss the causality with the investigator or designee. The medical monitor, like the 
investigator, will be blinded for the subjects’ study group assignments.  
10.1.5 
Independent Data Monitoring Committee 
The IDMC will operate according to the IDMC Charter. The IDMC will review study 
progress and oversee clinical, safety, and reactogenicity data on an ad hoc basis; the IDMC 
will meet only if a pausing rule is met. The IDMC will be composed of 3 members with 
expertise in the conduct and safety oversight of vaccine clinical studies. One of the IDMC 
members will serve as the IDMC chairperson.  
The IDMC may recommend suspension or resumption of enrollment and study vaccine 
administration after review of safety data. However, the sponsor will make the final decision 
to suspend or resume study activities. The recommendations of the IDMC, along with the 
sponsor’s decision, will be communicated to the investigators, the IRB, and regulatory 
agency.  
10.1.6 
Institutional Review Board 
The IRB has institutional responsibility for the safety of study subjects. The IRB has the 
authority to terminate, suspend, or require changes to a clinical study. The sponsor or its 
designee agrees to abide by any directives issued by the IRB. 
10.1.7 
Regulatory Authority 
As this study is conducted under a US Investigational New Drug Application, the FDA has 
the authority to place the study on a regulatory clinical hold for modification, suspension, or 
termination of the study. The sponsor or its designee agrees to abide by any directives issued 
by the regulatory agency. 
10.1.8 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 

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In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency (eg, FDA) access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Full amendments to the protocol must be approved by the IRB before subjects can 
be enrolled into an amended protocol. Letters of amendment or clarification do not need to be 
approved by the IRB. 
10.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject or that may 
affect the study outcome. Significant deviations can include nonadherence to inclusion or 
exclusion criteria or nonadherence to FDA regulations or ICH GCP guidelines, and may lead 
to the subject being withdrawn from the study (ie, no longer receive IP, see Section 4.2). 
Neither the sponsor nor designee will authorize deviations to the study. Deviations from the 
protocol are not permitted except to protect the safety of a subject. 

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Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Investigators will be notified in writing by the monitor of deviations. The 
IRB should be notified of all significant protocol deviations in a timely manner, as defined by 
the IRB. 
10.3 Study Termination 
Although BARDA has every intention of completing the study, BARDA reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes Visit 9 
(end-of-study visit) for Groups A-D and G-J (Table 12–1) and Visit 14 (end-of-study visit) 
for Groups E, F, K, and L (Table 12–2).  
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
CSRs are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The sponsor will also ensure that the CSRs in marketing 
applications meet the standards of the ICH harmonised tripartite guideline E3: Structure and 
content of CSRs. 
A final CSR will be written with unblinded data at the subject level through Day 142 for 
Groups A-D and G-J and through Day 262 for Groups E, F, K, and L. Additional long-term 
safety results will be included in an addendum to the final CSR. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the investigator with the full summary 
of the study results. The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. The study results will be posted on publicly available clinical 
study registers. 

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11 Reference List 
Afluria, Influenza Virus Vaccine Suspension for Intramuscular Injection [package insert]. 
CSL Limited (Australia); 2010.  
Belshe RB, Frey SE, Graham I, et al; National Institute of Allergy and Infectious Diseases-
Funded Vaccine and Treatment Evaluation Units. Safety and immunogenicity of influenza A 
H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. 
2011;203(5):666-73. 
Belshe RB, Frey SE, Graham IL, et al; National Institute of Allergy and Infectious Diseases-
Funded Vaccine and Treatment Evaluation Units. Immunogenicity of avian 
influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial. 
JAMA. 2014;312(14):1420-8. 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Biologics Evaluation and Research (CBER) (US). Guidance for industry: Toxicity 
grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine 
clinical trials. September 2007 [cited 2017 May 05] [10 screens]. Available from: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Vaccines/ucm091977.pdf  
Duffy J, Weintraub E, Vellozzi C, et al. Narcolepsy and influenza A (H1N1) pandemic 2009 
vaccination in the United States. Neurology. 2014;83(20):1823-30.  
FLUAD (Influenza Vaccine, Adjuvanted) Suspension for Intramuscular Injection [package 
insert]. Holly Springs (NC): Seqirus Vaccines Limited 2016.  
Flucelvax Quadrivalent (Influenza Vaccine) Suspension for Intramuscular Injection [package 
insert]. Seqirus, Inc. Holly Springs (NC); 2016.  
Fluzone Quadrivalent (Influenza Vaccine) Suspension for Intramuscular Injection [package 
insert]. Sanofi Pasteur Inc. Swiftwater (PA); 2016.  
Gillard P, Caplanusi A, Knuf M, et al. An assessment of prime-boost vaccination schedules 
with AS03A-adjuvanted prepandemic H5N1 vaccines: a randomized study in European 
adults. Influenza Other Respir Viruses. 2013;7(1):55-65. 

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Gillard P, Chu DW, Hwang SJ, et al. Long-term booster schedules with AS03A-adjuvanted 
heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults. 
BMC Infect Dis. 2014;14:142. 
Gu M, Liu W, Cao Y, et al. Novel reassortant highly pathogenic avian influenza (H5N5) 
viruses in domestic ducks, China. Emerg Infect Dis. 2011;17(6):1060-3. 
Hill SC, Lee YJ, Song BM, et al. Wild waterfowl migration and domestic duck density shape 
the epidemiology of highly pathogenic H5N8 influenza in the Republic of Korea. Infect 
Genet Evol. 2015;34:267-77. 
Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted; Emulsion for Intramuscular 
Injection [package insert]. Quebec City (QC, Canada); GlaxoSmithKline 2013. 
Leroux-Roels I, Roman F, Forgus S, et al. Priming with AS03 A-adjuvanted H5N1 influenza 
vaccine improves the kinetics, magnitude and durability of the immune response after a 
heterologous booster vaccination: an open non-randomised extension of a double-blind 
randomised primary study. Vaccine. 2010;28(3):849-57. 
Levine MZ, Holiday C, Liu F, et al. Cross-reactive antibody responses to novel H5Nx 
influenza viruses following homologous and heterologous prime-boost vaccination with a 
prepandemic stockpiled A(H5N1) vaccine in humans. J Infect Dis. 
2017;216(suppl 4):S555-9. 
Lind A, Ramelius A, Olsson T, et al. A/H1N1 antibodies and TRIB2 autoantibodies in 
narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in 
Sweden 2009-2010. J Autoimmun. 2014;50:99-106.  
Montplaisir J, Petit D, Quinn MJ, et al. Risk of narcolepsy associated with inactivated 
adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One. 
2014;9(9):e108489.  
Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with 
an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 
2012;7(3):e33536.  

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Pellegrini M, Nicolay U, Lindert K, et al. MF59-adjuvanted versus non-adjuvanted influenza 
vaccines: integrated analysis from a large safety database. Vaccine. 2009;27(49):6959-65. 
Schultze V, D’Agosto V, Wack A, et al. Safety of MF59 adjuvant. Vaccine. 
2008;26(26):3209-22. 
Shimabukuro TT, Weibel D, Sturkenboom MC, et al. Systematic Observational Method for 
Narcolepsy and Influenza Immunization Assessment (SOMNIA): risk of narcolepsy 
following adjuvanted 2009 H1N1 influenza vaccines. National Foundation for Infectious 
Diseases. 20th Annual Conference on Vaccine Research. 2017 Apr; Bethesda, Maryland.  
United States Department of Agriculture (USDA) [Internet]. 2016 HPAI Preparedness and 
Response Plan. 2016 Jan 11 [cited 2017 Mar 11]; [20 screens]. Available from: 
https://www.aphis.usda.gov/animal_health/downloads/animal_diseases/ai/hpai-preparedness-
and-response-plan-2015.pdf  
Wong FY, Phommachanh P, Kalpravidh W, et al. Reassortant highly pathogenic influenza A 
(H5N6) virus in Laos. Emerg Infect Dis. 2015;21(3):511-6. 
World Health Organization (WHO) [Internet]. Cumulative number of confirmed human cases 
for avian influenza A(H5N1) reported to WHO. 2017a Jul 25 [cited 2017 Mar 11]; [3 
screens]. Available from: 
http://www.who.int/influenza/human_animal_interface/2017_07_25_tableH5N1.pdf?ua=1  
World Health Organization (WHO) [Internet]. Influenza at the human-animal interface. 
2017b Feb [cited 2017 Sep 13]; [10 screens]. Available from: 
http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interf
ace_02_14_2017.pdf?ua=1  
Zhao G, Gu X, Lu X, et al. Novel reassortant highly pathogenic H5N2 avian influenza 
viruses in poultry in China. PLoS One. 2012;7(9):e46183. 
Zhao K, Gu M, Zhong L, et al. Characterization of three H5N5 and one H5N8 highly 
pathogenic avian influenza viruses in China. Vet Microbiol. 2013;163(3-4):351-7. 

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12 Appendices 
12.1 Appendix 1: Schedule of Events  
 

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Table 12–1 
Schedule of Events, Groups A to D, G to J 
Study visit 
Screening
V1 
V2a 
V3 
V4 
V5a 
V6 
V7 
V8 
V9a 
(EOS) 
ET 
Unsch 
Study day 
-14 to -3 
1 
4 
8 
22 
25 
29 
43 
142 
387 
N/A 
N/A 
Window allowance (days) 
 
 
V1+3 
(±1) 
V1+7 
(±1) 
V1+21 
(+3) 
V4+3 
(±1) 
V4+7 
(±1) 
V4+21 
(±3) 
V1+141 
(±7) 
V1+386 
(±7) 
N/A 
N/A 
Obtain informed consent 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurementsc 
X 
X 
 
X 
X 
 
X 
X 
   
 
X 
Xd 
Height and weight 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Perform subject interviewf 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review diary cardg 
 
   
X 
X 
X 
X 
X 
X 
 
 
Xh 
Xh 
Distribute diary cardg and 
review instructions 
 
X 
DCI 
 
X 
DCII 
X 
DCIII 
 
X 
DCIV 
 
 
 
 
 
Distribute measuring tool and 
thermometer and review 
instructions 
 
X 
 
 
X 
 
 
 
 
 
 
 
Collect diary cardg 
 
 
 
X 
DCI 
X 
DCII 
 
X 
DCIII 
X 
DCIV 
 
 
 
 
Concomitant medications  
Xi 
Xe,i 
X 
Xj 
Xe 
X 
Xj 
X 
X 
X 
X 
X 
Concomitant vaccinations 
Xi 
Xe,i 
X 
Xj 
Xe 
X 
Xj 
X 
X 
X 
X 
X 
Complete physical 
examination k 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examinationl 
 
Xe 
 
X 
Xe 
 
X 
 
 
 
Xd 
Xd 
Urine pregnancy test 
(WOCBP) 
X 
Xe,m 
 
 
Xe,m 
 
 
 
 
 
 
Xd 
Review inclusion and 
exclusion criteria 
X 
Xe 
 
 
Xe 
 
 
 
 
 
 
 

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Table 12–1 
Schedule of Events, Groups A to D, G to J 
Study visit 
Screening
V1 
V2a 
V3 
V4 
V5a 
V6 
V7 
V8 
V9a 
(EOS) 
ET 
Unsch 
Study day 
-14 to -3
1 
4 
8 
22 
25 
29 
43 
142 
387 
N/A 
N/A 
Window allowance (days) 
 
 
V1+3 
(±1) 
V1+7 
(±1) 
V1+21 
(+3) 
V4+3 
(±1) 
V4+7 
(±1) 
V4+21 
(±3) 
V1+141 
(±7) 
V1+386 
(±7) 
N/A 
N/A 
Venous blood sample 
collection for clinical safety 
laboratory testsn 
X 
 
 
Xo 
Xe,o 
 
Xo 
 
 
 
 
Xd 
Venous blood sample 
collection for antibody 
assays 
 
Xe 
 
 
Xe 
 
 
X 
X 
 
 
 
Cellular immunology (subset 
only) 
 
Xe 
 
 
Xe 
 
 
X 
X 
 
 
 
Randomization 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
Xp 
 
 
 
 
 
 
 
Monitor subject for 
30 minutes following 
vaccinationq 
 
X 
 
 
X 
 
 
 
 
 
 
 
Examine vaccination siter 
 
Xs 
 
X 
Xs 
 
X 
 
 
 
Xd 
Xt 
AE/MAAE/PIMMC/SAE 
assessmentu 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DC, diary card; eCRF, electronic case report form; EOS, end of 
study; ET, early termination; FDA, Food and Drug Administration; MAAE, medically attended adverse event; N/A, not applicable; PIMMC, potentially immune-
mediated medical condition; SAE, serious adverse event; SUSAR, suspected unexpected serious adverse reaction; ULN, upper limit of normal; Unsch, 
unscheduled; V, visit; WOCBP, women of childbearing potential. 
a 
Telephone call assessment. 
b 
Prior to the completion of any study-related procedures. 

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c 
Vital sign measurements include oral temperature, pulse rate, and blood pressure. Vital signs will be measured before blood is collected, at both pre-vaccination 
and 30±5-minute postvaccination time points on a vaccination day. Diastolic and systolic blood pressure will be measured after the subject is seated for at least 
5 minutes. 
d 
If clinically indicated. 
e 
Prior to vaccination. 
f 
Ask subject a standard nonleading question to elicit any medically related changes in their well-being. Ask if they have been hospitalized, had any accidents, used 
any new medications, received any vaccinations, or changed concomitant medication regimens (both prescription and over-the-counter medications). 
g 
Diary Card I (Days 1-8) and III (Days 22-29) will be used to collect unsolicited and solicited local and systemic reactions. Diary Card II (Days 9-21) and IV 
(Days 30-43) will be used to collect unsolicited AEs.  
h 
If applicable, according to the protocol period, collect and review DC with subject.  
i 
Use of all concomitant medications that the subject is taking at the time of Visit 1, medications taken up to 14 days prior to Visit 1, and vaccines received 
12 months prior to Visit 1 will be recorded in the subject’s eCRF. 
j 
Obtained by interview and by review of diary card completed by the subject. 
k 
Any physical examination findings will be collected in the eCRF for medical history data presentation.  
l 
Targeted physical examination will be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. Any 
findings from this examination will be collected in the eCRF for AEs. 
m 
A urine pregnancy test must be performed within 24 hours prior to vaccination and pregnancy test results must be final and negative prior to vaccination. 
n 
Hematology: complete blood count with differential, platelet count; coagulation: partial thromboplastin time and prothrombin time (international normalized 
ratio); chemistry/metabolic panel: ALT, AST, total bilirubin, creatinine, and blood urea nitrogen.  
o 
For abnormal laboratory results that are clinically significant and for ALT and/or AST elevations ≥2.6 × ULN, repeat test until resolved or results become stable 
(see Section 6.2.5.8). 
p 
Subjects with an acute illness, including body temperature greater than 100.4°F, immediately prior to each vaccination or, per subject report, within 3 days prior to 
a scheduled vaccination in this study can be rescheduled for vaccination as long as the vaccination visit is within the visit window. Subjects with a Grade ≥3 AE 
that has not returned to baseline or stabilized will not be revaccinated. Subjects with a serum ALT and/or AST elevation that is Grade 2 (moderate) or greater 
based on FDA toxicity grading (ie, ≥2.6 × ULN) will not be revaccinated unless the value resolves on repeat testing to the screening baseline value (ie, baseline 
toxicity score) and the subject remains within the visit window allowance (see Section 4.3). 
q 
At Visits 1 and 4, subjects will be monitored for solicited and unsolicited AEs, SAEs, MAAEs, PIMMCs, and SUSARs for at least 30 minutes after vaccination; 
concomitant medications will be recorded. 
r 
Examine vaccination site for erythema/redness and swelling and monitor for pain. 
s 
At Visits 1 and 4, complete a 30±5-minute postvaccination injection site examination for erythema/redness and swelling and monitor for pain. If a visible 
injection-site abnormality is observed, document with a photograph.  
t 
If the unscheduled visit occurs within 7 days after either of the 2 study vaccinations.  
u 
Only MAAEs, PIMMCs (see Appendix 2, Section 12.2), and SAEs will be collected after Day 43, all other AEs will be collected through 21 days following each 
vaccination.  
 

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Page 80 
Table 12–2 
Schedule of Events, Groups E, F, K, L 
Study visit 
Screening V1 V2a
V3 
V4 
V5a
V6 
V7 
V8 
V9a 
V10 
V11 
V12 
V13a 
V14a 
(EOS) 
ET Unsch
Study day 
-14 to -3 
1 
4 
8 
22 
25 
29 
43 
142 
145 
149 
163 
262 
322 
507 
N/A
N/A 
Window 
allowance (days) 
 
 
V1+3 
(±1)
V1+7 
(±1)
V1+21 
(+3) 
V4+3 
(±1)
V4+7 
(±1) 
V4+21 
(±3) 
V1+141 
(±7) 
V8+3 
(±1) 
V8+7 
(±1) 
V8+21 
(±3) 
V1+261 
(±7) 
V1+321 
(±7) 
V1+506 
(±7) 
N/A
N/A 
Obtain informed 
consent 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurementsc 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
Xd 
Height and weight 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform subject 
interviewf 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review diary 
cardg 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Xh 
Xh 
Distribute diary 
cardg and review 
instructions 
 
X 
DCI 
 
X
DCII
X 
DCIII
 
X 
DCIV
 
X 
DCV 
 
X 
DCVI 
 
 
 
 
 
 
Distribute 
measuring tool 
and thermometer 
and review 
instructions 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Collect diary cardg 
 
 
 
X
DCI
X 
DCII
 
X 
DCIII
X 
DCIV
 
 
X 
DCV 
X 
DCVI 
 
 
 
 
 
 

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Page 81 
Table 12–2 
Schedule of Events, Groups E, F, K, L 
Study visit 
Screening V1 
V2a 
V3 
V4 
V5a 
V6 
V7 
V8 
V9a 
V10
V11 
V12 
V13a 
V14a 
(EOS)
ET Unsch
Study day 
-14 to -3 
1 
4 
8 
22 
25 
29 
43 
142 
145 
149 
163 
262 
322 
507 
N/A
N/A 
Window allowance 
(days) 
 
 
V1+3 
(±1)
V1+7 
(±1) 
V1+21 
(+3) 
V4+3 
(±1)
V4+7 
(±1) 
V4+21 
(±3) 
V1+141 
(±7) 
V8+3 
(±1) 
V8+7 
(±1)
V8+21 
(±3) 
V1+261 
(±7) 
V1+321 
(±7) 
V1+506 
(±7) 
N/A
N/A 
Concomitant 
medications 
Xi 
Xe,i 
X 
Xj 
Xe 
X 
Xj 
X 
Xe 
X 
Xj 
X 
X 
X 
X 
X 
X 
Concomitant 
vaccinations 
Xi 
Xe,i 
X 
Xj 
Xe 
X 
Xj 
X 
Xe 
X 
Xj 
X 
X 
X 
X 
X 
X 
Complete physical 
examinationk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examinationl 
 
Xe 
 
X 
Xe 
 
X 
 
Xe 
 
X 
 
 
 
 
Xd 
Xd 
Urine pregnancy test 
(WOCBP) 
X 
Xe,m 
 
 
Xe,m 
 
 
 
Xe,m 
 
 
 
 
 
 
 
Xd 
Review inclusion 
and exclusion 
criteria 
X 
Xe 
 
 
Xe 
 
 
 
Xe 
 
 
 
 
 
 
 
 
Venous blood 
sample collection for 
clinical safety 
laboratory testsn,o 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Xd 
Venous blood 
sample collection for 
antibody assays 
 
Xe 
 
 
Xe 
 
 
X 
Xe 
 
 
X 
X 
 
 
 
 
Cellular 
immunology (subset 
only) 
 
Xe 
 
 
Xe 
 
 
X 
Xe 
 
 
X 
X 
 
 
 
 

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Protocol: BP-I-16-005 Version 2.0 
26 February 2018 
 
Page 82 
Table 12–2 
Schedule of Events, Groups E, F, K, L 
Study visit 
Screening V1 
V2a 
V3 
V4 
V5a 
V6 
V7 
V8 
V9a 
V10
V11 
V12 
V13a 
V14a 
(EOS)
ET Unsch
Study day 
-14 to -3 
1 
4 
8 
22 
25 
29 
43 
142 
145 
149 
163 
262 
322 
507 
N/A
N/A 
Window allowance 
(days) 
 
 
V1+3 
(±1)
V1+7 
(±1) 
V1+21 
(+3) 
V4+3 
(±1)
V4+7 
(±1) 
V4+21 
(±3) 
V1+141 
(±7) 
V8+3 
(±1) 
V8+7 
(±1)
V8+21 
(±3) 
V1+261 
(±7) 
V1+321 
(±7) 
V1+506 
(±7) 
N/A
N/A 
Randomization 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
Xp 
 
 
 
Xp 
 
 
 
 
 
 
 
 
Monitor subject for 
30 minutes 
following 
vaccinationq 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Examine vaccination 
siter 
 
Xs 
 
X 
Xs 
 
Xd 
 
Xs 
 
X 
 
 
 
 
Xd 
Xt 
AE/MAAE/PIMMC/ 
SAE assessmentu 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DC, diary card; eCRF, electronic case report form; EOS, end of 
study; ET, early termination; FDA, Food and Drug Administration; MAAE, medically attended adverse event; N/A, not applicable; PIMMC, potentially immune-
mediated medical condition; SAE, serious adverse event; SUSAR, suspected unexpected serious adverse reaction; ULN, upper limit of normal; Unsch, 
unscheduled; V, visit; WOCBP, women of childbearing potential. 
a 
Telephone call assessment. 
b 
Prior to the completion of any study-related procedures. 
c 
Vital sign measurements include oral temperature, pulse rate, and blood pressure. Vital signs will be measured before blood is collected, at both pre-vaccination 
and 30±5-minute postvaccination time points on a vaccination day. Diastolic and systolic blood pressure will be measured after the subject is seated for at least 
5 minutes. 
d 
If clinically indicated. 
e 
Prior to vaccination. 
f 
Ask subject a standard nonleading question to elicit any medically related changes in their well-being. Ask if they have been hospitalized, had any accidents, used 
any new medications, received any vaccinations, or changed concomitant medication regimens (both prescription and over-the-counter medications). 

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g 
Diary Card I (Days 1-8), III (Days 22-29), and V (Days 142-149) will be used to collect unsolicited and solicited local and systemic reactions. Diary Card II 
(Days 9-21), IV (Days 30-43), VI (Days 150-163) will be used to collect unsolicited AEs.  
h 
If applicable, according to the protocol period, collect and review DC with subject.  
i 
Use of all concomitant medications that the subject is taking at the time of Visit 1, medications taken up to 14 days prior to Visit 1, and vaccines received 
12 months prior to Visit 1 will be recorded in the subject’s eCRF. 
j 
Obtained by interview and by review of diary card completed by the subject. 
k 
Any physical examination findings will be collected in the eCRF for medical history data presentation.  
l 
Targeted physical examination will be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. Any 
findings from this examination will be collected in the eCRF for AEs. 
m 
A urine pregnancy test must be performed within 24 hours prior to vaccination and pregnancy test results must be final and negative prior to vaccination.  
n 
Hematology: complete blood count with differential, platelet count; coagulation: partial thromboplastin time and prothrombin time (international normalized 
ratio); chemistry/metabolic panel: ALT, AST, total bilirubin, creatinine, and blood urea nitrogen.  
o 
For abnormal laboratory results that are clinically significant and for ALT and/or AST elevations ≥2.6 × ULN, repeat test until resolved or results become stable 
(see Section 6.2.5.8). 
p 
Subjects with an acute illness, including body temperature greater than 100.4°F, immediately prior to each vaccination or, per subject report, within 3 days prior to 
a scheduled vaccination in this study can be rescheduled for vaccination as long as the vaccination visit is within the visit window. Subjects with a Grade ≥3 AE 
that has not returned to baseline or stabilized will not be revaccinated. Subjects with a serum ALT and/or AST elevation that is Grade 2 (moderate) or greater 
based on FDA toxicity grading (ie, ≥2.6 × ULN) will not be revaccinated unless the value resolves on repeat testing to the screening baseline value (ie, baseline 
toxicity score) and the subject remains within the visit window allowance (see Section 4.3). 
q 
At Visits 1, 4, and 8, subjects will be monitored for solicited and unsolicited AEs, SAEs, MAAEs, PIMMCs, and SUSARs for at least 30 minutes after 
vaccination; concomitant medications will be recorded. 
r 
Examine vaccination site for erythema/redness and swelling and monitor for pain. 
s 
At Visits 1, 4, and 8, complete a 30±5-minute postvaccination injection site examination for erythema/redness and swelling and monitor for pain. If a visible 
injection-site abnormality is observed, document with a photograph.  
t 
If the unscheduled visit occurs within 7 days after any of the study vaccinations.  
u 
Only MAAEs, PIMMCs (see Appendix 2, Section 12.2), and SAEs will be collected after Day 163; all other AEs will be collected through 21 days following each 
vaccination.  
 

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12.2 Appendix 2: Potentially Immune-Mediated Medical Conditions 
An adverse event of special interest (serious or nonserious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on 
the nature of the event, rapid communication by the trial sponsor to other parties (eg, 
regulators) might also be warranted (based on Council for International Organizations of 
Medical Sciences VI). 
For this study, adverse events of special interest will include the following list of PIMMCs: 
Gastrointestinal disorders 
• Autoimmune pancreatitis 
• Celiac disease 
• Crohn’s disease 
• Microscopic colitis 
• Ulcerative colitis 
• Ulcerative proctitis 
Liver disorders 
• Autoimmune cholangitis 
• Autoimmune hepatitis 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
Metabolic diseases 
• Addison’s disease 
• Autoimmune hypophysitis 
• Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• Diabetes mellitus type I 

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• Grave’s or Basedow’s disease 
Musculoskeletal 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 
Neuroinflammatory disorders 
• Acute disseminated encephalomyelitis, including site-specific variants (eg, noninfectious 
encephalitis, encephalomyelitis, myelitis, radiculomyelitis) 
• Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy) 
• Guillain-Barré 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 
• Multiple sclerosis 
• Narcolepsy 

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26 February 2018 
 
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• Optic neuritis 
• Transverse myelitis 
• Myasthenia gravis, including Eaton-Lambert syndrome 
Skin disorders 
• Alopecia areata 
• Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• Cutaneous lupus erythematosus 
• Erythema nodosum 
• Morphoea 
• Lichen planus 
• Psoriasis 
• Sweet’s syndrome 
• Vitiligo 
Vasculitides 
• Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and 
temporal arteritis 
• Medium sized and/or small vessels vasculitis including the following: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, Churg–
Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease thromboangiitis 
obliterans, necrotizing vasculitis and antineutrophil cytoplasmic antibody (ANCA) 
positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis 
Others 
• Antiphospholipid syndrome 
• Autoimmune hemolytic anemia 

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• Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, 
and mesangioproliferative glomerulonephritis) 
• Autoimmune myocarditis/cardiomyopathy 
• Autoimmune neutropenia 
• Autoimmune pancytopenia 
• Autoimmune thrombocytopenia 
• Goodpasture syndrome 
• Idiopathic pulmonary fibrosis 
• Pernicious anemia 
• Polyglandular autoimmune syndrome 
• Raynaud’s phenomenon 
• Sarcoidosis 
• Sjögren’s syndrome 
• Stevens-Johnson syndrome 
• Uveitis 

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12.3 Appendix 3: US FDA Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (a partial list) 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Vaccines/ucm091977.pdf 

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Page 89 
Local Reaction to 
Injectable Product 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room visit 
or hospitalization 
Erythema/rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/swellingb 
2.5-5 cm and does not 
interfere with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
a 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous 
variable. 
b 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
Vital Signsa 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Fever (°C)b 
(°F)b 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Tachycardia – beats per 
minute 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia – beats per 
minutec 
50-54 
45-49 
<45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) 
– mm Hg 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant hypertension
Hypertension (diastolic) 
– mm Hg 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant hypertension
Hypotension (systolic) 
– mm Hg 
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory rate – 
breaths per minute 
17-20 
21-25 
>25 
Intubation 
Abbreviation: ER, emergency room. 
a 
Subject should be at rest for all vital sign measurements. 
b 
Oral temperature; no recent hot or cold beverages or smoking. 
c 
When resting heart rate is between 60 to 100 beats per minute. Use clinical judgement when characterizing bradycardia among some 
healthy subject populations, for example, conditioned athletes. 
 

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Systemic (General) 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Fever (°C)a 
(°F)a 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Chillsb 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
and social functional 
activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
Not applicable 
Arthralgiab 
Joint pain causing no or 
minimal interference 
with usual and social 
functional activities 
Joint pain causing 
greater than minimal 
interference with usual 
and social functional 
activities 
Joint pain causing 
inability to perform 
usual and social and 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Nausea/vomiting 
No interference with 
activity or 1-2 
episodes/24 hours 
Some interference with 
activity or >2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2-3 loose stools or 
<400 g/24 hours 
4-5 loose stools or 
400-800 g/24 hours 
6 or more watery stools 
or 800 g/24 hours or 
requires outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
some interference with 
activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity 
ER visit or 
hospitalization  
Fatigue 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Abbreviations: ER, emergency room; IV intravenous. 
a 
Oral temperature; no recent hot or cold beverages or smoking. (Note, this same information is also provided in Vital 
Signs table above.) 
b 
Definition from Department of Health and Human Services, National Institutes of Health, National Institute of Allergy 
and Infectious Diseases (US). Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Version 2.1, July 2017 [35 screens]. Available from http://rsc.tech-res.com/docs/default-
source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-adverse-events-corrected-v-
2-1.pdf?sfvrsn=2.  
 

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Seruma 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)b 
Blood urea nitrogen mg/dL 
23-26 
27-31 
>31 
Requires dialysis 
Creatinine mg/dL 
1.5-1.7 
1.8-2.0 
2.1-2.5 
>2.5 or requires 
dialysis 
Liver function tests – ALT, 
AST increase by factor 
1.1-2.5 × ULN 
2.6-5.0 × ULN 
5.1-10 × ULN 
>10 × ULN 
Bilirubin – when 
accompanied by any 
increase in liver function 
test increase by factor 
1.1-1.25 × ULN 
1.26-1.5 × ULN 
1.51-1.75 × ULN 
>1.75 × ULN 
Bilirubin – when liver 
function test is normal; 
increase by factor 
1.1-1.5 × ULN 
1.6-2.0 × ULN 
2.0-3.0 × ULN 
>3.0 × ULN 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. 
a 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
b 
The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4).  
 

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Hematologya 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (female) –
 g/dL 
11.0-12.0 
9.5-10.9 
8.0-9.4 
<8.0 
Hemoglobin (female) 
change from baseline value 
– g/dL 
Any decrease – 1.5 
1.6-2.0 
2.1-5.0 
>5.0 
Hemoglobin (male) – g/dL 
12.5-13.5 
10.5-12.4 
8.5-10.4 
<8.5 
Hemoglobin (male) change 
from baseline value – g/dL 
Any decrease – 1.5 
1.6-2.0 
2.1-5.0 
>5.0 
WBC increase – cell/mm3 
10 800-15 000 
15 001-20 000 
20 001-25 000 
>25 000 
WBC decrease – cell/mm3 
2 500-3 500 
1 500-2 499 
1 000-1 499 
<1 000 
Lymphocytes decrease – 
cell/mm3 
750-1 000 
500-749 
250-499 
<250 
Neutrophils decrease – 
cell/mm3 
1 500-2 000 
1 000-1 499 
500-999 
<500 
Eosinophils – cell/mm3 
650-1 500 
1501-5 000 
>5 000 
Hypereosinophilic 
Platelets decrease – 
cell/mm3 
125 000-140 000 
100 000-124 000 
25 000-99 000 
<25 000 
PT – increase by factor 
1.0-1.10 × ULNb 
1.11-1.20 × ULN 
1.21-1.25 × ULN 
>1.25 ULN 
PTT – increase by factor 
1.0-1.2 × ULN 
1.21-1.4 × ULN 
1.41-1.5 × ULN 
>1.5 ULN 
Abbreviations: PPT, partial thromboplastin time; PT, prothrombin time; ULN, upper limit of normal; WBC, white blood 
cell. 
a 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
b 
ULN is the upper limit of the normal range. 

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12.4 Appendix 4: Protocol Amendments and Version Updates 
The original Protocol Version 1.0 was dated 19 October 2017. Additions to the study protocol 
are shown in bold and deletions are shown in strike through text. Corrections of obvious 
typing errors or omissions and other editorial changes are not highlighted. 
12.4.1 
Protocol Version 1.1 (Typographical Error Correction) 
Change Number 1 
The secondary immunogenicity objectives were corrected to accurately reflect the Day 142 
time point for the relevant assessments. 
Reason 
This correction was typographical. 
Protocol Section 
Synopsis – Objectives; Section 2.2.2 – Secondary Immunogenicity Objectives 
Change to or Section Deleted: 
Synopsis – Objectives; Section 2.2.2 – Secondary Immunogenicity Objectives 
• To assess the serum HAI antibody titers, SPRs, and seroconversion rates (SCRs) against 
each vaccine strain in the study through Day 163 142 of the prime-boost vaccination 
series.  
• To assess the serum HAI antibody titers, SPRs, and SCRs against each vaccine strain in 
the study through Day 262 of the prime prime-boost vaccination series.  
• To assess the serum microneutralization (MN) antibody titers and SCRs against each 
vaccine strain in the study through Day 163 142 of the prime-boost vaccination series. 
• To assess the serum MN antibody titers and SCRs against each vaccine strain in the study 
through Day 262 of the prime-prime-boost vaccination series. 

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12.4.2 
Protocol Version 1.2  
Change Number 1 
The PPD Medical Monitor changed. 
Reason 
The new medical monitor’s name and position were included. 
Protocol Section 
Cover page 
Change to or Section Deleted: 
Medical Monitor: 
 
Michael Barri John Sanders, MD 
 
 
 
 
Associate Medical Director, PPD 
Change Number 2 
The IND number was added to the protocol. 
Reason 
The IND number became available. 
Protocol Section 
Cover page 
Change to or Section Deleted: 
IND Number: 
 
17929 
Change Number 3 
The “A” designation was removed from A(H5) influenza throughout the protocol, except for 
the title of the study. 

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Reason 
The removal of the “A” was for simplification of the text and does not affect meaning. 
Protocol Section 
Global 
Change to or Section Deleted: 
All references to A(H5) influenza changed to H5.  
Change Number 4 
Potentially immune-mediated medical conditions were separated from medically attended 
adverse events in order to collect each event as a separate entity.  
Reason 
This update was made for accuracy of data collection and presentation.  
Protocol Section 
Global  
Change Number 5 
Secondary safety objectives were clarified to accurately reflect the duration of AE collection. 
Reason 
The change was made to increase clarity of the defined time points for AE assessments.  
Protocol Section 
Synopsis – Secondary Safety Objectives; Section 2.2.1 – Secondary Safety Objectives; 
Section 7.2 – Secondary Endpoints 

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Change to or Section Deleted: 
Synopsis – Secondary Safety Objectives 
Section 2.2.1 – Secondary Safety Objectives 
• To assess the occurrence of SAEs, and medically attended adverse events (MAAEs), and 
potentially immune-mediated medical conditions (PIMMCs; see Appendix 2, 
Section 12.2) including a subset of specific potentially immune-mediated medical 
conditions (PIMMCs) in the 12 treatment groups for through 12 months after the last 
dose of study vaccine and to.  
• To assess the occurrence of unsolicited AEs for 21 days after the last each dose of study 
vaccine.  
Section 7.2 – Secondary Endpoints 
• Occurrence of SAEs, and the occurrence of MAAEs, including a subset of specific and 
PIMMCs in 12 treatment groups for through 12 months after the last dose of study 
vaccine 
Change Number 6 
Objective revised for clarity. 
Reason 
Level of detail not needed here. 
• To assess the occurrence of serious adverse events, and medically attended adverse events 
(MAAEs), and potentially immune-mediated medical conditions (PIMMCs; see 
Appendix 2, Section 12.2) including a subset of specific potentially immune-mediated 
medical conditions (PIMMCs) in the 12 treatment groups for through 12 months after the 
last dose of study vaccine and to.  
• To assess the occurrence of unsolicited adverse events for 21 days after the last each dose 
of study vaccine.  

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Protocol Section 
Section 2.3 – Exploratory Immunogenicity Objectives 
Change to or Section Deleted: 
• To assess peripheral antibody responses to epitopes within the influenza virus surface 
proteins HA or neuraminidase induced by prime-boost or prime-prime-boost vaccination 
seriesadministered IM with AS03 or MF59 adjuvant 21 days apart or 141 days apart. 
Change Number 7 
Protocol exclusion criterion changed. 
Reason 
The change was made to increase clarity of timing for the urine pregnancy test. 
Protocol Section 
Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
Change to or Section Deleted: 
Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
2. 
A woman who has a positive urine pregnancy test within 24 hours prior to vaccination 
in this study or a woman who is breastfeeding. 
Change Number 8 
Clarification regarding the responsibilities of the independent data monitoring committee. 
Reason 
The IDMC meeting frequency was changed from ad hoc to only if a pausing rule is met.  

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Protocol Section 
Synopsis – Statistical Methods; Section 3.1 – Study Design; Section 10.1.5 – Independent 
Data Monitoring Committee 
Change to or Section Deleted: 
Synopsis – Statistical Methods 
No formal independent data monitoring committee meetings are planned for this study. The 
independent data monitoring committee will meet only if a pausing rule is met. Ad hoc 
meetings may occur for any immediate concerns that are observed. 
 
Section 3.1 – Study Design 
 
No formal independent data monitoring committee (IDMC) meetings are planned for this 
study. The IDMC will meet only if a pausing rule is met. Ad hoc meetings may occur for 
any immediate concerns that are observed. 
 
Section 10.1.5 – Independent Data Monitoring Committee 
 
The IDMC will operate according to the IDMC Charter and will monitor safety information 
on this study on an ad hoc basis. The IDMC will review study progress and oversee 
clinical, safety, and reactogenicity data on an ad hoc basis; the IDMC will meet only if a 
pausing rule is met. The IDMC will be composed of 3 members with expertise in the 
conduct and safety oversight of vaccine clinical studies. One of the IDMC members will 
serve as the IDMC chairperson.  
An IDMC will review study progress and oversee clinical, safety, and reactogenicity data on 
an ad hoc basis; ad hoc meetings may occur for any immediate concerns that are observed. 
 
Change Number 9 
Detail was provided to identify study staff blinding procedures. 
Reason 
Original text was not sufficiently clear as to blinding assignments at study sites. 

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Protocol Section 
Synopsis – Study Design; Section 3.1 – Study Design 
Change to or Section Deleted: 
Synopsis – Study Design; Section 3.1 – Study Design 
Study staff not involved in investigational product (IP) preparation and administration 
will be blinded to unique group assignment.  
Change Number 10 
Revised number of sites that will collect PBMC samples. 
Reason 
Original text was specific to number of sites; revised to present more general number of sites. 
Protocol Section 
Section 3.1 – Study Design 
Change to or Section Deleted: 
Section 3.1 – Study Design 
At least 4 A select number of the 6 sites will have capability for PBMC collections, and only 
subjects enrolled at those sites will be assigned to subjects who contribute to the PBMC 
subset.  
Change Number 11 
Revised description for clarity. 
Reason 
Further detail needed. 
Protocol Section  
Section 3.1.3 – Study Pausing Rules 

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Change to or Section Deleted: 
Study pausing rules will be monitored throughout the study by the medical monitor. The 
sponsor will pause study enrollment and study vaccine administration and the IDMC will 
review unblinded safety data if any of the following are met: 
Change Number 12 
Revised future investigations list. 
Reason 
Removed a subject question from study design. 
Protocol Section 
Section 3.1.4 – Future Investigations 
Change to or Section Deleted: 
3.  Permission to take a photograph of a visible injection site abnormality for the purpose 
of medical management and safety evaluations. 
Change Number 13 
Revised exclusion criterion for clarity. 
Reason 
Original text was reassessed and needed rewriting. 
Protocol Section 
Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
Change to or Section Deleted: 
Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 

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22. 
Has any condition that would, in the opinion of the investigator, place him or her at an 
unacceptable risk of injury or render him or her unable to meet the requirements of 
the protocol (including tattoos or scars on the skin where the vaccine is to be 
administeredsite of injection reactogenicity assessments). 
Change Number 14 
Placement of revaccination text was revised. 
Reason 
This correction was made to move revaccination eligibility criteria to a more appropriate 
location in the protocol. 
Protocol Section  
Section 5.2.1 – Revaccination Eligibility  
Change to or Section Deleted: 
Subjects with a Grade ≥2 AE that has not returned to baseline or stabilized will not be 
revaccinated. 
Subjects with an acute illness, including body temperature greater than 100.4°F immediately 
prior to a scheduled vaccination or, per subject report, within 3 days prior to a scheduled 
vaccination in this study can be rescheduled for vaccination as long as the vaccination visit is 
within the visit window.  
Section 4.3 
Revaccination Eligibility 
Subjects are free to withdraw from further study vaccination at any time upon request. 
A subject may not be eligible to receive further study vaccination for any of the 
following reasons: 
1. 
Does not meet the protocol inclusion or exclusion criteria at the time of the 
second or, if applicable, third vaccination. 
2. 
Noncompliance with the protocol. 

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3. 
Serious or intolerable AE(s) that in the investigator’s opinion precludes further 
study vaccination.  
4. 
Laboratory safety assessment that remains clinically significant prior to planned 
vaccination.  
5. 
Symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justifies no further study vaccination. 
6. 
Other (eg, pregnancy, development of contraindications precluding further study 
vaccination). 
All subjects who discontinue from study treatment prematurely will follow the same 
visit schedule as other subjects. 
Change Number 15 
Revision to clarify allowed influenza vaccinations in study. 
Reason 
Prior paragraph was not clear. 
Protocol Section 
Section 5.7 – Prior Vaccinations and Concomitant Medications 
Change to or Section Deleted: 
Section 5.7 – Prior Vaccinations and Concomitant Medications 
Sites may contact the medical monitor regarding use of concomitant medications prior to 
enrollment for guidance as necessary. If it is discovered that a subject is using a prohibited 
concomitant medication after he or she is enrolled in the study, the site should contact the 
medical monitor to resolve the situation. All instances of use of prohibited concomitant 
medications must be documented in the eCRF. All vaccinations obtained outside of the study 
itself will be recorded while the subject is enrolled. Should a subject inadvertently receive a 
live seasonal influenza vaccination that interferes with the window of vaccination free period 

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prior to any trial vaccination, that vaccination can be withheld until the appropriate time has 
passed. Such a subject will not be deemed out of compliance or out of study visit window. All 
future visits will be adjusted accordingly. 
Change Number 16 
Paragraph rewritten for clarity. 
Reason 
Details in paragraph did not align with exclusion criteria details. 
Protocol Section 
Section 5.7.1 – Prohibited Prior and Concomitant Medications 
Change to or Section Deleted: 
Section 5.7.1 – Prohibited Prior and Concomitant Medications 
Immunosuppression as a result of an underlying illness or treatment or the use of anticancer 
chemotherapy or radiation therapy (cytotoxic) within the preceding 36 months prior to Day 1 
(first vaccination)screening is prohibited.    
Change Number 17 
Paragraph rewritten for clarity. 
Reason 
Details in paragraph did not align with permitted medication guidelines. 
Protocol Section 
Section 5.7.2 – Permitted Prior and Concomitant Medication 

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Change to or Section Deleted: 
Section 5.7.2 – Permitted Prior and Concomitant Medication 
Prohibited concomitant medication deemed necessary for the welfare of the subject during 
the study may be given at the discretion of the investigator if deemed in the best interest of 
the subject’s health. However, iIt is the responsibility of the investigator to ensure that 
details regarding the medication will be recorded in full in the eCRF.    
Change Number 18 
Text rewritten for clarity. 
Reason 
Change made to align with schedule of events. 
Protocol Section 
Section 6.2.2 – Postvaccination Evaluation 
Change to or Section Deleted: 
Section 6.2.2 – Postvaccination Evaluation 
At Visits 1 and 4 (Groups A-D, G-J) and at Visits 1, 4, and 8 (Groups E, F, K, L), subjects 
will be monitored for solicited (Section 6.2.5.2) and unsolicited AEs, SAEs, and MAAEs, 
PIMMCs, and serious and suspected unexpected adverse reactions (SUSARs) for at least 
30 minutes after vaccination.  
Change Number 19 
Platelet count was added to the hematology profile. 
Reason 
This correction was due to an omission. 

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Protocol Section 
Section 6.2.4 – Clinical Safety Laboratory Tests; Table 12-1; Table 12-2 
Change to or Section Deleted: 
Section 6.2.4 – Clinical Safety Laboratory Tests 
Clinical safety laboratory tests will include the following according to Table 12-1 and 
Table 12-2: 
• hematology: complete blood count with differential and platelet count.  
Table 12-1; Table 12-2 
n 
Hematology: complete blood count with differential, platelet count; coagulation: partial thromboplastin time and 
prothrombin time (international normalized ratio); chemistry/metabolic panel: alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, creatinine, and blood urea nitrogen.  
 
Change Number 20 
Definitions added for clarity. 
Reason 
Definitions of MAAEs and PIMMCs not provided in last version of the document. 
Protocol Section 
Section 6.2.5.1 – Definitions of Adverse Events 
Change to or Section Deleted: 
Medically attended AEs are defined as AEs with medically attended visits, including 
hospital, emergency room, urgent care clinic, or other visits to or from medical 
personnel (medical doctor, physician assistant, nurse practitioner) for any reason. 
Potentially immune-mediated medical conditions are considered unexpected events and 
should be reported as adverse events of special interest. The PIMMCs of concern for 
this study are detailed in Appendix 2, Section 12.2. 

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Change Number 21 
Details of laboratory findings that qualified as AEs were corrected to accurately represent 
intended grading and assessment process. 
Reason 
Original text was not clear in regard to clinical significance and Toxicity Grading Scale. 
Protocol Section 
Section 6.2.5.3 – Assessing and Documenting Adverse Events; Section 6.2.5.5 – Assessment 
of Severity; Section 6.2.5.8 – Follow-up of Subjects Reporting Adverse Events  
Change to or Section Deleted: 
Section 6.2.5.3 – Assessing and Documenting Adverse Events 
Laboratory findings that qualify as AEs and nonqualifying laboratory abnormalities 
outside the laboratory’s reference range will be toxicity graded according to the FDA 
Toxicity Grading Scale (Appendix 3, Section 12.3). Any Similarly, vital signs outside the 
clinic reference range will be graded according to the same scale. The toxicity grade for 
each identified laboratory finding and out-of-reference range vital sign will be 
documented in the study dataset.  
The investigator will assess each Toxicity Scale Grade 1 and Grade 2-4 finding and 
determine whether the finding is clinically significant observations and all hematology, 
coagulation, or serum chemistry/metabolic panel results that are at least. Grade 1-3 
clinically significant findings will be categorized as AEs. All Grade 3 (irrespective 4 
findings (regardless of investigator-assessed clinical significance) that occurs after 
vaccination will be recorded graded as an AE AEs. Other safety assessments (eg, vital sign 
measurements), or those identified from review of other documents (eg, diary card), 
including those that worsen from baseline, or are felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. 
For a laboratory assessment finding assessed as an AE (see above), the investigator should 
report a medical condition rather than the name of the laboratory test abnormality whenever 

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possible. For example, for if the subject has a clinically significant Grade 1/Grade, 2, or 
Grade 3 increased white blood cell count was due to bronchitis, then the investigator should 
report the medical condition of “bronchitis” rather than “high white blood cell count.” 
Similarly, a clinically significant decreased hemoglobin should be reported as “anemia” 
rather than “low hemoglobin,” and a clinically significant decreased platelet count should be 
reported as “thrombocytopenia” rather than “low platelets.”  
The severity of solicited AEs will be classified. Laboratory findings that qualify as AEs and 
nonqualifying laboratory abnormalities outside the laboratory’s reference range will be 
toxicity graded according to the FDA Toxicity Grading Scale (Appendix 3, Section 12.3). 
This grading is distinct from and does not translate directly to the AE grading by the 
investigator, which is based on clinical judgment.  
Section 6.2.5.5 – Assessment of Severity 
Laboratory abnormalities (hematology and serum chemistries) that are abnormal will be 
entered into the AE reporting page only if the investigator determines there is clinical 
significance. Grade 1-3 hematology or serum chemistry values determined by the 
investigator to be clinically significant will be entered into the AE reporting page. All 
Grade 4 laboratory findings are considered AEs regardless of the investigator’s 
determination of clinical significance.  
Section 6.2.5.8 – Follow-up of Subjects Reporting Adverse Events  
In the case of an abnormal laboratory value that is entered as an AE due to toxicity grade 
parameters (ie, clinically significant Grade 1 to 3 or above or any Grade 3,4 [regardless of 
clinical significance]), the subject will be required to have a repeat laboratory test with 
results assessed by the investigator and continued monitoring as determined appropriate for 
the clinical situation. 
Change Number 22 
Clarification to identify types of AEs reported immediately to PPD and the length of time 
after the first vaccine dose that SAEs and PIMMCs will be collected was revised. 

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Reason 
The MAAEs group was removed, as any AE that meets SAE criteria would include MAAEs. 
The length of time for event follow-up postvaccination was revised. 
Protocol Section 
Section 6.2.5.4 – Reporting Adverse Events 
Change to or Section Deleted: 
Section 6.2.5.4 – Reporting Adverse Events 
Any AE that meets SAE or MAAE PIMMC criteria (Section 6.2.5.1 and Appendix 2, 
Section 12.2) must be reported to PPD immediately (ie, within 24 hours) after the time site 
personnel first learn about the event. The following contact information is to be used for SAE 
reporting: 
 
SAE Hotline:
 
 
SAE Fax line:
 
The safety event reporting periods are shown in Figure 6-1 for Groups A to D and G to J and 
Figure 6-2 for Groups E, F, K, and L. Solicited AEs will be collected for 7 days after each 
vaccination. Unsolicited AEs will be collected for 21 days after each of 2 vaccine doses 
(Groups A-D and G-J) and for 21 days after each of 3 vaccine doses (Groups E, F, K, and L). 
Serious adverse events, MAAEs, and PIMMCs will be collected for approximately 13 
months after the first study vaccine dose (Groups A-D and G-J) and for approximately 17 
months after the first study vaccine dose (Groups E, F, K, and L).  
Change Number 23 
Assessment of severity procedures revised. 
Reason 
Clarity regarding laboratory-related AEs was needed. 

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Protocol Section 
Section 6.2.5.5 – Assessment of Severity 
Change to or Section Deleted: 
Section 6.2.5.5 – Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. All solicited AEs will be graded according to the FDA Toxicity Grading Scale 
(Appendix 3, Section 12.3) and entered into the AE reporting page. Grade 1-3 hematology 
or serum chemistry values determined by the investigator to be clinically significant will 
be entered into the AE reporting page. All Grade 4 laboratory findings are considered 
AEs regardless of the investigator’s determination of clinical significance. The severity 
of each Laboratory abnormalities (hematology and serum chemistries) that are abnormal will 
be entered into the AE reporting page only if the investigator determines there is clinical 
significance. For any clinically significant AEs that are entered into the AE eCRF, the 
intensity of the AE will be rated as mild, moderate, or severe using the following criteria: 
Change Number 24 
Identification of analyses for immunogenicity-full analysis set. 
Reason 
Original text was not clear on what endpoint summaries would be performed.  
Protocol Section 
Section 7.5 – Analysis Sets 
Change to or Section Deleted: 
Section 7.5 – Analysis Sets 
Immunogenicity-full analysis set (IFAS): The IFAS will consist of all subjects who are 
randomly assigned, receive at least 1 dose of IP, and have at least 1 valid postvaccination and 
determinate assay result. OnlyAs supportive analysis, all the primary immunogenicity 

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endpoint summaries will be performed on the IFAS using treatment as randomized by actual 
treatments received. 
Change Number 25 
Clarification needed regarding template standard text. 
Reason 
Respective obligations of sponsor and designee are clear without this text. 
Protocol Section 
Section 9.2 – Financial Disclosure  
Change to or Section Deleted: 
9.2 
Financial Disclosure and Obligations 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 
Change Number 26 
Clarification needed regarding consistency of presentation in Table 12-1 and Table 12-2. 
Reason 
Same text should be used in both tables to define procedures. 
Protocol Section 
Table 12-1; Table 12-2 
Change to or Section Deleted: 

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Table 12-1; Table 12-2 
Removed “Review Diary Card” for Visit 1. 
Table 12-2 
Revised “Review diary cardg and toxicity grade for solicited reactions”.   
Change Number 27 
Adverse event severity identification was corrected for global consistency. 
Reason 
This correction was made to be consistent with presentation of laboratory-related AE severity 
grade throughout the protocol. 
Protocol Section 
Table 12-1; Table 12-2 
Change to or Section Deleted: 
Table 12-1; Table 12-2 
p 
Subjects with an acute illness, including body temperature greater than 100.4°F, immediately prior to each 
vaccination or, per subject report, within 3 days prior to a scheduled vaccination in this study can be rescheduled for 
vaccination as long as the vaccination visit is within the visit window. Subjects with a Grade ≥23 AE that has not returned to 
baseline or stabilized will not be revaccinated. 

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12.4.3 
Protocol Amendment 1, Version 2.0  
Additions to the study protocol are shown in bold and deletions are shown as strikethrough 
text. Administrative changes are not highlighted. 
Change Number 1 
Added text to indicate that subjects with US Food and Drug Administration (FDA) toxicity 
Grade 2 or greater (ie, ≥2.6 × upper limit of normal [ULN]) serum alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) elevations should not receive revaccination, 
and provided guidance that FDA toxicity Grade 2 or greater ALT and/or AST elevations will 
be reported as an adverse event (AE). 
Reason 
Revaccination text was added based on feedback from the US FDA, and the associated AE 
text was added to ensure that FDA toxicity Grade 2 or greater ALT and/or AST elevations 
(≥2.6 × ULN) are appropriately identified. 
Protocol Section 
Section 4.2.1 – Reasons for Withdrawal/Discontinuation 
4. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
elevation that is Grade 2 (moderate) or greater based on FDA toxicity grading (ie, 
≥2.6 × upper limit of normal [ULN]; see Appendix 3, Section 12.3) that does not resolve 
on repeat testing to the screening baseline value (eg, baseline toxicity score). (Note, 
subjects with elevated ALT and/or AST values cannot be revaccinated until resolution 
occurs [see Section 4.3].) 
45. Other Llaboratory safety assessments that reveal Grade ≥3 hematological or biochemical 
values. 
Section 4.3 – Revaccination Eligibility 
4. A serum ALT or AST elevation that is Grade 2 (moderate) or greater based on FDA 
toxicity grading (ie, ≥2.6 × ULN; see Appendix 3, Section 12.3) regardless of 

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investigator-assessed clinical significance. Note, such an elevated ALT and/or AST value 
must be resolved on repeat testing to the screening baseline value (eg, baseline toxicity 
score) before revaccination can occur. Only those subjects who have resolution of the 
ALT and/or AST elevations within the visit window are eligible for revaccination. 
4.5. Other Llaboratory safety assessments that remains clinically significant prior to planned 
vaccination. 
Section 6.2.5.3 – Assessing and Documenting Adverse Events 
The investigator will assess each Toxicity Scale Grade 1-4 finding and determine whether the 
finding is clinically significant. Grade 1-3 clinically significant findings will be categorized 
as AEs. An FDA toxicity Grade 2 (moderate) or greater (ie, ≥2.6 × ULN; see Appendix 3, 
Section 12.3) ALT and/or AST elevation (regardless of investigator-assessed clinical 
significance) will be entered into the AE reporting page. All Grade 4 findings (regardless 
of investigator-assessed clinical significance) will be graded as AEs. Other safety 
assessments (eg, vital sign measurements), or those identified from review of other 
documents (eg, diary card), including those that worsen from baseline, or are felt to be 
clinically significant in the medical and scientific judgment of the investigator are to be 
recorded as AEs or SAEs. 
… 
Any clinically significant safety assessment that is associated with an underlying disease 
(unless explicitly identified above), unless judged by the investigator to be more severe than 
expected for the subject’s condition, should not be reported as an AE. 
Section 6.2.5.5 – Assessment of Severity 
The severity of an AE refers to the extent to which an AE affects the subject’s daily activities. 
All solicited AEs will be graded according to the FDA Toxicity Grading Scale (Appendix 3, 
Section 12.3) and entered into the AE reporting page. Grade 1-3 hematology or serum 
chemistry values determined by the investigator to be clinically significant will be entered 
into the AE reporting page. An FDA toxicity Grade 2 (moderate) or greater (ie, 
≥2.6 × ULN; see Appendix 3, Section 12.3) ALT and/or AST elevation (regardless of 
investigator-assessed clinical significance) will be entered into the AE reporting page, 

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and the grading will be consistent with the FDA toxicity score. All Grade 4 laboratory 
findings are considered AEs regardless of the investigator’s determination of clinical 
significance and should also be entered using the FDA toxicity score for severity. In all 
other cases, tThe severity of each AE will be rated as mild, moderate, or severe using the 
following criteria. 
Section 6.2.5.8 – Follow-up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. In the case of an abnormal 
laboratory value that is entered as an AE due to toxicity grade parameters (ie, clinically 
significant Grade 1 to 3, Grade 4 [regardless of clinical significance], and ALT and/or AST 
elevations ≥2.6 × ULN), the subject will be required to have a repeat laboratory test with 
results assessed by the investigator and continued monitoring as determined appropriate for 
the clinical situation until the results return to the screening baseline value (ie, baseline 
toxicity score) or are considered stable with a new baseline. Subjects may not receive 
revaccination if ALT and/or AST elevations reach ≥2 by FDA toxicity score and do not 
return to the screening baseline value (ie, baseline toxicity score) by the time of 
revaccination. 
Table 12-1 – Schedule of Events, Groups A to D, G to J; and  
Table 12-2 – Schedule of Events, Groups E, F, K, L 
o For abnormal laboratory results that are clinically significant and for ALT and/or AST elevations 
≥2.6 × ULN, repeat test until resolved or results become stable (see Section 6.2.5.8). 
p Subjects with an acute illness, including body temperature greater than 100.4°F, immediately prior to each 
vaccination or, per subject report, within 3 days prior to a scheduled vaccination in this study can be 
rescheduled for vaccination as long as the vaccination visit is within the visit window. Subjects with a Grade ≥3 
AE that has not returned to baseline or stabilized will not be revaccinated. Subjects with a serum ALT and/or 
AST elevation that is Grade 2 (moderate) or greater based on FDA toxicity grading (ie, ≥2.6 × ULN) will 
not be revaccinated unless the value resolves on repeat testing to the screening baseline value (ie, baseline 
toxicity score) and the subject remains within the visit window allowance (see Section 4.3). 

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Change Number 2 
Adverse event severity grading definitions for fever, chills, and arthralgia were added to the 
FDA systemic reactions table in Appendix 3. 
Reason 
Solicited systemic reactions of fever, myalgia, arthralgia, fatigue, headache, nausea, 
vomiting, diarrhea, and chills are being collected in this study (as defined in Section 6.2.5.2). 
However, fever, chills, and arthralgia are not included in the FDA systemic events table. The 
additional guidance was added to the FDA systemic events table to ensure accuracy and 
consistency in the evaluation of these AEs during the study and as a resource to the study 
centers (so all information is in one location). 
Protocol Section 
Appendix 3: US FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials (a partial list) 

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Systemic (General) 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Fever (°C)a 
(°F)a 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Chillsb 
Symptoms causing no 
or minimal 
interference with 
usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual and social 
functional activities 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
Not applicable 
Arthralgiab 
Joint pain causing no 
or minimal 
interference with 
usual and social 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual and social 
functional activities 
Joint pain causing 
inability to perform 
usual and social and 
functional activities 
Disabling joint pain 
causing inability to 
perform basic 
self-care functions 
Nausea/vomiting 
No interference with 
activity or 1-2 
episodes/24 hours 
Some interference with 
activity or >2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2-3 loose stools or 
<400 g/24 hours 
4-5 loose stools or 
400-800 g/24 hours 
6 or more watery stools 
or 800 g/24 hours or 
requires outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
some interference with 
activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity 
ER visit or 
hospitalization  
Fatigue 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
Abbreviations: ER, emergency room; IV intravenous. 
a 
Oral temperature; no recent hot or cold beverages or smoking. (Note, this same information is also provided in 
Vital Signs table above.) 
b 
Definition from Department of Health and Human Services, National Institutes of Health, National Institute of 
Allergy and Infectious Diseases (US). Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events. Version 2.1, July 2017 [35 screens]. Available from http://rsc.tech-
res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-
adverse-events-corrected-v-2-1.pdf?sfvrsn=2.