A Phase 1, Randomized, Controlled, Observer-blind Study to Assess the Reactogenicity, Safety, and Immunogenicity of a Live Attenuated Universal Influenza Vaccine (cH8/1N1 LAIV) Administered as a Single Priming Dose Followed Three Months Later by a Single Booster Dose of an Inactivated Universal Influenza Vaccine (cH5/1N1 IIV) (Adjuvanted With AS03A or Unadjuvanted) in 18 Through 39 Year-old Healthy Subjects, Contrasted With a Two Dose Schedule of an Inactivated Universal Influenza Vaccine (cH8/1N1 IIV + AS03A Followed Three Months Later by cH5/1N1 IIV + AS03A)
Phase: PHASE1
Conditions: Influenza, Vaccine
Sponsor: PATH

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PROTOCOL NUMBER: CVIA 057 
Title: A Phase 1, randomized, controlled, observer-blind study to assess the reactogenicity, 
safety, and immunogenicity of a live attenuated universal influenza vaccine (cH8/1N1 LAIV) 
administered as a single priming dose followed three months later by a single booster dose of 
an inactivated universal influenza vaccine (cH5/1N1 IIV) (adjuvanted with AS03A or unadjuvanted) 
in 18 through 39 year-old healthy subjects, contrasted with a two dose schedule of an 
inactivated universal influenza vaccine (cH8/1N1 IIV + AS03A followed three months later 
by cH5/1N1 IIV + AS03A) 
 
 
Trial Registration: 
Clinical Trials.gov NCT 03300050 
 
 
FDA Reference Number: 
BB-IND 17706
Sponsor:  
PATH  
 
 
 
Collaborating Partner: 
Icahn School of Medicine  
at Mount Sinai 
  
 
 
Funding: 
 
 
Pharmaceutical Support: 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
Protocol Chair: 
 
 
  
 
Protocol Version Number: 5.0 
Version Date: 09 December 2018 
 
Confidentiality Statement: This document is confidential and is to be distributed for review only to 
investigators, potential investigators, consultants, study staff, and applicable independent ethics committees 
or institutional review boards. The contents of this document shall not be disclosed to others without written 
authorization from PATH (or others, as applicable), unless it is necessary to obtain informed consent from 
potential study subjects. 

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TABLE OF CONTENTS 
TABLE OF TABLES ................................................................................................................... 9 
TABLE OF FIGURES ............................................................................................................... 10 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 11 
GLOSSARY OF TERMS ........................................................................................................... 13 
KEY ROLES AND CONTACT INFORMATION ............................................................................ 17 
PROTOCOL SUMMARY ......................................................................................................... 20 
1. BACKGROUND AND RATIONALE ....................................................................................... 30 
1.1 
Background ....................................................................................................................... 30 
1.1.1 
Universal influenza virus vaccine based on chimeric HAs ...................................................................... 31 
1.1.2 
Summary results of preclinical trials ...................................................................................................... 32 
1.1.3 
Summary results of related clinical trials ............................................................................................... 33 
1.1.4 
Rationale for the LAIV-IIV prime-boost .................................................................................................. 33 
1.1.5 
Dose rationale ........................................................................................................................................ 34 
1.1.6 
Rationale for use of adjuvants ............................................................................................................... 35 
1.2 
Rationale for the study design ........................................................................................... 35 
1.3 
Risk/Benefit assessment .................................................................................................... 35 
1.3.1 
Risk assessment ...................................................................................................................................... 36 
1.3.1.1 
Risks to subjects ....................................................................................................................... 36 
1.3.1.2 
Risks to the community ........................................................................................................... 40 
1.3.2 
Benefit assessment ................................................................................................................................ 43 
1.3.3 
Overall Risk/Benefit conclusion ............................................................................................................. 44 
2 
HYPOTHESES, OBJECTIVES, AND ENDPOINTS .......................................................... 44 
2.1 
Study hypotheses .............................................................................................................. 44 
2.2 
Study objectives ................................................................................................................ 44 
2.2.1 
Primary objective ................................................................................................................................... 44 
2.2.2 
Secondary objectives ............................................................................................................................. 45 
2.2.2.1 
Safety ....................................................................................................................................... 45 
2.2.2.2 
Viral shedding - post-Dose 1 .................................................................................................... 45 
2.2.2.3 
Immunogenicity - descriptive, post-Dose 2 ............................................................................. 45 
2.2.2.4 
Immunogenicity - descriptive, post-Dose 2 - breadth ............................................................. 45 
2.2.2.5 
Immunogenicity - descriptive, post-Dose 2 - persistence ........................................................ 46 
2.2.2.6 
Immunogenicity - descriptive, by vaccine regimen, post-Dose 1 ............................................ 46 
2.2.2.7 
Immunogenicity - comparative, post-Dose 2 ........................................................................... 46 
2.2.3 
Tertiary objectives .................................................................................................................................. 47 
3 
STUDY DESIGN ....................................................................................................... 47 
3.1 
Screening .......................................................................................................................... 48 
3.2 
Randomization and dosing ................................................................................................ 49 

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3.2.1 
Dose 1 LAIV-IIV treatment arms (Groups 1, 2, and 3) ............................................................................ 49 
3.2.2 
Dose 1 IIV-IIV treatment arms (Groups 4 and 5) .................................................................................... 49 
3.2.3 
Dose 2 all treatment arms (Groups 1, 2, 3, 4, and 5) ............................................................................. 50 
3.3 
Safety monitoring ............................................................................................................. 50 
3.3.1 
Safety follow-up for all subjects ............................................................................................................. 50 
3.3.2 
Special safety monitoring during inpatient stay post-Dose 1 of cH8/1N1 LAIV (or placebo) ................ 51 
3.4 
Immunogenicity / Transcriptomic testing ........................................................................... 52 
4 
STUDY POPULATION .............................................................................................. 52 
4.1 
Description of study population ......................................................................................... 52 
4.2 
Inclusion criteria for enrollment ........................................................................................ 53 
4.3 
Exclusion criteria for enrollment ........................................................................................ 54 
4.4 
Temporary exclusion criteria for receipt of Dose 1 ............................................................. 57 
5 
STUDY PRODUCTS .................................................................................................. 57 
5.1 
cH8/1N1 LAIV .................................................................................................................... 58 
5.1.1 
Product description ................................................................................................................................ 58 
5.1.2 
Manufacturer ......................................................................................................................................... 59 
5.1.3 
Presentation and formulation ................................................................................................................ 59 
5.1.4 
Stability and storage ............................................................................................................................... 59 
5.2 
cH8/1N1 IIV ...................................................................................................................... 60 
5.2.1 
Product description ................................................................................................................................ 60 
5.2.2 
Manufacturer ......................................................................................................................................... 60 
5.2.3 
Presentation and formulation ................................................................................................................ 60 
5.2.4 
Stability and storage ............................................................................................................................... 60 
5.3 
cH5/1N1 IIV ...................................................................................................................... 60 
5.3.1 
Product description ................................................................................................................................ 60 
5.3.2 
Manufacturer ......................................................................................................................................... 61 
5.3.3 
Presentation and formulation ................................................................................................................ 61 
5.3.4 
Stability and storage ............................................................................................................................... 61 
5.4 
AS03 ................................................................................................................................. 61 
5.5 
Dose preparation and administration ................................................................................ 62 
5.6 
Contraindications to subsequent vaccination ..................................................................... 62 
5.7 
Warnings and precautions ................................................................................................. 63 
5.8 
Accountability and disposal ............................................................................................... 63 
5.9 
Concomitant medications/products/vaccines that may lead to the elimination of a subject 
from Per-Protocol analyses ............................................................................................... 64 
5.10 
Intercurrent medical conditions that may lead to the elimination of a subject from Per-
Protocol analyses .............................................................................................................. 64 

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STUDY SCHEDULE AND PROCEDURES ..................................................................... 65 
6.1 
Study visits ........................................................................................................................ 65 
6.1.1 
Visit 00: Screening visit (up to 56 days prior to Dose 1) ......................................................................... 65 
6.1.2 
Visit 01: Enrollment Visit (up to 2 days prior to Dose 1) ........................................................................ 66 
6.1.3 
Initial Visits for LAIV-IIV (or placebo) arms (Groups 1, 2, & 3) ............................................................... 67 
6.1.3.1 
Visit 02: Day of admission into the isolation unit (Day -1) ....................................................... 67 
6.1.3.2 
Visit 03: Day of receipt of study LAIV (Day 1) .......................................................................... 68 
6.1.3.3 
Visit 04: First day after receipt of study LAIV (Day 2) .............................................................. 68 
6.1.3.4 
Visit 05: Second day after receipt of study LAIV (Day 3) .......................................................... 69 
6.1.3.5 
Visit 06: Third day after receipt of study LAIV (Day 4) ............................................................. 69 
6.1.3.6 
Visit 07: Fourth day after receipt of study LAIV (Day 5) ........................................................... 69 
6.1.3.7 
Visit 08: Day of discharge after receipt of study LAIV (Day 6) ................................................. 70 
6.1.4 
Initial Visits for IIV-IIV (or placebo) arms (Groups 4 & 5) ....................................................................... 71 
6.1.4.1 
Visit 03: Day of receipt of study IIV (Day 1) ............................................................................. 71 
6.1.4.2 
Visit 05: Second day after receipt of study IIV (Day 3) ............................................................. 72 
6.1.5 
Subsequent Visits for all study subjects (Groups 1, 2, 3, 4, & 5) ............................................................ 73 
6.1.5.1 
Visit 09: 7 + 2 days post-Dose 1 (post-Visit 03) ........................................................................ 73 
6.1.5.2 
Visit 10: 28 + 10 days post-Dose 1 (post-Visit 03) .................................................................... 74 
6.1.5.3 
Visit 11: 84 + 10 days post-Dose 1 (post-Visit 03) .................................................................... 74 
6.1.5.4 
Visit 12: 7 + 3 days post-Dose 2 (post-Visit 11) ........................................................................ 76 
6.1.5.5 
Visit 13: 28 + 10 days post-Dose 2 (post-Visit 11) .................................................................... 77 
6.1.5.6 
Visit 14: 168 + 28 days post-Dose 2 (post-Visit 11) .................................................................. 77 
6.1.5.7 
Visit 15: 336 + 28 days post-Dose 2 (post-Visit 11) .................................................................. 78 
6.1.6 
ILI Visits .................................................................................................................................................. 79 
6.1.7 
Unscheduled visits.................................................................................................................................. 80 
6.2 
Discontinuation of vaccination or study procedures ........................................................... 80 
6.3 
Subject withdrawal (premature termination) ..................................................................... 81 
6.3.1 
Handling of withdrawals ........................................................................................................................ 81 
6.3.2 
Withdrawals at specific time-points....................................................................................................... 82 
6.3.2.1 
During screening ...................................................................................................................... 82 
6.3.2.2 
As a result of erroneous inclusion............................................................................................ 82 
6.3.2.3 
For violation of the protocol .................................................................................................... 82 
6.3.2.4 
As a result of withdrawal of informed consent ....................................................................... 82 
6.3.2.5 
As a result of occurrence of an adverse event/serious adverse event .................................... 83 
6.4 
Loss to follow-up ............................................................................................................... 83 
6.5 
Concomitant medications/products/vaccines .................................................................... 83 
6.6 
Unblinding procedure ........................................................................................................ 84 
6.7 
Management of birth control and pregnancy during study ................................................. 84 
6.8 
Clinical procedures ............................................................................................................ 85 
6.8.1 
Medical history ....................................................................................................................................... 85 
6.8.2 
Physical examination .............................................................................................................................. 86 
6.8.2.1 
Vital signs ................................................................................................................................. 86 
6.8.2.2 
Height and weight .................................................................................................................... 87 

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6.8.2.3 
Included systems...................................................................................................................... 87 
6.8.3 
Assessment of local and general adverse events ................................................................................... 87 
7 
LABORATORY EVALUATIONS / REQUIREMENTS ...................................................... 87 
7.1 
Sample collection, processing, storage ............................................................................... 87 
7.1.1 
Nasal and oropharyngeal swab specimens ............................................................................................ 87 
7.1.1.1 
Collection of nasal and oropharyngeal swab specimens ......................................................... 87 
7.1.1.2 
Conditions for transport, processing and storage of swab specimens .................................... 88 
7.1.2 
Blood specimens .................................................................................................................................... 88 
7.1.2.1 
Collection of blood ................................................................................................................... 88 
7.1.2.2 
Processing, storage, and transport of blood ............................................................................ 90 
7.1.2.2.1 
Processing of sera for biochemistry, HIV screening, and serum pregnancy testing (as 
applicable) ................................................................................................................................ 90 
7.1.2.2.2 
Processing of whole blood for hematology ............................................................................. 90 
7.1.2.2.3 
Processing of sera for humoral immunology ........................................................................... 90 
7.1.2.2.4 
Processing of whole blood for plasmablast and stimulated B memory cell assays ................. 90 
7.1.2.2.5 
Processing of whole blood for T cell assays ............................................................................. 90 
7.1.2.2.6 
Processing of whole blood for transcriptomic assays .............................................................. 91 
7.1.3 
Saliva specimens .................................................................................................................................... 91 
7.1.4 
Urine specimens ..................................................................................................................................... 91 
7.2 
Clinical laboratory tests ..................................................................................................... 91 
7.2.1 
Hematology and biochemistry ............................................................................................................... 91 
7.2.2 
Pregnancy testing ................................................................................................................................... 91 
7.2.3 
HIV testing .............................................................................................................................................. 92 
7.3 
Immunological laboratory assays ....................................................................................... 93 
7.3.1 
Humoral and mucosal immune responses ............................................................................................. 93 
7.3.1.1 
cH6/1 stalk IgG by ELISA .......................................................................................................... 94 
7.3.1.2 
cH6/1 stalk IgA ELISA (serum) .................................................................................................. 94 
7.3.1.3 
cH6/1 stalk secretory IgA ELISA (saliva) ................................................................................... 94 
7.3.1.4 
cH6/1 stalk total IgA ELISA (saliva) ........................................................................................... 94 
7.3.1.5 
cH6/1 stalk total IgG ELISA (saliva)........................................................................................... 94 
7.3.1.6 
H2 IgG ELISA ............................................................................................................................. 95 
7.3.1.7 
H9 IgG ELISA ............................................................................................................................. 95 
7.3.1.8 
H18 IgG ELISA ........................................................................................................................... 95 
7.3.1.9 
H3 IgG ELISA ............................................................................................................................. 95 
7.3.1.10 
N1 IgG ELISA ............................................................................................................................. 95 
7.3.1.11 
cH6/1N5 MN assay................................................................................................................... 96 
7.3.1.12 
pH1N1 MN assay ...................................................................................................................... 96 
7.3.1.13 
asH1N1 MN assay .................................................................................................................... 96 
7.3.1.14 
H5N8 MN assay ........................................................................................................................ 96 
7.3.1.15 
Serum ADCC activity ................................................................................................................ 96 
7.3.1.16 
Phagocytic serum activity ........................................................................................................ 96 
7.3.1.17 
cH6/1N5 challenge after passive transfer ................................................................................ 96 
7.3.1.18 
H1N1 challenge after passive transfer ..................................................................................... 97 
7.3.1.19 
cH8/1N1 HI ............................................................................................................................... 97 
7.3.1.20 
cH5/1N1 HI ............................................................................................................................... 97 

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7.3.1.21 
cH6/1N5 HI ............................................................................................................................... 97 
7.3.1.22 
H1N1 HI .................................................................................................................................... 97 
7.3.1.23 
Avian-swine H1N1 HI ............................................................................................................... 97 
7.3.1.24 
H5N8 HI .................................................................................................................................... 97 
7.3.2 
Cell-mediated immunity ....................................................................................................................... 101 
7.3.2.1 
Plasmablast response (ELISPOT for cH6/1) ............................................................................ 101 
7.3.2.2 
Memory B-cell response (ELISPOT for cH6/1) ........................................................................ 101 
7.3.2.3 
T-cell response (ELISPOT) ....................................................................................................... 102 
7.4 
Transcriptomic laboratory assays ..................................................................................... 104 
7.5 
Influenza virologic assays ................................................................................................ 104 
7.6 
Assays qualification, standardization, validation .............................................................. 106 
7.7 
Future use of stored samples ........................................................................................... 106 
7.8 
Biohazard containment ................................................................................................... 106 
8 
SAFETY ASSESSMENT AND REPORTING ................................................................ 106 
8.1 
Definitions ...................................................................................................................... 106 
8.1.1 
Adverse event (AE) ............................................................................................................................... 106 
8.1.1.1 
Solicited local and general reactions ..................................................................................... 107 
8.1.1.2 
Unsolicited adverse events .................................................................................................... 108 
8.1.2 
Adverse drug reaction / suspected adverse reaction .......................................................................... 109 
8.1.3 
Serious adverse event (SAE) ................................................................................................................. 109 
8.1.4 
Clinical laboratory parameters and other abnormal assessments qualifying as adverse events or 
serious adverse events ......................................................................................................................... 110 
8.1.5 
Medically attended event (MAE) ......................................................................................................... 110 
8.1.6 
Influenza-like illness (ILI) ...................................................................................................................... 110 
8.1.7 
Potential immune-mediated disease (pIMD) ....................................................................................... 111 
8.1.8 
Pregnancy ............................................................................................................................................. 113 
8.2 
Monitoring periods for safety events ............................................................................... 113 
8.3 
Severity of adverse events ............................................................................................... 114 
8.3.1 
Severity of solicited AEs ....................................................................................................................... 114 
8.3.2 
Severity of unsolicited AEs, including SAEs, MAEs, pIMDs, and ILIs ..................................................... 116 
8.4 
Causality of adverse event ............................................................................................... 117 
8.5 
Outcome assessment ...................................................................................................... 118 
8.6 
Follow-up of adverse events, serious adverse events, and pregnancies ............................. 118 
8.6.1 
Follow-up of adverse events and serious adverse events.................................................................... 118 
8.6.1.1 
Follow-up during the study .................................................................................................... 118 
8.6.1.2 
Follow-up after the subject is discharged from the study ..................................................... 119 
8.6.2 
Follow-up of pregnancies ..................................................................................................................... 119 
8.7 
General guidance on recording adverse event .................................................................. 119 
8.8 
Reporting of SAE ............................................................................................................. 120 
8.8.1 
Investigator reporting to sponsor ........................................................................................................ 120 

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8.8.2 
Notification and review of SAEs ........................................................................................................... 121 
8.8.3 
Sponsor reporting to regulatory agency .............................................................................................. 121 
8.9 
Other events requiring expedited reporting ..................................................................... 121 
9 
SAFETY MONITORING .......................................................................................... 122 
9.1 
Routine reviews by protocol safety review team .............................................................. 122 
9.2 
Independent data monitoring committee ........................................................................ 122 
9.3 
Study pause rules ............................................................................................................ 123 
9.4 
Study hold procedure ...................................................................................................... 124 
10 
DATA HANDLING AND RECORDKEEPING .............................................................. 125 
10.1 
Source documents and access to source data/documents ................................................ 125 
10.2 
Data capture methods (case report form development and completion) .......................... 125 
10.3 
Data management ........................................................................................................... 126 
10.4 
Retention of study record ................................................................................................ 126 
11 
STATISTICAL CONSIDERATIONS ............................................................................ 127 
11.1 
Overview and general design ........................................................................................... 127 
11.2 
Randomization procedures .............................................................................................. 127 
11.3 
Primary endpoints ........................................................................................................... 128 
11.3.1 Reactogenicity and safety .................................................................................................................... 128 
11.4 
Secondary endpoints ....................................................................................................... 128 
11.4.1 Reactogenicity and safety .................................................................................................................... 128 
11.4.2 Immunogenicity - descriptive, post-Dose 2 .......................................................................................... 129 
11.4.3 Immunogenicity - descriptive, post-Dose 2 - breadth .......................................................................... 129 
11.4.4 Immunogenicity - descriptive, post-Dose 2 - persistence .................................................................... 130 
11.4.5 Immunogenicity - comparative, post-Dose 2 ....................................................................................... 130 
11.5 
Tertiary endpoints ........................................................................................................... 131 
11.6 
Sample size ..................................................................................................................... 132 
11.6.1 Descriptive objectives .......................................................................................................................... 133 
11.6.1.1 
Safety ..................................................................................................................................... 133 
11.6.1.2 
Immunogenicity ..................................................................................................................... 134 
11.7 
Comparative objectives ................................................................................................... 135 
11.8 
Analysis sets.................................................................................................................... 136 
11.9 
Exposed set ..................................................................................................................... 136 
11.10 Per-protocol set .............................................................................................................. 136 
11.11 Statistical analyses .......................................................................................................... 136 
11.11.1 Analysis of demographics ..................................................................................................................... 136 

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11.11.2 Analysis of safety .................................................................................................................................. 137 
11.11.3 Analysis of immunogenicity ................................................................................................................. 137 
11.11.3.1 
Within group assessment ...................................................................................................... 137 
11.11.3.1.1 Humoral and mucosal immunogenicity assessment ............................................................. 137 
11.11.3.1.2 CMI assessment ..................................................................................................................... 138 
11.11.3.2 
Between group assessment ................................................................................................... 138 
11.12 Interpretation of analyses ............................................................................................... 139 
11.13 Conduct of analysis ......................................................................................................... 139 
11.13.1 Sequence of analyses ........................................................................................................................... 139 
11.13.2 Statistical considerations for interim analyses ..................................................................................... 139 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ..................................................... 140 
12.1 
General considerations .................................................................................................... 140 
12.2 
External monitoring ........................................................................................................ 140 
12.3 
Independent auditing ...................................................................................................... 141 
12.4 
Regulatory agency auditing ............................................................................................. 141 
13 
ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) ....................................... 141 
13.1 
Ethical standards ............................................................................................................. 141 
13.2 
Ethical review ................................................................................................................. 142 
13.3 
Recruitment .................................................................................................................... 142 
13.4 
Informed consent process ............................................................................................... 142 
13.5 
Participant confidentiality ............................................................................................... 143 
13.6 
Reimbursement .............................................................................................................. 143 
13.7 
Compensation for research related Injury ........................................................................ 143 
14 
FINANCING AND INSURANCE ............................................................................... 144 
15 
PUBLICATION POLICY ........................................................................................... 144 
16 
LITERATURE CITED ............................................................................................... 145 
APPENDIX 1 Summary of Study Procedures for LAIV-IIV and IIV-IIV Treatment Arms ........... 149 
APPENDIX 2 FDA Severity Grading Tables for Hematologic and Biochemical Parameters .... 152 

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TABLE OF TABLES 
Table 1 
Important risks to subjects .......................................................................................37 
Table 2 
Community risk mitigation policies and procedures ..................................................42 
Table 3 
Study groups and treatment and route of administration by dose .............................48 
Table 4 
Study Vaccines/Products .........................................................................................57 
Table 5 
Dosage and administration ......................................................................................62 
Table 6 
Intervals between study visits ..................................................................................65 
Table 7  
Volume Estimates of whole blood drawn for clinical and immunologic assays at each 
visit. .........................................................................................................................89 
Table 8 
Hematology/biochemistry/virology ...........................................................................92 
Table 9 
Read-outs for hematology/biochemistry/virology ......................................................93 
Table 10 Humoral and mucosal immunity assays ...................................................................98 
Table 11 Humoral and mucosal immunologic read-outs ....................................................... 100 
Table 12 Cell-mediated immunologic assays ........................................................................ 103 
Table 13 Cell-mediated immunologic read-outs .................................................................... 103 
Table 14 Transcriptomic read-outs .......................................................................................... 104 
Table 15 Influenza virology ................................................................................................... 105 
Table 16 Read-outs for influenza virology ............................................................................. 105 
Table 17 Solicited local adverse events - post-LAIV dose .................................................... 107 
Table 18 Solicited local adverse events - post-IIV dose ........................................................ 108 
Table 19 Solicited general adverse events - post-LAIV or post-IIV dose ............................... 108 
Table 20 List of potential immune-mediated diseases .......................................................... 112 
Table 21 Severity grading scales for solicited symptoms in adults ........................................ 115 
Table 22 Study pause rules .................................................................................................. 124 
Table 23  Assumed losses of evaluable subjects from randomization until immunogenicity 
analyses at Visit 13 ................................................................................................ 132 
Table 24 True proportions associated with a 90% probability to observe a certain number of 
adverse events pooled LAIV groups (30 subjects) ................................................. 133 
Table 25 True proportions associated with a 90% probability to observe a certain number of 
adverse events within an IIV group (15 subjects) ................................................... 133 
Table 26 2-sided 95% exact confidence intervals for the true adverse event rate at different 
possible observed adverse event rates (30 subjects) ............................................. 134 

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Table 27 2-sided 95% exact confidence intervals for the true adverse event rate at different 
possible observed adverse event rates (15 subjects) ............................................. 134 
Table 28 2-sided 95% exact confidence intervals for the true immunological response rate at 
different possible observed response rates (28 evaluable subjects) ...................... 134 
Table 29 2-sided 95% exact confidence intervals for the true immunological response rate at 
different possible observed response rates (16 evaluable subjects) ...................... 135 
Table 30 2-sided 95% exact confidence intervals for the true immunological response rate at 
different possible observed response rates (14 evaluable subjects) ...................... 135 
Table 31 Power to detect fold increases in GMT ratios for different values of alpha (type I 
error) assuming a standard deviation of 0.4* in the log10 titer values in both 
comparison groups (14** evaluable subjects per group) ........................................ 135 
Table 32 List of study procedures for LAIV-IIV subjects (Groups 1, 2, & 3) ........................... 149 
Table 33 List of study procedures for IIV-IIV subjects (Groups 4 & 5) ................................... 151 
 
TABLE OF FIGURES 
 
Figure 1 
Phylogenetic diagram showing Group 1 and 2 HAs for influenza A and influenza B 31 
Figure 2 
Vaccination regimen to induce anti-stalk antibodies for group 1 in humans..............32 
Figure 3 
LAIV virus detections by RT-PCR post-administration of a single dose of pre-
pandemic monovalent LAIV candidates containing avian full-length HAs.* ..............41 
Figure 4 
Study design overview .............................................................................................48 

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ABBREVIATIONS AND ACRONYMS 
AE: adverse event 
ADCC: antibody-dependent cell-mediated cytotoxicity 
ADCP: antibody-dependent cellular phagocytosis 
ALT: alanine aminotransferase 
ARI: acute respiratory illness 
ASC: antibody-secreting cells 
AST: aspartate aminotransferase 
BUN: blood urea nitrogen 
CCHMC Cincinnati Children’s Hospital Medical Center 
CDC: Centers for Disease Control and Prevention, United States 
cHA: chimeric hemagglutinin 
CFR Code of Federal Regulations 
CI: confidence interval 
CMI: cell-mediated immune responses 
CSR: clinical study report 
eCRF: electronic case report form 
ELISA: enzyme-linked immunosorbent assay 
ELISPOT Enzyme-Linked ImmunoSpot 
EoS: end of study 
FDA: United States Food and Drug Administration 
GMT: geometric mean titer 
GSK: GlaxoSmithKline 
HA: hemagglutinin 
HI: hemagglutination inhibition 
ICF: informed consent form 
ICH-GCP: International Conference on Harmonisation Good Clinical Practices 
ICMJE The International Committee of Medical Journal Editors 
IDMC: Independent Data Monitoring Committee  
IgA: immunoglobulin A 
IgG: immunoglobulin G 
IIV: inactivated influenza vaccine 

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ILI: influenza-like illness 
IM: intramuscular 
IN: intranasal 
IND: Investigational New Drug 
IRB: Institutional Review Board 
ISMMS: Icahn School of Medicine at Mount Sinai 
IWRS: interactive web response system 
LAIV: live attenuated influenza vaccine 
mAB: monoclonal antibody  
MAE: medically attended event 
MDCK: Madin Darby canine kidney 
MedDRA: Medical Dictionary for Regulatory Activities 
mg: milligram 
MGI: mean geometric increase 
mL: milliliter 
MN: microneutralization 
NA: neuraminidase 
OP: oropharyngeal  
PBMC: peripheral blood mononuclear cell 
PBS: phosphate buffered saline 
PI: principal investigator 
pIMD: potential immune-mediated disease 
PSRT: Protocol Safety Review Team 
rHA: recombinant HA 
RT-PCR: reverse transcription polymerase chain reaction 
SAE: serious adverse event 
SOP: standard operating procedure 
TVC: total vaccinated cohort 
VAERD: Vaccine-associated enhanced respiratory disease  
WBC: white blood cell 
 

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GLOSSARY OF TERMS 
Adequate contraception: 
Adequate contraception is defined as a contraceptive 
method with a 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, when this is 
their preferred and usual lifestyle, 
 
Combined estrogen and progesterone oral 
contraceptives, 
 
Injectable progestogen, 
 
Implants of etonogestrel or levonorgestrel, 
 
Contraceptive vaginal ring, 
 
Percutaneous contraceptive patches, 
 
Intrauterine device or intrauterine system, 
 
Male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive. 
Adequate contraception does not apply to subjects of child 
bearing potential with same sex partners or for subjects who 
are and will continue to be abstinent from penile-vaginal 
intercourse on a long term and persistent basis, when this is 
their preferred and usual lifestyle. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of 
a medicinal product, whether or not considered related to the 
medicinal product. 
An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed 
medicinal products, this also includes failure to produce 
expected benefits (i.e., lack of efficacy), abuse or misuse. 

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Blinding: 
A procedure in which one or more parties to the trial are kept 
unaware of the treatment assignment in order to reduce the 
risk of biased study outcomes. The level of blinding is 
maintained throughout the conduct of the trial, and only 
when the data are cleaned to an acceptable level of quality 
will appropriate personnel be unblinded or when required in 
case of a serious adverse event. In an observer-blind study, 
the subject and the site and sponsor personnel involved in 
the clinical evaluation of the subjects are blinded while other 
study personnel may be aware of the treatment assignment. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study (EoS): 
(Synonym of End of Trial) 
For studies with collection of Human Biologicals Samples or 
imaging data, EoS is defined as the date of the last 
testing/reading released of the Human Biological Samples 
or imaging data, related to primary and secondary endpoints. 
EoS must be achieved no later than 12 months after last 
subject last visit. 
Epoch: 
An epoch is a set of consecutive time points or a single time 
point from a single protocol. Epochs are defined to support 
a main purpose which is either to draw conclusions on 
participation or to draw a complete conclusion to define or 
refine the targeted label of the product. Supporting means 
that data collected at the time points included in an epoch 
must be sufficient to fulfill the purpose of the epoch. 
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-ups, 
and surveillance periods for efficacy or safety. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the per-
protocol analysis. 
Immunological correlate 
of protection: 
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent. 

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Investigational 
vaccine/product: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient being tested 
in a clinical trial, including a product with a marketing 
authorization when used in a way different from the 
approved form, or when used for an unapproved indication, 
or when used to gain further information about an approved 
use.  
Mean Geometric 
Increase: 
Geometric mean of the within-subject ratios of the post-
vaccination reciprocal titer to the pre-vaccination reciprocal 
titer. 
Medically attended 
event: 
An event for which the subject received medical attention 
defined as hospitalization, an emergency room visit, or a visit 
to or from medical personnel (e.g., medical doctor) for any 
reason. 
Menarche: 
Menarche is the onset of menses for the first time in a young 
female and is preceded by several changes associated with 
puberty including breast development and pubic hair growth. 
Menarche usually occurs within 1-2 years of breast 
development, thelarche. However, a young female can 
become pregnant before her first menses. Thus, a 
conservative definition of non-childbearing potential in a pre-
menarcheal female is a young female who has not yet 
entered puberty as evidenced by lack of breast development 
(palpable glandular breast tissue). 
Menopause: 
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g., > 45 years. 
Potential Immune-
Mediated Diseases: 
Potential immune-mediated diseases are a subset of AEs 
that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not 
have an autoimmune etiology. 
Primary completion date: The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all 
primary outcomes, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated. 
Randomization: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 

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Self-contained study: 
Study with objectives not linked to the data of another study. 
Seroconversion rate: 
The percentage of vaccinees with either a pre-vaccination 
hemagglutination inhibition (HI) titer < 1:10 and a post-
vaccination HI titer  1:40 or a pre-vaccination HI titer  
 1:10 and at least 4-fold increase in post-vaccination HI 
titer. 
Seropositivity rate: 
The percentage of vaccinees with an antibody titer of at least 
the cut-off in assays where the cut-off is defined. 
Seroprotection rate: 
The percentage of vaccinees with serum HI titer  1:40; 
usually accepted as indicating protection in at least 50% of 
the vaccinees. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
post-vaccination follow-up period. 
Study vaccine/product 
Any investigational vaccine/product being tested and/or any 
authorized use of a vaccine/product/placebo as a reference 
or administered concomitantly, in a clinical trial that 
evaluates the use of an investigational vaccine/product. 
Sub-cohort: 
A group of subjects for whom specific study procedures are 
planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g., ages, 
vaccination schedule, etc.) at the time of enrollment. 
Subject: 
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or 
participates in the clinical study, either as a recipient of the 
vaccine(s)/product(s) or as a control. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo 
intended to be administered to a subject. 
Treatment number: 
A number identifying a treatment to a subject, according to 
the treatment allocation. 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any “solicited” AE with onset outside the 
specified period of follow-up for solicited AEs will be reported 
as an unsolicited AE. 

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KEY ROLES AND CONTACT INFORMATION 
List names of individuals or organizations serving in key roles (or contributed to the development 
of the protocol). Including contact information, such as name of organization and address.  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
Title 
A Phase 1, randomized, controlled, observer-blind study to assess the 
reactogenicity, safety, and immunogenicity of a live attenuated universal 
influenza vaccine (cH8/1N1 LAIV) administered as a single priming dose 
followed three months later by a single booster dose of an inactivated 
universal influenza vaccine (cH5/1N1 IIV) (adjuvanted with AS03A or 
unadjuvanted) in 18 through 39 year-old healthy subjects, contrasted with 
a two dose schedule of an inactivated universal influenza vaccine 
(cH8/1N1 IIV + AS03A followed three months later by cH5/1N1 IIV + 
AS03A) 
Short Title 
Reactogenicity, safety and immunogenicity study of an investigational 
live-attenuated universal influenza vaccine (prime) followed by an 
investigational inactivated universal influenza vaccine (boost) 
Protocol Number 
CVIA 057 
Trial Phase 
Phase 1 
Investigational Products 
 
Investigational chimeric H8/1N1 live attenuated influenza vaccine 
(cH8/1N1 LAIV) 
 
GlaxoSmithKline (GSK) Biologicals’ investigational chimeric 
H8/1N1 inactivated influenza vaccine (cH8/1N1 IIV) and 
investigational chimeric H5/1N1 inactivated influenza vaccine 
(cH5/1N1 IIV) 
 
AS03A-like adjuvant (AS03A-like will be obtained by dilution of the 
AS03 with PBS) 
 
Normal saline 
 
Phosphate buffered saline  
Study Hypotheses 
 
Primary 
 
 
 
Secondary 
 
 
cH8/1N1 LAIV administered by intranasal route is acceptably safe 
and well-tolerated in healthy adults and cH5/1N1 IIV +/- AS03A 
administered by intramuscular route in those previously primed with 
cH8/1N1 LAIV or cH8/1N1 IIV + AS03A is acceptably safe and well-
tolerated in healthy adults. 
 
Prime-boost with cH8/1N1 LAIV followed by cH5/1N1 IIV +/- AS03A 
results in immune responses against conserved antigenic sites 
among influenza A Group 1 viruses that are acceptable. 
Study Objectives 
 
Primary 
 
 
To assess the reactogenicity and safety through 28 days after each 
priming dose of cH8/1N1 LAIV (or placebo) and the booster dose of 
cH5/1N1 IIV +/- AS03A (or placebo) and through 28 days after each dose 
of IIV (cH8/1N1 IIV + AS03A and cH5/1N1 IIV + AS03A) (or placebo) in 

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Secondary 
terms of rates of solicited local and general adverse events (AEs) through 
7 days post-vaccination, unsolicited AEs through 28 days post-
vaccination, hematological and biochemical laboratory abnormalities up 
to Visit 13, and medically attended event (MAEs), laboratory-confirmed 
influenza-like illness (LC-ILI), potential immune-mediated disease 
(pIMDs), and serious adverse events (SAEs) through Visit 13. 
To assess the safety of each treatment group during the entire study 
period in terms of rates of primary endpoints and additionally 
hematological and biochemical laboratory abnormalities up to Visit 15, 
and MAEs, LC-ILIs, pIMDs, and SAEs through Visit 16. 
Viral shedding – post-Dose 1 
To describe the shedding of vaccine virus through 5 days after 
administration of cH8/1N1 LAIV (Groups 1, 2, and 3 only) in terms of the 
proportions of subjects with influenza type A vaccine virus ribonucleic 
acid (RNA) detected by reverse transcription polymerase chain reaction 
(RT-PCR) in nasal and oropharyngeal (OP) swabs and the proportion of 
subjects with vaccine virus isolated in cell culture each day post-
vaccination. 
Immunogenicity - descriptive, post-Dose 2 
To describe the anti-H1 hemagglutinin (HA)-stalk humoral immune 
responses (anti-H1 HA-stalk serum immunoglobulin G [IgG], anti-H1 HA-
stalk 
serum 
neutralizing 
antibodies, 
anti-H1 
HA-stalk 
serum 
immunoglobulin 
A 
[IgA], 
and 
antibody-dependent 
cell-mediated 
cytotoxicity [ADCC] activity) 28 days after the booster dose of cH5/1N1 
IIV +/- AS03A (or placebo) (Groups 1, 2, and 3) and 28 days after the 
second dose of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 
5) in terms of seropositivity rates, geometric mean titers (GMTs), 
percentages of subjects with a 4-fold or greater increase in titer from Day 
1, percentages of subjects with a 10-fold or greater increase in titer from 
Day 1, and mean geometric increases (MGIs) from Day 1. 
To describe the anti-H1 HA-stalk mucosal immune responses (anti-
H1 HA-stalk salivary total IgA, anti-H1 HA-stalk secretory IgA in saliva, 
and anti-H1 HA-stalk salivary IgG) 28 days after the booster dose of 
cH5/1N1 IIV +/- AS03A (or placebo) (Groups 1, 2, and 3) and 28 days 
after the second dose of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 
4 and 5) in terms of seropositivity rates, GMTs, percentages of subjects 
with a 4-fold or greater increase in titer from Day 1, percentages of 
subjects with a 10-fold or greater increase in titer from Day 1, and MGIs 
from Day 1. 

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Immunogenicity - descriptive, post-Dose 2 - breadth 
To describe the breadth of the anti-H1 HA-stalk humoral immune 
responses (anti-H2 HA-full length serum IgG, anti-H9 HA-full length 
serum IgG, anti-H18 HA-full length serum IgG, anti-H5N8 serum 
neutralizing antibodies, anti-avian swine H1N1 serum neutralizing 
antibodies, and anti-H1pdm09-like serum neutralizing antibodies) to 
Group 1 influenza A viruses 28 days after the booster dose of cH5/1N1 
IIV +/- AS03A (or placebo) (Groups 1, 2, and 3) and 28 days after the 
second dose of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 
5) in terms of seropositivity rates, GMTs, percentages of subjects with a 
4-fold or greater increase in titer from Day 1, percentages of subjects with 
a 10-fold or greater increase in titer from Day 1, and MGIs from Day 1.  
Immunogenicity - descriptive, post-Dose 2 - persistence 
To describe the persistence of the anti-H1 HA-stalk humoral immune 
responses (anti-H1 HA-stalk serum IgG, anti-H1 HA-stalk serum 
neutralizing antibodies, anti-H1 HA-stalk serum IgA, and ADCC activity) 
up to 12 months after the booster dose of cH5/1N1 IIV +/- AS03A (or 
placebo) (Groups 1, 2, and 3) and up to 12 months after the second dose 
of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in terms of 
seropositivity rates, GMTs, percentages of subjects with a 4-fold or 
greater increase in titer from Day 1, percentages of subjects with a 10-
fold or greater increase in titer from Day 1, and MGIs from Day 1. 
To describe the persistence of the anti-H1 HA-stalk mucosal immune 
responses (anti-H1 HA-stalk salivary total IgA, anti-H1 HA-stalk 
secretory IgA in saliva and anti-H1 HA-stalk salivary IgG) up to 12 months 
after the booster dose of cH5/1N1 IIV +/- AS03A (or placebo) (Groups 1, 
2, and 3) and up to 12 months after the second dose of IIV (cH5/1N1 IIV 
+ AS03A) (or placebo) (Groups 4 and 5) in terms of seropositivity rates, 
GMTs, percentages of subjects with a 4-fold or greater increase in titer 
from Day 1, percentages of subjects with a 10-fold or greater increase in 
titer from Day 1, and MGIs from Day 1. 
Immunogenicity - descriptive, by vaccine regimen, post-Dose 1 
To describe the anti-H1 HA-stalk humoral immune responses (anti-
H1 HA-stalk serum IgG, anti-H1 HA-stalk serum neutralizing antibodies, 
anti-H1 HA-stalk serum IgA, and ADCC activity) 28 days after the prime 
dose of cH8/1N1 LAIV (or placebo) (Groups 1, 2, and 3) and 28 days 
after the first dose of IIV (cH8/1N1 IIV + AS03A) (or placebo) (Groups 4 
and 5) in terms of seropositivity rates, GMTs, percentages of subjects 
with a 4-fold or greater increase in titer from Day 1, percentages of 
subjects with a 10 fold or greater increase in titer from Day 1, and MGIs 
from Day 1. 

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To describe the anti-H1 HA-stalk mucosal immune responses (anti-
H1 HA-stalk salivary total IgA, anti-H1 HA-stalk secretory IgA in saliva 
and anti-H1 HA-stalk salivary IgG) 28 days after the prime dose of 
cH8/1N1 LAIV (or placebo) (Groups 1, 2, and 3) and 28 days after the 
first dose of IIV (cH8/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in 
terms of seropositivity rates, GMTs, percentages of subjects with a 4-fold 
or greater increase in titer from Day 1, percentages of subjects with a 10 
fold or greater increase in titer from Day 1, and MGIs from Day 1. 
Immunogenicity - comparative, post-dose two 
To compare the anti-H1 HA-stalk humoral immune responses (anti-
H1 HA-stalk serum IgG, anti-H1 HA-stalk serum neutralizing antibodies, 
anti-H1 HA-stalk serum IgA, and ADCC activity) 28 days after the booster 
dose with cH5/1N1 IIV +/- AS03A after previous receipt of cH8/1N1 LAIV 
(Groups 1 or 2) to that after priming with two doses of IIV (cH8/1N1 IIV 
+ AS03A and cH5/1N1 IIV + AS03A) (Group 4) in terms of the adjusted 
GMT ratio and the seroresponse (≥4-fold) rate difference. 
To compare the anti-H1 stalk mucosal immune responses (anti-H1 
HA-stalk salivary IgA, anti-H1 HA-stalk secretory IgA in saliva, and anti-
H1 HA-stalk salivary IgG) 28 days after the booster dose with cH5/1N1 
IIV +/- AS03A after previous receipt of cH8/1N1 LAIV (Groups 1 or 2) to 
that after priming with two doses of IIV (cH8/1N1 IIV + AS03A and 
cH5/1N1 IIV + AS03A) (Group 4) in terms of the adjusted GMT ratio and 
the seroresponse (≥4-fold) rate difference. 
To evaluate the adjuvant effect of AS03A on the anti-H1 stalk humoral 
immune response (anti-H1 HA-stalk serum IgG, anti-H1 HA-stalk serum 
neutralizing antibodies, anti-H1 HA-stalk serum IgA, and ADCC activity) 
after one booster dose of cH5/1N1 IIV + AS03A after priming with 
cH8/1N1 LAIV (Group 1) compared to boosting with cH5/1N1 IIV, 
unadjuvanted (Group 2) in terms of the adjusted GMT ratio and 
seroresponse (≥4-fold) rate difference. 
Study Endpoints 
 
Primary 
 
Secondary 
 
Endpoints are included in objective statements, above. For more details, 
see Protocol Section 11. 
Study Design 
This is a prospective, multi-center, randomized, controlled, observer-
blind, Phase 1 trial in healthy male and female adults 18 through 39 years 
of age. Up to 65 eligible subjects will participate and will be randomized 
4:3:1:3:2 to one of five groups to receive a first dose of study cH8/1N1 
LAIV (or placebo) or study cH8/1N1 IIV + AS03A adjuvant (or placebo) 
followed three months later by study cH5/1N1 IIV +/- AS03A adjuvant (or 
placebo). See below table. 

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Two sites, Duke Early Phase Clinical Research at Duke University and 
the Gamble Program for Clinical Studies at Cincinnati Children's Hospital 
Medical Center, will participate and enroll 39 and 26 subjects, 
respectively. Prospective subjects will be carefully screened to determine 
eligibility. Subjects will be screened for eligibility through medical history 
review, physical examination, testing for serologic evidence of human 
immunodeficiency virus (HIV) infection, with proper pre- and post-test 
counseling, urine drug test, and routine biochemical and hematological 
blood tests. Women of childbearing potential will undergo pregnancy 
tests using urine samples or serum samples, as required. Screening may 
occur up to 8 weeks prior to receipt of Dose 1 of study vaccines or 
placebo. Subjects will be considered enrolled only after a subject has 
satisfied all eligibility criteria. 
Eligible enrolled subjects will be randomized to any of the treatment arms 
(LAIV-IIV, Groups 1, 2, and 3; or IIV-IIV, Groups 4 and 5) under one 
allocation sequence, stratified by site, to allow comparability between 
study groups, such as LAIV-IIV vs IIV-IIV regimens (Groups 1 vs 4). While 
subjects will be blinded to their exact treatment group and whether they 
received active study vaccine versus placebo, subjects will certainly know 
if they received LAIV (or placebo) vs IIV (or placebo) at Dose 1, given the 
different treatment group requirements, presentations, and routes of 
administration of these products. 
Enrolled subjects will be randomized to study groups as soon as eligibility 
is confirmed and at least 2 days (ideally at least 7 days) in advance of 
receipt of Dose 1 of study vaccines. This is because subjects randomized 
to LAIV-IIV treatment arms (Groups 1, 2, and 3) will receive Dose 1 of 
study cH8/1 LAIV (or placebo) in an inpatient clinical isolation unit and 
may need some time to plan for a specific admission date, to be 
scheduled by each site. Subjects randomized to IIV-IIV treatment arms 
(Groups 4 and 5) will receive Dose 1 in an outpatient research study 
clinic. 
LAIV-IIV treatment arms (Groups 1, 2, and 3): Subjects in the LAIV-IIV 
treatment arms will be admitted into the inpatient clinical isolation unit the 
day before (at least 18 hours prior to) receipt of Dose 1 in order to observe 
the subject for acute onset of respiratory illness of some other etiology 
which the subject might be developing. At the first site to dose subjects 
with study LAIV (or placebo), only six subjects will be admitted initially. 
On Day 1 for these subjects, vaccination with Dose 1 (cH8/1 LAIV or 
Study 
groups 
Number of 
subjects 
Dose 1 
Dose 2 
Treatment 
Administration 
Route 
Treatment 
Administration 
Route 
Group 1 
20 
cH8/1N1 LAIV 
intranasal 
cH5/1N1 IIV + AS03A 
intramuscular 
Group 2 
15 
cH8/1N1 LAIV 
intranasal 
cH5/1N1 IIV 
intramuscular 
Group 3 
5 
Normal saline 
intranasal 
PBS 
intramuscular 
Group 4 
15 
cH8/1N1 IIV + AS03A 
intramuscular 
cH5/1N1 IIV + AS03A 
intramuscular 
Group 5 
10 
PBS 
intramuscular 
PBS 
intramuscular 

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placebo) will be staged such that each subject is dosed and observed for 
at least 60 minutes prior to the next subject being dosed. Consecutive 
dosing will proceed only if no adverse events meeting halting rules or 
other adverse events of concern to the site principal investigator (PI) are 
observed. Also on this day at the first site, the remaining subjects in LAIV-
IIV treatment arms at this site will be admitted to the inpatient clinical 
isolation unit, again for observation of acute onset respiratory illness. 
After at least 18 hours since the sixth subject in the study to have received 
study LAIV (or placebo) have passed with no adverse events meeting 
halting rules or other adverse events of concern to the site PI, the 
remaining subjects in the LAIV-IIV treatment arms will be dosed. At the 
second site to dose subjects in the LAIV-IIV treatment arms, all subjects 
at this site will also be admitted into the inpatient clinical isolation unit the 
day before (at least 18 hours prior to) receipt of Dose 1 in order to observe 
subjects for acute onset of respiratory illness. Again, if no adverse events 
meeting halting rules or other adverse events of concern to the site PI 
were observed in the first six subjects to receive study LAIV (or placebo) 
in the trial at the first site, dosing of subjects at the second site will 
proceed. PATH or the Emmes Study Coordinating Center will coordinate 
communication between the two sites. The second site will not be allowed 
to dose any subjects with study LAIV (or placebo) until PATH has 
provided written approval to the site. 
IIV-IIV treatment arms (Groups 4 and 5): Vaccination with Dose 1 of 
cH8/1N1 IIV + AS03A (or placebo) in the IIV-IIV groups at each site will 
occur without limitation on the number of vaccinees per day or time 
between consecutive subjects, as initial cH8/1N1 IIV safety data (through 
7 days post-vaccination) will have been collected and reviewed by an 
Independent Data Monitoring Committee (IDMC) for GSK's separate 
Phase 1 study of this IIV product prior to initiation of the current trial. 
All treatment arms (Groups 1, 2, 3, 4, and 5): Vaccination with Dose 2 
(cH5/1 IIV +/- AS03A or placebo) at each site will occur in a staggered 
manner, with one half of the subjects at each site vaccinated initially and 
the remaining subjects vaccinated only after at least 5 days has passed 
since the initial half of subjects have all received their Dose 2. In addition, 
initial cH5/1 IIV safety data (through 7 days post-vaccination) will have 
been collected and reviewed by an IDMC for GSK's separate Phase 1 
study of this IIV product prior to initiation of the current trial. 
Planned safety assessments will provide the data for active monitoring of 
vaccine safety during conduct of the trial and for the primary 
reactogenicity and safety endpoints. Immediate reactogenicity and vital 
signs will be assessed by a medically qualified study staff at 60 (+ 10) 
minutes following vaccination in all subjects. Immediate reactogenicity 
will include solicited local and general adverse events and unsolicited 
AEs, including AEs leading to withdrawal from the study and SAEs. 
During the 7-day follow-up period after each vaccination (day of 
vaccination and subsequent 6 days) subjects will complete diary cards 

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for solicited local and general adverse events and unsolicited AEs, 
including scoring for severity, and for use of concomitant medications. 
Reactogenicity scoring will be reviewed by a research clinician prior to 
being entered into the electronic case report form (eCRF). Solicited local 
reactions will include runny nose/nasal congestion at the site of 
administration of study LAIV (or placebo) and pain/tenderness, 
erythema/redness, and induration/swelling at the site of injection of study 
IIV (or placebo). Solicited general reactions will be common for all study 
subjects and include arthralgia, cough, fatigue, fever (based on oral 
temperature), gastrointestinal symptoms (nausea, vomiting, diarrhea 
and/or abdominal pain), headache, myalgia, shivering, sore throat, and 
wheeze. 
For additional assessment of safety, both targeted physical examination 
and collection of blood specimens for analysis of biochemical (alanine 
aminotransferase, aspartate aminotransferase, creatinine, and urea 
nitrogen) and hematologic (leukocytes, neutrophils, lymphocytes, 
basophils, 
monocytes, 
eosinophils, 
hemoglobin, 
platelets, 
and 
erythrocytes) clinical laboratory parameters will also be done at each 
study visit. (Results for clinical laboratory tests conducted just prior to 
receipt of Dose 1 will serve to define baseline status for each subject prior 
to receipt of study vaccine or placebo but will not be used for screening 
purposes.) Clinical laboratory results assessed as AEs will be scored for 
severity using Food and Drug Administration Toxicity Tables (see 
Appendix 2). 
Subjects will be asked to further complete diary cards for unsolicited AEs 
and concomitant medications through the end of the study. At the study 
visits 7 days after each dose, medically qualified study staff will review 
diary cards and document AEs in the eCRF, along with severity, 
relatedness and duration. For each solicited and unsolicited AE the 
subject experiences, the subject will also be asked if he/she received 
medical attention defined as hospitalization, or an otherwise unscheduled 
visit to or from medical personnel for any reason, including emergency 
room visits. This information will also be recorded in the eCRF. Adverse 
events of specific interest for safety monitoring include pIMDs, a subset 
of AEs that include autoimmune diseases and other inflammatory and/or 
neurologic disorders of interest which may or may not have an 
autoimmune etiology. Both pIMDs (serious or non-serious) and SAEs will 
be documented in the eCRF and an Expedited Adverse Events Report 
will be completed. Additionally, occurrence of MAEs and ILIs (with 
laboratory confirmation) will be recorded and evaluated. 
All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (version 15.1 or later). Any SAE ongoing at the time of the 
subject’s end of study (EoS) visit will be attempted to be followed up until 
resolved, or assessed to be resolved with sequelae by the site PI, or his 
designee, until last subject last visit (LSLV) in the trial. If any SAE remains 
unresolved at the time of LSLV, it will be classified as ongoing. To 

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facilitate rigorous safety monitoring, data captured at each visit will be 
entered into the electronic data capture (EDC) system within 72 hours 
from the date of the clinic visit. For ancillary data that may be obtained 
after a visit (e.g., laboratory test results, inpatient records) the goal of data 
entry will be to maintain data integrity and timely safety assessments.  
PATH will convene a Protocol Safety Review Team to regularly review 
blinded safety data and trial conduct. In addition, an IDMC will monitor 
vaccine safety. Prior to receipt of Dose 2 of study vaccines, the IDMC will 
perform a first interim safety review. The IDMC will review all AEs through 
Visit 10, including clinical laboratory evaluations pre- and post-
vaccination, for all subjects. This will include a formal, unblinded review 
of all safety data accrued. The IDMC will also review all shedding data for 
LAIV-IIV treatment arms (see below). The IDMC will then advise if the 
participants may receive Dose 2 of study vaccines. The IDMC will also 
review all AEs through Visit 13 and through Visit 15 at separate safety 
reviews. The need for additional meetings to review unblinded safety data 
will be determined by the IDMC on an ad hoc basis, or as specifically 
requested by PATH. 
Special safety monitoring during inpatient stay post-Dose 1 of cH8/1N1 
LAIV or placebo: To reduce the risk that subjects bring wild-type influenza 
into the inpatient clinical isolation unit or that subjects receiving study 
cH8/1N1 LAIV return to the community while shedding potentially viable 
vaccine virus, all subjects in Groups 1, 2, and 3 will be monitored for acute 
respiratory infection and for virologic evidence of influenza infection. 
Subjects will be admitted to the inpatient clinical isolation unit at least 
18 hours prior to receipt of Dose 1 of study LAIV (or placebo) and 
monitored to ensure no subject is developing an acute respiratory illness. 
On day of entry to the unit, all subjects will have nasal and oropharyngeal 
(OP) swab specimens collected and tested for the presence of influenza 
type A viral RNA by RT-PCR. All subjects must be baseline influenza A 
negative prior to dosing of any subject. Subjects will also have nasal and 
OP swab specimens collected daily thereafter until day of discharge from 
the inpatient clinical isolation unit. Post-vaccination specimens will be 
used to determine discharge of subjects from the unit. All subjects will 
remain in the isolation unit for at least 5 days after receipt of study 
cH8/1N1 LAIV or placebo. Any subject exhibiting influenza A virus 
shedding, as determined by real-time RT-PCR positivity on a nasal and 
OP swab specimen, in the 2 days prior (D4 or D5) or on the day of 
planned discharge (D6) will be kept in the inpatient clinical isolation unit 
until 3 daily consecutive swab specimens taken over a 48 hours period 
all test influenza A negative by RT-PCR. RT-PCR testing of swab 
specimens collected on D6 (or later) will be completed on day of 
specimen collection. Any subject still exhibiting evidence of influenza 
virus shedding in a nasal and OP swab on Days 6 or later will be offered 
anti-neuraminidase treatment (e.g., oral oseltamivir, 75 milligrams [mg] 
twice a day for 5 days). To study virus infectivity, swab specimens that 
test influenza A positive by RT-PCR will be further tested for viability of 

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virus in Madin Darby canine kidney cell culture and stained with 
monoclonal antibody specific to the cH8/1 LAIV virus to confirm detected 
virus is of vaccine origin. Nasal and OP swab specimens may also be 
tested by RT-PCR using primer-probe sets designed to detect specifically 
genes of A/Leningrad/134/17/1957, the master donor virus used to create 
study LAIV.  
For the evaluation of humoral and mucosal immune responses, sera and 
saliva will be collected pre-vaccination and on Visits 10, 11, 13, 14, 
and 15. Sera and saliva will also be collected at Visit 16 with testing for 
humoral and mucosal immune responses dependent upon the outcome 
analysis of primary and secondary objectives. Multiple assays (enzyme-
linked immunosorbent assay, micro-neutralization, ADCC, antibody-
dependent cellular phagocytosis, and hemagglutination inhibition) will be 
used to probe the presence, breadth and persistence of immune 
responses to study vaccines, including functional responses. Sera from 
Day 1 and Visits 13 and 15 will also be pooled for passive transfer to mice 
in an influenza challenge model. For evaluation of cell-mediated immune 
responses (CMI) whole blood will be collected. To assess vaccine 
induction of cytotoxic T lymphocytes and other cytokine indicators, as well 
as circulating T-follicular helper cells, whole blood for isolation of 
peripheral blood mononuclear cell will be collected pre-vaccination and 
on Visits 9, 11, 12, and 15. To assess vaccine induction of plasmablasts, 
whole blood will be collected on Visits 9 and 12. To assess vaccine 
induction of B memory cells, whole blood will be collected pre-vaccination 
and on Visits 10, 11, 13, and 15. Because of the need to process and 
ship whole blood for CMI in a timely manner, strong preference will be 
made to enroll all subjects in Groups 4 and 5 at each site on one day. 
Finally, for evaluation of blood biomarkers associated with vaccination 
and immune responses whole blood will be collected pre-vaccination and 
on Visits 5, 9, 10, 11, 12, 13, 14, and 15. 
A summary of study visits is shown in the below figure. A more detailed 
listing of study procedures by Visit is contained in the tables in 
Appendix 1. 
 

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Study population 
65 healthy male and female adults 18 through 39 years of age in 
metropolitan areas of Cincinnati, Ohio and Durham, North Carolina 
Number of participating 
sites 
Two sites 
 
 
 
 
 
 
 
 
 
 
Study Duration 
Each participant will participate from 21 to 23 months. Two months (8 
weeks) are planned for screening to accrue necessary sample size. 
 
 
 

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1. BACKGROUND AND RATIONALE 
1.1 
Background  
Influenza is a contagious disease caused by influenza viruses that infect the upper and lower 
respiratory tract of humans. The overall public health impact (e.g., infections, hospitalizations, and 
deaths) of an influenza season varies from year to year. Worldwide seasonal influenza virus 
epidemics cause between 3-5 million cases of severe illness and up to 250,000-500,000 deaths 
per year 1. 
Influenza virus of humans is mainly caused by two different influenza A subtypes (H1N1 and 
H3N2) and two lineages of influenza B virus (Yamagata-like and Victoria-like) 2. The main 
reservoir of influenza A virus is wild aquatic birds where all the influenza A virus subtypes exist in 
different combinations. There are 16 different hemagglutinins (HAs) and 9 different 
neuraminidases (NAs), with two more HA-like and two more NA-like proteins found in bats 3-6. 
The HA and NA are the main glycoproteins found on the viral membrane. Their primary roles are 
to facilitate viral entry into and egress out of the host cell. Since these glycoproteins are the main 
components located on the viral membrane, the immune system recognizes them and generates 
a protective antibody response. This is primarily true for HA and to a lesser extent for NA. 
However, these glycoproteins, specifically the HA globular head domain, are very plastic 7,8 and 
change from season to season causing a phenomenon known as antigenic drift. As a result, 
currently licensed influenza virus vaccines need to be updated annually to incorporate changes 
that accumulate in circulating strains 8. 
Influenza virus infection can be prevented by vaccination. However, seasonal influenza virus 
vaccines must be reformulated every year because of antigenic changes that affect vaccine 
efficacy 8. The traditional influenza inactivated vaccine (IIV) consists of reassortants of those 
strains with laboratory donor strains that result in vaccine strains with internal genes/proteins from 
the laboratory donor strains and the surface antigens of the circulating viruses. Those reassortant 
viruses are usually grown in embryonated eggs, and are then inactivated and split with detergents 
and administered through intramuscular injection. Live attenuated influenza vaccines (LAIV) have 
been used in Russia since the 1970s. Using a cold adapted/temperature sensitive/attenuated 
influenza strain as donor (A/Leningrad/134/17/1957), reassortant viruses containing the surface 
antigens of the circulating strains are generated. This vaccine is then administered intranasally. 
The vaccine viruses are able to replicate in the upper respiratory tract (low temperature) inducing 
an immune response but are unable to replicate in the lower respiratory (high temperature) tract. 
Since 2003, a similar strategy using a different donor strain was approved in the US and marketed 
under the name FluMist. 
In certain instances, adjuvants are added to vaccine formulations to create stronger immune 
responses. Pandemrix™(H1N1), an antigen-sparing pandemic influenza vaccine containing only 
3.75 µg of HA (as compared with 15 µg in the conventional vaccines) but adjuvanted with AS03A 
(squalene, DL-α-tocopherol and polysorbate 80), was developed by GlaxoSmithKline (GSK) and 
licensed for use in the 2009 H1N1 influenza pandemic. GSK estimates that more than 90 million 

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persons have received Pandemrix™ (H1N1). Other pandemic influenza vaccines have also been 
tested in clinical trials with adjuvants, after initial trials with unadjuvanted vaccines failed to induce 
strong immune responses. Currently, an H5N1 monovalent pandemic vaccine adjuvanted with 
AS03 is approved in the US 9, Europe, and multiple countries in Asia and Latin America. 
1.1.1 
Universal influenza virus vaccine based on chimeric HAs 
As mentioned above, influenza virus vaccines must be reformulated every year because of 
antigenic changes that affect vaccine efficacy 8. These antigenic changes occur predominantly in 
the globular head region of the HA molecule, in so-called “antigenic sites” that are the target of 
neutralizing antibodies. The current correlate of protection for influenza virus vaccines is the 
hemagglutination inhibition (HI) titer, as measured in an HI assay, which measures immune 
responses in terms of antibodies directed to the HA head 10,11. Antibodies that target other, more 
conserved regions of HA, such as the stalk domain, are potentially protective but since they are 
immunosubdominant, are not efficiently induced by current influenza virus vaccines. Stalk reactive 
antibodies do not show activity in the HI assay. As a result, novel assays and new correlates of 
protection might need to be developed for HA stalk based vaccines. Anti-HA stalk antibodies have 
been isolated from humans and are broadly neutralizing 12-15. Unfortunately, they are usually only 
present at low titers. Therapeutic monoclonal antibodies that target the conserved stalk domain 
of the influenza virus hemagglutinin and stalk-based universal influenza virus vaccine strategies 
are being developed as promising countermeasures for influenza virus infections. The epitopes 
recognized by these antibodies are conformational and involve HA1 as well as HA2 residues 16. 
Due to the conservation of the stalk domain these antibodies are able to broadly neutralize a wide 
spectrum of influenza virus strains and subtypes. Influenza A HAs can be divided into two 
phylogenetic groups (Group 1 and Group 2) with the influenza B HA more distantly related (Figure 
1) 3. Within groups, the stalk domain of the HAs is relatively conserved while the head domains 
are more divergent and responsible for different antigenicities. For instance, the stalk of H1 HA is 
very similar to the stalk of H5 HA (both are group 1 HAs) and antibodies elicited against the H1 
stalk will likely cross-react with the H5 stalk and stalks of other group 1 HAs. Similar cross-
reactivity exists within group 2 HAs.  
Figure 1 
Phylogenetic diagram showing Group 1 and 2 HAs for influenza A and 
influenza B 
 

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Based on these observations, a novel approach to induce broadly protective antibody responses 
against influenza viruses, developed at the Icahn School of Medicine at Mount Sinai (ISMMS) and 
funded by the Bill & Melinda Gates Foundation in collaboration with GSK, utilizes chimeric HA 
(cHA) molecules that pair the globular head region of an exotic (for example, avian) HA with the 
HA stalk region of a currently circulating seasonal influenza virus 17,18. These chimeric HAs are 
then used in vaccination regimens (Figure 2) in which the same stalk domain but different head 
domains are sequentially presented to the immune system. 
Figure 2 
Vaccination regimen to induce anti-stalk antibodies for group 1 in humans.  
 
The purpose of this approach is to boost pre-existing cross-reactive memory responses (or de 
novo-induced in infants lacking such immunity) to the HA stalk without further boosting strain-
specific responses against the head region of HA. This approach has been shown to provide 
effective protection in mice and ferrets 19-24 but has not yet been tested in humans. 
1.1.2 
Summary results of preclinical trials 
A preclinical experiment was performed in ferrets using a similar approach. Ferrets were used as 
the animal model since they mimic influenza disease in humans, including clinical signs, 
pathogenesis and transmission. As the ferrets used in the study were naïve for influenza, animals 
were first immunized with an influenza B virus carrying a chimeric HA containing the H9 head and 
the H1 stalk (fluB-cH9/1). The ferrets then received regimens of heterologous-head chimeric HA 
LAIV followed by heterologous chimeric IIV or heterologous chimeric HA IIV followed by 
heterologous-head chimeric IIV. IIVs were given with or without adjuvant. As control, a group of 
ferrets was vaccinated with the standard of care (two human doses of trivalent vaccine). Another 
control group included unvaccinated animals. After vaccination, all ferrets were challenged with 
pandemic H1N1 virus. All vaccines were safe and well tolerated. All chimeric approaches provided 
good protection against challenge as determined by the absence of viral replication in the lung. 
Importantly, LAIV-IIV plus adjuvant induced a strong stalk antibody response as measured by 
enzyme-linked immunosorbent assay (ELISA) (Nachbagauer, et al. npj Vaccines 2, Article 
number: 26 (2017); doi: 10.1038/s41541-017-0026-4). The observations of the ferret challenge 

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experiment generated the hypothesis that is to be explored in this clinical trial. The hypothesis is 
that administration of a live-attenuated cHA vaccine via the intranasal route as the first dose in a 
prime boost immunization sequence, followed by an inactivated cHA vaccine boost via the 
intramuscular route, offers superior active immunization relative to 2 intramuscular doses of 
inactivated cHA vaccine. 
A preclinical repeat-dose toxicology study has been completed in ferrets with the current study 
vaccines (please see IB for further details). In this study, ferrets were administered two doses of 
intranasal LAIV (or placebo) two weeks apart followed four weeks later by two doses of 
intramuscular IIV with or without AS03A adjuvant (or saline) two weeks apart. Twenty ferrets per 
group underwent necropsy two days after the second IIV dose and ten ferrets per group after a 
28-day recovery period. In seven of twenty ferrets in the AS03A adjuvant group, following the 
second IIV dose, at the site of the second injection, despite an absence of any gross observations, 
there was an observation on microscopy of either moderate (in six) or severe (in one) necrosis; 
however, there was no evidence of any local necrosis on microscopy in any of the ferrets, 
including the ten in the AS03A adjuvant group, at the 28-day recovery time-point.  
1.1.3 
Summary results of related clinical trials 
Indirect evidence that this approach could work has been obtained from clinical trials with H5N1 
vaccines. Although these vaccines were originally designed to induce anti-head neutralizing 
antibodies, retrospective analysis of sera from vaccinees confirmed an increase in anti-stalk 
antibodies post-H5N1 vaccination 25-27. The immune systems of these human subjects had never 
previously seen the exotic novel H5 HA component, but the H5 stalk is very similar to other stalks 
in Group 1, particularly the H1 stalk. As a result, anti-stalk antibody responses were boosted since 
the vaccines induced proliferation of pre-existing memory B cells, with specificities in the Group 
1 HA stalk. While there is not data for in vivo protection of humans, it has been shown that these 
human antibodies are able to provide protection in passive transfer experiments in mice against 
viral challenge 25. This evidence, plus evidence of stalk-specific neutralizing titers post-
vaccination, confirms the functionality of the induced anti-stalk antibodies 25. In the clinical trial 
design, the H1 stalk will be kept constant in all vaccines while the head domain will vary from 
prime to boost (H8 and H5 respectively). This approach is expected to boost anti-Group 1 stalk 
antibodies which are already present in adult humans (Figure 2). It is expected that these 
antibodies will confer protection against H1 viruses circulating in humans as well as other Group 
1 viruses. 
1.1.4 
Rationale for the LAIV-IIV prime-boost 
It has previously been shown in animal models and humans that priming with either live-
attenuated influenza vaccines or DNA vaccines followed by boosting with inactivated influenza 
virus vaccines induces broader and possibly longer lasting immune responses 28-34. Hence, for 
this initial clinical trial, the study team will test an LAIV as prime followed by an IIV booster 
vaccination with or without adjuvant. LAIV with an HA having the head domain from H8 and the 
stalk domain from H1 influenza (termed a cH8/1 chimera) has been produced for human clinical 
studies in an ongoing collaboration between PATH and ISMMS. This LAIV also incorporates the 

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N1 neuraminidase and uses the Leningrad cold-adapted backbone to provide attenuation. A 
booster immunization will be given with IIV comprising a different chimeric HA, with head domain 
from another novel influenza virus such as H5 and the same stalk domain as used previously. In 
this trial, IIV will be adjuvanted with AS03A or administered unadjuvanted. The proposed vaccines 
are the following: 
 
cH8/1N1 LAIV A/mallard/Sweden/24/2002-A/California/04/2009 (cH8/1N1)-
A/Leningrad/134/17/1957) 
 
 
cH8/1N1 IIV A/mallard/Sweden/24/2002-A/California/04/2009 (cH8/1N1)-(PR8 Mt Sinai) 
 
 
cH5/1N1 IIV A/Vietnam/1203/04-A/California/04/2009 (cH5/1N1)-(PR8 Mt Sinai) 
Antibody responses against the stalk domain will be measured in novel assays (ELISA and 
antibody-dependent cell-mediated cytotoxicity [ADCC]). Neutralizing antibody responses and 
neuraminidase inhibiting antibodies will also be measured. However, this study will not assess 
the ability of the vaccine to protect against live influenza infection and will not assess the 
functional role of NA in the protective response to the candidate vaccine. If this Phase 1 study 
demonstrates that one or more vaccine combinations is both safe and immunogenic, further 
Phase 2 work may be considered including a challenge study to determine protection against a 
live, influenza virus. 
The inactivated vaccines to be used in this study are split inactivated cH8/1N1 and cH5/1N1 
monovalent antigens produced by GSK Biologicals at its Dresden facility. The bulk manufacturing 
process for the candidate vaccines follow the Fluarix® process that was licensed until influenza 
season Northern Hemisphere 2016-17 (Submission Track Number: Biologics License number 
125127). GSK will be initiating a Phase 1/2 trial of these chimeric IIVs prior to PATH initiating 
this trial. For this trial, PATH will be cross-referencing GSK’s IND for its Phase 1/2 trial of these 
chimeric influenza vaccine candidates. The Investigator’s Brochure (IB) for the chimeric IIVs will 
be provided by GSK to PATH for this trial. Information on the AS03 adjuvant to be used in this 
trial will also be contained in that IB. 
1.1.5 
Dose rationale 
For this trial, one of the study vaccines, live-attenuated influenza vaccine (cH8/1N1 LAIV, 
manufactured by Meridian Life Science, Memphis, Tennessee) will be tested for the first time in 
humans. The two inactivated influenza vaccines (cH8/1N1 IIV and cH5/1N1 IIV, manufactured by 
GSK) with and without AS03A adjuvant, will be tested for the first time in humans in a trial initiated 
by GSK prior to initiation of our trial. Although the main focus of this trial is the LAIV-IIV approach, 
an IIV-IIV adjuvanted arm has been included as a bridging group to the trial conducted by GSK 
in parallel and as a comparator for the LAIV-IIV approach. For this study, the vaccine will use a 
dose of 107.5 EID50 for the LAIV (a dose similar to the doses used in Russia with the Leningrad 
backbone) and 15 µg of split HA for the IIV (conventional dose) with or without AS03A adjuvant. 

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1.1.6 
Rationale for use of adjuvants 
The use of adjuvants enhanced the induction of stalk-reactive antibodies in animal models 23,35. 
For this study, the trial will include use of AS03A, a proprietary GSK adjuvant. AS03A has been 
shown to act through two mechanisms for seasonal influenza vaccination in humans: 1) the 
adjuvant stimulated increased activation of naïve B cells, thus reducing immune interference with 
previous vaccine responses; 2) the adjuvant was able to increase the adaptability of the recalled 
memory cells to give improved specificity to the new vaccine antigen 36. Therefore, the use of 
AS03A in the cHA vaccination experiments is expected to assist in the induction of high titers of 
broadly protective antibodies. 
1.2 
Rationale for the study design 
Sixty-five subjects 18-39 years of age will be enrolled and randomized to five different treatment 
groups. All subjects will receive two doses of study vaccines (or placebo) three months apart. 
Subjects receiving active study vaccine will receive vaccines that are based on an influenza virus 
expressing a chimeric HA with the same stalk domain (H1 stalk) at each dose but which have a 
different exotic group A1 head domain. Three groups totaling 40 subjects will be randomized 4:3:1 
to receive a priming LAIV dose (Groups 1, 2) or placebo, (Group 3) on study Day 1 followed by a 
booster IIV dose with AS03A (Group 1) or without (Group 2) or placebo (Group 3) at Visit 11 (about 
3 months later). Two groups totaling 25 subjects will be randomized 3:2 to receive a first priming 
IIV dose with AS03A (Group 4) or placebo (Group 5) on study Day 1 followed by a second priming 
IIV dose with AS03A (Group 4) or placebo (Group 5) at Visit 11 (about 3 months later). All eligible 
enrolled subjects will be randomized to any of the treatment arms (LAIV-IIV, Groups 1, 2, and 3; 
or IIV-IIV, Groups 4 and 5) under one allocation sequence, stratified by site, to preserve 
comparability between study groups, particularly LAIV-IIV vs IIV-IIV regimens (e.g., Groups 1 vs 4). 
The main purpose of this study is to assess the safety and reactogenicity of each dose of LAIV or 
IIV. The study will also evaluate 1) acceptability of the immune responses of the LAIV-IIV prime-
boost regimen contrasted with those of the IIV-IIV two-dose prime regimen and 2) the adjuvant 
effect of AS03A on the immune response to the IIV booster dose in the LAIV-IIV regimen when 
compared to the non-adjuvanted formulation. Because influenza vaccines based on influenza 
virus containing a chimeric HA have not been studied in humans previously, the study will evaluate 
both humoral and secretory immune responses, as well as cell-mediated immune responses. To 
ensure comparability of group level data across study regimens, one cohort of subjects will be 
recruited, enrolled, and randomized, stratified by site, to the five study arms. 
1.3 
Risk/Benefit assessment 
The Investigator Brochures for the study products summarize the potential risks and benefits of 
the investigational LAIV and IIV. Neither the investigational LAIV nor the investigational IIVs to be 
used in this study have been administered previously to humans. However, this trial will not be 
initiated until a letter of approval to proceed is received from GSK following its Independent Data 

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Monitoring Committee's (IDMC) review of safety and reactogenicity data for the seven days post-
Dose 1 from all 80 subjects in GSK's Phase 1/2 trial of IIVs with chimeric HAs. 
1.3.1 
Risk assessment 
1.3.1.1 Risks to subjects 
Intranasal administration of LAIV or placebo may cause the subject only mild discomfort or a 
tickling sensation in the nasal passages. The live, attenuated study vaccine to be used for this 
trial is based on the same master donor influenza virus upon which seasonal LAIV currently 
approved for use in Russia is based; therefore, adverse events may be similar. These may 
include, minimally, mild flu-like symptoms 37,38. Intramuscular administration of IIV or placebo may 
cause the subject immediate mild pain in the deltoid region. The inactivated study vaccine to be 
used for this trial is similar to inactivated split virion pandemic vaccine (i.e., H5N1/AS03) 
manufactured by GSK and currently approved for use in the US, although the HA content of that 
product is lower (3.75 µg HA). Therefore, adverse events may also be similar. These may include 
pain and inflammation at the injection site or systemic symptoms such as fever and body aches. 
However, for either LAIV or IIV serious or allergic reactions may be possible. Study subjects will 
be observed closely by qualified clinicians, and emergency care will be immediately available to 
subjects. Clinical units administering vaccines will have all the necessary resources onsite to 
provide emergency care.  
Despite the absence of a local reactogenicity safety concern with the use of licensed AS03A-
adjuvanted inactivated influenza vaccines with non-chimeric hemagglutinin in human populations, 
in light of the microscopic observation of reversible local necrosis at the injection site in some 
ferrets in the preclinical toxicology study, the administration of the second dose of inactivated 
influenza vaccine in the study population will be staggered so that at least 5 days will have passed 
after one half of the subjects are vaccinated before the remaining half shall be vaccinated. 
Other important potential or known risks to subjects for receipt of study vaccines or participation 
in this trial are listed in Table 1 
 
 
 

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Table 1 
Important risks to subjects 
Important 
Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
study LAIV 
Risk of coinfection with 
wild-type seasonal 
influenza 
Reassortment between vaccine virus and wild type-
influenza could result in a new strain with epidemic 
potential. 
See 1.3.1.2. 
Anaphylaxis 
Anaphylaxis reactions have been reported in 
people who had influenza vaccination. People 
allergic to any ingredients in the study vaccines 
could have an allergic reaction to the vaccine. The 
viruses for the vaccine are grown in eggs; 
therefore, people allergic to eggs could have an 
allergic reaction to study vaccines. 
The investigators are advised of possible 
anaphylaxis following study vaccine 
administration by information included in 
the Investigator Brochures.  
As with all vaccines, appropriate medical 
treatment and supervision should always 
be readily available in case of an 
anaphylactic event following the 
administration of the vaccine. Subjects will 
be closely monitored for at least 60 minutes 
after vaccination. Subjects with history of 
any reaction or hypersensitivity likely to be 
exacerbated by any component of the 
vaccine, or anaphylaxis following the 
administration of influenza vaccine(s) will 
be excluded from the study. 
AS03A-adjuvanted study IIV 
Theoretical risk of 
acquiring a vaccine-
induced autoimmune 
disease after 
vaccination  
Theoretical safety concerns have arisen from 
studies in which adjuvants have induced 
autoimmune diseases in various animal models 
and literature reports that diverse compounds with 
“adjuvant” activity could be associated with 
autoimmunity 39. However, a pooled safety analysis 
of data from prospective clinical trials with AS03-
adjuvanted pandemic IIVs (both H5N1 and 
H1N1pdm09) found no increased incidence of 
autoimmunity induced by vaccination with these 
products 40.  
Close monitoring of pIMDs (see Table 20) 
in clinical development programs using 
adjuvants systems. The potential risk of 
events of possible autoimmune etiology to 
occur is mentioned in the Informed Consent 
Form (ICF). 
Subjects with a history or with a current 
diagnosis of an auto-immune disease will 
be excluded from this study. 

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Important 
Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
study IIV with or without AS03A adjuvant 
Anaphylaxis 
Anaphylaxis reactions have been reported in 
people who had influenza vaccination. People 
allergic to any ingredients in the study vaccines 
could have an allergic reaction to the vaccine. The 
viruses for the vaccine are grown in eggs; 
therefore, people allergic to eggs could have an 
allergic reaction to study vaccines. 
The investigators are advised of possible 
anaphylaxis following study vaccine 
administration by information included in 
the Investigator Brochures.  
As with all vaccines, appropriate medical 
treatment and supervision should always 
be readily available in case of an 
anaphylactic event following the 
administration of the vaccine. Subjects will 
be closely monitored for at least 60 minutes 
after vaccination. Subjects with history of 
any reaction or hypersensitivity likely to be 
exacerbated by any component of the 
vaccine, or anaphylaxis following the 
administration of influenza vaccine(s) will 
be excluded from the study. 
Narcolepsy 
Epidemiological data developed by organizations 
not associated with GSK suggest an increased risk 
of narcolepsy following vaccination with 
Pandemrix™ H1N1 in children and adolescents. 
Due to the methodological limitations of the studies, 
which are retrospective observational studies, 
further research is needed to determine whether 
the observed risk is related to the vaccine, 
environmental effects, genetic factors, other 
factors, or a combination of factors. Arepanrix, 
another AS03-adjuvanted vaccine produced in 
Quebec, Canada, with a slightly different H1N1 
viral antigen manufacturing process, has not been 
associated with an increased risk of narcolepsy 
comparable to Pandemrix 41.  
GSK considers narcolepsy to be a clear signal that 
requires further investigation, and continues to 
support both epidemiological and mechanistic 
studies.  
No such risk has been identified in clinical trials of 
AS03-adjuvanted vaccines against other pandemic 
influenza antigens. 
Close monitoring of pIMDs in clinical 
development programs using adjuvants 
systems. The potential risk of events of 
possible autoimmune etiology to occur (like 
narcolepsy) is mentioned in the ICF.  
Subjects with a history or with a current 
auto-immune disease will be excluded from 
this study.  

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Important 
Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Other study procedures 
Risk from blood 
sampling 
Blood sampling-associated risk of discomfort, 
syncope, dizziness, infection at the site after or 
during venipuncture. 
Blood samples will be obtained by a trained 
professional and medical assistance will be 
available.  
The potential risk of feeling faint, or 
experiencing mild local pain, bruising, 
irritation or redness at the site where blood 
was taken, will be mentioned in the ICF. 
The amount of blood to be taken for 
sampling will not be harmful to the subject’s 
health. 
Other risks of study participation 
Risk of influenza 
Because study subjects will be required to forego 
seasonal influenza vaccination for the duration of 
the trial, they will be at risk of infection with 
influenza. 
Subjects will be informed that immediately 
upon development of an influenza-like 
illness i.e., fever or muscle aches and 
cough or sore throat, they should present to 
the study outpatient clinic free of charge for 
nasal and throat swab collection, influenza 
diagnostic testing and physician’s 
assessment. If they test positive for 
influenza, or if in the case of a negative 
diagnostic test, signs and symptoms (and 
local influenza activity) indicate a high 
likelihood of influenza, they will be offered 
anti-neuraminidase treatment free of 
charge. 
 
Vaccine-associated enhanced respiratory disease (VAERD) has been described in influenza-
naïve pigs vaccinated with inactivated H1 influenza vaccine and subsequently challenged with an 
antigenically mismatched H1 virus 42,43. Although VAERD is a reproducible observation under 
well-controlled laboratory conditions with pigs, it has never been observed in natural conditions 
or in other laboratory animal model used to study influenza viruses (i.e. mice and ferrets). VAERD 
has not been described with GSK Biologicals’ AS03-adjuvanted H5N1-pandemic vaccination. The 
latter is a relevant surrogate for the SUIV candidate since it elicits a robust immune response to 
the H1 HA stalk domain without inducing a strong serum neutralizing antibody response to 
A/H1N1pdm09 virus. Although VAERD is not considered as a potential safety risk in the current 
study, surveillance will be performed to capture all influenza like illnesses for the duration of the 
study. 

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In addition, all cases of respiratory illness, as any safety data, will be closely monitored by the 
Independent Data Monitoring Committee (IDMC). The theoretical risk of VAERD will be stated in 
the ICF. 
1.3.1.2 Risks to the community 
The influenza virus A/mallard/Sweden/24/2002 (H8N4) was used to construct the chimeric H8/1 
HA in the LAIV to be used in this study. It is a low pathogenicity influenza virus found to infect 
poultry. It does not contain the multi-basic cleavage site of H5 and H7 influenza viruses which 
facilitates systemic virus replication and results in switching from a low-pathogenic avian influenza 
phenotype to a highly pathogenic avian influenza phenotype. Moreover, H8 influenza virus 
infections have never been detected in humans 44. Nonetheless, it is theoretically possible that 
live study vaccine virus and a wild-type seasonal human influenza virus could co-infect and re-
assort in cells of the upper respiratory tract of a single human, resulting in a new strain of influenza 
of epidemic potential. 
In previous trials of pre-pandemic monovalent candidate LAIVs based on A/Ann Arbor and 
A/Leningrad master donor viruses with avian full-length HAs (not chimeric HAs) administered to 
healthy adults, shedding has been generally low, with most detections by reverse transcription 
polymerase chain reaction (RT-PCR) occurring in the first two days post-vaccination 37,45-51 
(Figure 3).  

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Table 2 
Community risk mitigation policies and procedures 
Site/Community-level mitigation procedures 
 
Study site will not administer study LAIV from December 15 through March 31, the period indicating usual influenza 
circulation in prospective sites. Influenza activity will be monitored through virologic surveillance from November 1 or 
through May 31 if the study will have active study LAIV dosing prior to December 15 or after March 31. 
 
Study site will coordinate with local virologic influenza surveillance, or will establish local virologic influenza surveillance, 
and will closely monitor local influenza circulation during at least the four-week period prior to planned study initiation and 
during study conduct until at least one week after discharge from inpatient clinical unit of final subject receiving study 
LAIV. The site will provide timely reporting on all influenza-positive specimens (including type and subtype of influenza 
and number of specimens tested locally per week) to PATH. 
 
In case of identification of at least 2 laboratory-confirmed influenza A cases in each of the previous 2 weeks at a study 
site, subjects will not be enrolled to receive study LAIV. 
 
Study site will use an inpatient clinical unit with self-contained ventilation system which exhausts air to the outside or if air 
is recirculated which returns air filtered through a high-efficiency particulate air (HEPA) filter. 
 
Study site inpatient clinical unit will be staffed 24 hours each day for the duration of the inpatient portion of the trial and 
unit exits will be monitored 24 hours each day to ensure unauthorized persons do not enter and study subjects not 
cleared for discharge do not leave the unit unless the subject withdraws from the trial. 
 
The study site Principal Investigator (PI) will inform the local city and/or county public health officials of planned conduct 
of the study and will inform officials in real time when the study initiates. 
 
The inpatient clinical unit will follow standard infection control guidelines, including environmental management practices 
such as laundry, cleaning, and disinfection of the facility and subject care equipment, and proper waste management. All 
unit procedures will be documented in a manual prior to study initiation. 
 
The site PI will ensure the study is reviewed by the site Institutional Biosafety Committee and follow all 
guidelines/procedures required by the Institutional Biosafety Committee. 
Site staff-level mitigation procedures 
 
Unit staff will agree to "annual" seasonal influenza vaccination with available inactivated vaccine containing latest World 
Health Organization-recommended strains at least two weeks prior to site initiation. 
 
Unit staff will be trained on and monitored for adherence to infection control procedures. 
 
Unit staff will sign an agreement to adhere to infection control and other study procedures. 
 
Unit staff will agree to monitor any household members for acute respiratory illness (ARI), record oral body temperature 
daily for any such ARI, and report occurrence of the ARI to the site PI. Staff reporting such illness in the household may 
be barred from working in the inpatient clinical unit at the discretion of the site PI. 
 
Unit staff will agree to provide nasal and/or oropharyngeal swab specimens for testing for influenza virus (and other 
respiratory pathogens) for any ARI occurring in the staff member from one week prior to admission of subjects to the 
inpatient clinical unit until one week after discharge of the last subject from the inpatient clinical unit for each sub-cohort. 
Staff reporting such illness may be barred from working in the inpatient clinical unit at the discretion of the site PI. 
 
Unit staff will agree to immediately begin anti-neuraminidase treatment—oseltamivir (75 mg taken orally twice daily for 5 
days) or zanamivir (10 mg taken by oral inhalation twice daily for 5 days)—for any febrile acute respiratory illness, at least 
until time that first nasal/oropharyngeal swab specimen test returns influenza negative by RT-PCR. Staff who test 
influenza positive by RT-PCR for influenza and have other persons sharing his/her household may be offered 
complimentary single occupancy stay in a hotel for up to 72 hours. 
 
Unit staff will agree to possible prophylactic use of anti-neuraminidase drugs—oseltamivir (75 mg taken orally once daily) 
or zanamivir (10 mg taken by oral inhalation once daily) for 10 days—if influenza is detected in the community (single 
influenza positive specimen detected through established site surveillance), either starting from day of detection or from 
day prior to study LAIV dosing in subjects until after discharge from the inpatient clinical unit (second sub-cohort) of last 
subject receiving study LAIV. The decision to initiate prophylaxis of all staff shall be the responsibility of the site PI. 

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 
Unit staff will agree to wear a surgical face mask, eye protection, fluid-resistant gown, and gloves when conducting 
intranasal administration of study LAIV to any subject. 
 
Unit staff will agree to wear gloves while working with healthy subjects and perform hand hygiene a) before touching any 
subject, b) before performing any aseptic procedure, c) after exposure to any body-fluid of any subject, d) after touching 
any subject, and e) after touching any subject surroundings. 
 
Unit staff will agree to a surgical face mask, eye protection, fluid-resistant gown, and gloves when in close proximity 
(within 2 meters) of any subject exhibiting any signs or symptoms of acute respiratory illness. 
Subject-level mitigation procedures 
 
Subjects will consent to enter the inpatient clinical unit one day (at least 18 hours) prior to study LAIV dosing to allow for 
orientation and monitoring for acute respiratory illness caused by a pathogen for which they might already be infected. 
 
Subjects will consent to daily nasal and OP swabbing for RT-PCR testing for influenza virus (and other respiratory 
pathogens) as part of protocol-specified study procedures. 
 
Subjects will consent to remain in the inpatient clinical unit for at least 5 days post-administration of study LAIV. Protocol-
allowed discharge begins on study Day 6. Only those subjects whose nasal and OP swab specimens from Day 4, Day 5, 
and Day 6 all test influenza negative by RT-PCR (3 negative tests over 48 elapsed hours) may be discharged on Day 6. 
Any subject exhibiting influenza A virus shedding, as determined by real-time RT-PCR positivity on a nasal and OP swab 
specimen, in the 2 days prior (Day 4 or Day 5) or on the day of planned discharge (Day 6) will be kept in the inpatient 
clinical isolation unit until either a) three daily consecutive swab specimens taken over a 48 hour period all test influenza 
A negative by RT-PCR or b) the subject agrees to initiation of anti-neuraminidase treatment—oseltamivir (75 mg taken 
orally twice daily for 5 days) or zanamivir (10 mg taken by oral inhalation twice daily for 5 days)—24 hours after which 
point the subject may be discharged as long as the last nasal and OP swab specimen prior to discharge tested influenza 
A negative by RT-PCR. Subjects whose nasal and OP swab specimen from Day 6 (or thereafter) tests positive but who 
decline anti-neuraminidase treatment may be discharged only after three subsequent negative nasal and OP swab 
specimens (3 negative tests over 48 elapsed hours). Subjects who agree to initiate anti-neuraminidase treatment will still 
be requested to return to the clinical daily for nasal and OP swab collection until 3 nasal and OP swab specimens test 
negative over 48 elapsed hours in order to document loss of detectable virus. 
 
Subjects will consent to remain in the inpatient clinical unit until Day 6 if they develop any acute respiratory illness 
regardless of cause. This is to ensure that no subject is discharged prematurely and then begins to shed study LAIV in 
the community. Such subjects will be informed that they might be confined to their room to reduce spread of the agent to 
other subjects in the unit. 
 
Subjects exiting the inpatient clinical unit prior to meeting discharge criteria will be informed that they may be requested 
to begin anti-neuraminidase treatment—oseltamivir (75 mg taken orally twice daily for 5 days) or zanamivir (10 mg taken 
by oral inhalation twice daily for 5 days)—and will be counseled on the theoretical risks to their household contacts and 
the community. 
1.3.2 
Benefit assessment 
Known benefits include: 
 
Medical evaluation/assessments associated with this study, i.e., physical examination for all 
subjects and blood testing (hematology, biochemistry, and virologic data). 
Potential benefits include: 
 
Subjects receiving one of the investigational universal influenza vaccines may potentially have 
the benefit of being protected against influenza A Group 1 viruses. However, since the efficacy 
of these investigational vaccines has not yet been assessed, it is not known whether they are 
effective in protecting against influenza A Group 1 infection in humans. 
 
Contribution to the process of developing a universal influenza vaccine that might provide 
protection against all influenza A or B strains in the future. 

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1.3.3 
Overall Risk/Benefit conclusion 
It has been demonstrated in mice that the chimeric HA-based vaccination regimen with 
investigational inactivated influenza vaccines similar to those being used in this study induced 
higher stalk antibody titers than the seasonal inactivated influenza vaccine. These stalk antibody 
responses were long lasting, cross-reactive to distantly related HAs and provided protection in 
vivo in a serum passive transfer challenge mouse model 52. As already discussed, the LAIV-IIV 
approach may also offer superior immune responses to the IIV-IIV approach. The investigational 
universal influenza vaccines being used in this study are currently in a very early stage of clinical 
development and no vaccine efficacy has been demonstrated in humans. Taking into account the 
measures taken to minimize risk to subjects participating in this study and the measures taken to 
minimize risk of co-infection with the study LAIV and wild-type influenza virus in a subject or 
community member, the potential risks identified in association with these universal influenza 
vaccine products are justified by the potential benefits linked to the development of such an 
influenza vaccine. 
2 HYPOTHESES, OBJECTIVES, AND ENDPOINTS 
2.1 
Study hypotheses 
Primary hypothesis, safety: cH8/1N1 LAIV administered by intranasal route is acceptably safe 
and well-tolerated in healthy adults and cH5/1N1 IIV +/- AS03A administered by intramuscular 
route in those previously primed with cH8/1N1 LAIV or cH8/1N1 IIV + AS03A is acceptably safe 
and well-tolerated in healthy adults. 
Secondary hypothesis, immunogenicity: Prime-boost with cH8/1N1 LAIV followed by cH5/1N1 
IIV +/- AS03A results in immune responses against conserved antigenic sites among influenza A 
Group 1 viruses that are acceptable and at least comparable to those elicited by one dose of 
cH8/1N1 IIV + AS03A followed by cH5/1N1 IIV + AS03A. 
2.2 
Study objectives 
2.2.1 
Primary objective  
 
To assess the reactogenicity and safety through 28 days after each priming dose of cH8/1N1 
LAIV (or placebo) and the booster dose of cH5/1N1 IIV +/- AS03A (or placebo) and through 28 
days after each dose of IIV (cH8/1N1 IIV + AS03A and cH5/1N1 IIV + AS03A) (or placebo) in 
terms of rates of solicited local and general AEs through 7 days post-vaccination, unsolicited 
AEs through 28 days post-vaccination, hematological and biochemical laboratory 
abnormalities up to Visit 13, and medically attended event (MAEs), influenza-like illnesses 
(ILIs), potential immune-mediated disease (pIMDs), and serious adverse events (SAEs) 
through Visit 13. 

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2.2.2 
Secondary objectives  
2.2.2.1 Safety 
 
To assess the safety of each treatment group during the entire study period in terms of rates 
of primary endpoints and additionally hematological and biochemical laboratory abnormalities 
up to Visit 15, and MAEs, ILIs, pIMDs and SAEs through Visit 16. 
2.2.2.2 Viral shedding - post-Dose 1 
 
To describe the shedding of vaccine virus through 5 days after administration of cH8/1N1 
LAIV (Groups 1, 2, and 3 only) in terms of the proportions of subjects with influenza type A 
vaccine virus RNA detected by RT-PCR in nasal and OP swabs and the proportion of subjects 
with vaccine virus isolated in cell culture each day post-vaccination. 
2.2.2.3 Immunogenicity - descriptive, post-Dose 2 
 
To describe the anti-H1 HA-stalk humoral immune responses (anti-H1 HA-stalk serum 
immunoglobulin G [IgG], anti-H1 HA-stalk serum neutralizing antibodies, anti-H1 HA-stalk 
serum immunoglobulin A [IgA], and ADCC activity 28 days after the booster dose of cH5/1N1 
IIV +/- AS03A (or placebo) (Groups 1, 2, and 3) and 28 days after the second dose of IIV 
(cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in terms of seropositivity rates, 
geometric mean titers (GMTs), percentages of subjects with a 4-fold or greater increase in 
titer from Day 1, percentages of subjects with a 10-fold or greater increase in titer from Day 1, 
and mean geometric increases (MGIs) from Day 1. 
 
To describe the anti-H1 HA-stalk mucosal immune responses (anti-H1 HA-stalk salivary 
total IgA, anti-H1 HA-stalk secretory IgA in saliva, and anti-H1 HA-stalk salivary IgG) 28 days 
after the booster dose of cH5/1N1 IIV +/- AS03A (or placebo) (Groups 1, 2, and 3) and 28 
days after the second dose of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in 
terms of seropositivity rates, GMTs, percentages of subjects with a 4-fold or greater increase 
in titer from Day 1, percentages of subjects with a 10-fold or greater increase in titer from 
Day 1, and MGIs from Day 1. 
2.2.2.4 Immunogenicity - descriptive, post-Dose 2 - breadth 
 
To describe the breadth of the anti-H1 HA-stalk humoral immune responses (anti-H2 
HA-full length serum IgG, anti-H9 HA-full length serum IgG, anti-H18 HA-full length serum 
IgG, anti-H5N8 serum neutralizing antibodies, anti-avian-swine H1N1 serum neutralizing 
antibodies, and anti-H1pdm09-like serum neutralizing antibodies) to Group 1 influenza A 
viruses 28 days after the booster dose of cH5/1N1 IIV +/- AS03A (or placebo) (Groups 1, 2, 
and 3) and 28 days after the second dose of IIV (cH5/1N1 IIV + AS03A) (or placebo) (Groups 
4 and 5) in terms of seropositivity rates, GMTs, percentages of subjects with a 4-fold or greater 
increase in titer from Day 1, percentages of subjects with a 10-fold or greater increase in titer 
from Day 1, and MGIs from Day 1.  

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2.2.2.5 Immunogenicity - descriptive, post-Dose 2 - persistence 
 
To describe the persistence of the anti-H1 HA-stalk humoral immune responses  
(anti-H1 HA-stalk serum IgG, anti-H1 HA-stalk serum neutralizing antibodies, anti-H1 HA-stalk 
serum IgA, and ADCC activity) up to 12 months after the booster dose of cH5/1N1 IIV +/- 
AS03A (or placebo) (Groups 1, 2, and 3) and up to 12 months after the second dose of IIV 
(cH5/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in terms of seropositivity rates, GMTs, 
percentages of subjects with a 4-fold or greater increase in titer from Day 1, percentages of 
subjects with a 10-fold or greater increase in titer from Day 1, and MGIs from Day 1. 
 
To describe the persistence of the anti-H1 HA-stalk mucosal immune responses  
(anti-H1 HA-stalk salivary total IgA, anti-H1 HA-stalk secretory IgA in saliva and anti-H1 HA-
stalk salivary IgG) up to 12 months after the booster dose of cH5/1N1 IIV +/- AS03A (or 
placebo) (Groups 1, 2, and 3) and up to 12 months after the second dose of IIV (cH5/1N1  
IIV + AS03A) (or placebo) (Groups 4 and 5) in terms of seropositivity rates, GMTs, 
percentages of subjects with a 4-fold or greater increase in titer from Day 1, percentages of 
subjects with a 10-fold or greater increase in titer from Day 1, and MGIs from Day 1. 
2.2.2.6 Immunogenicity - descriptive, by vaccine regimen, post-Dose 1 
 
To describe the anti-H1 HA-stalk humoral immune responses (anti-H1 HA-stalk serum 
IgG, anti-H1 HA-stalk serum neutralizing antibodies, anti-H1 HA-stalk serum IgA, and ADCC 
activity) 28 days after the prime dose of cH8/1N1 LAIV (or placebo) (Groups 1, 2, and 3) and 
28 days after the first dose of IIV (cH8/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in 
terms of seropositivity rates, GMTs, percentages of subjects with a 4-fold or greater increase 
in titer from Day 1, percentages of subjects with a 10 fold or greater increase in titer from 
Day 1, and MGIs from Day 1. 
 
To describe the anti-H1 HA-stalk mucosal immune responses (anti-H1 HA-stalk salivary 
IgA, anti-H1 HA-stalk secretory IgA in saliva and anti-H1 HA-stalk salivary IgG) 28 days after 
the prime dose of cH8/1N1 LAIV (or placebo) (Groups 1, 2, and 3) and 28 days after the first 
dose of IIV (cH8/1N1 IIV + AS03A) (or placebo) (Groups 4 and 5) in terms of seropositivity 
rates, GMTs, percentages of subjects with a 4-fold or greater increase in titer from Day 1, 
percentages of subjects with a 10 fold or greater increase in titer from Day 1, and MGIs from 
Day 1. 
2.2.2.7 Immunogenicity - comparative, post-Dose 2 
 
To compare the anti-H1 HA-stalk humoral immune responses (anti-H1 HA-stalk serum 
IgG, anti-H1 HA-stalk serum neutralizing antibodies, anti-H1 HA-stalk serum IgA, and ADCC 
activity) 28 days after the booster dose with cH5/1N1 IIV +/- AS03A after previous receipt of 
cH8/1N1 LAIV (Groups 1 or 2) to that after priming with two doses of IIV (cH8/1N1 IIV + 
AS03A and cH5/1N1 IIV + AS03A) (Group 4) in terms of the adjusted GMT ratio and the 
seroresponse (≥4-fold) rate difference. 

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 
To compare the anti-H1 stalk mucosal immune responses (anti-H1 HA-stalk salivary IgA, 
anti-H1 HA-stalk secretory IgA in saliva, and anti-H1 HA-stalk salivary IgG) 28 days after the 
booster dose with cH5/1N1 IIV +/- AS03A after previous receipt of cH8/1N1 LAIV (Groups 1 
or 2) to that after priming with two doses of IIV (cH8/1N1 IIV + AS03A and cH5/1N1 IIV + 
AS03A) (Group 4) in terms of the adjusted GMT ratio and the seroresponse (≥4-fold) rate 
difference. 
 
To evaluate the adjuvant effect of AS03A on the anti-H1 stalk humoral immune response 
(anti-H1 HA-stalk serum IgG, anti-H1 HA-stalk serum neutralizing antibodies, anti-H1 HA-stalk 
serum IgA, and ADCC activity) after one booster dose of cH5/1N1 IIV + AS03A after priming 
with cH8/1N1 LAIV (Group 1) compared to boosting with cH5/1N1 IIV, unadjuvanted 
(Group 2) in terms of the adjusted GMT ratio and seroresponse (≥4-fold) rate difference. 
2.2.3 
Tertiary objectives 
 
To explore the cell-mediated immune responses (B-cells and T-cells) after each vaccination. 
 
To explore blood biomarkers associated with different vaccination regimens (transcriptomic 
analysis). 
 
To explore the immune response against the HA head of cH8/1N1, cH5/1N1, cH6/1N5, and 
H1N1pdm2009-like virus after each vaccination using a HI assay against these viruses. 
 
To explore the anti-H3 stalk response (i.e. influenza A Group 2). 
 
To explore the immune response in terms of anti-NA antibodies after each vaccination. 
 
To explore the protective effect of the stalk-reactive antibodies induced by vaccination in a 
passive transfer challenge experiment in mice. 
 
To develop assays for evaluation/characterization of the humoral and cellular immune 
responses. 
 
To explore the anti-stalk antibodies’ activity (e.g. antibody-dependent cellular phagocytosis 
[ADCP]. 
For a detailed listing of study endpoints, see Section 11. 
3 STUDY DESIGN 
This is a prospective, multi-center, randomized, controlled, observer-blind, Phase 1 trial in healthy 
male and female adults 18 through 39 years of age. Up to 65 eligible subjects will participate and 
will be randomized 4:3:1:3:2 to one of five groups (Table 3) to receive a first dose of study 
cH8/1N1 LAIV (or placebo) or study cH8/1N1 IIV + AS03A adjuvant (or placebo) followed three 
months later by study cH5/1N1 IIV +/- AS03A adjuvant (or placebo). Two sites, Duke Early Phase 
Clinical Research at Duke University and the Gamble Program for Clinical Studies at Cincinnati 

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Children's Hospital Medical Center, will participate and enroll 39 and 26 subjects, respectively. 
Eligible enrolled subjects will be randomized to any of the treatment arms (LAIV-IIV, Groups 1, 2, 
and 3; or IIV-IIV, Groups 4 and 5) under one allocation sequence, stratified by site, to allow 
comparability between study groups, such as LAIV-IIV vs IIV-IIV regimens (Groups 1 vs 4). While 
subjects will be blinded to their exact treatment group and whether they received active study 
vaccine versus placebo, subjects will certainly know if they received LAIV (or placebo) vs IIV (or 
placebo) at Dose 1, given the different presentations and routes of administration of these 
products.  
Table 3 
Study groups and treatment and route of administration by dose 
Study 
groups 
Number of 
subjects 
Dose 1 
Dose 2 
Treatment 
Administration 
Route 
Treatment 
Administration 
Route 
Group 1 
20 
cH8/1N1 LAIV 
intranasal 
cH5/1N1 IIV + AS03A 
intramuscular 
Group 2 
15 
cH8/1N1 LAIV 
intranasal 
cH5/1N1 IIV 
intramuscular 
Group 3 
5 
Normal saline 
intranasal 
PBS 
intramuscular 
Group 4 
15 
cH8/1N1 IIV + AS03A 
intramuscular 
cH5/1N1 IIV + AS03A 
intramuscular 
Group 5 
10 
PBS 
intramuscular 
PBS 
intramuscular 
 
The study design is summarized in Figure 4. The following sections provide details of study 
procedures by visit and these are summarized in the tables in Appendix 1. 
Figure 4 
Study design overview 
 

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Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, including 
those specified in the outline of study procedures (Section 6), are essential and required for study 
conduct. 
3.1 
Screening 
Prospective subjects will be carefully screened to determine eligibility. Subjects will be screened 
for eligibility through medical history review, physical examination, testing for serologic evidence 
of human immunodeficiency virus (HIV) infection, with proper pre- and post-test counseling, urine 
drug test, and routine biochemical and hematological blood tests. Women of childbearing potential 
will undergo pregnancy tests using urine samples or serum samples, as applicable. Screening 
may occur up to 8 weeks prior to receipt of Dose 1 of study vaccines or placebo. Subjects will be 
considered enrolled only after a subject has satisfied all eligibility criteria. 
3.2 
Randomization and dosing 
Enrolled subjects will be randomized to study groups as soon as eligibility is confirmed and at 
least 2 days (ideally at least 7 days) in advance of receipt of Dose 1 of study vaccines. This is 
because subjects randomized to LAIV-IIV treatment arms (Groups 1, 2, and 3) will receive Dose 
1 of study cH8/1 LAIV (or placebo) in an inpatient clinical isolation unit and may need some time 
to plan for a specific admission date, to be scheduled by each site. Subjects randomized to IIV-
IIV treatment arms (Groups 4 and 5) will receive Dose 1 in an outpatient research study clinic. 
3.2.1 
Dose 1 LAIV-IIV treatment arms (Groups 1, 2, and 3) 
Subjects in the LAIV-IIV treatment arms will be admitted into the inpatient clinical isolation unit 
the day before (at least 18 hours) prior to receipt of Dose 1 in order to observe the subject for 
acute onset of respiratory illness of some other etiology which the subject might be developing.  
At the first site to dose subjects with study LAIV (or placebo), only six subjects will be admitted 
initially. On Day 1 for these subjects, vaccination with Dose 1 (cH8/1 LAIV or placebo) will be 
staged such that each subject is dosed and observed for at least 60 minutes prior to the next 
subject being dosed. Consecutive dosing will proceed only if no adverse events meeting halting 
rules or other adverse events of concern to the site principal investigator (PI) are observed. Also 
on this day at the first site, the remaining subjects in LAIV-IIV treatment arms at this site will be 
admitted to the inpatient clinical isolation unit, again for observation of acute onset respiratory 
illness. After at least 18 hours since the sixth subject in the study to have received study LAIV (or 
placebo) have passed with no adverse events meeting halting rules or other adverse events of 
concern to the site PI, the remaining subjects in the LAIV-IIV treatment arms will be dosed. 
At the second site to dose subjects in the LAIV-IIV treatment arms, all subjects at this site will also 
be admitted into the inpatient clinical isolation unit the day before (at least 18 hours prior to) receipt 
of Dose 1 in order to observe subjects for acute onset of respiratory illness. Again, if no adverse 

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events meeting halting rules or other adverse events of concern to the site PI were observed in 
the first six subjects to receive study LAIV (or placebo) in the trial at the first site, dosing of subjects 
at the second site will proceed.  
PATH or the Emmes Study Coordinating Center will coordinate communication between the two 
sites. The second site will not be allowed to dose any subjects with study LAIV (or placebo) until 
PATH has provided written approval to the site. 
3.2.2 
Dose 1 IIV-IIV treatment arms (Groups 4 and 5) 
Vaccination with Dose 1 of (cH8/1N1 IIV + AS03A or placebo) in the IIV-IIV groups at each site 
will occur without limitation on the number of vaccinees per day or time between consecutive 
subjects, as initial cH8/1N1 IIV safety data (through 7 days post-vaccination) will have been 
collected and reviewed by an IDMC for GSK's separate Phase 1 study of this IIV product prior to 
initiation of the current trial. 
3.2.3 
Dose 2 all treatment arms (Groups 1, 2, 3, 4, and 5) 
Vaccination with Dose 2 (cH5/1 IIV +/- AS03A or placebo) at each site will occur in a staggered 
manner, with one half of the subjects at each site vaccinated initially and the remaining subjects 
vaccinated only after at least 5 days has passed since the initial half of subjects have all received 
their Dose 2. In addition, initial cH5/1 IIV safety data (through 7 days post-vaccination) will have 
been collected and reviewed by an IDMC for GSK's separate Phase 1 study of this IIV product 
prior to initiation of the current trial. 
3.3 
Safety monitoring 
3.3.1 
Safety follow-up for all subjects 
Planned safety assessments will provide the data for active monitoring of vaccine safety during 
conduct of the trial and for the primary reactogenicity and safety endpoints (see Section 8).  
Immediate reactogenicity and vital signs will be assessed by medically qualified study staff at 60 
(+ 10) minutes following vaccination in all subjects. Immediate reactogenicity will include solicited 
local and general adverse events and unsolicited AEs, including AEs leading to withdrawal from 
the study and SAEs. 
During the 7-day follow-up period after each vaccination (day of vaccination and subsequent 6 
days) subjects will complete diary cards for solicited local and general adverse events and 
unsolicited AEs, including scoring for severity, and for use of concomitant medications. 
Reactogenicity scoring will be reviewed by a research clinician prior to being entered into the 
electronic case report form (eCRF). Solicited local reactions will include runny nose/nasal 
congestion at the site of administration of study LAIV (or placebo) and pain/tenderness, 
erythema/redness, and induration/swelling at the site of injection of study IIV (or placebo). 
Solicited general reactions will be common for all study subjects and include arthralgia, cough, 

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fatigue, fever (based on oral temperature), gastrointestinal symptoms (nausea, vomiting, diarrhea 
and/or abdominal pain), headache, myalgia, shivering, sore throat, and wheeze.  
For additional assessment of safety, both targeted physical examination and collection of blood 
specimens 
for 
analysis 
of 
biochemical 
(alanine 
aminotransferase 
[ALT], 
aspartate 
aminotransferase [AST], creatinine, and urea nitrogen) and hematologic (leukocytes, neutrophils, 
lymphocytes, basophils, monocytes, eosinophils, hemoglobin, platelets, and erythrocytes) clinical 
laboratory parameters will also be done at each study visit. (Results for clinical laboratory tests 
conducted just prior to receipt of Dose 1 will serve to define baseline status for each subject prior 
to receipt of study vaccine or placebo but will not be used for screening purposes.) Clinical 
laboratory results assessed as AEs will be scored for severity using FDA Toxicity Tables. 
Subjects will be asked to further complete diary cards for unsolicited AEs and concomitant meds 
through the end of the study. At the study visits 7 days after each dose, medically qualified study 
staff will review diary cards and document AEs in the eCRF, along with severity, relatedness and 
duration. For each solicited and unsolicited AE the subject experiences, the subject will also be 
asked if he/she received medical attention defined as hospitalization, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency room visits. 
This information will also be recorded in the eCRF. Adverse events of specific interest for safety 
monitoring include pIMDs, a subset of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in Table 20. 
Both pIMDs (serious or non-serious) and SAEs will be documented in the eCRF and an Expedited 
Adverse Events Report will be completed. Additionally, occurrence of MAEs and LC-ILI will be 
recorded and evaluated. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 15.1 or later). Any SAEs ongoing at the time of the subject’s EoS visit will be attempted 
to be followed up until resolved, or assessed to be resolved with sequelae by the site PI or his 
designee, until last subject last visit (LSLV) in the trial. If any SAE remains unresolved at the time 
of LSLV, it will be classified as ongoing. To facilitate rigorous safety monitoring, data captured at 
each visit will be entered into the electronic data capture (EDC) system within 72 hours from the 
date of the clinic visit. For ancillary data that may be obtained after a visit (e.g., laboratory test 
results, inpatient records) the goal of data entry will be to maintain data integrity and timely safety 
assessments.  
PATH will convene a Protocol Safety Review Team (PSRT) to regularly review blinded safety 
data and trial conduct (see Section 9). In addition, an IDMC will monitor vaccine safety. Prior to 
receipt of Dose 2 of study vaccines, the IDMC will perform a first interim safety review. The IDMC 
will review all AEs through Visit 10, including clinical laboratory evaluations pre- and post-
vaccination, for all subjects. This will include a formal, unblinded review of all safety data accrued. 
The IDMC will also review all shedding data for LAIV-IIV treatment arms (see below). The IDMC 
will then advise if the subjects may receive Dose 2 of study vaccines. The IDMC will also review 
all AEs through Visit 13 and through Visit 15 at separate safety reviews. The need for additional 

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meetings to review unblinded safety data will be determined by the IDMC on an ad hoc basis, or 
specifically requested by PATH. 
3.3.2 
Special safety monitoring during inpatient stay post-Dose 1 of cH8/1N1 
LAIV (or placebo) 
To reduce the risk that subjects do not bring wild-type influenza into the inpatient clinical isolation 
unit or that subjects receiving study cH8/1N1 LAIV do not return to the community while shedding 
potentially viable vaccine virus, all subjects in Groups 1, 2, and 3 will be monitored for acute 
respiratory infection and for virologic evidence of influenza infection. Subjects will be admitted to 
the inpatient clinical isolation unit at least 18 hours prior to receipt of Dose 1 of study LAIV (or 
placebo) and monitored to ensure no subject is developing an acute respiratory illness. On day 
of entry to the unit, all subjects will have nasal and OP swab specimens collected and tested for 
the presence of influenza type A viral RNA by RT-PCR. All subjects must be baseline influenza A 
negative prior to dosing of any subject. Subjects will also have nasal and OP swab specimens 
collected daily thereafter until day of discharge from the inpatient clinical isolation unit. Post-
vaccination specimens will be used to determine discharge of subjects from the unit. All subjects 
will remain in the isolation unit for at least 5 days after receipt of study cH8/1 LAIV or placebo. 
Any subject exhibiting influenza A virus shedding, as determined by real-time RT-PCR positivity 
on a nasal and OP swab specimen, in the 2 days prior (Day 4 or Day 5) to or on the day of planned 
discharge (Day 6) will be kept in the inpatient clinical isolation unit until three daily consecutive 
swab specimens taken over a 48 period all test influenza A negative by RT-PCR. RT-PCR testing 
of nasal and OP swab specimens collected on Day 6 (or later) will be completed on day of 
specimen collection. Any subject still exhibiting evidence of influenza virus shedding in a nasal 
and OP swab on Day 6 or later will be offered anti-neuraminidase treatment (e.g., oral oseltamivir, 
75 milligrams [mg] twice a day for 5 days), 24 hours after which point the subject may be 
discharged as long as the last nasal and OP swab specimen prior to discharge tested influenza 
A negative by RT-PCR. To study virus infectivity, nasal and OP swab specimens that test 
influenza A positive by RT-PCR will be further tested for viability of virus in Madin Darby canine 
kidney (MDCK) cell culture and stained with monoclonal antibody specific to the cH8/1N1 LAIV 
virus to confirm detected virus is of vaccine origin. Nasal and OP swab specimens may also be 
tested by RT-PCR using primer-probe sets designed to detect specifically genes of 
A/Leningrad/134/17/1957, the master donor virus used to create study LAIV, or of the cH8/1 HA.  
3.4 
Immunogenicity / Transcriptomic testing  
For the evaluation of humoral and mucosal immune responses, sera and saliva will be collected 
on pre-vaccination and on Visits 10, 11, 13, 14, and 15. Sera and saliva will also be collected at 
Visit 16 with testing for humoral and mucosal immune responses dependent upon the outcome 
of primary and secondary analyses. . Multiple assays [ELISA, microneutralization (MN), ADCC, 
ADCP, HI] will be used to probe the presence, breadth and persistence of immune responses to 
study vaccines, including functional responses. Sera from pre-vaccination or Visit 13 or Visit 15 
will also be pooled for passive transfer to mice in an influenza challenge model. For evaluation of 
cell-mediated immune responses (CMI) whole blood will be collected. To assess vaccine 

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induction of cytotoxic T lymphocytes, whole blood for isolation of peripheral blood mononuclear 
cells (PBMCs) will be collected on pre-vaccination and on Visits 9, 11, 12, and 15. To assess 
vaccine induction of plasmablasts, whole blood will be collected on Visits 9 and 12. To assess 
vaccine induction of B memory cells, whole blood will be collected on pre-vaccination and on 
Visits 10, 11, 13, and 15. Because of the need to process and ship whole blood for CMI in a timely 
manner, strong preference will be made to enroll all subjects in Groups 4 and 5 at each site on 
one day. For transcriptomics, whole blood will be collected pre-vaccination and on Visits 5, 9, 10, 
11, 12, 13, 14, and 15. 
4 STUDY POPULATION 
4.1 
Description of study population 
This study will be conducted at two major medical research centers in the US. They are the 
Gamble Program for Clinical Studies at Cincinnati Children’s Hospital Medical Center (CCHMC) 
located in Cincinnati, Ohio, and the Duke Early Phase Clinical Research Unit at Duke Clinical 
Research Institute in Durham, North Carolina. A total of 65 subjects aged 18 through 39 years old 
will be enrolled in this study. 
4.2 
Inclusion criteria for enrollment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity, regulatory acceptability of the study or subject safety. Therefore, adherence to 
the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
 
Able to understand planned study procedures and demonstrate comprehension of the 
protocol procedures and knowledge of study by passing a written examination* prior to 
vaccination 
*Passing grade ≥70% 
 
In the opinion of the investigator, can and will comply with the requirements of the protocol 
(e.g., completion of the diary cards, return for follow-up visits). 
 
Written informed consent obtained from the subject prior to performance of any study specific 
procedure. 
 
Male or non-pregnant female between, and including, 18 and 39 years of age at the time of 
the first vaccination. 
 
Healthy subjects without acute or chronic, clinically significant pulmonary, cardiovascular, 
hepatic or renal functional abnormality*. 
*As determined by medical history, physical examination or laboratory screening tests. 

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 
Female subjects of non-childbearing potential may be enrolled in the study. 
 
Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or 
occlusion, hysterectomy, bilateral ovariectomy or post-menopause. Please refer to the 
glossary of terms for the definition of menarche and menopause. 
 
Female subjects of childbearing potential must have a negative pregnancy test within 24 hours 
of vaccination. 
 
Female subjects of childbearing potential must have practiced adequate contraception for 30 
days prior to first vaccination and agree to continue adequate contraception until 2 months 
after completion of the vaccination series (Month 5). Please refer to the glossary of terms for 
the definition of adequate contraception. 
 
Male subjects must be surgically sterile (e.g., vasectomy) or agree to practice adequate 
contraception from the first vaccination until 2 months after completion of the vaccination 
series (Month 5). Please refer to the glossary of terms for the definition of adequate 
contraception. 
4.3 
Exclusion criteria for enrollment 
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity, regulatory acceptability of the study, or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
The following criteria should be checked at the time of study entry. If ANY exclusion criterion 
applies, the subject must not be included in the study: 
 
Use of any investigational or non-registered product (drug or vaccine) other than the study 
vaccines†  
†During the period starting 30 days before the first dose of study vaccines (Day -29 to Day 1), or 
planned use during the study period Between Visit 15 and Visit 16, the subject may participate in 
other clinical studies except for those in which investigational influenza vaccines would be 
administered..  
 
Concurrently participating in another clinical study, at any time during the study period, in 
which the subject has been or will be exposed to an investigational or a non-investigational 
vaccine/product‡. Between Visit 15 and Visit 16, the subject may participate in other clinical 
studies except for those in which investigational influenza vaccines would be administered. 
‡Pharmaceutical product or device. 
 
Any medical condition that in the judgment of the investigator would make study participation 
(including intramuscular injection) unsafe. 
 
Medically diagnosed deviated nasal septum or nasal obstruction. 

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 
Chronic administration (defined as more than 14 days in total) of immunosuppressants or 
other immune-modifying drugs within 6 months before the first dose.  
 
For corticosteroids, this will mean prednisone  20 mg/day, or equivalent.  
 
For high-dose inhaled corticosteroids this will mean beclomethasone dipropionate 
chlorofluorocarbon  840 mcg/day, or equivalent. 
 
Topical steroids are allowed. 
 
Administration of long-acting immune-modifying drugs (e.g., infliximab, rituximab) within 6 
months before the first dose (Visit 03), or planned administration any time during the study 
period. 
 
Planned administration/administration of a vaccine not foreseen by the study protocol in the 
period starting 30 days before the first dose (Visit 03) up to Month 15 (Visit 15)§. 
§30 days before the first the first dose (Visit 03) up to the blood sampling at Day 113 (Visit 13) and 
in the period starting 30 days before blood sampling at Month 9 (Visit 14) and Month 15 (Visit 15) 
 
Persons who should be annually vaccinated against influenza, if they themselves are or they 
live with or care for persons at high risk for influenza-related complications.ǁ  
ǁincluding:  
 
health care personnel such as physicians, nurses, and other workers in inpatient and 
outpatient-care settings, medical emergency-response workers, such as paramedics and 
emergency medical technicians) employees of nursing home and long-term care facilities who 
have contact with patients or residents, and students in these professions who will have contact 
with patients, and 
 
household contacts and caregivers of persons not eligible for seasonal influenza vaccination 
(e.g. children aged <6 months) or among whom seasonal influenza vaccine effectiveness is 
diminished (e.g. the elderly ≥65 years). 
 
[Medical conditions that put persons at high risk for severe complications from  
influenza are identified by the Advisory Committee on Immunization Practices (see 
https://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm) and include the following: 
o 
Persons who have chronic pulmonary (including asthma) or cardiovascular (except 
isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders 
(including diabetes mellitus); 
o 
Persons who have immunosuppression (including immunosuppression caused by 
medications or by HIV infection); 
o 
Persons who have extreme obesity (body mass index [BMI] ≥40)] 
 
History of influenza vaccination within 6 months prior to study enrollment or unwillingness to 
forego seasonal influenza vaccination during the entire study period. 

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 
History of vaccination with an investigational pandemic influenza vaccine other than an 
H1N1pdm09 vaccine. 
 
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on 
medical history and physical examination. 
 
Infection with human immunodeficiency virus regardless of clinical stage of immunodeficiency. 
 
History of current infection with hepatitis B virus or hepatitis C virus regardless of clinical 
presentation. 
 
History of or current autoimmune disease. 
 
Subjects diagnosed with excessive daytime sleepiness¶ or narcolepsy; or history of 
narcolepsy in a subject’s parent or sibling. 
¶Unintended sleep episodes during the day present almost daily for at least one month 
 
History of Guillain-Barré syndrome. 
 
History of any reaction or hypersensitivity likely to be exacerbated by any component of the 
vaccines (including egg proteins); a history of anaphylactic-type reaction to consumption of 
eggs; or a history of severe adverse reaction to a previous influenza vaccine. 
 
Hypersensitivity to latex. 
 
Administration of immunoglobulins and/or any blood products during the period starting 3 
months before the first dose of study vaccines or planned administration during the study 
period. 
 
Pregnant or lactating female. 
 
Female planning to become pregnant or male planning to father a child or either planning to 
discontinue contraceptive precautions. 
 
Current smoker. 
 
During screening, have a positive test for opiates without a prescription. 
 
History of chronic alcohol consumption and/or drug abuse as deemed by the investigator to 
render the potential subject unable/unlikely to provide accurate safety reports. 
 
Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination. 
 
Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric 
diagnosis that may interfere with subject compliance or safety evaluations. 

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 
Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for 
danger to self or others within 10 years prior to study vaccination. 
 
Blood donation or planned blood donation within 30 days prior to the study vaccination through 
30 days after the last blood drawn for this study. 
 
Have signs or symptoms that could confound or confuse assessment of study vaccine 
reactogenicity.  
 
Any hematological# or biochemical** parameter that is out of range of normal††, and is 
considered clinically significant by the investigator. 
#Complete blood cell count [red blood cells, white blood cells], white blood cells differential count 
[lymphocytes, neutrophils and eosinophils], platelet count or hemoglobin level 
**Creatinine, blood urea nitrogen [BUN], ALT or AST  
††Per the site clinical laboratory’s reference ranges. All tests with out of range results must be 
repeated before any subject is allowed to be enrolled. 
 
 
The following hematological or biochemical laboratory results will be considered exclusionary, 
irrespective of assessment of clinical significance: 
Hemoglobin (Male) 
< 13.0 g/dL 
Hemoglobin (Female) 
< 11.7 g/dL 
White Blood Cell count < 3,000 cells/mm3 
Neutrophil count 
< 1,500 cells/mm3 
Eosinophil count 
> 600 cells/mm3 
Platelet count 
 
< 130,000 cells/mm3 
Creatinine 
 
> 1.4 mg/dL 
ALT 
 
 
> Upper limit of the normal range (ULN) ††  
AST 
 
 
> Upper limit of the normal range (ULN) †† 
††Per the site clinical laboratory’s reference ranges. 
4.4 
Temporary exclusion criteria for receipt of Dose 1 
 
Travel within 7 days of planned receipt of Dose 1 of study LAIV (or placebo) to a region with 
known or suspected ongoing influenza circulation (Groups 1, 2, and 3 only). 
 
Acute disease and/or fever¶¶ at the time of planned receipt of Dose 1 of study vaccine. 
¶¶Fever for this purpose is defined as temperature  38.0°C or 100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity. 
 
5 STUDY PRODUCTS 
The quality control standards and requirements for each study vaccine are described in separate 
quality assurance documents (e.g., release protocols, certificate of analysis) and the required 
approvals will be obtained prior to study initiation. The study vaccines are labelled and packed 
according to applicable regulatory requirements. Commercial sterile normal saline will be 

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purchased for use as intranasal placebo and phosphate buffered saline (PBS) will be provided by 
GSK for use as intramuscular placebo. Table 4 provides an overview of the study 
vaccines/products. 
Table 4 
Study Vaccines/Products 
Treatment 
Product 
name 
Formulation 
Presentation 
Volume 
 to be 
administered 
Number 
of 
doses 
cH8/1N1 
LAIV 
cH8/1N1 
LAIV 
HA head, A/mallard/Sweden/24/2002 (H8N4); 
HA stalk, A/California/04/2009 (H1N1); 
NA,A/California/04/2009 (H1N1) containing 
the backbone of the cold adapted/temperature 
sensitive of the Russian LAIV 
A/Leningrad/134/17/1957 (Len17 IDCDC-
RG46D); LAIV dose=107.5 +/- 0.5 EID50 
Frozen liquid 
0.5 mL** 
1 
Normal saline 0.9% Sodium chloride solution 
Liquid in vial 
cH8/1N1 
IIV 
+ AS03A-
like* 
cH8/1N1 
HA head, A/mallard/Sweden/24/2002 (H8N4); 
HA stalk, A/California/04/2009 (H1N1); NA, 
A/California/04/2009 (H1N1); HA=15μg 
Freeze-dried pellet 
0.5 mL** 
1 
AS03 
Emulsion containing tocopherol, 
tocopherol=47.44mg/ml 
Whitish to yellowish 
homogenous milky 
liquid emulsion in 
multi-dose vial 
PBS 
Na₂HPO₄=1.3mg; KH₂PO₄=186μg; 
NaCl=3.85mg; KCl=100μg; MgCl₂=50μg 
Liquid in vial 
cH5/1N1 
IIV  
+ AS03A-
like* 
cH5/1N1 
HA head, A/Vietnam/1203/2004 (H5N1); HA 
stalk, A/California/04/2009 (H1N1); NA, 
A/California/04/2009 (H1N1); HA=15μg 
Freeze-dried pellet 
0.5 mL** 
1 
AS03 
Emulsion containing tocopherol, 
tocopherol=47.44mg/ml 
Whitish to yellowish 
homogenous milky 
liquid emulsion in 
multi-dose vial 
PBS 
Na₂HPO₄=1.3mg; KH₂PO₄=186μg; 
NaCl=3.85mg; KCl=100μg; MgCl₂=50μg 
Liquid in vial 
cH5/1N1 
IIV 
cH5/1N1 
HA head, A/Vietnam/1203/2004 (H5N1); HA 
stalk, A/California/04/2009 (H1N1); NA, 
A/California/04/2009 (H1N1); HA=15μg 
Freeze-dried pellet 
0.5 mL*** 
1 
PBS 
Na₂HPO₄=1.3mg; KH₂PO₄=186μg; 
NaCl=3.85mg; KCl=100μg; MgCl₂=50μg 
Liquid in vial 
Normal 
saline 
Normal 
saline 
0.9% Sodium chloride solution 
Liquid in vial 
0.5 mL 
1 
PBS 
PBS 
Na₂HPO₄=1.3mg; KH₂PO₄=186μg; 
NaCl=3.85mg; KCl=100μg; MgCl₂=50μg 
Liquid in vial 
0.5 mL 
1 
*AS03A-like will be obtained by dilution of the AS03 with PBS 
**After dilution and reconstitution   

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***After reconstitution   
5.1 
cH8/1N1 LAIV  
5.1.1 
Product description 
The cH8/1N1 LAIV was developed utilizing chimeric HA molecules that pair the globular head 
region of an exotic avian HA (A/mallard/Sweden/24/2002 [H8N4]) with the HA stalk region and 
the complete sequence of the NA molecule of a currently circulating seasonal influenza virus 
(A/California/04/2009 [H1N1]), and the remaining genes from the cold adapted, attenuated 
A/Leningrad/134/17/1957 (Len17 IDCDC-RG46D).  
The LAIV was generated from plasmid DNA by reversed genetics in Vero cells and passaged in 
Specific Pathogen Free (SPF) embryonated chicken eggs to generate a Master Virus Bank 
(MVB). For GMP manufacturing of the vaccine, the master virus was further expanded in SPF 
eggs, and the allantoic fluid was harvested, formulated with SPG buffer, sterile filtered and filled 
in cryovials (SPG: 5 mM Glutamic acid, 10% sucrose in PBS, pH 7.2). Each vial contains 0.75 
milliliter (mL) of a sterile solution of LAIV in allantoic fluid (approx. 20% v/v) and SPG buffer 
(approx. 80% v/v). Filled vials were snap frozen in liquid nitrogen and are stored at ≤-65°C (part 
number: 88135, batch number: 16072281). The sterile LAIV contained in the filled vials will be 
diluted before use in saline, following a procedure provided to the pharmacy, to generate the final 
product for intranasal delivery at the target titer of 107.5 +/- 0.5 EID50 per dose (0.5 mL total). 
5.1.2 
Manufacturer 
The cH8/1N1 LAIV was manufactured by Meridian Life Science, Memphis, Tennessee. Meridian 
is an ISO 9001:2008 certified, USDA licensed (9 Code of Federal Regulations [CFR]), FDA 
registered facility that follows all applicable portions of the Quality System Regulations (21 CFR 
820) and cGMP regulations (21 CFR 210 and 211). In addition, Meridian is EC1774/2002 
registered and follows Export Administration Regulations and Department of Transportation/ 
International Air Transport Association regulations.  
5.1.3 
Presentation and formulation 
The cH8/1 LAIV is presented as 0.75 mL frozen concentrated liquid of IDCDC-RG46D cH8/1 in a 
2 mL cryovial. Prior to administration, the vaccine will be diluted per the procedures set forth in 
the Pharmacy Manual. Briefly, four vials of LAIV will be thawed in a water bath and placed within 
a biosafety cabinet (BSC). Inside the BSC, 0.5 mL of vaccine from each vial will be removed, 
pooled, and mixed in a 15 mL conical tube. The study vaccine will be diluted with 9 mL of sterile 
saline solution. After dilution with sterile saline, one 0.5 mL dose contains cH8/1N1 LAIV titer of 
107.5 +/- 0.5 EID50. The prepared vaccine may be stored between 2°C to 8°C for up to 8 hours. For 
administration of the vaccine, a needle-less syringe will be prepared with 0.25 mL administered 
per nostril (0.5 mL total).  

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5.1.4 Stability and storage  
cH8/1N1 LAIV must be stored at ≤-65°C prior to dilution in a safe and locked place. Access to the 
storage space should be limited to authorized study personnel. The storage conditions will be 
assessed during pre-trial monitoring visits. The storage temperature should be continuously 
monitored with calibrated temperature monitoring device(s) and recorded. Temperature 
excursions must be reported in degrees Celsius. Once the dilution process is completed, the 
prepared vaccine must be stored between 2°C to 8°C and administered within 8 hours.  
Any temperature excursion outside the ranges specified in the Pharmacy Manual must be 
reported within 24 hours of site awareness. The impacted study vaccines must not be used and 
must be stored in quarantine at label temperature conditions until usage approval has been 
obtained from PATH. Refer to the Pharmacy Manual for more details on storage of the study 
vaccines and instructions on the temperature excursion reporting and usage decision process, 
packaging and accountability of the study vaccines/products. 
5.2 
cH8/1N1 IIV 
5.2.1 
Product description 
The cH8/1N1 IIV is an inactivated split virion influenza A virus vaccine bearing chimeric HA 
molecules that pair the globular head region of an exotic avian HA (A/mallard/Sweden/24/2002 
[H8N4]) with the HA stalk region of a currently circulating seasonal influenza virus 
(A/California/04/2009 [H1N1]), and the relevant NA from the seasonal influenza virus 
(A/California/04/09 [H1N1]). After filling 3mL vials with 0.5 mL of formulated vaccine, the vaccine 
is freeze dried, sealed, and stored at 2°C to 8°C.  
5.2.2 
Manufacturer 
The cH8/1N1 IIV is manufactured by GSK in Dresden, Germany. 
5.2.3 
Presentation and formulation 
cH8/1N1 IIV for intramuscular injection, will be supplied in a 0.5mL dose as a sterile, lyophilized 
powder in 3mL glass vials. At the time of use, the vaccine will be reconstituted with either PBS for 
the unadjuvanted group or AS03A-like for the adjuvanted group. Each reconstituted 0.5 mL dose 
contains 15µg split HA.  
5.2.4 
Stability and storage  
cH8/1N1 IIV must be stored at 2°C to 8°C prior to reconstitution in a safe and locked place. Access 
to the storage space should be limited to authorized study personnel. The storage conditions will 
be assessed during pre-trial monitoring visits. The storage temperature should be continuously 
monitored with calibrated temperature monitoring device(s) and recorded. Temperature 
excursions must be reported in degree Celsius. Once the reconstitution process is completed, the 

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prepared vaccine should be kept at room temperature for at least 15 minutes. cH8/1N1 IIV must 
be administered within one hour of reconstitution/preparation.  
Any temperature excursion outside the ranges specified in the Pharmacy Manual must be 
reported within 24 hours of site awareness. The impacted study vaccines must not be used and 
must be stored in quarantine at label temperature conditions until usage approval has been 
obtained from PATH. Refer to the Pharmacy Manual for more details on storage of the study 
vaccines and instructions on the temperature excursion reporting and usage decision process, 
packaging and accountability of the study vaccines/products. 
5.3 
cH5/1N1 IIV 
5.3.1 
Product description  
The cH5/1N1 IIV is an inactivated split virion influenza A virus vaccine bearing chimeric HA 
molecules that pair the globular head region of an exotic avian HA (A/Vietnam/1203/2004 [H5N1]) 
with the HA stalk region of a currently circulating seasonal influenza virus (A/California/04/2009 
[H1N1]), and the relevant NA from the seasonal influenza virus (A/California/04/09 [H1N1]). After 
filling 3 mL vials with 0.5 mL of formulated vaccine, the vaccine is freeze dried, sealed, and stored 
at 2°C -8°C. 
5.3.2 
Manufacturer 
The cH5/1N1 IIV is manufactured by GSK in Dresden, Germany. 
5.3.3 
Presentation and formulation 
cH5/1N1 for intramuscular injection, will be supplied in a 0.5 mL dose as a sterile, lyophilized 
powder in 3 mL glass vials. At the time of use, the vaccine will be reconstituted with either PBS 
for the unadjuvanted group or AS03A-like for the adjuvanted group. Each reconstituted 0.5 mL 
dose contains 15µg split HA.  
5.3.4 
Stability and storage 
cH5/1N1 IIV must be stored at 2°C-8°C prior to reconstitution in a safe and locked place. Access 
to the storage space should be limited to authorized study personnel. The storage conditions will 
be assessed during pre-trial monitoring visits. The storage temperature should be continuously 
monitored with calibrated temperature monitoring device(s) and recorded. Temperature 
excursions must be reported in degree Celsius. Once the reconstitution process is completed, the 
prepared vaccine should be kept at room temperature for at least 15 minutes. cH5/1N1 IIV must 
be administered within one hour of reconstitution/preparation.  
Any temperature excursion outside the ranges specified in the Pharmacy Manual must be 
reported within 24 hours of site awareness. The impacted study vaccines must not be used and 
must be stored in quarantine at label temperature conditions until usage approval has been 

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obtained from PATH. Refer to the Pharmacy Manual for more details on storage of the study 
vaccines and instructions on the temperature excursion reporting and usage decision process, 
packaging and accountability of the study vaccines/products. 
5.4 
AS03 
For study vaccines adjuvanted with AS03, preparation of the AS03A-like adjuvant through dilution 
of AS03 (presented in multi-dose vials) with the accompanying PBS diluent is required prior to 
mixing with the investigational flu freeze-dried cake for reconstitution. After reconstitution (as 
described in the Pharmacy Manual), the individual dose of the appropriate study vaccine will be 
withdrawn into a syringe using aseptic technique. The needles used for vial withdrawal are to be 
disposed of and replaced by new needles for intramuscular (IM) injection. 
5.5 
Dose preparation and administration 
Dose preparation, as described in the Pharmacy Manual, will be carried out by a qualified 
unblinded research pharmacist and witnessed by another un-blinded study staff member. 
Investigational product will be dispensed in a masked syringe, labeled with subject number, and 
administered by an unblinded study staff member.  
Investigational product is prepared at the research pharmacy at each of the trial sites. The 
prepared LAIV vaccine may be stored in the research pharmacy refrigerator (2°C to 8°C) for up 
to 8 hours after preparation prior to administration. The prepared IIV must be used within 1 hour 
of preparation.  
Dosage and administration of study vaccines by study group and visit are shown in Table 5. 
Table 5 
Dosage and administration 
Type of contact 
and time point 
Study group 
Treatment name 
Volume to be 
administered 
Route 
Site 
Location 
Laterality 
Visit 03 (Day 1) 
Group 1 
cH8/1N1 LAIV 
0.25 mL* 
(0.5 mL total) 
(Intranasal) 
IN 
Nares 
Bilateral 
Group 2 
Group 3 
Normal Saline 
0.25 mL* 
(0.5 mL total) 
IN 
Nares 
Bilateral 
Group 4 
cH8/1N1 IIV + AS03A-like 
0.5 mL* 
IM 
Deltoid 
Non-Dominant** 
Group 5 
PBS 
0.5 mL 
IM 
Deltoid 
Non-Dominant** 
 
Visit 11 
Group 1 
cH5/1N1 IIV + AS03A-like 
0.5 mL* 
IM 
Deltoid 
Non-Dominant** 
Group 2 
cH5/1N1 IIV 
0.5 mL* 
IM 
Deltoid 
Non-Dominant** 
Group 3 
PBS 
0.5 mL 
IM 
Deltoid 
Non-Dominant** 
Group 4 
cH5/1N1 IIV + AS03A-like 
0.5 mL* 
IM 
Deltoid 
Non-Dominant** 
Group 5 
PBS 
0.5 mL 
IM 
Deltoid 
Non-Dominant** 
*After reconstitution  
**The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the 
non-dominant arm, an injection in the dominant arm may be performed. 

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5.6 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of any study 
vaccines. If any of these events occur during the study, the subject must not receive additional 
doses of vaccine but may continue other study procedures at the discretion of the investigator: 
 
Anaphylaxis following the administration of vaccine(s). 
 
Pregnancy. 
 
Any condition that in the judgment of the investigator would make intramuscular injection 
unsafe. 
 
Ineligibility (either arising during the trial or retrospectively having been overlooked at 
screening). 
 
Significant non-compliance with treatment regimen or trial requirements. 
 
Occurrence of a new pIMD or the exacerbation of an existing pIMD. Refer to Table 20 for the 
definition of pIMDs. 
 
Discovery of any health condition which, in the investigator’s opinion, places the subject at 
increased risk from receiving further study vaccines dose(s); or discovery of a change in the 
subject’s health status which make him/her unable to comply with protocol-mandated safety 
follow-up. 
 
Hypersensitivity to the active substances or to any of the excipients or to any component that 
may be present as traces. 
The following events constitute contraindications to administration of any study vaccine at that 
point in time; if any of these events occur at the time scheduled for vaccination, the subject may 
be vaccinated at a later date, within the time window specified in the protocol, or withdrawn at the 
discretion of the investigator: 
 
Acute disease and/or fever at the time of vaccination. 
 
Fever for this purpose is defined as temperature  38.0°C or 100.4°F. The preferred 
location for measuring temperature in this study will be the oral cavity. 
5.7 
Warnings and precautions 
None. 

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5.8 
Accountability and disposal 
The site pharmacist is required to maintain complete records of all study products received from 
the Sponsor and will be responsible for maintaining an accurate record of the randomization 
codes, inventory, and an accountability record of vaccine/s, adjuvant, and placebo supplies for 
this study. The site pharmacist will also be responsible for ensuring the security of these 
documents. Partially used vials will not be used for human administration or for in vitro 
experimental studies. At the end of the study, the site will receive instruction from the Sponsor 
regarding the final disposition of any remaining study products.  
5.9 
Concomitant medications/products/vaccines that may lead to 
the elimination of a subject from Per-Protocol analyses 
The use of the following concomitant medications/products/vaccines will not require withdrawal 
of the subject from the study but may determine a subject’s evaluability in the Per-Protocol 
analysis: 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine(s)/product(s) used during the study period. 
 
Immunosuppressants or other immune-modifying drugs administered chronically (i.e., more 
than 14 days in total) during the study period. For corticosteroids, this will mean prednisone  
 20 mg/day, or equivalent. For high-dose inhaled corticosteroids this will mean 
beclomethasone dipropionate chlorofluorocarbon  840 mcg/day, or equivalent. Topical 
steroids are allowed. 
 
Long-acting immune-modifying drugs administered at any time during the study period (e.g., 
infliximab, rituximab). 
 
A vaccine not foreseen by the study protocol administered during the period starting 30 days 
before the first dose (Visit 03) up to the blood sampling at Visit 13. In case an emergency 
mass vaccination for an unforeseen public health threat (e.g., a pandemic) is organized by 
the public health authorities, outside the routine immunization program, the time period 
described above can be reduced if necessary for that vaccine provided it is licensed and used 
according to its Prescribing Information and according to the local governmental 
recommendations and provided a written approval of PATH is obtained. 
 
Seasonal influenza vaccine administered at any time during the study period. 
 
Immunoglobulins and/or any blood products administered during the study period. 
 
Drug and/or alcohol abuse. 

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5.10 
Intercurrent medical conditions that may lead to the elimination 
of a subject from Per-Protocol analyses  
Subjects may be eliminated from the Per-Protocol cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or are confirmed 
to have an alteration of their initial immune status (i.e., if any confirmed or suspected 
immunosuppressive or immunodeficient condition appears during the study period). These 
conditions would include any cases of lab-confirmed influenza-like illnesses. 
6 STUDY SCHEDULE AND PROCEDURES 
It is the responsibility of the investigator to ensure only medically qualified study staff perform 
medical assessments and procedures which require medical training. Results of assessments 
should be reviewed with the subject, as appropriate, in a timely manner. It is also the responsibility 
of the investigator to ensure strict observance of the intervals between visits/procedures. These 
intervals are precisely defined for subjects in accordance with the protocol and are reflected in 
the study schedule outlined below. Where not specified, time windows (for example, plus or minus 
a certain number of days) are not allowed. 
Table 6 
Intervals between study visits 
Interval 
Optimal length of interval 
Allowed interval 
Visit 00 to Visit 03 
7-56 
2*-56 
Visit 03  Visit 05 
2 days 
2 days 
Visit 03  Visit 09 
7 days 
7-10 days 
Visit 03  Visit 10 
28 days 
28-38 days 
Visit 03  Visit 11 
84 days 
84-94 days 
Visit 11  Visit 12 
7 days 
7-10 days 
Visit 11  Visit 13 
28 days 
28-38 days** 
Visit 11  Visit 14 
168 days 
168-196 days** 
Visit 11  Visit 15 
336 days 
336-364 days** 
Visit 15  Visit 16 
504 days 
504-532 days** 
*Subjects should be screened no later than 2 days prior to Day 1 to allow time to complete screening.  
**Subjects may not be eligible for inclusion in the Per-Protocol set for post-booster immunogenicity analysis for the 
specified interval if blood samples are collected outside this interval. 
6.1 
Study visits 
Prior to any screening activities, study staff will review the informed consent process with the 
volunteer. The investigator, or a person designated by the investigator, will fully inform the 
volunteer of all pertinent aspects of the study and individual consent will be documented by a 
signature. The subject will be required to pass a written exam about the study prior to any study 

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vaccination. Subjects will be screened through multiple procedures, including medical history 
review, physical examination, and clinical laboratory testing.  
6.1.1 
Visit 00: Screening visit (up to 56 days prior to Dose 1) 
After subject consents, the below activities will occur. Sites may complete screening procedures 
over two visits (completed at Enrollment Visit, Visit 01, as is standard practice for each site). Final 
confirmation of eligibility, enrollment, and randomization may only occur at the Enrollment Visit. 
1. The subject will be assigned a screening identification number. 
2. The subject will be interviewed to collect demographic data. 
3. The subject will be interviewed and any available medical records will be reviewed to 
collect a comprehensive medical history, including details of previous vaccinations and 
reaction to such vaccinations, and history of any chronic or recurrent medical and 
psychiatric conditions. Females will be interviewed to determine childbearing potential, 
and if of childbearing potential, will be interviewed as to use of adequate contraception. 
Males will be interviewed as to surgical sterility, and if not, as to the use of adequate 
contraception. 
4. Collected information will be reviewed to confirm eligibility prior to conduct of further 
procedures. 
5. Blood (serum and whole) specimens will be collected for clinical laboratory testing of 
biochemical and hematological parameters. For any subject with a clinical laboratory 
parameter out of local reference range, one retest may be performed for that parameter. 
Results of clinical laboratory tests should be reviewed with the subject. 
6. Serum specimens will also be collected for testing of HIV infection. Results of serologic 
testing for HIV infection will also be reviewed with the subject with appropriate post-test 
counseling (and referral provided to any subjects testing HIV positive). 
7. A urine specimen will be collected for drug screening (opioids). 
8. A urine (or serum, as required by site) specimen will be collected for a pregnancy test if 
the subject is a female of childbearing potential. 
9. A targeted physical examination of the subject will be performed for any signs or symptoms 
experienced by the subject. 
10. Vital signs, height and weight will be measured.  
6.1.2 
Visit 01: Enrollment Visit (up to 2 days prior to Dose 1) 
1. At the second screening visit, the subject will be queried regarding any new medical events 
since medical histories were recorded and eligibility will be confirmed prior to conduct of 

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further procedures, including a complete physical examination. If the subject is a female 
of childbearing potential or non-sterile male, they will be interviewed as to continued use 
of adequate contraception. 
2. Results of all assessments will be reviewed to confirm eligibility. If the subject is eligible to 
continue in the study, the subject will be assigned a subject identification number and 
considered enrolled. 
3. The subject will be randomized per the pre-defined procedure and informed as to whether 
he/she will be an inpatient or outpatient subject for Dose 1. 
4. The subject will be informed as to when he/she must return to the inpatient clinical isolation 
unit for Visit 02 or to the outpatient clinic for Visit 03. 
6.1.3 
Initial Visits for LAIV-IIV (or placebo) arms (Groups 1, 2, & 3) 
The following Visits 02-08 and accompanying procedures apply only to those subjects 
randomized to receive study LAIV (or placebo) at Dose 1 (Groups 1, 2, & 3) 
Subjects randomized to receive study IIV (or placebo) at Dose 1 (Groups 4 & 5) will have a similar Visit 03 
(Section 6.1.4). Subsequent visits will be common to subjects in all study groups. 
At the first site to begin dosing subjects in Groups 1, 2, & 3, six subjects will enter the unit together 
one day prior to the remaining subjects in the LAIV-IIV treatment arms. Thus, the following 
schedule of events will be staggered by a day for a portion of the subjects in these three study 
groups at that site. At the second site to begin dosing subjects in Groups 1, 2 & 3, all subjects will 
enter the unit a day prior to receipt of Dose 1. 
6.1.3.1 Visit 02: Day of admission into the isolation unit (Day -1)  
1. The subject will be admitted to the inpatient clinical isolation unit at least 18 hours prior to 
receipt of Dose 1 of study LAIV (or placebo). 
2. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
3. A nasal and OP swab specimen will be collected for testing for virologic evidence of 
influenza A infection (to ensure the subject is not incubating wild-type influenza virus). 
Specimen collection information must be documented in the eCRF and in specimen 
collection logs. 
4. Blood specimens will also be collected for biochemistry and hematology. Results need not 
be obtained and reviewed prior to administration of study vaccine or placebo; these results 
will only serve to define baseline status for subjects. 
5. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 

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6. If the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception, and a urine specimen will be collected for a pregnancy 
test. If the subject is a non-sterile male, he will be interviewed as to continued use of 
adequate contraception. 
7. The subject will be observed for at least 18 hours for the development of acute respiratory 
illness (ARI) for an infection the subject may already have.  
8. If the subject develops signs or symptoms of ARI, a nasal and OP specimen will be 
collected for testing of etiology by multiplex PCR and the subject will be discharged from 
the inpatient unit and excluded from receipt of Dose 1 of study LAIV (or placebo).  
6.1.3.2 Visit 03: Day of receipt of study LAIV (Day 1) 
Prior to dosing of any subject, results of virologic testing of nasal and oropharyngeal (OP) swab 
specimens for influenza A must be reviewed by the investigator. No subject may be dosed if any 
subject tests influenza A positive by RT-PCR. If any subject tests influenza A positive, the Sponsor 
should be alerted immediately and the study will be terminated for all subjects in Groups 1, 2, and 
3 at the site. 
For the first 6 subjects at the first site to begin dosing, the next subject cannot be administered 
study LAIV (or placebo) until the previous subject has been observed for at least 60 minutes post-
vaccination. The following day at this first site, after the first 6 subjects have received study LAIV 
(or placebo), the remaining subjects receiving study LAIV (or placebo) will be vaccinated as 
convenient. At the second site to begin dosing, subjects will be vaccinated with study LAIV (or 
placebo), also as convenient. 
1. Vital signs will be collected from the subject. A targeted physical examination will be 
performed for any signs or symptoms experienced by the subject. 
2. The subject will be administered one dose of study vaccine or placebo per the allocation 
sequence.  
3. The subject will be observed for at least 60 minutes after administration in case of any 
immediate adverse reactions. If the subject experiences an immediate adverse reaction, 
he/she will be treated and the event will be recorded in the eCRF. If the event meets a 
pause rule event definition 1a-1d, dosing of remaining subjects may not proceed. 
4. The subject will be instructed on the use of a diary card for solicited and unsolicited 
reactions and requested to document signs and symptoms, including oral temperature, 
he/she may be experiencing each day on the diary card. 
5. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the case report form (CRF), and an expedited reporting form must be completed, if 
required. If the event meets a pause rule event definition 1a-1d, dosing of remaining 
subjects may not proceed. 

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6.1.3.3 Visit 04: First day after receipt of study LAIV (Day 2)  
1. Each morning a nasal and OP swab specimen will be collected. Specimen collection 
information must be documented on the CRF and in specimen collection logs. 
2. Subject diary card completion will be reviewed.  
3. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 
4. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the CRF, and an appropriate expedited reporting form must be completed, if required. 
If the event meets a pause rule event definition 1a-1d, dosing of remaining subjects 
may not proceed. 
6.1.3.4 Visit 05: Second day after receipt of study LAIV (Day 3)  
1. Each morning a nasal and OP swab specimen will be collected. Specimen collection 
information must be documented on the CRF and in specimen collection logs. 
2. Subject diary card completion will be reviewed.  
3. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 
4. Whole blood will be collected for transcriptomic assays. 
5. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the CRF, and an appropriate expedited reporting form must be completed, if required. 
If the event meets a pause rule event definition 1a-1d, dosing of remaining subjects 
may not proceed. 
6.1.3.5 Visit 06: Third day after receipt of study LAIV (Day 4)  
1. Each morning a nasal and OP swab specimen will be collected. Specimen collection 
information must be documented on the CRF and in specimen collection logs. 
2. Subject diary card completion will be reviewed.  
3. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 

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4. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the CRF, and an appropriate expedited reporting form must be completed, if required. 
If the event meets a pause rule event definition 1a-1d, dosing of remaining subjects 
may not proceed. 
6.1.3.6 Visit 07: Fourth day after receipt of study LAIV (Day 5)  
1. Each morning a nasal and OP swab specimen will be collected. Specimen collection 
information must be documented on the CRF and in specimen collection logs. 
2. Subject diary card completion will be reviewed.  
3. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 
4. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the CRF, and an appropriate expedited reporting form must be completed, if required. 
If the event meets a pause rule event definition 1a-1d, dosing of remaining subjects 
may not proceed. 
6.1.3.7 Visit 08: Day of discharge after receipt of study LAIV (Day 6)  
Only subjects influenza A negative by RT-PCR on Days 4, 5, and 6 may be discharged on Day 6. 
Subjects testing influenza A positive on Days 4, 5 or 6 will be offered anti-neuraminidase treatment 
on Day 6. Any subject influenza A positive by RT-PCR on Days 4, 5, or 6 must remain in the 
inpatient clinical isolation unit until 3 consecutive daily nasal and OP swab specimens collected 
over 48 hours (3 daily time points) all test influenza negative or until 24 hours after the subject 
initiates anti-neuraminidase treatment and the last nasal and OP swab specimen prior to 
discharge tests influenza A negative by RT-PCR. 
1. In the morning, a nasal and OP swab specimen will be collected. Specimen collection 
information must be documented on the CRF and in specimen collection logs. 
2. Subject diary card completion will be reviewed.  
3. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 
4. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF and an appropriate 
expedited reporting form must be completed, if required. If the event meets a pause rule 
event definition 1a-1d, dosing of remaining subjects may not proceed. 
5. The subject will be asked to continue diary card completion until their next study visit. 

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6. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, the subject should inform the health care provider(s) of participation 
in this study, provide the health care provider(s) with contact information for the 
investigator, and separately contact the investigator to inform the investigator of the 
medically attended illness. 
7. Day 4, 5, and 6 influenza A virologic testing results for the subject will be reviewed by a 
designated unblinded member of the site team. If all results are negative, the designated 
member of the site team will inform the clinical team that the subject may be discharged.  
If any result in the 2 days prior (Day 4 or Day 5) to or on the day of planned discharge 
(Day 6) is positive, the subject will be requested to remain in the inpatient clinical isolation 
unit until either a) three daily consecutive swab specimens taken over a 48 hour period all 
test influenza A negative by RT-PCR or b) the subject agrees to initiation of anti-
neuraminidase treatment—oseltamivir (75 mg taken orally twice daily for 5 days) or 
zanamivir (10 mg taken by oral inhalation twice daily for 5 days)—on Day 6, 24 hours after 
which point the subject may be discharged, as long as the last nasal and OP swab 
specimen prior to discharge tested influenza A negative by RT-PCR. Subjects whose nasal 
and OP swab specimen from Day 6 (or thereafter) tests positive but who decline anti-
neuraminidase treatment may be discharged only after three subsequent negative nasal 
and OP swab specimens (3 negative tests over 48 elapsed hours). Subjects who agree to 
initiate anti-neuraminidase treatment will still be requested to return to the clinical daily for 
nasal and OP swab collection until 3 daily nasal and OP swab specimens test negative 
over 48 elapsed hours in order to document loss of detectable virus. 
8. For subjects testing negative for influenza A, the subject will be discharged from the 
isolation unit and informed of the scheduled date of return to the outpatient clinic for 
Visit 09. 
6.1.4 
Initial Visits for IIV-IIV (or placebo) arms (Groups 4 & 5) 
The following visits and accompanying procedures apply only to those subjects 
randomized to receive IIV (or placebo) at Dose 1 (Groups 4 & 5). 
Subsequent visits will be common to subjects in all study groups. 
6.1.4.1 Visit 03: Day of receipt of study IIV (Day 1)  
At each site, preference will be to schedule administration of Dose 1 to all subjects in IIV-IIV arms 
on the same day. 
1. Vital signs will be collected from the subject. A targeted physical examination will be 
performed for any signs or symptoms experienced by the subject. 
2. Blood specimens will be collected for biochemistry and hematology. Results need not be 
obtained and reviewed prior to administration of study vaccine or placebo; these results 
will only serve to define baseline status for subjects. 

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3. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 
4. If the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception, and a urine specimen will be collected for a pregnancy 
test. If the subject is a non-sterile male, he will be interviewed as to continued use of 
adequate contraception. 
5. The subject will be administered one dose of study vaccine or placebo per the allocation 
sequence. 
6. The subject will be observed for at least 60 minutes after administration in case of any 
immediate reactions. If the subject experiences an immediate adverse reaction, he/she 
will be treated and the event will be recorded on the eCRF. If the event meets a pause 
rule event definition 1a-1d, dosing of remaining subjects may not proceed. 
7. The subject will be instructed on the use of a diary card for solicited and unsolicited 
reactions and requested to document signs and symptoms, including oral temperature, 
he/she may be experiencing each day on the diary card. 
8. The subject will be instructed that if the subject later experiences any illness for which they 
seek medical care, the subject should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 05. 
6.1.4.2 Visit 05: Second day after receipt of study IIV (Day 3) 
1. Subject diary card completion will be reviewed.  
2. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. Subjects will be encouraged to spontaneously 
report any concern or symptom they are experiencing. 
3. Whole blood will be collected for transcriptomic assays. 
4. If the subject develops an MAE, pIMD, SAE, or pregnancy, the event will be documented 
on the CRF, and an appropriate expedited reporting form must be completed, if required. 
If the event meets a pause rule event definition 1a-1d, dosing of remaining subjects 
may not proceed. 
5. The subject will be asked to continue diary card completion until their next study visit. 

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6. The subject will be instructed that if the subject later experiences any illness for which they 
seek medical care, the subject should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 
7. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 09. 
6.1.5 
Subsequent Visits for all study subjects (Groups 1, 2, 3, 4, & 5) 
This and all following Visits and accompanying procedures apply to all study subjects (in 
any of the 5 treatment arms. 
6.1.5.1 Visit 09: 7 + 2 days post-Dose 1 (post-Visit 03) 
1. The subject will be interviewed regarding any recent medical events since the last visit, 
including study vaccine administration site reactions. If the subject is a female of 
childbearing potential, she will be interviewed as to continued use of adequate 
contraception and occurrence of pregnancy. If the subject is a non-sterile male, he will be 
interviewed as to continued use of adequate contraception and occurrence of pregnancy 
in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an expedited 
reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. The subject will be given an unsolicited AE 
diary card to complete and return at the next visit. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Whole blood will be collected for cell-mediated immunologic and transcriptomic assays. 
7. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, he/she should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 
8. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 

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clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 10. 
6.1.5.2 Visit 10: 28 + 10 days post-Dose 1 (post-Visit 03) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception and occurrence of pregnancy. If the subject is a non-sterile 
male, he will be interviewed as to continued use of adequate contraception and 
occurrence of pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. Subject diary card will be collected and reviewed with the subject. Diary card information 
will be transferred to the eCRF by the study clinician. The subject will be given an 
unsolicited AE diary card to complete and return at the next visit. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 
7. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, the subject should inform the health care provider(s) of participation 
in this study, provide the health care provider(s) with contact information for the 
investigator, and separately contact the investigator to inform the investigator of the 
medically attended illness. 
8. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 
clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 11. 

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6.1.5.3 Visit 11: 84 + 10 days post-Dose 1 (post-Visit 03)  
The following procedures apply to all subjects in all treatment arms. At each site, Dose 2 will be 
administered in a staggered manner. Initially, at each site, one half of the subjects from those who 
received LAIV or from those who received IIV on Day 1 may be vaccinated. Once 5 days have 
passed following the vaccination of the initial half of subjects at each site and documentation that 
there has been no significant Investigator clinical concerns with regard to any unexpected severity 
of solicited adverse events having been reported from any of these subjects to the site, then the 
remaining subjects may be vaccinated. This would imply that one half of the subjects at each site 
could not be scheduled any earlier than study Day 91 for their Visit 11.  
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception and occurrence of pregnancy. If the subject is a non-sterile 
male, he will be interviewed as to continued use of adequate contraception and 
occurrence of pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. Subject diary card will be collected and reviewed with the subject. Diary card information 
will be transferred to the eCRF by the study clinician. 
4. Vital signs will be collected from the subject. A targeted physical examination will be 
performed for any signs or symptoms experienced by the subject. 
5. Blood specimens will be collected for biochemistry and hematology. Results need not be 
obtained and reviewed prior to administration of study vaccine or placebo; these results 
will only serve to define baseline status for subjects pre-Dose 2. 
6. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 
7. If the subject is a female of childbearing potential, a urine specimen will be collected for a 
pregnancy test. 
8. The subject will be administered one dose of study vaccine or placebo per the allocation 
sequence.  
9. The subject will be observed for at least 60 minutes after administration in case of any 
immediate reactions. If the subject experiences an immediate adverse reaction, he/she 
will be treated and the event will be recorded on the CRF. If the event meets a pause 
rule event definition 1a-1d, dosing of remaining subjects may not proceed. 

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10. The subject will be instructed on the use of a diary card for solicited and unsolicited 
reactions and requested to document signs and symptoms, including oral temperature, 
he/she may be experiencing each day on the diary card. 
11. The subject will be instructed that if the subject later experiences any illness for which they 
seek medical care, he/she should inform the health care provider(s) of participation in this 
study, provide the health care provider(s) with contact information for the investigator, and 
separately contact the investigator to inform the investigator of the medically attended 
illness. 
12. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 
clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
13. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 12. 
6.1.5.4 Visit 12: 7 + 3 days post-Dose 2 (post-Visit 11) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception and occurrence of pregnancy. If the subject is a non-sterile 
male, he will be interviewed as to continued use of adequate contraception and 
occurrence of pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. The subject will be given an unsolicited AE 
diary card to complete and return at the next visit. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject.  
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Whole blood will be collected for cell-mediated immunologic and transcriptomic assays. 
7. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, he/she should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 

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8. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 
clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 13. 
6.1.5.5 Visit 13: 28 + 10 days post-Dose 2 (post-Visit 11) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception and occurrence of pregnancy. If the subject is a non-sterile 
male, he will be interviewed as to continued use of adequate contraception and 
occurrence of pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. The subject will be given an unsolicited AE 
diary card to complete and return at the next visit. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject.  
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 
7. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, he/she should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 
8. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 
clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 14. 

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6.1.5.6 Visit 14: 168 + 28 days post-Dose 2 (post-Visit 11) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception (protocol requirement until Month 5) and occurrence of 
pregnancy. If the subject is a non-sterile male, he will be interviewed as to continued use 
of adequate contraception (protocol requirement until Month 5) and occurrence of 
pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. The subject will be given an unsolicited AE 
diary card to complete and return at the next visit. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Serum will be collected for humoral immunologic assays and whole blood will be collected 
for transcriptomic assays. 
7. The subject will be instructed that if he/she later experiences any illness for which he/she 
seeks medical care, he/she should inform the health care provider(s) of participation in 
this study, provide the health care provider(s) with contact information for the investigator, 
and separately contact the investigator to inform the investigator of the medically attended 
illness. 
8. The subject will also be instructed that if he/she later experiences symptoms of ILI (fever 
[oral temperature, ≥ 37.8°C or 100°F] or myalgia AND cough or sore throat), he/she should 
contact the investigator. The subject will be requested to present to the study outpatient 
clinic as soon as possible for an unscheduled ILI visit at which a nasal and OP swab 
specimen will be collected for testing for seasonal influenza virus by RT-PCR. 
9. The subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 15. 
6.1.5.7 Visit 15: 336 + 28 days post-Dose 2 (post-Visit 11) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception (protocol requirement until Month 5) and occurrence of 
pregnancy. If the subject is a non-sterile male, he will be interviewed as to continued use 
of adequate contraception (protocol requirement until Month 5) and as to occurrence of 
pregnancy in a female partner. 

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2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
5. Blood (serum and whole) specimens will be collected for biochemistry and hematology. 
6. Serum will be collected for humoral immunologic assays, saliva will be collected for 
mucosal immunologic assays, and whole blood will be collected for cell-mediated 
immunologic and transcriptomic assays. 
7. The investigator, or a person designated by the investigator, will fully inform the volunteer 
of the study extension to include an additional visit (Visit 16). If the subject agrees to 
continued participation in the study, individual consent will be documented by a signature 
and the subject will be informed of the scheduled date of return to the outpatient clinic for 
Visit 16.  
8. If the subject does not consent to continued participation in the study, study staff will 
complete the final visit CRF and the subject will be exited from the study. 
6.1.5.8 Visit 16: 504 + 28 days post-Dose 2 (post-Visit 11) 
1. The subject will be interviewed regarding any recent medical events since the last visit. If 
the subject is a female of childbearing potential, she will be interviewed as to continued 
use of adequate contraception (protocol requirement until Month 5) and occurrence of 
pregnancy. If the subject is a non-sterile male, he will be interviewed as to continued use 
of adequate contraception (protocol requirement until Month 5) and as to occurrence of 
pregnancy in a female partner. 
2. Any MAE, pIMD, SAE, or pregnancy will be documented on the CRF, and an appropriate 
expedited reporting form must be completed, if required. 
3. The subject diary card will be collected and reviewed with the subject. Diary card 
information will be transferred to the eCRF. 
4. A targeted physical examination (including vital signs) will be performed for any signs or 
symptoms experienced by the subject. 
5. Serum and saliva will be collected for humoral immunologic and mucosal immunologic 
assays, with testing dependent upon the outcome of primary and secondary analyses. 
6. Study staff will complete the final visit CRF and the subject will be exited from the study. 

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6.1.6 
ILI Visits 
Beginning from Visit 09 (Day 8), all subjects will be monitored for the occurrence of laboratory-
confirmed influenza like illness (see Section 8.1.6). During the typical influenza season period 
(November 1 through April 30) during the study, subjects will also be reminded biweekly by phone, 
email, or text messages to notify the investigator in case of ILI symptoms: at least 1 systemic 
symptom (fever [oral temperature ≥ 37.8°C or 100°F] or myalgia) AND at least 1 respiratory 
symptom (cough or sore throat). Subjects will be provided with a calibrated thermometer to 
measure temperature and an ILI diary card to record temperatures and symptoms during any ILI 
episode. After notifying the investigator, the subject will be asked to present for collection of a 
nasal and OP swab as soon as possible and no later than 5 days following the ILI onset. At this 
visit, the investigator will also document signs and symptoms of ILI on the eCRF. Any physician-
diagnosed 
pneumonia, 
lower 
respiratory 
tract 
infection, 
bronchiolitis, 
bronchitis, 
or 
laryngotracheitis will also be documented. A nasal and OP swab specimen will be collected for 
testing for virologic evidence of seasonal influenza infection by RT-PCR. Specimen collection 
information must be documented in the eCRF and in specimen collection logs. Fourteen days 
after ILI onset, subjects will be contacted by phone to document outcome of their ILI. 
6.1.7 
Unscheduled visits 
Subjects may present to the study center during operating hours for an unscheduled visit should 
they experience any other AE of concern to the subject. Data for any examinations performed on 
the subject at an unscheduled visit must be recorded in the CRF. If an unscheduled visit is 
performed, the procedures for the next following visit should not be made earlier than scheduled 
above. 
6.2 
Discontinuation of vaccination or study procedures  
Participants have the right to decline study vaccinations or procedures for any reason and at any 
time during the study. If a subject declines further vaccination or study procedures this will be 
recorded as a study deviation and the reason will be clearly documented in the source document. 
The subject will be encouraged to complete all remaining safety related follow-up visits and 
procedures through Visit 16, including unscheduled ILI visits. Participants refusing to receive 
Dose 2 will be encouraged to complete all immunogenicity blood draws through Visit 10 if 
notification of such refusal occurs prior to Visit 10. (Participants refusing to receive Dose 1 will be 
immediately withdrawn from the study.) 
Subjects will be discontinued from further vaccination if they experience an event which qualifies 
as a contraindication to subsequent vaccination (see Section 5.6). At each study visit subsequent 
to the first vaccination visit, it must be verified if the subject has experienced or is experiencing 
any intercurrent medical condition. Any intercurrent medical condition(s) must be recorded in the 
eCRF. Acute intercurrent febrile illness may delay receipt of Dose 2. Discontinuation from further 
vaccination may also be at the discretion of the investigator if it is in the interest of the subject or 
is recommended by the PSRT or IDMC based on safety reviews. 

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After administration of Dose 1 of study LAIV (or placebo), procedures may be discontinued for a 
subject who is scheduled to be in the inpatient clinical isolation unit and the subject may be 
removed from the unit by the investigator if the subject develops a reaction to study vaccine which 
the investigator believes threatens the subject’s well-being and requires the subject to be 
transferred to a separate facility for treatment. 
The reason for all discontinuations will be documented in source documents and the eCRF. 
6.3 
Subject withdrawal (premature termination) 
After enrollment, a subject might be withdrawn from participation for various reasons, including: 
 
The investigator requests withdrawal of participation of the subject because the subject 
develops a contraindication to subsequent vaccination or is non-compliant with study 
procedures; 
 
A subject voluntarily withdraws participation at his/her own request; 
 
A subject is lost to follow-up; or 
 
The trial is terminated prematurely by PATH. 
Participation in the study is strictly voluntary. Participants have the right to withdraw from the study 
at any time and for any reason, without penalty. Withdrawal of a subject by the investigator should 
occur only if the subject is identified to have a contraindication to subsequent vaccination or if 
continued participation of the subject threatens the subject’s well-being or the integrity of the study 
(or the well-being of other subjects in the isolation unit). 
6.3.1 
Handling of withdrawals 
In case of premature withdrawal for any reason, the investigator should exert his/her best effort to: 
1. Review the subject's diary card if it is still in use at the time of withdrawal. 
2. Update any ongoing AE/SAEs that remained ongoing at the time of the subject’s last visit 
prior to withdrawal. 
3. Conduct an interview to determine if the subject has had any reaction or AE (serious or 
non-serious) since the last visit. Where possible, the investigator should visibly or 
physically assess any reported adverse reaction or AE and document whether it led to the 
withdrawal. 
4. Conduct a physical examination. 
5. Collect blood for biochemical and hematological clinical laboratory parameters if the 
previous collection for these safety evaluations was greater than 21 days prior. 
6. Collect blood and saliva from the subject for Visit 13 immunologic evaluations if the 
withdrawal occurs between 28 and 38 days post-Dose 2. 

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7. Document the reason for premature withdrawal on the CRF. 
8. Update the subject's contact information. 
PATH must be informed within 24 hours of awareness about all instances of the premature 
termination of a subject's participation in the trial. Any withdrawal that occurs while a subject is 
scheduled to be in the isolation unit requires immediate notification to the Sponsor. While 
participation in the trial is voluntary and subjects are free to withdraw consent at any time, subjects 
will be told that local public health authorities might be notified of any subject’s premature exiting 
from the isolation unit. A standard operating procedure (SOP) for the isolation unit will detail 
procedures to be followed for any withdrawal that occurs while a subject is scheduled to be in the 
isolation unit. 
6.3.2 
Withdrawals at specific time-points 
6.3.2.1 During screening 
If after the subject signs the informed consent form, the investigator ascertains that the subject 
does not meet the inclusion/exclusion criteria, the investigator only needs to note the reason for 
subject exclusion on the screening log. The subject should not be assigned a subject identification 
number, as only eligible subjects will be assigned an identification number. 
6.3.2.2 As a result of erroneous inclusion  
If a subject who does not meet the inclusion/exclusion criteria is inadvertently included in the trial, 
the investigator must terminate the subject’s participation in the trial and the Sponsor should be 
informed immediately prior to administration of Dose 1 and a protocol deviation must be 
completed. In the event, study vaccine (or placebo) has already been given, the subject will be 
encouraged to complete all remaining safety related follow-up visits and procedures through Visit 
15, but a protocol deviation must be completed. However, the subject’s data will be excluded from 
the analysis. 
If determination of ineligibility occurs while the subject is in the inpatient clinical isolation unit after 
receipt of Dose 1, the subject allocation will be unblinded, and if the subject was administered 
study LAIV, the subject should be maintained in the unit for the specified period, if possible.  
6.3.2.3 For violation of the protocol 
A subject will be considered as largely not in compliance with the requirements of the protocol 
and may be withdrawn if any of the following conditions apply: 
 
The subject egregiously violates the rules of the inpatient clinical isolation unit per the opinion 
of the investigator; 
 
The subject refuses to complete the self-observation diary;  
 
The subject skips entirely a scheduled visit, especially Visits 11 and 13;  

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 
Non-compliance at a scheduled visit for planned procedures; or 
 
Failure to inform the investigator of the appearance of any AE or SAE in the subject. 
6.3.2.4 As a result of withdrawal of informed consent 
If a subject wishes to withdraw consent for participation in the trial, the subject should indicate the 
reasons for the termination of participation, if possible. If such withdrawal occurs after the subject 
has been admitted to the inpatient clinical isolation unit and has been administered study LAIV, 
the subject allocation will be unblinded, and if the subject was administered study LAIV, the 
subject will be asked to remain in the unit for the specified period, if possible. The subject will also 
be requested to initiate anti-neuraminidase treatment—oseltamivir (75 mg taken orally twice daily 
for 5 days) or zanamivir (10 mg taken by oral inhalation twice daily for 5 days) and to return to the 
clinic daily for collection of nasal and OP swab specimens until 3 specimens collected over a 48-
hour period all test influenza A negative by RT-PCR. The subject will be informed that the public 
health authorities may be notified of the subject’s premature discharge from the isolation unit, as 
well as of the results of RT-PCR testing of the subject’s nasal and OP swab specimens for 
detection of viral shedding. For any subject leaving the unit prematurely, the subject will be 
advised to remain at home and avoid close contact with other persons until 7 days post-
administration of study LAIV have passed unless they have agreed to initiation anti-
neuraminidase treatment. 
6.3.2.5 As a result of occurrence of an adverse event/serious adverse event 
If any subject develops an AE/SAE leading to premature withdrawal, the event will be fully 
followed-up to resolution of the problem, to acknowledgement of the diagnosis of the AE/SAE, or 
to change in status of the acute AE/SAE as chronic or stable or as long as such a change is 
justified from a clinical point of view. However, for premature withdrawal in connection with the 
emergence of an AE/SAE that is considered to be clinically relatively favorable (for example, the 
diagnosis is known, and it is expected to be resolved completely within a week), intermittent 
follow-up may be accepted as long as the plan for follow-up of the event is fully described in the 
notes section of the subject’s CRF. Follow-up visits will be carried out for all subjects who are 
withdrawn due to occurrence of an AE or in connection with a change in any other safety indicator 
(vital sign or clinical laboratory result). 
6.4 
Loss to follow-up 
To prevent lost to follow-up, subjects will be reminded by phone, email, or text message of their 
next study visit. In the event of a missed visit, subject will be contacted by phone within 1 day. A 
subject who misses two consecutive visits and cannot be reached / located after 5 attempts will 
be considered lost to follow-up. Efforts to contact the subject will be documented in source 
documents. Any subject who fails to attend the final study visit will also be classified as lost to 
follow-up. There will be no replacement for subjects who are lost to follow-up. 

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6.5 
Concomitant medications/products/vaccines 
At each study visit, subjects will be queried about use of concomitant medications, products and 
vaccinations. The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF: 
 
All concomitant medications/products, except vitamins and dietary supplements, administered 
during the period starting on the day of administration of the first dose of study vaccines (Day 
1) and ending at the last study visit (Visit 16). 
 
Any concomitant vaccination administered in the period starting 30 days before the first dose 
of study vaccines and ending at the last study visit (Day -29 to Visit 16). 
 
Prophylactic medication (i.e., medication administered in the absence of ANY symptom and 
in anticipation of a reaction to the vaccination). E.g., an anti-pyretic is considered to be 
prophylactic when it is given in the absence of fever and any other symptom, to prevent fever 
from occurring (fever for this purpose is defined as an oral temperature 38.0°C or 100.4°F). 
 
Any concomitant medications/products/vaccines relevant to an SAE/pIMD or administered 
during the study period for the treatment of an SAE/pIMD. In addition, concomitant 
medications relevant to SAEs and pIMDs need to be recorded on the expedited reporting 
form. 
6.6 
Unblinding procedure 
In the event of a medical emergency, the site Investigator may require that the blind be broken 
for the subject experiencing the emergency when knowledge of the subject’s treatment 
assignment may influence the subject’s clinical care. Unblinding will occur through the secure 
interactive web response system (IWRS) to which there will be 24-hour access.  
Details and documentation surrounding such unblinding will be described in the relevant 
operations manual and will be trained on during the site initiation visit. Documentation of the 
unblinding event (including the rationale and requestor) will be captured by the IWRS. Every effort 
will be made not to unblind the subject unless it is considered necessary for the welfare of the 
subject. Prior to unblinding, the site Investigator is encouraged (to the extent possible, without 
jeopardizing the subject’s health) to contact the Sponsor (or designee) to discuss the decision to 
break the blind. The site PI will be expected to provide a rationale for the necessity of unblinding 
based on the expectation that knowledge of the subject’s treatment assignment will have a 
meaningful impact on the subject’s medical care in the short term. If a subject’s treatment 
assignment is unblinded, the subject will remain in the study and continue with protocol-defined 
study visits, but not receive further study vaccines. The decision to unblind will be communicated 
to any regulatory bodies (e.g., institutional review boards [IRBs]) as required. At the end of the 
study, documentation of all unblinded subjects (and the rationale for unblinding) will be 
incorporated into the Trial Master File.  

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6.7 
Management of birth control and pregnancy during study 
All females of childbearing potential and males who are not surgically sterile will be monitored for 
use of adequate contraception and pregnancy (in female subject or female partner of male 
subject) during the trial.  
Adequate contraception will be assessed at each study visit during the entire study period. 
Adequate contraception is defined as a contraceptive method with a 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, when this is their preferred and usual lifestyle; 
 
Combined estrogen and progesterone oral contraceptives; 
 
Injectable progestogen; 
 
Implants of etonogestrel or levonorgestrel; 
 
Contraceptive vaginal ring; 
 
Percutaneous contraceptive patches; 
 
Intrauterine device or intrauterine system; 
 
Male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository), 
and/or progesterone alone oral contraceptive. 
Adequate contraception does not apply to subjects of child bearing potential with same sex 
partners or for subjects who are and will continue to be abstinent from penile-vaginal intercourse 
on a long term and persistent basis, when this is their preferred and usual lifestyle. 
If any female subject becomes pregnant after randomization, study vaccination will be 
discontinued and the subject will be encouraged to complete all safety-related study visits and 
procedures to the end of the trial. The investigator should fully follow the subject to term and 
document the outcome of the pregnancy, even if birth occurs after the scheduled end of the trial 
for the subject.  
If the pregnancy occurs prior to receipt of Dose 2 of study vaccine, the subject will discontinue 
participation in all remaining immunogenicity blood draws. If the pregnancy occurs after receipt of 
Dose 2 of study vaccine, the subject will be requested to participate in all remaining 
immunogenicity related study visits and procedures. 
6.8 
Clinical procedures  
6.8.1 
Medical history 
At enrollment, medical histories must be thoroughly reviewed through interview with the subject. 
The following medical conditions, especially, will be assessed: 

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 
Current or recent (within two weeks of enrollment) acute respiratory illness with or without 
fever; 
 
Recent vaccination history and history of influenza vaccination since the 2014/2015 season; 
 
Practice of nasal irrigation on a regular basis within the past six months; 
 
Recent history of frequent nose bleeds (>5 within the past year); 
 
Clinically relevant abnormal paranasal anatomy; 
 
Recent history (within the past month) of rhino or sinus surgery, or surgery for any traumatic 
injury of the nose; 
 
Recent receipt of immune globulin or other blood products, or injected or oral corticosteroids 
or other immune modulator therapy within 6 months (before) of enrollment; 
 
Hypersensitivity of any kind; 
 
Asthma; 
 
Tuberculosis; 
 
Clinically 
relevant 
history 
of 
renal, 
gastrointestinal, 
cardiovascular, 
hematological, 
dermatological, endocrine, neurological or immunological diseases; 
 
History of excessive daytime sleepiness or narcolepsy; familial history of narcolepsy; 
 
Seizures, including history of febrile seizures, or any other neurologic disorder; 
 
Known or suspected immunologic function impairment of any kind and/or known HIV infection; 
 
Known Hepatitis B or Hepatitis C infection; 
 
Mental illness; 
 
Tobacco, alcohol, or drug use; 
 
Medications taken (in the past 6 months, for screening), including trade name, dosing or 
change in dosing, indications, start date, and termination date; 
 
For women, pregnancy and menstrual status, and for both men and women, contraceptive 
use and/or history of surgical sterility. 
6.8.2 
Physical examination 
A qualified clinician (study physician or differently qualified person) will conduct a complete 
physical examination at the V01 screening visit and targeted physical examinations (including 
vital signs) directed to any subject symptoms or signs at all other study visits. Vital signs will be 
measured at the initial screening visit and prior to each scheduled vaccination at the V03 and V11 
study visits. Site SOPs will provide instruction on the details for procedures for measurement of 
routine clinical parameters to ensure standardized measurement. These will include the following:  

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6.8.2.1 Vital signs 
 
Body temperature will be measured in degrees Celsius or Fahrenheit as per site SOPs 
(recorded to the nearest 0.1 degree) by oral thermometer.  
 
Respiratory rate will be measured in breaths per minute.  
 
Pulse rate will be measured in beats per minute. 
 
Blood pressure will be measured in millimeters of mercury (Hg). 
6.8.2.2 Height and weight 
 
Height will be measured to the nearest centimeter.  
 
Weight will be measured in kilograms and recorded to the nearest 0.1 kilogram.  
6.8.2.3 Included systems 
The complete physical examination will include an assessment of general appearance and 
examination of the head, eyes, ears, nose, oropharynx, neck, chest (by auscultation), lymph 
nodes (neck, supraclavicular, axillary, inguinal), abdomen (auscultation and palpation), skin and 
musculoskeletal system, and nervous system. 
6.8.3 
Assessment of local and general adverse events 
Study staff will train subjects on use of diary cards for self-assessment of solicited local and 
general adverse events through 7 days (day of vaccination and subsequent 6 days) post-
administration of study vaccine (or placebo) and for self-assessment of unsolicited adverse events 
and concomitant medications through the end of the study. Timing and severity grading of adverse 
events will be according to protocol Section 8 (Safety Assessment and Reporting). Study staff will 
review and discuss with the subject all recorded events to ensure appropriate documentation and 
scoring prior to transferring of the diary card record to the eCRF. 
7 LABORATORY EVALUATIONS / REQUIREMENTS 
The time points and amounts of blood drawn for clinical laboratory and immunologic / 
transcriptomic evaluations are shown in the Schedule of Events tables (Appendix 1). Good 
Clinical Laboratory Practice audits may be conducted by the Sponsor, PATH, to ensure safety 
clinical laboratory testing meets state-required quality standards (e.g., Clinical Laboratory 
Improvement Amendments). Laboratories conducting immunologic evaluations may also be 
audited for Good Clinical Laboratory Practice compliance. 

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7.1 
Sample collection, processing, storage 
7.1.1 
Nasal and oropharyngeal swab specimens 
7.1.1.1 Collection of nasal and oropharyngeal swab specimens 
Nasal and oropharyngeal swab specimens are the upper respiratory tract specimens that are to 
be collected for the detection of influenza virus RNA by RT-PCR assays and for virus isolation in 
MDCK cell culture. Collection instructions will be contained in site SOPs. All specimen collection 
will be conducted by trained individuals. 
7.1.1.2 Conditions for transport, processing and storage of swab specimens 
Collected nasal and OP swab specimens will be stored at refrigerator temperatures until transport 
to the site's research laboratory. Specimens will be securely transported on ice each day. In the 
laboratory, vials/tubes containing swab specimens will be opened and swab specimen applicator 
sticks will be agitated to remove collected material, fluid will be expressed, and swabs discarded. 
Each swab specimen will be divided into two aliquots of approximately 0.5 mL, one tube for RT-
PCR testing and one tube for backup for virus isolation for specimens influenza A positive by RT-
PCR. Day 6 specimens must be tested by RT-PCR within 6 hours of collection. Specimen material 
not used for virus identification will be stored at –65˚C or lower in each laboratory. Handling and 
storage of specimens will emphasize avoidance of freeze-thaw cycles. 
7.1.2 
Blood specimens 
Blood will be collected for testing in multiple standard clinical (biochemical and hematological) 
and research immunologic and transcriptomic assays. Therefore, attention must be given to 
proper collection and processing per the requirements of each assay. 
7.1.2.1 Collection of blood 
Following universal precautions, blood will be collected by venipuncture into vacutainer tubes. If 
collection is from the subject’s forearm, preference will be for blood collection to occur from 
forearm contralateral to arm of study IIV injection. Blood specimens will be affixed with coded 
labels that link the specimen to the subject, specimen type, specimen collection date, and 
specimen number and time-point. Specimen collection tube must be appropriate for type of 
specimen required. See Laboratory Manual for further specifications.  
Blood should be held at room temperature (+18°C to +25°C) until processing. Volumes of blood 
required for the different categories of assays at different time-points and total to be collected are 
shown in the below table. No subject will have more than 400 mL of blood drawn in any 8 week 
period of the study. The cumulative blood draw for each subject over the entire course of study 
participation is approximately 906 mL.  
 
 

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Table 7  
Volume Estimates of whole blood drawn for clinical and immunologic assays 
at each visit. 
Assay 
V00 
or 
V01 
V03* 
V05 
V09 
V10 
V11 
V12 
V13 
V14 
V15 
V16*** 
 
 
D1 
D3 
D8 
D29 
D85 
D92 
D113 
M9 
M15 
M21 
Biochemistry 
3.5 
3.5 
-- 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
-- 
Hematology 
3 
3 
-- 
3 
3 
3 
3 
3 
3 
3 
-- 
HIV screening 
3.5 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
Humoral immunologic testing** 
-- 
40 
-- 
-- 
20 
20 
-- 
40 
1 
40 
40 
ELISA 
-- 
1.4 
-- 
-- 
1.4 
1.4 
-- 
1.4 
1.0 
1.4 
 
Microneutralization 
-- 
1.2 
-- 
-- 
1.2 
1.2 
-- 
1.2 
-- 
1.2 
 
Hemagglutination inhibition 
-- 
1.2 
-- 
-- 
1.2 
1.2 
-- 
1.2 
-- 
1.2 
 
Serum ADCC activity 
-- 
0.5 
-- 
-- 
0.5 
0.5 
-- 
0.5 
-- 
0.5 
 
Serum ADCP activity 
-- 
0.5 
-- 
-- 
0.5 
0.5 
-- 
0.5 
-- 
0.5 
 
Passive Transfer 
-- 
20 
-- 
-- 
-- 
-- 
-- 
20 
-- 
20 
 
Backup sera 
-- 
15 
-- 
-- 
15 
15 
-- 
15 
-- 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cell-mediated immunologic testing** 
-- 
118 
-- 
58 
86 
118 
58 
86 
-- 
110 
-- 
Stimulated plasmablasts 
-- 
-- 
-- 
26 
-- 
-- 
26 
-- 
-- 
0 
-- 
Stimulated B memory cells 
-- 
86 
-- 
-- 
86 
86 
-- 
86 
-- 
86 
-- 
Stimulated T cells 
-- 
32 
-- 
32 
-- 
32 
32 
-- 
-- 
24 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
Transcriptomics (using 
extracted RNA) 
-- 
5 
5 
5 
5 
5 
5 
5 
5 
5 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
Total Blood Volume** 
10 
170 
5 
70 
118 
150 
70 
138 
13 
162 
40 
*Will occur at Visit 02 (one day prior to Visit 03) for subjects in LAIV-IIV treatment arms (Groups 1, 2, & 3) 
**Rounded up to nearest whole mL 
***Assays performed at Visit 16 will be determined following analysis of primary and secondary endpoints  
 

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7.1.2.2 Processing, storage, and transport of blood 
7.1.2.2.1 Processing of sera for biochemistry, HIV screening, and serum 
pregnancy testing (as applicable) 
Immediately after collection, the serum separator tubes will be inverted 6-10 times, stood upright, 
and transferred immediately to the site clinical laboratory for further processing and testing. 
7.1.2.2.2 Processing of whole blood for hematology 
Immediately after collection, the tube of blood for hematology will be inverted 6-10 times, stood 
upright, and transferred immediately to the site clinical laboratory for further processing and 
testing. Whole blood for hematology will not be divided. 
7.1.2.2.3 Processing of sera for humoral immunology 
Immediately after collection, the serum separator tubes for humoral immunologic testing will be 
inverted 6-10 times and stood upright to clot for at least 30 minutes at room temperature. Tubes 
will then be transferred to the site research laboratory for processing. At the laboratory, specimens 
will be centrifuged before division and storage. Centrifuging and aliquoting procedures will be 
defined in specimen handling SOPs. 
Serum specimens for humoral immunology will be immediately frozen to –65˚C or lower after 
division. Frozen sera will be at all times maintained in a frozen state during transport between the 
sites and the designated immunology laboratories. All handling will be done to prevent 
unnecessary freeze-thaw cycles. 
7.1.2.2.4 Processing of whole blood for plasmablast and stimulated B memory cell 
assays 
Immediately after collection, the sodium citrate tubes for stimulated plasmablasts and stimulated 
B memory cells testing will be inverted 6-10 times and stood upright at room temperature. Tubes 
will then be shipped overnight to the research laboratory of Dr. Patrick Wilson at the University of 
Chicago for further processing and testing. 
7.1.2.2.5 Processing of whole blood for T cell assays 
Immediately after collection, the sodium citrate tubes for stimulated T cells will be inverted 6-10 
times and stood upright at room temperature. Tubes will then be processed by the site research 
laboratory within 2 hours of collection per the tube manufacturer instructions. Recovered PBMCs 
will be immediately resuspended in a freezing solution, placed in cryovials and the cryovials 
placed into a freezing container filled with isopropyl alcohol before freezing to -65°C or lower. 
PBMCs will be shipped frozen to the laboratory of Dr. Florian Krammer at ISMMS in New York, 
New York for further processing and testing. During the processing of the blood collection tubes, 
cellular components will be separated from plasma. The leftover plasma (which would otherwise 
be discarded) will be collected, aliquoted and frozen to -65°C or lower for future use. No 

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serum/plasma is otherwise collected for this time point and these samples could be used to 
integrate findings in the cellular assays with humoral responses. 
7.1.2.2.6 Processing of whole blood for transcriptomic assays 
Immediately after collection, the PAXgene Blood RNA Tube for transcriptomic assays will be 
inverted 8-10 times and stood upright at room temperature before being processed as per 
instructions provided in the Laboratory Manual prior to long-term storage at -65˚C or lower. Tubes 
will be shipped frozen to the laboratory of Dr. Adolfo Garcia-Sastre at ISMMS in New York, New 
York for further processing and testing. 
7.1.3 
Saliva specimens 
Saliva will be collected via an oral swab for quantification of anti-stalk salivary and secretory IgA. 
The subject will be asked to chew on the cotton swab until the subject cannot keep themselves 
from swallowing the collected saliva, before the swab is removed and placed back into the test 
tube and the cap inserted. The sample will be sent to the laboratory for processing. Processing 
procedures will be further defined in specimen handling SOPs. 
7.1.4 
Urine specimens 
Urine (or serum, as required by site) will be collected for pregnancy testing during screening and 
prior to administration of any dose of study vaccine (or placebo). Urine will also be collected at 
initial screening for opiate use (e.g., 6-MAM, codeine, fentanyl, hydrocodone, hydromorphone, 
meperidine, 
morphine, 
naloxone, 
naltrexone, 
norfentanyl, 
normeperidine, 
oxycodone, 
oxymorphone, sufentanil, tramadol). 
No urine specimens will be stored after testing. 
7.2 
Clinical laboratory tests 
Protocol mandated clinical screening and safety laboratory tests will be conducted in real time by 
laboratories that are properly accredited and subscribe to a proficiency testing program.  
7.2.1 
Hematology and biochemistry 
Hematology and biochemistry assays for safety assessment will be performed using standardized 
procedures in a certified clinical laboratory at the site (Table 8). 
7.2.2 
Pregnancy testing 
Pregnancy testing will be performed using standardized procedures in a certified clinical 
laboratory at the site (Table 8). 

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7.2.3 
HIV testing 
HIV testing for screening will be performed using standardized procedures in a certified clinical 
laboratory at the site (Table 8). 
Table 8 
Hematology/biochemistry/virology 
System 
Discipline 
Component 
Method 
Scale** 
Laboratory 
Whole 
blood 
Hematology 
Leukocytes (White Blood Cells) 
As per site clinical 
laboratory 
procedure 
Quantitative 
Site 
Neutrophils* 
Lymphocytes* 
Basophils* 
Monocytes* 
Eosinophils* 
Hemoglobin 
Platelets 
Erythrocytes (Red Blood Cells) 
Serum 
Biochemistry 
ALT 
As per site clinical 
laboratory 
procedure 
Quantitative 
AST 
Creatinine*** 
Urea nitrogen*** 
Urine 
Biochemistry 
Human chorionic gonadotropin 
(hCG) 
As per site clinical 
laboratory 
procedure 
Qualitative 
Serum 
Virology 
HIV-1/2 antigen/antibody and/or 
nucleic acid 
As per site clinical 
laboratory 
procedure 
Qualitative 
*For White Blood Cell differential count. 
**Grading of laboratory parameters assessed as AEs will be based on the FDA Guidance for Industry “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see 
Appendix 2) 
***BUN-to-creatinine ratio is to be calculated. 
Laboratory results will be reviewed promptly by the site PI or designee. Participants will be notified 
of any clinically significant abnormalities. If clinically significant abnormalities are identified during 
screening, subjects will be referred to their primary health provider or appropriate medical center. 
If identified during the study, subjects may be asked to return to the study site for further 
evaluation, including clinical evaluation and repeat laboratory testing as warranted. 
Table 9 specifies hematologic, biochemical, and virologic read-outs by sampling time point and 
study group. 

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Table 9 
Read-outs for hematology/biochemistry/virology 
Sampling time point 
Number of 
subjects 
Component 
Visit time point 
Sampling time 
point 
Screening 
SCR 
All screened 
subjects 
Hematology: leukocytes, neutrophils, lymphocytes, 
basophils, monocytes, eosinophils, hemoglobin, platelets, 
erythrocytes 
Biochemistry: ALT, AST, creatinine*, urea nitrogen* 
Virology: HIV antibody/antigen 
Visit 03** 
Visit 09 
Visit 10 
Visit 11 
Visit 12 
Visit 13 
Visit 14 
Visit 15 
PRE 
PId7 
PId28 
PId84 
PIId7 
PIId28 
PIIm6 
PIIm12 
All Subjects 
Hematology: leukocytes, neutrophils, lymphocytes, 
basophils, monocytes, eosinophils, hemoglobin, platelets, 
erythrocytes 
Biochemistry: ALT, AST, creatinine*, urea nitrogen* 
SCR = screening 
*The BUN-to-creatinine ratio is to be calculated. 
**Will occur at Visit 02 (one day prior to Visit 03) for subjects in LAIV-IIV treatment arms (Groups 1, 2, & 3) 
7.3 
Immunological laboratory assays  
7.3.1 
Humoral and mucosal immune responses 
Multiple assays will be used to probe humoral immunologic responses to the study LAIV and IIVs 
with chimeric HAs. Serological assays for quantification of 1) anti-stalk IgG and IgA and anti-
neuraminidase antibodies detected by ELISA, 2) neutralizing antibodies detected by MN assay, 
3) antibodies with anti-H1 stalk activity demonstrated after passive transfer in an influenza 
challenge model in mice, 4) antibodies with Fc-receptor ADCC activity, and 5) antibodies with Fc-
receptor mediated ADCP activity will be performed at ISMMS (laboratory of Dr. Florian Krammer) 
or in a laboratory designated by ISMMS (e.g., Neomed) using standardized procedures. Serologic 
assays for quantification of antibodies with HI activity will be performed by a designated research 
laboratory using standardized procedures. Additional assays for quantification of anti-stalk 
salivary and secretory IgA will be performed at ISMMS (laboratory of Dr. Florian Krammer) or in 
a laboratory designated by ISMMS (e.g., Neomed) using standardized procedures. All planned 
assays for characterization of humoral and mucosal immune responses are listed in Table 10. 
Additionally, Table 10 specifies humoral and mucosal immunologic read-outs by sampling time 
point and study group. In case of insufficient blood or saliva sample volume to perform assays for 
all antibodies, the samples will be analyzed according to priority ranking provided in Table 11. 
 
 

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Below are brief descriptions of each planned assay. 
7.3.1.1 cH6/1 stalk IgG by ELISA 
This ELISA will measure IgG antibodies against the H1 stalk domain by using a chimeric protein 
that contains an exotic HA head domain (that the vaccinees have not previously been exposed 
to) and the H1 stalk domain as substrate. Most subjects are expected to have been previously 
exposed to H1N1 seasonal influenza viruses and have baseline titers to H1 stalk; thus, this assay 
is more aimed at detecting increases from baseline. This assay is considered the primary 
immunologic read-out of the trial and one of the five key immunologic read-outs of the 
trial. 
7.3.1.2 cH6/1 stalk IgA ELISA (serum) 
Likewise, this ELISA will measure serum IgA antibodies against the H1 stalk domain by using a 
chimeric protein that contains an exotic hemagglutinin head domain (that the vaccinees have not 
previously been exposed to) and the H1 stalk domain as substrate. Again, most subjects are 
expected to have been previously exposed to H1N1 seasonal influenza viruses and have baseline 
titers to H1 stalk; thus, this assay is more aimed at detecting increases from baseline. 
7.3.1.3 cH6/1 stalk secretory IgA ELISA (saliva) 
Likewise, this ELISA will specifically measure secretory IgA antibodies against the H1 stalk 
domain in saliva by using a chimeric protein that contains an exotic HA head domain (that the 
vaccinees have not previously been exposed to) and the H1 stalk domain as substrate. Secretory 
IgA is actively secreted into the mucosa. Again, most subjects are expected to have been 
previously exposed to H1N1 seasonal influenza viruses and may have baseline titers to H1 stalk; 
thus, this assay is more aimed at detecting increases from baseline. This assay is considered 
one of the five key immunologic read-outs of the trial. 
7.3.1.4 cH6/1 stalk total IgA ELISA (saliva) 
Likewise, this ELISA will measure total IgA antibodies against the H1 stalk domain in saliva by 
using a chimeric protein that contains an exotic HA head domain (that the vaccinees have not 
previously been exposed to) and the H1 stalk domain as substrate. This includes IgA present in 
the mucosa through both active and passive transfer processes. Again, most subjects are 
expected to have been previously exposed to H1N1 seasonal influenza viruses and may have 
baseline titers to H1 stalk; thus, this assay is more aimed at detecting increases from baseline. 
7.3.1.5 cH6/1 stalk total IgG ELISA (saliva) 
Likewise, this ELISA will measure IgG antibodies against the H1 stalk domain in saliva by using 
a chimeric protein that contains an exotic HA head domain (that the vaccinees have not previously 
been exposed to) and the H1 stalk domain as substrate. Again, most subjects are expected to 
have been previously exposed to H1N1 seasonal influenza viruses and have baseline titers to H1 
stalk; thus, this assay is more aimed at detecting increases from baseline. 

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7.3.1.6 H2 IgG ELISA 
This ELISA will measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A 
virus with a heterosubtypic HA that is moderately distantly related to the currently circulating 
influenza A/H1 viruses. Influenza viruses expressing H2 HAs have previously circulated in the 
human population. See Figure 1. H2N2 viruses circulated for only 11 years, from 1957 to 1968. 
Subjects born after 1968 typically do not possess neutralizing titers against H2N2 viruses because 
of lack of exposure, and hence it is not expected that subjects in the current trial would have any 
immunologic history with this virus. For this study, an avian H2 HA antigen will be used for 
detection of cross-reactive antibodies to H2. 
7.3.1.7 H9 IgG ELISA 
This ELISA will measure the induction of cross-reactive antibodies to a Group 1 influenza A virus 
with heterosubtypic HA that is moderately distantly related to the currently circulating influenza 
A/H1 viruses. See Figure 1. H9N2 viruses circulate in multiple avian species and are the source 
of some genes for H9N7 viruses that have infected humans over the past several years. For this 
study, an avian H9 HA antigen will be used for detection of cross-reactive antibodies to H9. 
7.3.1.8 H18 IgG ELISA 
This ELISA will measure the induction of cross-reactive antibodies to a Group 1 influenza A virus 
with heterosubtypic HA that is distantly related to the currently circulating influenza A/H1 viruses. 
See Figure 1. H18 viruses have only been detected in bat species. For this study, a chiropteran 
H18 antigen will be used for detection of cross-reactive antibodies to H18. 
7.3.1.9 H3 IgG ELISA 
This ELISA will measure the induction of cross-reactive antibodies to a Group 2 influenza A virus 
with heterosubtypic HA. See Figure 1. Antibodies that cross-react between Group 1 and Group 2 
influenza A viruses are rare. H3N2 viruses have widely circulated in humans since 1968. Thus, 
most subjects are expected to have baseline antibody levels of antibodies to H3. However, 
increases from baseline, in the absence of detected laboratory-confirmed H3N2 ILI in a subject 
or substantial H3N2 circulation during the trial period, would suggest cross-reactive responses to 
this Group 2 influenza A virus. 
7.3.1.10 
N1 IgG ELISA 
This ELISA will measure the induction of antibodies against the NA of H1N1. All vaccine 
components contain N1 and antibodies against NA could confer additional protection. Most 
subjects are expected to have been previously exposed to H1N1 seasonal influenza viruses and 
have baseline titers to N1; thus, this assay is more aimed at detecting increases from baseline. 

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7.3.1.11 
cH6/1N5 MN assay 
This MN assay will measure neutralizing antibodies against the H1 stalk domain by using a virus 
that expresses a cHA that contains an exotic HA head domain (that the vaccinees have not 
previously been exposed to) and the H1 stalk domain. This virus furthermore contains an exotic 
neuraminidase for which humans are generally naïve. This assay is considered one of the five 
key immunologic read-outs of the trial. 
7.3.1.12 
pH1N1 MN assay 
This MN assay will measure the neutralizing potential of antibodies against the currently 
circulating human H1N1 isolate which is similar to the stalk used in study vaccines. 
7.3.1.13 
asH1N1 MN assay 
This MN assay will measure the neutralizing potential of cross-reactive antibodies to a Group 1 
influenza against an H1N1 virus isolate that currently circulates in animals and is antigenically 
different from current human isolates. This avian-swine H1N1 virus, while isolated in swine, is 
believed to be of avian origin. 
7.3.1.14 
H5N8 MN assay 
This MN assay will measure the neutralizing potential of cross-reactive antibodies to a Group 1 
influenza virus with a heterosubtypic HA from a recent avian influenza virus. 
7.3.1.15 
Serum ADCC activity 
This assay will measure the potential of the vaccination regimens to induce antibodies that 
mediate ADCC activity via the Fc-receptor. This assay is considered one of the five key 
immunologic read-outs of the trial. 
7.3.1.16 
Phagocytic serum activity 
This assay will measure the potential of the vaccination regimens to induce antibodies that 
mediate antibody-dependent cellular phagocytosis (ADCP) via the Fc-receptor. 
7.3.1.17 
cH6/1N5 challenge after passive transfer 
This passive serum transfer assay will measure in vivo in an influenza challenge model in mice 
protective antibodies against the H1 stalk domain by using a virus that expresses a cHA that 
contains an exotic HA head domain (that the vaccinees have not previously been exposed to) 
and the H1 stalk domain. This virus furthermore contains an exotic neuraminidase for which 
humans are generally naïve. Sera from subjects in each study group will be pooled, and sets of 
mice will each receive a peritoneal injection of either the pre- or post-vaccination serum pool. Mice 
will then be challenged with the cH6/1N5 virus, with survival, weight loss, and viral lung titers 
subsequently measured 14 days post-challenge. 

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7.3.1.18 
H1N1 challenge after passive transfer 
This passive serum transfer assay will measure in vivo in an influenza challenge model in mice 
protective antibodies against the currently circulating human H1N1 isolate. Sera from subjects in 
each study group will be pooled, and sets of mice will each receive a peritoneal inoculum from 
either the pre- or post-vaccination serum pool. Mice will then be challenged with the H1N1 virus, 
with survival, weight loss, and viral lung titers subsequently measured 14 days post-challenge. 
7.3.1.19 
cH8/1N1 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of the 
cH8/1 in study LAIV. Subjects receiving study cH8/1 LAIV are expected to have measurable HI 
responses post-vaccination. 
7.3.1.20 
cH5/1N1 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of the 
cH5/1 in study IIV. Subjects receiving study cH5/1 IIV are expected to have measurable HI 
responses post-vaccination. 
7.3.1.21 
cH6/1N5 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of a 
cH6/1. As neither study vaccine contains an H6 head, induction of antibodies against this domain 
is not expected. If cH6/1 HI antibodies are measured, it would imply that the study vaccines 
induced broadly cross-reactive HA head antibodies. 
7.3.1.22 
H1N1 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of the 
H1 of the currently circulating human H1N1 virus. As neither study vaccine contains an H1 head, 
induction of antibodies against this domain is not expected. If H1 HI antibodies are measured, it 
would imply that the study vaccines induced broadly cross-reactive HA head antibodies. 
7.3.1.23 
Avian-swine H1N1 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of an 
H1N1 virus isolate that currently circulates in animals and is antigenically different from H1N1 
current circulating in humans. As neither study vaccine contains an asH1 head, induction of 
antibodies against this domain is not expected. If asH1 HI antibodies are measured, it would imply 
that the study vaccines induced broadly cross-reactive HA head antibodies. This H1N1 virus, 
while isolated in swine, is believed to be of avian origin. 
7.3.1.24 
H5N8 HI 
This HI assay will measure the induction of antibodies reactive against the head domain of a 
group 1 influenza virus with a heterosubtypic HA from a recent avian influenza virus. As the 
cH8/1N1 LAIV and IIV do not contain an H5 head, lack of measurable antibodies in this assay 
post cH8/1N1 administration would suggest most of the responses measured in the H5N8 MN 
are stalk associated. 

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Table 10 
Humoral and mucosal immunity assays 
System 
Component (Strain or Antigen Description) 
Method 
Kit/Manufacturer 
Unit 
Cut-off* 
Laboratory 
ELISAs 
Serum 
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with stalk 
domain from HA of H1N1 virus A/California/04/09 
Anti-H1 HA-stalk IgG ELISA 
In-house assay 
(Developed by GSK) 
 
ELISA units 
per mL 
(EU/mL) 
 
65.3 
Neomed 
H2 HA full length = Recombinant antigen based on 
A/mallard/Netherlands/5/1999 (H2N9) HA 
Anti- H2 HA-full length IgG ELISA 
22.0 
 
H18 HA full length = Recombinant antigen based on A/flat-
faced bat/Peru/033/2010 (H18N11) HA 
Anti- H18 HA-full length IgG ELISA 
42.3 
 
H9 HA full length = Recombinant antigen based on 
A/chicken/Hong Kong/G9/1997 (H9N2) HA 
Anti-H9 HA-full length IgG ELISA 
31 
 
N1 NA = Recombinant antigen based on 
A/California/04/2009 (H1N1) NA 
Anti-N1 NA ELISA 
In-house assay 
Endpoint 
titer 
100 
ISMMS 
H3 HA full length = Recombinant antigen based on A/Hong 
Kong/4801/2014 (H3N2) HA 
Anti- H3 HA-full length IgG ELISA 
In-house assay 
Endpoint 
titer 
100 
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with stalk 
domain from HA of H1N1 virus A/California/04/09 
Anti-H1 HA-stalk IgA ELISA 
In-house assay 
Endpoint 
titer 
100 
Saliva 
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with stalk 
domain from HA of H1N1 virus A/California/04/09 
Anti-H1 HA-stalk secretory IgA ELISA 
In-house assay 
Endpoint 
titer 
4 
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with stalk 
domain from HA of H1N1 virus A/California/04/09 
Anti-H1 HA-stalk total IgA ELISA 
In-house assay 
Endpoint 
titer 
10 
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with stalk 
domain from HA of H1N1 virus A/California/04/09 
Anti-H1 HA-stalk IgG ELISA 
In-house assay 
Endpoint 
titer 
10 
 
 

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Table 10 
Humoral and mucosal immunity assays (continued) 
System 
Component (Strain or Antigen Description) 
Method 
Kit/Manufacturer 
Unit 
Cut-off* 
Laboratory 
Microneutralization (MN) assays 
Serum 
cH6/1N5 virus (on PR8 backbone [A/Puerto Rico/8/34]): 
HA head: A/mallard/Sweden/81/2002 (H6N1) 
stalk: A/California/04/2009 (H1N1pandemic) 
N5: A/mallard/Sweden/86/2003 (H12N5) 
Anti-H1 HA-stalk MN Assay 
In-house assay 
1/DIL 
Endpoint 
titer  
10 
ISMMS 
H5N8 virus: 
RG reassortant virus based on PR8 for 6 genes with 2 
surface proteins: HA and NA from 
A/Gyrfalcon/Washington/41088-6/2014 (H5N8) 
Anti-heterosubtypic HA Group 1 virus 
MN Assay 
10 
H1N1 avian-swine influenza virus: 
A/Swine/Jiangsu/40/2011 (asH1N1) 
Anti-heterologous HA Group 1 virus 
MN Assay 
10 
H1N1 strains** 
Anti-heterologous HA Group 1 virus 
MN Assay 
10 
Hemagglutination Inhibition (HI) Assay 
Serum 
Chimeric vaccine strain cH8/1N1; cH5/1N1;  
(cH6/1N5; H5N8; asH1N1; H1N1)*** 
HI assays 
In-house assay 
1/DIL 
10 
CCHMC 
Other Assays 
Serum 
cH6/1N5 challenge 
Passive Transfer to mice 
In-house assay 
NA 
NA 
ISMMS 
Serum 
H1N1** challenge 
Passive Transfer to mice 
In-house assay 
NA 
NA 
ISMMS 
Serum 
cH6 
ADCC 
In-house assay 
AUC 
1 
ISMMS 
Serum 
cH6 
ADCP 
In-house assay 
AUC 
1 
ISMMS 
TBD = to be determined; DIL = dilution; NA = not applicable 
*Cut-off value may change following set-up/qualification data 
**The H1N1 strain will depend on the World Health Organization recommendation for the 2017/2018 season. 
***These additional HI assays will also use the same four antigens as used for MNs

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Table 11 
Humoral and mucosal immunologic read-outs 
Blood sampling time point 
Component 
Components 
priority rank 
Visit time point 
Sampling 
time point 
ELISAs 
Visit 03* 
Visit 10 
Visit 11 
Visit 13 
Visit 14** 
Visit 15 
PRE 
PId28 
PId84 
PIId28 
PIIm6 
PIIm12 
Anti-H1 HA-stalk IgG ELISA (serum) 
1 
Anti-H1 HA-stalk IgG ELISA (saliva) 
(3)*** 
Anti-H1 HA-stalk total IgA ELISA (serum) 
4 
Anti-H1 HA-stalk total IgA ELISA (saliva) 
(2)*** 
Anti-H1 HA-stalk secretory IgA ELISA (saliva) 
(1)*** 
Anti-H2 HA-full length IgG ELISA 
6 
Anti-H9 HA-full length IgG ELISA 
7 
Anti-H18 HA-full length IgG ELISA 
8 
Anti-H3 HA-full length IgG ELISA 
14 
Anti-N1 NA ELISA 
15 
Microneutralization (MN) Assays 
Visit 03* 
Visit 10 
Visit 11 
Visit 13 
Visit 15 
PRE 
PId28 
PId84 
PIId28 
PIIm12 
Anti-H1 HA-stalk MN assay 
2 
Anti-heterosubtypic HA Group 1 virus MN assay (H5N8) 
9 
Anti-heterosubtypic HA Group 1 virus MN assay (avian-swine 
H1N1) 
10 
Anti-heterosubtypic HA Group 1 virus MN assay (H1N1) 
11 
Hemagglutination Inhibition (HI) Assays 
Visit 03* 
Visit 10 
Visit 11 
Visit 13 
Visit 15 
PRE 
PId28 
PId84 
PIId28 
PIIm12 
HI with cH5/1N1 
16 
HI with cH8/1N1 virus 
17 
HI with cH6/1N5 
18 
HI with H5N8 
19 
HI with asH1N1 
20 
H1 with H1N1 
21 
Other Assays 
Visit 03* 
Visit 10 
Visit 11 
Visit 13 
Visit 15 
PRE 
PId28 
PId84 
PIId28 
PIIm12 
ADCC Activity 
3 
ADCP Activity 
5 
Visit 03* 
Visit 13 
Visit 15 
PRE 
PIId28 
PIIm12 
Passive transfer to mice with cH6/1N5 challenge 
12 
Passive transfer to mice with H1N1 challenge 
13 
*Will occur at V02 (one day prior to V03) for subjects in LAIV-IIV treatment arms (Groups 1, 2, & 3) 
**At Visit 14, only anti-H1 HA-stalk IgG detection by ELISA in serum will be done. 
***Parentheses indicate components priority rank for testing of saliva. All other rankings are for testing of serum. 
 
 

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7.3.2 
Cell-mediated immunity 
Multiple assays will be used to probe cell-mediated immunologic responses to the chimeric HA 
LAIV and IIVs. T-cell responses will be evaluated by ISMMS (laboratory of Dr. Florian Krammer) 
using standardized procedures (Table 12). B-memory cell and plasmablast responses will be 
evaluated by the University of Chicago (laboratory of Dr. Patrick Wilson) using standardized 
procedures (Table 12). 
Table 13 specifies cell-mediated immunologic read-outs by sampling time point and study group. 
In case of insufficient blood sample volume to perform assays for all antibodies, the samples will 
be analyzed according to priority ranking provided in Table 13 
7.3.2.1 Plasmablast response (ELISPOT for cH6/1) 
Plasmablasts represent predominantly the reactivation of past memory B cells with little further 
adaptation to the current immunogen. Plasmablasts are expected to be present at peak levels 7 
days post-vaccination with study vaccine. One third to one quarter of each sample will be used 
for Enzyme-Linked ImmunoSpot (ELISPOT) assays to evaluate total IgG and IgA+ antibody-
secreting cells (ASC) and the proportions of these cells that are reactive to the cH6/1 recombinant 
HA (rHA) protein and to control rHA protein. The units this assay generates is ASCs/106 PBMCs. 
The frequency of ASCs to rHA proteins will be calculated as (ASCs to rHA per million 
PBMCs)/(ASCs to IgG per million PBMCs). 
To reduce cell deaths plasmablasts will not be frozen before processing. The laboratory will also 
sort single plasmablast cells for use in generating monoclonal antibodies (mABs) and evaluating 
the immunoglobulin gene repertoires. The antibodies will be used to evaluate the frequency and 
functionality of the antibody response as well as the epitopes that are targeted. 
7.3.2.2 Memory B-cell response (ELISPOT for cH6/1) 
Memory B-cells generated at baseline, 4 weeks post-vaccination and maintained out to 12 months 
post-Dose 2 will be studied. Day 28 memory B cells represent B cells that may have undergone 
further adaptation to the immunogen. Memory B cells can be detected by ELISPOT after in vitro 
stimulation to induce differentiation into IgG and IgA secreting cells. The lab will test the PBMCs 
for antigen specific B cells in ELISPOT assays. This will determine the proportions of these cells 
that are reactive to the cH6/1 rHA protein and to control rHA protein. Again, the units this assay 
generates is ASCs/106 PBMCs. The frequency of memory cells to rHA proteins will be calculated 
as (memory cells to rHA per million PBMCs)/(memory cells to IgG per million PBMCs). This assay 
is considered one of the five key immunologic read-outs of the trial. 
In addition, the laboratory will isolate antigen-specific memory B cells by flow cytometry with 
memory B cell-specific cell surface markers. The antibodies will be used to evaluate the frequency 
and functionality and maturation of the antibody response in response to vaccination.  

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7.3.2.3 T-cell response (ELISPOT) 
This assay will allow us to measure the potential of the vaccination regimens to induce T cell 
responses. The protective role of antibodies in the context of influenza virus vaccination has been 
well established. However, less is known about T cell responses to influenza virus vaccination. It 
has been previously shown that T cell responses can be elicited with live virus vaccination. In this 
study, a live-attenuated virus prime, followed by an inactivated intramuscular vaccination will be 
compared to two intramuscular vaccinations with inactivated vaccine. To measure differences in 
T cell activation, as well as long term T cell responses specific to influenza viruses, the lab will 
collect PBMCs and quantify the number of cytokine producing cells in response to influenza 
specific antigens (including whole virus stimulation and peptide pools) and compare them to the 
response against an irrelevant peptide as a negative control. 
To perform an interferon gamma ELISPOT assay, for example, a standardized amount of PBMCs 
are pipetted into each well, stimulated with the antigen of choice and incubated overnight. Cells 
that become activated will release interferon gamma that gets bound to the bottom of the well. 
The plates are then developed and the individual spots (representing a single interferon gamma 
releasing cell) are counted. 

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Table 12 
Cell-mediated immunologic assays 
System 
Component 
Challenge 
Method 
Unit 
Laboratory 
PBMCs 
B-cells reactive to “challenge” 
antigens 
cH6/1 
B-memory cells and ELISPOT 
(monoclonal antibodies will also 
be cloned from select subjects) 
Frequencies of antigen-specific memory B-
cells/millions memory B-cells 
UChicago 
PBMCs 
Plasmablasts detected using HA-SA 
biotinylated probe 
cH6/1 
Plasmablast detection to HA by 
flow cytometry 
Frequencies of antigen-specific 
plasmablasts/millions plasmablasts 
UChicago 
PBMCs 
T-cells 
cH6/1 and other antigens, 
to be determined 
ELISPOT 
Frequencies of IFN- positive spots 
ISMMS 
PBMC = Peripheral blood mononuclear cells; IFN- = interferon-gamma 
Table 13 
Cell-mediated immunologic read-outs 
Cell-mediated immunity 
Visit time point 
Sampling 
time point 
Component 
Components 
priority rank  
Visit 03* 
Visit 10 
Visit 11** 
Visit 13 
Visit 15** 
PRE 
PId28 
PId84 
PIId28 
PIIm12 
B memory cells (including ELISPOT for cH6/1) 
1 
Visit 09 
Visit 12 
PId7 
PIId7 
Plasmablast detection to HA by flow cytometry 
2 
Visit 03* 
Visit 09 
Visit 11 
Visit 12 
Visit 15 
PRE 
PId7 
PId84 
PIId7 
PIIm12 
T-cell response (ELISPOT) 
3 
PRE = pre-vaccination; PI = post-Dose 1; PII = post-Dose 2; D = day; M = month 
*Will occur at V02 (one day prior to V03) for subjects in LAIV-IIV treatment arms (Groups 1, 2, & 3) 
**ELISPOT only  

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For "universal" influenza vaccines based on the approach of using vaccines with chimeric HA 
constructs, no generally accepted immunological correlate of protection has been demonstrated 
so far. 
Additional exploratory testing related to the vaccine and/or to the disease under study may be 
performed within the framework of the study if deemed necessary for accurate interpretation of 
the data, for test improvement or development of analytical methods, or should such assay(s) 
become available. 
7.4 
Transcriptomic laboratory assays  
Analysis of global changes in blood associated with vaccination might allow the identification of 
biomarkers associated with protection. Changes to the blood transcriptome and cell composition 
will be analyzed using RNA sequencing at ISMMS (laboratory of Dr. Adolfo Garcia-Sastre) using 
standardized procedures (see Table 14). Comparison of the differences between the different 
vaccination regimens, induced immune responses, blood transcriptomes and cell type 
compositions will tell us the specific blood parameters associated with immunogenicity, and in the 
long run, potentially with protection. 
Table 14 Transcriptomic read-outs 
Transcriptomics 
Visit time point 
Sampling 
time point 
Component 
Components 
priority rank  
Visit 03* 
Visit 05 
Visit 09 
Visit 10 
Visit 11* 
Visit 12 
Visit 13 
Visit 14 
Visit 15* 
PRE 
PId2 
PId7 
PId28 
PId84 
PIId7 
PIId28 
PIIm6 
PIIm12 
RNA sequencing 
1 
*Will occur at V02 (one day prior to V03) for subjects in LAIV-IIV treatment arms (Groups 1, 2, & 3) 
7.5 
Influenza virologic assays 
At each site, nasal and OP swab specimens collected from subjects in Groups 1, 2, & 3 while 
they are in the inpatient clinical isolation unit will be tested daily (within 24 hours of collection) for 
the presence of influenza A virus using standardized procedures. Primer-probe sets appropriate 
for the detection of seasonal influenza A viral RNA by real time RT-PCR will be used. Swab 
specimens may also be tested by RT-PCR using primer-probe sets designed to detect specifically 
genes of A/Leningrad/134/17/1957, the master donor virus used to create study LAIV and/or to 
detect the cH8/1 HA gene. Specimens testing positive will be shipped to a single designated 

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laboratory for detection of viable vaccine virus in MDCK cell culture using standardized 
procedures (Table 15). 
To maintain the observer-blind study status insofar as is possible, the results of the daily influenza 
A virus test performed on subjects in the inpatient clinical isolation unit will only be provided to a 
designated unblinded member of the site team. The unblinded member will only communicate 
positive results to the blinded Investigator and study team members on a need to know basis. For 
example, positive results from the Day 4 and later specimens need to be communicated so that 
the study team can ensure that the subject has met all the required discharge criteria prior to 
discharge from the inpatient clinical unit. 
For subjects in any study arm (Groups 1-5) reporting ILI during the course of the study follow-up, 
nasal and OP swab specimens will be tested for evidence of seasonal influenza infection by RT-
PCR (A/B typing followed by A/H1 or A/H3 subtyping). 
Table 15 
Influenza virology 
System 
Discipline 
Component 
Method 
Scale** 
Laboratory 
Nasal 
and OP 
swabs 
Virology 
Influenza A RNA detection 
As per research 
laboratory 
procedure 
Qualitative 
Site 
H3N2 HA RNA detection 
H1N1 HA RNA detection 
Influenza B RNA detection 
cH8/1 HA RNA detection 
Qualitative 
CCHMC 
Cytopathic effect in MDCK cell 
culture 
Qualitative 
CCHMC 
 
Table 16 specifies influenza virologic read-outs by sampling time point and study group. 
 
Table 16 
Read-outs for influenza virology 
Sampling time point 
Number of 
subjects 
Component 
Type of contact and 
time point 
Sampling 
time point 
Visit 02 (Day -1) 
Visits 04-08 (Days 2-6) 
PRE 
PId1-6 
Subjects in 
Groups 1-3 
Influenza A RNA detection (may also include second 
detection of master donor virus specific or cH8/1 specific 
RNA segments) 
Visit 02 (Day -1) 
Visits 04-08 (Days 2-6) 
PRE 
PId1-6 
Subjects in 
Groups 1-3 
Cytopathic effect in MDCK cell culture and staining with 
cH8/1 monoclonal antibody* 
ILI Visit 
(unscheduled visit) 
Any 
All Subjects 
Influenza A RNA detection 
 
H3N2 HA RNA detection 
 
H1N1 HA RNA detection 
Influenza B RNA detection 
*Only for those specimens influenza A positive by RT-PCR in post-vaccination specimens.  

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7.6 
Assays qualification, standardization, validation 
Immunologic and transcriptomic assays used in this first-in-humans trial are for research purposes 
only and have adequate reference standards and controls, where available. No immunologic or 
transcriptomic assay is qualified or validated at this stage. 
7.7 
Future use of stored samples 
At the completion of all the testing at the laboratories, the samples will be either destroyed or 
stored at an appropriate place in a designated freezer at the laboratories or at a PATH-designated 
facility. PATH will be responsible for the oversight of sample storage and destruction. As part of 
the consent process, subjects will be asked whether they consent to any remaining samples being 
used for other, ethically approved research which could be used in new or different laboratory 
tests, to provide information for the development of new vaccines, or for the studies of influenza 
or other infections. The samples might be shared with researchers at other study centers. All 
samples will be used only for research purposes. Human genetic (DNA) tests will not be 
performed on these samples. Samples obtained in this study may result in the development of a 
product that could be patented or licensed. There are no plans to provide financial compensation 
to the subject should this occur. 
7.8 
Biohazard containment 
As exposure to blood-borne pathogens can occur through contact with contaminated needles, 
blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and shipping and handling of all specimens for this study as 
recommended by the US Centers for Disease Control and Prevention (CDC). All biological 
specimens will be transported using packaging mandated by CFR 42 Part 72. All dangerous 
goods materials, including diagnostic specimens and infectious substances, must be transported 
according to instructions detailed in the International Air Transport Association Dangerous Goods 
Regulations. 
Biohazardous 
waste 
will 
be 
contained 
according 
to 
institutional, 
transportation/carrier, and all other applicable regulations.  
8 SAFETY ASSESSMENT AND REPORTING 
8.1 
Definitions 
8.1.1 
Adverse event (AE) 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, finding during physician examination, or disease 

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temporally associated with the use of the investigational medical product(s), whether or not 
considered related to the investigational medical product(s).  
The occurrence of an AE might come to the attention of study personnel during study visits or 
during interviews of a study subject who presents separately for medical care. Information to be 
collected on AEs includes event description, time of onset, assessment of severity, relationship 
to study product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event.  
This definition includes exacerbations of pre-existing conditions. Stable pre-existing conditions 
which do not change in nature or severity during the study are not considered AEs; however, 
these should be reported as part of the medical history. However, if this condition deteriorates 
(e.g., increases in frequency or severity grade) during the study, it should be recorded as an AE. 
8.1.1.1 Solicited local and general reactions 
Solicited AEs are pre-specified local and general (systemic) adverse events that are common or 
known to be associated with vaccination that are actively monitored as indicators of vaccine 
reactogenicity. Investigators are not required to assess causality of solicited adverse events if the 
onset is during the solicitation periods. Solicited adverse events with onset after the solicitation 
period should be captured as unsolicited AEs. 
For this trial, solicited AEs will be assessed by study staff 60 (+10) minutes after each vaccination 
and then by study subjects daily for 7 days (day of vaccination and subsequent 6 days). 
Participants will be provided a diary card for recording the presence or absence of solicited (and 
unsolicited) AEs, for scoring for severity of the solicited (and unsolicited) AEs and for documenting 
use of concomitant medication and any pain relief and/or antipyretics taken by the subject to 
correct the AE(s). Subjects will be instructed to measure and record the oral body temperature in 
the evening regardless of the occurrence of any symptoms. Should additional temperature 
measurements be performed at other times of day, subjects will be instructed to record the highest 
temperature in the diary card. Solicited local AEs will be tailored to the site of administration of 
each product. However, because influenza vaccines containing chimeric HAs have not been 
previously administered to humans (outside of GSK's parallel Ph1/2 trial), solicited general AEs 
will be common across both study LAIV and IIV products. 
The following local site (nasal) AEs will be solicited post-administration of study LAIV (or placebo) 
for subjects in Groups 1, 2, and 3: 
Table 17 
Solicited local adverse events - post-LAIV dose 
Nasal congestion 
Rhinorrhea 
 

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The following local site (injection) AEs will be solicited post-administration of any study IIV (or 
placebo). This includes post-Dose 1 for subjects in Groups 4 and 5 and post-Dose 2 for subjects 
in all groups: 
Table 18 
Solicited local adverse events - post-IIV dose 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
 
The following general AEs will be solicited post-administration of study LAIV (or placebo) and 
study IIV (or placebo) for subjects in all Groups: 
Table 19 
Solicited general adverse events - post-LAIV or post-IIV dose 
Abdominal pain 
Arthralgia 
Cough 
Diarrhea 
Fatigue 
Fever 
Headache 
Myalgia 
Nausea 
Shivering 
Sore throat 
Vomiting 
Wheezing 
Investigators will review diary cards with the subject to ensure the solicited AEs are appropriately 
documented. The investigator will then transcribe all solicited AEs to the appropriate section of 
the eCRF. 
8.1.1.2 Unsolicited adverse events 
Unsolicited AEs are any AEs reported spontaneously by the subject, observed by the study 
personnel during study visits or those identified during review of medical records or source 
documents, such as diary cards.  
Subjects will be instructed to record any unsolicited symptoms or other illness description in their 
diary card during the 28 days after each vaccination (day of vaccination and subsequent 27 days) 
and then until the end of the study. Investigators will review diary cards with the subject to ensure 
the unsolicited AE is appropriately described. The investigator will then transcribe unsolicited AEs 
to the appropriate section of the eCRF. 

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8.1.2 
Adverse drug reaction / suspected adverse reaction 
An adverse drug reaction is any AE in which the casual relationship to the investigational vaccine 
is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Having a reasonable 
suspected causal relationship to the investigational vaccine qualify as an adverse drug reaction. 
The concept of “reasonable causal relationship” is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship.  
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug (vaccine) caused the adverse event. For the purposes of IND safety reporting, 
"reasonable possibility" means there is evidence to suggest a causal relationship between the 
drug (vaccine) and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug (vaccine). 
Adverse reaction is any adverse event caused by the drug (vaccine). Adverse reaction is a 
subset of suspected adverse reactions where there is reason to conclude that the drug (vaccine) 
caused the event. 
Unexpected suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed. 
8.1.3 
Serious adverse event (SAE)  
A serious adverse event is an AE that meets one of the following conditions: 
 
Results in death. 
 
Is life threatening (i.e., puts the subject at immediate risk of death). (The term “life-threatening” 
in the definition of “serious” refers to an event in which the subject is/was, in the opinion of the 
investigator or Sponsor, at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. (Continuation of 
stay in the isolation unit beyond 7 days post-administration of either dose of study vaccine or 
placebo because of late detected viral shedding in a subject shall not be considered a 
“prolongation of existing hospitalization” for SAE recording or reporting.) 
 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
 
Results in congenital anomaly/birth defect. (Only in the case of a woman becoming pregnant 
during the study period after administration of at least one dose of study vaccine. All 
pregnancies must be followed to term and outcome reported to the Sponsor and regulatory 
agencies.) 

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 
Is an important medical event that may not meet one of the above conditions, but may 
jeopardize the well-being of the subject or require medical or surgical intervention to prevent 
one of the outcomes listed above. (Appropriate medical judgment should be exercised in 
deciding whether reporting these events is appropriate.) 
Suspected unexpected serious adverse reaction is any suspected adverse reaction that is 
both unexpected and serious. 
8.1.4 
Clinical laboratory parameters and other abnormal assessments qualifying 
as adverse events or serious adverse events 
In absence of diagnosis, abnormal clinical laboratory findings (i.e., clinical biochemistry and 
hematology) or other abnormal assessments (i.e., physical examination findings) that are judged 
by the investigator to be clinically significant will be recorded as an AE or SAE if they meet the 
definition of an AE or SAE. To the extent possible, all normal ranges for clinical laboratory test 
results will be pre-specified in site reference range documents, but the investigator will exercise 
his/her medical and scientific judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are present at baseline and significantly worsen 
following the start of the study will also be reported as AEs or SAEs.  
Any finding not normalizing by the end of the study should be followed by the investigator, as 
would be done under normal clinical care circumstances. After termination of the trial, the 
investigator should assure that the subject is referred for medical follow-up, as appropriate. 
8.1.5 
Medically attended event (MAE) 
For each solicited and unsolicited AE the subject experiences, the subject will be asked if he/she 
received medical attention defined as hospitalization, or an otherwise unscheduled visit to or from 
medical personnel for any reason, including emergency room visits. This information will be 
recorded in the eCRF. 
8.1.6 
Influenza-like illness (ILI) 
Beginning from Visit 09 (Day 8), all subjects will be monitored for ILI in order to assess the 
possibility of increased susceptibility to influenza due to vaccine inducing HA stalk antibodies that 
are not sufficiently neutralizing and that assist wild-type influenza virus in fusion with the human 
cell membrane. Laboratory confirmed ILI (LC-ILI) will be considered the safety outcome of interest 
although all ILI, regardless of laboratory confirmation, will also be analyzed. For the purpose of 
this study, ILI is defined as at least 1 systemic symptom (fever [oral temperature, ≥ 37.8°C 
or ≥ 100°F] or myalgia) AND at least 1 respiratory symptom (cough or sore throat).  

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Moderate-to-severe ILI will be defined as ILI accompanied by any of the following: 
 
maximum recorded oral body temperature of >39°C or 102.2°F 
 
physician-diagnosed pneumonia, lower respiratory tract infection, bronchiolitis, bronchitis, or 
laryngotracheitis; or  
 
physician-diagnosed serious extrapulmonary complications of influenza 
For analysis and reporting purposes, only ILIs laboratory-confirmed (Nasal and OP swab positive 
by RT-PCR) as caused by seasonal influenza virus will be included. 
8.1.7 
Potential immune-mediated disease (pIMD) 
Adverse events of specific interest for safety monitoring include pIMDs, a subset of AEs that 
include autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology. AEs that need to be recorded and reported 
as pIMDs include those listed in Table 20. 
However, the investigator will exercise his/her medical and scientific judgment in deciding whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or organ-
specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
designate) must complete, date and sign an electronic Expedited Adverse Events Report. 
When there is enough evidence to make any of the diagnoses listed in Table 20, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent the below 
diagnoses, should be recorded and reported as AEs but not as pIMDs until the final or definitive 
diagnosis has been determined, and alternative diagnoses have been eliminated or shown to be 
less likely. 

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Table 20 
List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
 
Cranial nerve disorders, including 
paralyses/paresis (e.g., Bell’s palsy)  
 
Optic neuritis 
 
Multiple sclerosis 
 
Transverse myelitis 
 
Guillain-Barré syndrome, including Miller 
Fisher syndrome and other variants 
 
Acute disseminated encephalomyelitis, 
including site specific variants: e.g., non-
infectious encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis 
 
Myasthenia gravis, including Lambert-
Eaton myasthenic syndrome  
 
Immune-mediated peripheral neuropathies 
and plexopathies, (including chronic 
inflammatory demyelinating 
polyneuropathy, multifocal motor 
neuropathy and polyneuropathies 
associated with monoclonal gammopathy). 
 
Narcolepsy 
 
Systemic lupus erythematosus and 
associated conditions 
 
Systemic scleroderma (Systemic 
sclerosis), including diffuse systemic 
form and CREST syndrome 
 
Idiopathic inflammatory myopathies, 
including dermatomyositis 
 
Polymyositis  
 
Antisynthetase syndrome 
 
Rheumatoid arthritis, and associated 
conditions including juvenile chronic 
arthritis and Still’s disease 
 
Polymyalgia rheumatica 
 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated spondyloarthritis 
 
Psoriatic arthropathy 
 
Relapsing polychondritis 
 
Mixed connective tissue disorder 
 
Psoriasis 
 
Vitiligo 
 
Erythema nodosum 
 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
 
Alopecia areata 
 
Lichen planus 
 
Sweet’s syndrome 
 
Localized Scleroderma 
(Morphoea) 
 
Cutaneous lupus 
erythematosus 
Vasculitides 
Blood disorders 
Others 
 Large vessels vasculitis including: giant cell 
arteritis such as Takayasu's arteritis and 
temporal arteritis.  
 Medium sized and/or small vessels 
vasculitis including: polyarteritis nodosa, 
Kawasaki's disease, microscopic 
polyangiitis, Wegener's granulomatosis, 
Churg–Strauss syndrome (allergic 
granulomatous angiitis), Buerger’s disease 
(thromboangiitis obliterans), necrotizing 
vasculitis and anti-neutrophil cytoplasmic 
antibody (ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein purpura, 
Behcet's syndrome, leukocytoclastic 
vasculitis. 
 Autoimmune 
hemolytic anemia 
 Autoimmune 
thrombocytopenia 
 Antiphospholipid 
syndrome 
 Pernicious anemia 
 Autoimmune 
aplastic anemia 
 Autoimmune 
neutropenia 
 Autoimmune 
pancytopenia 
 
Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis) 
 
Ocular autoimmune diseases (including 
autoimmune uveitis and autoimmune 
retinopathy) 
 
Autoimmune myocarditis/cardiomyopathy  
 
Sarcoidosis 
 
Stevens-Johnson syndrome 
 
Sjögren’s syndrome 
 
Idiopathic pulmonary fibrosis 
 
Goodpasture syndrome 
 
Raynaud’s phenomenon 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
 Autoimmune hepatitis 
 Primary biliary cirrhosis 
 Primary sclerosing cholangitis 
 Autoimmune cholangitis 
 Inflammatory Bowel disease, 
including Crohn’s disease, 
ulcerative colitis, microscopic 
colitis, ulcerative proctitis  
 Celiac disease 
 Autoimmune pancreatitis 
 Autoimmune thyroiditis (including Hashimoto 
thyroiditis) 
 Grave's or Basedow’s disease 
 Diabetes mellitus type I 
 Addison’s disease 
 Polyglandular autoimmune syndrome 
 Autoimmune hypophysitis 

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8.1.8 
Pregnancy 
Any confirmed pregnancy among female subjects after receipt of Dose 1 of study vaccine (or 
placebo) will be recorded but will not be considered an AE. Only if the pregnancy outcome is 
stillbirth or any congenital anomaly, then this outcome will be reported as an SAE. 
The following should always be considered as SAE and will be reported as described in 
Section 8.6: 
 
Spontaneous pregnancy loss, including: 
 
Spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of gestation). 
 
Ectopic and molar pregnancy. 
 
Stillbirth (intrauterine death of fetus after 22 weeks of gestation). 
 
Any early neonatal death (i.e., death of a live born infant occurring within the first 7 days of 
life).  
 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) identified in the 
offspring of a study subject (either during pregnancy, at birth or later) regardless of whether 
the fetus is delivered dead or alive. This includes anomalies identified by prenatal ultrasound, 
amniocentesis or examination of the products of conception after elective or spontaneous 
abortion. 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered by the 
investigator to be reasonably related to the study vaccines/products will be reported to GSK 
Biologicals as described in Section 8.6.2. While the investigator is not obligated to actively seek 
this information from former study participants, he/she may learn of a pregnancy through 
spontaneous reporting.  
8.2 
Monitoring periods for safety events 
Adverse events will be collected during the study during the following periods: 
 
Solicited local and general AEs commonly associated with intranasal or intramuscular 
influenza vaccination occurring through 7 days following any dose (day of vaccination and 
subsequent 6 days); 
 
Unsolicited AEs occurring through 28 days following any dose (day of vaccination and 
subsequent 27 days); 
 
Hematological and biochemical clinical laboratory abnormalities during the entire study period 
post-Dose 1; 

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 
AEs (including SAEs) leading to withdrawal from the study during the entire study period post-
Dose 1; 
 
SAEs during the entire study period post-Dose 1; 
 
SAEs related to study participation during the entire study period beginning from enrollment 
in screening; 
 
MAEs during the entire study period post-Dose 1; 
 
ILIs during the entire study period post-Dose 1; 
 
pIMDs during the entire study period post-Dose 1; and 
 
Pregnancies during the entire study period post-Dose 1. 
Any solicited AE that starts during the 7 days post-vaccination and is still ongoing after 7 days 
post-vaccination should still be reported as a solicited AE and not an unsolicited AE. Any AE, 
SAE, or other safety event should be followed to resolution or stabilization, if possible, even if 
resolution or stabilization is after its required reporting period or the end of the trial.  
AEs/SAEs that are assessed as being “related” to study participation or study procedures during 
the study period from enrollment in screening until administration of a study vaccine, even if they 
occur prior to administration of a pharmaceutical product are also to be collected and reported. 
8.3 
Severity of adverse events 
All AEs, including clinical laboratory test results, will be assessed by a study clinician and the 
study subject (as applicable) to quantify severity using a protocol-defined grading system stated 
below. For certain study clinical laboratory parameters, the US Food and Drug Administration 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” will be used (see Appendix 2). 
8.3.1 
Severity of solicited AEs 
Solicited symptoms will be graded by subjects as described (see Table 21). 
 
 

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Table 21 
Severity grading scales for solicited symptoms in adults 
Adverse Event 
Intensity 
Grade 
Parameter 
Runny nose/nasal 
congestion 
0 
None 
1 
Mild: Runny nose and/or nasal congestion not interfering with daily activity 
2 
Moderate: Runny nose and/or nasal congestion causing some interference with daily activity 
3 
Severe: Runny nose and/or nasal congestion preventing daily activity 
Pain at injection 
site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing normal every day activities. 
2 
Moderate: Painful when limb is moved and interferes with every day activities. 
3 
Severe: Significant pain at rest. Prevents normal every day activities. 
Cough 
0 
None 
1 
Mild: Cough that is easily tolerated 
2 
Moderate: Cough that interferes with normal activity 
3 
Severe: Cough that prevents normal activity 
Fever*  
(record 
temperature in °F) 
0 
< 38.0°C or 100.4°F  
1 
≥ 38.0°C or 100.4°F -  38.5°C or 101.3°F 
2 
> 38.5°C or 101.3°F -  39.0°C or 102.2°F  
3 
> 39.0°C or 102.2°F  
Headache 
0 
None 
1 
Mild: Headache that is easily tolerated 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
None 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal 
symptoms 
(nausea, 
vomiting, diarrhea 
and/or abdominal 
pain) 
0 
None 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with normal activity 
3 
Severe: Gastrointestinal symptoms that prevent normal activity 
Arthralgia 
0 
None 
1 
Easily tolerated 
2 
Interferes with normal activity 
3 
That prevents normal activity 
Myalgia 
0 
None 
1 
Easily tolerated 
2 
Interferes with normal activity 
3 
That prevents normal activity 
Redness (record 
greatest surface 
diameter in mm) 
0 
 20 mm 
1 
> 20 mm -  50 mm 
2 
> 50 mm -  100 mm 
3 
> 100 mm 

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Adverse Event 
Intensity 
Grade 
Parameter 
Shivering 
0 
None 
1 
Easily tolerated 
2 
Interferes with normal activity 
3 
That prevents normal activity 
Sore throat 
0 
None 
1 
Mild: Sore throat that is easily tolerated 
2 
Moderate: Sore throat that interferes with normal activity 
3 
Severe: Sore throat that prevents normal activity 
Swelling (record 
greatest surface 
diameter in mm) 
0 
 20 mm 
1 
> 20 mm -  50 mm 
2 
> 50 mm -  100 mm 
3 
> 100 mm 
Wheeze 
0 
None 
1 
Mild: Wheeze that is easily tolerated 
2 
Moderate: Wheeze that interferes with normal activity 
3 
Severe: Wheeze that prevents normal activity 
*Fever is defined as temperature  38.0°C or 100.4°F. The preferred location for measuring temperature in this 
study will be the oral cavity. 
8.3.2 
Severity of unsolicited AEs, including SAEs, MAEs, pIMDs, and ILIs 
The subject will record his/her assessment of unsolicited AEs on diary cards through the end of 
the study. The investigator will review all such recorded unsolicited AEs with the subject and 
ensure that the maximum intensity that occurred over the duration of the event is recorded. For 
other unsolicited AEs not captured on the diary card (including SAEs, MAEs, pIMDs, and ILIs), 
the investigator will make his/her assessment of maximum severity based on the investigator's 
clinical judgment after reviewing signs and symptoms of the event and how the event affected the 
subject. 
The intensity should be assigned to one of the following categories: 
Grade 1 
(Mild) An AE that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
Grade 2 
(Moderate) An AE that is sufficiently discomforting to interfere with normal everyday 
activities. 
Grade 3 
(Severe) An AE that prevents normal, everyday activities. In adults, such an AE would, 
for example, prevent attendance at work/school and would necessitate the 
administration of corrective therapy. 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 3 is a 
category used for rating the intensity of an event; and both AEs and SAEs can be assessed as 
Grade 3. Any AE that places the subject, in the view of the investigator, at moderately high risk of 
death from the reaction as it occurred should be considered as life-threatening and reported as 

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an SAE (The investigator should not grade a reaction as potentially life-threatening that, had it 
occurred in a more severe form, might have caused death). 
8.4 
Causality of adverse event  
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each AE/SAE using clinical judgment. In case of concomitant administration of 
multiple vaccines/products (e.g., study IIV + AS03A), if possible, the investigator should specify if 
the AE could be causally related to a specific vaccine/product administered (i.e., investigational, 
control/placebo, or co-administered vaccine). When causal relationship to a specific 
vaccine(s)/product(s) cannot be determined, the investigator should indicate the AE to be related 
to all products. 
Alternative plausible causes, such as natural history of any underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study vaccines will be 
considered and investigated. The investigator will also consult the Investigator Brochure(s) and/or 
Summary of Product Characteristics to determine his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to the Sponsor. However, it is very important that the investigator 
always makes an assessment of causality for every event prior to submission of an expedited 
report form to the Sponsor. The investigator may change his/her opinion of causality in light of 
follow-up information and update the SAE information accordingly. The causality assessment is 
one of the criteria used when determining regulatory reporting requirements. 
During the 7-day follow-up period post each dose, all solicited local reactions will be considered 
causally related to vaccination. Also, relatedness will also not be assessed for any solicited 
general (systemic) reactions occurring during this period. Causality of unsolicited AEs occurring 
at any time should be assessed by the investigator using the following question: “Is there a 
reasonable possibility that the AE may have been caused by the study vaccine/product?” 
YES:  There is a reasonable possibility that the study vaccine(s)/product(s) contributed to the 
AE. "Reasonable possibility” means that there is evidence to suggest a causal relationship 
between the study product and the AE. (RELATED) 
NO:  
There is not a reasonable possibility that the AE is causally related to the administration 
of the study vaccine(s)/product(s). There are other, more likely causes and administration 
of the study vaccine(s)/product(s) is not suspected to have contributed to the AE. (NOT 
RELATED) 
If an event meets the criteria to be determined as ‘serious’ (i.e., SAE), additional 
examinations/tests should be performed by the investigator in order to determine ALL possible 
contributing factors for the SAE. Possible contributing factors include: 
 
Medical history. 
 
Other medication. 

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 
Protocol required procedure. 
 
Other procedure not required by the protocol. 
 
Lack of efficacy of the vaccine, if applicable. 
 
Erroneous administration. 
 
Other cause (specify). 
8.5 
Outcome assessment 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during 
the study as: 
 
Recovered/resolved without sequelae. 
 
Recovered/resolved with sequelae. 
 
Recovering/resolving. 
 
Not recovered/Not resolved. 
 
Fatal (SAEs only). 
8.6 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
8.6.1 
Follow-up of adverse events and serious adverse events 
8.6.1.1 Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each subject and 
provide additional relevant information on the subject’s condition to the Sponsor (within 24 hours 
for SAEs). 
All MAEs, SAEs, and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at subsequent 
visits/contacts until the last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until 28 days after the last 
vaccination. 

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8.6.1.2 Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
 
With MAEs, SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilized, disappeared, or until the 
event is otherwise explained, or the subject is lost to follow- up. 
 
With other non-serious AEs, until the event is otherwise explained or they are lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, he/she 
will provide this information to the Sponsor using a paper/electronic SAE and/or pregnancy report, 
as applicable. 
The Sponsor may request that the investigator performs or arranges the conduct of additional 
clinical examinations/tests and/or evaluations to elucidate as fully as possible the nature and/or 
causality of the AE or SAE. The investigator is obliged to assist. If a subject dies during 
participation in the study or during a recognized follow-up period, the Sponsor will be provided 
with any available post-mortem findings, including histopathology. 
8.6.2 
Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end of the 
pregnancy, whether full-term or premature, information on the status of the mother and child will 
be forwarded to the Sponsor using the electronic pregnancy report and the SAE Report, if 
applicable. Generally, the follow-up period does not need to be longer than six to eight weeks 
after the estimated date of delivery. Regardless of the reporting period for SAEs for this study, if 
the pregnancy outcome is an SAE, it should always be reported as an SAE. 
 
After consent is obtained from the pregnant female partner of a male subject, the pregnancy 
must be reported and outcome followed-up in the same manner as for female subjects.  
8.7 
General guidance on recording adverse event  
To improve the quality and precision of acquired AE data, the investigator should observe the 
following guidelines: 
 
Whenever possible, use recognized medical terms when recording AEs on the AE CRF. Do 
not use colloquialisms and/or abbreviations. 
 
If known, record the diagnosis (i.e., disease or syndrome) rather than component signs, 
symptoms and laboratory values (e.g., record congestive heart failure rather than dyspnea, 
rales, and cyanosis). However, signs and symptoms that are considered unrelated to an 
encountered syndrome or disease should be recorded as individual AEs (e.g., if congestive 
heart failure and severe headache are observed at the same time, each event should be 
recorded as an individual AE). 

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 
AEs occurring secondary to other events (e.g., sequelae) should be identified by the primary 
cause. A “primary” AE, if clearly identifiable, generally represents the most accurate clinical 
term to record. If a primary SAE is recorded, events occurring secondary to the primary event 
should be described in the narrative description of the case. (For example: Orthostatic 
hypotensionFainting and fall to floorHead traumaNeck pain. The primary AE is 
orthostatic hypotension.) 
 
Death is an outcome of an event. The event that resulted in the death should be recorded and 
reported on the SAE CRF. 
 
For hospitalizations for surgical or diagnostic procedures, the illness leading to the surgical or 
diagnostic procedure should be recorded as the SAE, not the procedure itself. The procedure 
should be captured in the case narrative as part of the action taken in response to the illness. 
 
Pregnancies that occur in study subjects are not considered AEs and will be recorded on a 
separate Pregnancy CRF. Pregnancy outcomes that include stillbirth and any congenital 
anomalies must be reported as SAEs. 
8.8 
Reporting of SAE 
8.8.1 
Investigator reporting to sponsor 
PATH has designated Emmes Corporation as the Study Coordinating Center with authority to 
coordinate SAE/pIMD and pregnancy reporting activities. An appropriate expedited reporting 
form must be completed and submitted within 24 hours of an investigator’s awareness of 
an SAE or pIMD, as defined in the protocol. The site investigator is required to notify the PATH 
Medical Officer and the Emmes Medical Monitor within 24 hours of knowledge of a pregnancy. A 
pregnancy report form must be submitted within 2 weeks of an investigator's awareness 
of a pregnancy. Details of the process will be specified in a study-specific Safety Monitoring Plan 
document. 
The investigator must not wait to collect additional information to fully document the event before 
submitting the appropriate expedited reporting form (e.g., SAE Form). When additional 
information becomes available, follow-up submission(s) must be completed. The initial expedited 
reporting form should be completed with all information known at the time and should include as 
much as possible the following: 
 
Name and contact of the investigator submitting the expedited reporting form  
 
Subject ID number  
 
Date subject received study vaccine/s, including inpatient/outpatient cohort group 
 
Description of the SAE or pIMD and date of event onset 
 
Investigator’s assessment of severity, causality, and expectedness  

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 
Action taken and current status 
 
If available, any diagnostic test reports or hospital records that may help the sponsor to 
evaluate the SAE or pIMD  
The investigator will be responsible for notifying his/her institution's IRB. The Sponsor will notify 
the other site investigator, who will be responsible for notifying his/her IRB, as applicable. The 
Sponsor will also be responsible for notifying regulatory authorities, as required, and for notifying 
GSK Biologicals if the event occurs post-administration of any GSK-provided study vaccines. 
8.8.2 
Notification and review of SAEs 
The Sponsor is responsible for evaluating SAEs/pIMDs submitted by the investigator within 24 
hours to convene a safety review if the investigator reported the SAE as fatal or life-threatening 
and suspected to be related to study vaccine. Medical Officers from PATH serving as technical 
consultants will provide technical guidance regarding SAE management including classification 
and reporting. 
The Study Coordinating Center is responsible for notifying the Sponsor and also convening a 
safety review within 24 hours by the IDMC if the investigator reported the SAE as fatal or life-
threatening and suspected to be related to study vaccine. The designated medical monitor will 
review all unanticipated events involving risk to subjects or others, SAEs and all subject deaths 
associated with the protocol and will provide a written report. At a minimum, the designated 
medical monitor must comment on the outcomes of the event or problem and, in case of an SAE 
or death, comment on the relationship to participation in the study. The designated medical 
monitor must also indicate whether he/she concurs with the details of the report provided by the 
site PI. 
8.8.3 
Sponsor reporting to regulatory agency 
The Sponsor has authorized the Study Coordinating Center to execute its responsibility for safety 
reporting to the FDA within the following time periods: 
 
Suspected unexpected serious adverse reaction within 15 days of Sponsor’s awareness. 
 
Fatal or life-threatening suspected adverse reaction within 7 days of Sponsor’s awareness. 
8.9 
Other events requiring expedited reporting 
All unanticipated problems will be reported in the continuing review report submitted to the IRBs 
and regulatory authorities per reporting requirements of each regulatory body. All serious 
unanticipated problems involving risk to subjects or others will be promptly reported (within 48 
hours) by telephone, by email, or by facsimile to the Coordinating Center. Follow-up reports will 
be submitted as soon as additional information becomes available. 

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9 SAFETY MONITORING 
The site PIs and/or designated site clinical staff will be responsible for continuous safety 
monitoring of all study subjects and for alerting the Sponsor if unexpected concerns arise or study 
pause/hold criteria are met. 
9.1 
Routine reviews by protocol safety review team  
The PSRT, comprised of the site Principal Investigators, the PATH Medical Officer, and the 
Emmes medical monitor, will routinely monitor safety throughout the duration of the trial. The 
PSRT will be chaired by the PATH Medical Officer and may seek additional independent expert 
medical opinion as dictated by needs. An Emmes statistician with assistance of Emmes Data 
Management staff will prepare blinded safety reports for review by the PSRT. These reports will 
provide at a minimum the following information:  
 
Accrual data and subject status data with regard to completion of/discontinuation from the 
study, sorted by site.   
 
Summaries of solicited adverse events, classified by severity. 
 
Unsolicited AEs (including SAEs/pIMDs) sorted by MedDRA term, severity and relatedness 
to study vaccine.  
 
Safety laboratory test results outside of normal institution reference ranges, classified by 
severity grading scale (irrespective of whether assessed as AEs). 
 
Any new or updated AEs that have occurred in the interval from the previous report.    
All SAEs/pIMDs will be provided to the PSRT, with history and subsequent follow-up information 
as pertains to the SAE/pIMD, within the first 24 hours following site awareness and notification of 
the SAE/pIMD. 
The PSRT safety review will be conducted by teleconference approximately one month post 
completion of dosing with each dose and at approximately 6 and 12 months after completion of 
dosing with the second dose. In addition to safety review, the PSRT may elect to discuss trial 
conduct issues that impact study integrity and subject safety. These may include but not limited 
to data quality, critical monitoring findings, study product, research specimens, etc. The Study 
Coordinating Center will also notify the PSRT of ad hoc safety reviews whenever it is aware of a 
suspected unexpected serious adverse reaction or adverse events that meet pre-specified study 
pause criteria as per section 9.3 
9.2 
Independent data monitoring committee 
An Independent Data Monitoring Committee will be established by PATH for the purpose of 
monitoring the study and to provide independent, non-binding advice on safety and ethics. The 
IDMC will be comprised of independent medical experts in vaccinology and infectious diseases 

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who will periodically review the conduct and safety of study. The IDMC will be supported by an 
unblinded secretary and an unblinded biostatistician, both from Emmes. The responsibilities and 
procedures of the IDMC are defined in the IDMC Charter. During the whole study period, there 
will be IDMC reviews at pre-defined time points (The frequency of these reviews may be adapted 
upon IDMC recommendation if deemed necessary). At least three pre-defined meeting time points 
will be as follows: 
 
The IDMC will review safety data through Visit 10 (28 days post-Dose 1) for all subjects prior 
to any subject receiving Dose 2 of study vaccine. 
 
The IDMC will review safety data through Visit 13 (28 days post-Dose 2) for all subjects.  
 
The IDMC will review safety data through Visit 15 (12 months post-Dose 2) for all subjects.  
 
The IDMC may also be convened to review events meeting pause rules if deemed necessary 
by the PSRT. In such cases, the IDMC and PSRT may convene by teleconference to jointly 
review the data. 
The IDMC reviews will be summarized with recommendations to the study Sponsor as to whether 
there are safety concerns and whether the study should continue without change, be modified, or 
be terminated. If at any time, a decision is made to permanently discontinue administration of 
study vaccinations in all subjects, the Sponsor will notify the FDA and the site PIs will notify the 
responsible IRBs expeditiously. 
9.3 
Study pause rules 
Study pause rules based on safety data are defined in Table 22. If a pause rule 1a through 1d is 
observed by the investigator, it will be reported promptly to the Study Coordinating Center within 
24 hours. In order to assess pause rules 2a through 2c, these pause rules have been written 
under the assumption that the safety data of all subjects will be available. Therefore, the 
investigator will be requested to record safety data in the eCRF within 72 hours after reception of 
the data to ensure that all necessary information is available for timely PSRT and IDMC reviews. 
If the data from all subjects are not available, the pause rules will be assessed on a pro-rata basis. 
The pause rules will automatically pause or halt further vaccinations. However, subjects already 
enrolled will continue to be followed for safety during the hold. These pause rules pertain to 
suspected adverse reactions and will be triggered automatically if any of the events are met during 
the conduct of the study at the parameters specified. 
 

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Table 22 
Study pause rules 
Pause rules 
Event 
Number of 
subjects 
1a 
Death or any life-threatening SAE 
 1 
1b 
Any SAE that cannot reasonably be attributed to a cause other than vaccination 
 1 
1c 
Any withdrawal from the study or withdrawal from study vaccine(s)/product(s) (by 
investigator or subject request) following a grade 3 AE that cannot reasonably be 
attributed to a cause other than vaccination 
 1 
1d 
Any local or general solicited AE leading to hospitalization, or fever > 40°C or 
104°F (oral route) that cannot reasonably be attributed to a cause other than 
vaccination, or necrosis at the injection site, within the 7-day (Days 1-7) post-
vaccination period 
 1 
2a 
Any grade 3 solicited local AE lasting 48h or more in an investigational group, 
within the 7-day (Days 1-7) post-vaccination period 
 15% (and  2 
subjects in one 
group) 
2b 
Any grade 3 solicited general AE lasting 48h or more in an investigational group, 
that cannot reasonably be attributed to a cause other than vaccination, within the 7-
day (Days 1-7) post-vaccination period 
 20% (and  2 
subjects in one 
group) 
2c 
Any grade 3 unsolicited AE in an investigational group, that cannot reasonably be 
attributed to a cause other than vaccination, within the 7-day (Days 1-7) post-
vaccination period 
OR 
Any grade 3 abnormality in the same pre-specified hematological or biochemical 
laboratory parameters* in an investigational group, that cannot reasonably be 
attributed to a cause other than vaccination, within the 7 days post-vaccination 
 20% (and  2 
subjects in one 
group) 
*Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer to Appendix 2). 
9.4 
Study hold procedure 
Once a pause rule criterion has been met, vaccinations at both sites must be put on hold as a 
consequence. The Study Coordinating Center will ensure immediate notification to both sites and 
the PSRT and IDMC, which will convene ad hoc reviews. The investigators are not permitted to 
continue enrollment or administering any dose of study vaccines to enrolled subjects until receipt 
of approval to continue dosing is received by the PSRT and IDMC. 
If a study pause is initiated, randomized subjects will continue with their scheduled follow-up visits, 
but not vaccination visits. In that case, the visit will be on hold during the pause; when the study 
is resumed, the subject will still be considered to be within their vaccination window, and all future 
visits adjusted based on the date of resumed vaccination. Such a pause in the study would not 
constitute a protocol deviation in regards to subject visit windows, and the pause would be taken 
into consideration for restarting the assigned vaccination visit schedule.  
The PSRT and IDMC will expeditiously (within 48 hours) convene to review all available, relevant 
information. The PSRT and IDMC reviews will be summarized with consensus recommendations 
to the study Sponsor as to whether there are safety concerns and whether the study should 

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continue without change, be modified, or be stopped. To be clear, the IDMC must approve lifting 
the hold in order for enrollment and study vaccination to continue. 
If at any time, a decision is made to discontinue administration of study product in all subjects, 
expeditious notification will be provided by the Sponsor to the FDA and by the site PIs to their 
IRBs within 48 hours. 
10 DATA HANDLING AND RECORDKEEPING 
The Principal Investigator is responsible for assuring that the data collected is complete, legible, 
attributable, accurate, and recorded in a timely manner. Data collection is the responsibility of the 
clinical trial staff at the site under the supervision of the site PI. All source documents and 
laboratory reports must be reviewed by the clinical team and data entry staff, who will ensure that 
they are accurate and complete 
Emmes has been designated by PATH for data management activities, including quality review, 
analysis, and reporting. The study will utilize Advantage eClinical, an EDC system uniquely suited 
for clinical research. Site staff will use the EDC tool to securely enter data into eCRFs from source 
documents, or from medical or clinical records, directly into the database. 
10.1 
Source documents and access to source data/documents 
Prior to the start of the trial it will be determined which documents completed by the investigative 
team will be considered source documents. Only authorized study staff and representatives of 
the Sponsor and authorized regulatory agencies may have direct access to source documents 
containing study data. Data for this study will include biographical, medical history, clinical (signs, 
symptoms, prescription and non-prescription medical treatments, and non-study vaccinations), 
safety data, and immunologic laboratory data. All information in original records and certified 
copies of original records, clinical findings, or observations will be considered source data for this 
study.  
Documents and data pertaining to the study will be kept in a locked cabinet under the 
responsibility of the investigator. PATH and/or Emmes will conduct periodic monitoring visits to 
ensure that the data is safe and stored in this secure place and that only those authorized study 
staff have access to the data. 
10.2 
Data capture methods (case report form development and 
completion) 
The clinical data in CRFs or other source documents (such as clinical laboratory results) will be 
entered directly into a 21 CFR Part 11-compliant electronic data capture system (Advantage 
eClinical) provided by The Emmes Corporation by trained and qualified study staff. The eCRF for 
the EDC system will be developed by Emmes with input from study staff and approval of PATH. 
The data system includes password protection and internal quality checks, such as automatic 

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range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data 
for each subject will be entered directly into the eCRF from the CRFs or source documents. 
It is the site PIs’ responsibility to ensure the accuracy, completeness, and timeliness of the data 
reported in the subject’s eCRF and any supporting documentation. All CRF source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data. All source 
documentation supporting the eCRF data should document the dates and details of study 
procedures, AEs, and subject status. The site PIs/institutions will maintain the information 
collected from CRFs and in the eCRFs and all source documents that support the data collected 
from each subject in a secure area and treated as confidential material. 
10.3 
Data management 
Emmes will develop the data management plan describing the tools and processes for the 
generation of the clinical database and data management activities from project set-up through 
data lock and transfer. The project set-up period will include a planning phase for the design of 
the system environment and the development of a detailed structure for logistical operations. 
Instructions for database management tasks will include data processing, data coding, query 
generation and tracking, and any other tasks that are unique to project requirements. The plan 
for managing electronic laboratory generated data will include instructions for data import, and 
upload directly into the Advantage eClinical system. The system and programmatic requirements 
for the transfer of data sets and associated data components will be identified in the plan. Emmes’ 
data management SOPs will be referenced to ensure that the data management plan for the study 
addresses the risk management aspects for all processes and accommodates for shifts in 
workload activity. 
Emmes will generate reports through Advantage eClinical for missing forms and missing values, 
and quality control checks between the clinical and laboratory results. Anomalies will be 
communicated to the designated site personnel and documented at the site using procedures 
compliant with International Conference on Harmonisation Good Clinical Practices (ICH-GCP), 
and the site will update the data system if any of these anomalies require modifications to the 
records.  
10.4 
Retention of study record 
Clinical trial data will be stored securely for a period of 2 years following the date that a marketing 
application is approved or not approved or until 2 years after the study is closed and the national 
regulatory authority is notified. PATH will be responsible for providing the site with date of approval 
or IND/regulatory withdrawal. 
No records will be destroyed without the written consent of PATH. Storage of all trial-related 
documents will be such that confidentiality will be strictly maintained to the extent provided by 
local law. 

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11 STATISTICAL CONSIDERATIONS 
11.1 
Overview and general design  
This is a prospective, multi-center, randomized, controlled, observer-blind, Phase 1 trial in healthy 
male and female adults 18 through 39 years of age. Up to 65 eligible subjects will participate and 
will be randomized to one of five groups to receive a first dose of study cH8/1N1 LAIV (or placebo) 
or study cH8/1N1 IIV + AS03A adjuvant (or placebo) followed three months later by study cH5/1N1 
IIV +/- AS03A adjuvant (or placebo). Eligible enrolled subjects will be randomized to any of the 
treatment arms (LAIV-IIV, Groups 1, 2, and 3 or IIV-IIV, Groups 4 and 5) under one allocation 
sequence to allow comparability between study groups, particularly LAIV-IIV vs IIV-IIV regimens 
(Groups 1 vs 4). While subjects will be blinded to their exact treatment group and whether they 
received active study vaccine versus placebo, subjects will certainly know if they received LAIV 
(or placebo) vs IIV (or placebo) at Dose 1, given the different presentations and routes of 
administration of these products. The primary objective is to assess the reactogenicity and safety 
after each dose of study vaccine, a key secondary objective is to assess the potential superiority 
of the immune responses elicited by LAIV-IIV prime-boost compared to those by IIV-IIV. 
11.2 
Randomization procedures 
The randomization plan will be developed in coordination with Emmes. Randomization will be 
stratified by site and include a blocking factor. The original allocation ratio for LAIV-LAIV Groups 
1, 2 and 3 was 3:3:1, and the original allocation ratio for IIV-IIV Groups 4-5 was 3:2. To preserve 
comparability of subjects across treatment groups, subjects will be randomized to all groups under 
one allocation sequence. Among LAIV-LAIV subjects, Group 1 is our primary interest, especially 
for comparison to Group 4. To guard against loss of power from possible drop-out between 
randomization and admission into the inpatient clinical isolation unit, Group 1 will be over-
randomized by five subjects, for a final randomization scheme of 4:3:1:3:2. A secure IWRS will 
be utilized for eligibility verification, subject registration, randomization, and treatment 
assignment. IWRS allows authorized staff from study centers to perform subject enrollment 24 
hours a day, 7 days a week. The system guides users through the process of specifying the 
subject identifier, completing demographic information, and finally, completing the protocol-
specific inclusion-exclusion checklist, which confirms a subject's eligibility, which is generally 
predetermined at the site from screening information. 

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11.3 
Primary endpoints 
11.3.1 Reactogenicity and safety 
 
Occurrence of solicited local and general AEs post-vaccination: 
 
Occurrence of solicited local AEs during a 7-day follow-up period (i.e., on the day of 
vaccination and 6 subsequent days) after the first and the second dose in each study 
group. 
 
Occurrence of solicited general AEs during a 7-day follow-up period (i.e., on the day of 
vaccination and 6 subsequent days) after the first and the second dose in each study 
group. 
 
Occurrence of unsolicited AEs post-vaccination: 
 
Occurrence of unsolicited AEs during a 28-day follow-up period (i.e., on the day of 
vaccination and 27 subsequent days) after the first and the second dose in each study 
group. 
 
Occurrence of hematological and biochemical laboratory abnormalities post-vaccination: 
 
Any hematological (red blood cell, white blood cell, and differential count, platelets count 
and hemoglobin level) or biochemical (ALT, AST, creatinine, BUN and BUN-to-creatinine 
ratio) laboratory abnormality on Visits 9, 10, 11, 12, and 13 in each study group. 
 
Occurrence of MAEs, LC-ILIs, pIMDs, and SAEs up to Visit 13: 
 
Occurrence of MAEs, LC-ILIs, pIMDs, and SAEs up to Visit 13 in each study group. 
(Because Groups 1 and 2 will receive the same study LAIV at Dose 1, data for the period post-
Dose 1 will be pooled for these groups.) 
11.4 
Secondary endpoints 
11.4.1 Reactogenicity and safety 
 
Occurrence of hematological and biochemical laboratory abnormalities: 
 
Any hematological (red blood cell, white blood cell, and differential count, platelets count 
and hemoglobin level) or biochemical (ALT, AST, creatinine, BUN and BUN-to-creatinine 
ratio) laboratory abnormality at Visits 14 and 15 in each study group. 
 
Occurrence of MAEs, LC-ILIs, pIMDs and SAEs up to study end at Visit 16: 
 
Occurrence of MAEs, LC-ILIs, pIMDs and SAEs up to Visit 16 in each study group. 

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 
Shedding of vaccine virus through 5 days post-vaccination (Groups 1, 2 & 3 only): 
 
Percentages of subjects with vaccine virus detectable by RT-PCR each day and overall 
(at any time). 
 
Percentages of subjects with recovery of viable vaccine virus in MDCK culture each day 
and overall (at any time). 
11.4.2 Immunogenicity - descriptive, post-Dose 2 
 
Humoral and mucosal immunity in terms of anti-H1 stalk immune response measured by 
ELISA, neutralizing antibodies by MN assay, and activity by ADCC assay at Visit 13 (28 days 
post-boost): 
 
Levels of anti-H1 stalk antibody titers by ELISA, by MN, and by ADCC. 
 
The following aggregate variables will be calculated for the above parameters with 95% 
confidence interval (CI): 
 
Seropositivity rates and GMTs at Day 1 and Visit 13. 
 
Percentage of subjects with a  4-fold increase from Day 1 to Visit 13. 
 
Percentage of subjects with a  10-fold increase from Day 1 to Visit 13. 
 
MGI from Day 1 to Visit 13. 
 
(Post-dose one descriptive immunogenicity will be similarly analyzed at Visit 10 . Because 
Groups 1 and 2 will receive the same study LAIV at Dose 1, data for the period post-
Dose 1 will be pooled for these groups.) 
11.4.3 Immunogenicity - descriptive, post-Dose 2 - breadth 
 
Breadth of the humoral immune response as measured by levels of anti-H2, anti-H9 and anti-
H18 antibody titers by ELISA. The following aggregate variables will be calculated for the 
above parameters with 95% CI: 
 
Anti-H2, anti-H9, and anti-H18 seropositivity rates and GMTs at Day 1 and Visit 13. 
 
Percentage of subjects with a  4-fold increase in anti-H2, anti-H9 and anti-H18 antibody 
titers from Day 1 to Visit 13. 
 
Percentage of subjects with a  10-fold increase in anti-H2, anti-H9 and anti-H18 antibody 
titers from Day 1 to Visit 13. 
 
MGI in anti-H2, anti-H9 and anti-H18 antibody titers from Day 1 to Visit 13. 

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 
Levels of antibody titers by MN for H5N8; H1N1 avian-swine influenza, and current 
H1N1pdm09-like vaccine strains. The following aggregate variables will be calculated for the 
above parameters with 95% CI: 
 
Seropositivity rates and GMTs for H5N8, H1N1 avian-swine, and H1pdm09-like 
neutralizing antibody at Day 1 and Visit 13. 
 
Percentage of subjects with a  4-fold increase in H5N8, H1N1 avian-swine, and 
H1pdm09-like neutralizing antibody titers from Day 1 to Visit 13. 
 
Percentage of subjects with a  10-fold increase in H5N8, H1N1 avian-swine, and 
H1pdm09-like neutralizing antibody titers from Day 1 to Visit 13. 
 
MGI in H5N8, H1N1 avian-swine, and H1pdm09-like neutralizing antibody titers from 
Day 1 to Visit 13. 
 
(Post-Dose 1 descriptive immunogenicity for breadth will be similarly analyzed at Visit 10 
and additional post-Dose 2 descriptive immunogenicity for breadth may be analyzed at 
Visit 15.) 
11.4.4 Immunogenicity - descriptive, post-Dose 2 - persistence 
 
Persistence of the both humoral and mucosal immune responses as measured by levels of 
anti-H1 stalk antibody titers by ELISA, by MN, and by ADCC. The following aggregate 
variables will be calculated for the above parameters with 95% CI: 
 
Seropositivity rates and GMTs at Visits 14* and 15. 
 
Percentage of subjects with a  4-fold increase from Day 1 to Visits 14* and 15.  
 
Percentage of subjects with a  10-fold increase from Day 1 to Visits 14* and 15. 
 
MGI from Day 1 to Visits 14* and 15. 
*Only for anti-H1 HA-stalk IgG detection by ELISA in serum 
11.4.5 Immunogenicity - comparative, post-Dose 2 
 
Humoral and mucosal immunity in terms of anti-H1 stalk immune response as measured by 
ELISA, neutralizing antibodies by MN assay, and activity by ADCC assay 28 days post-boost 
with LAIV-IIV prime-boost compared to two doses of IIV: 
 
Adjusted GMT ratio of the LAIV / IIV + AS03A group (Group 1) versus the IIV + AS03A / IIV 
+ AS03A group (Group 4), 28 days post-vaccination (i.e., at Visit 13 to evaluate the  
LAIV-IIV prime-boost effect). 

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 
Seroresponse (≥4-fold) rate difference of the LAIV / IIV + AS03A group (Group 1) versus 
the IIV + AS03A / IIV + AS03A group (Group 4), 28 days post-vaccination (i.e., at Visit 13 
to evaluate the LAIV-IIV prime-boost effect). 
 
Adjusted GMT ratio of the LAIV / IIV group (Group 2) versus the IIV + AS03A / IIV + AS03A 
group (Group 4), 28 days post-vaccination (i.e., at Visit 13 to evaluate the LAIV-IIV prime-
boost effect). 
 
Seroresponse (≥4-fold) rate difference of the LAIV / IIV group (Group 2) versus the IIV + 
AS03A / IIV + AS03A group (Group 4), 28 days post-vaccination (i.e., at Visit 13 to evaluate 
the LAIV-IIV prime-boost effect). 
 
LAIV-IIV groups might be pooled in an exploratory analysis if the adjuvant effect appears 
minimal. Adjuvant effect on the anti-stalk immune response in term of: 
 
GMT ratio of the LAIV- IIV + AS03A group (Group 1) versus the LAIV-IIV unadjuvanted 
group (Group 2), 28 days post-boost (i.e., at Visit 13 to evaluate the adjuvant effect 
post-boost). 
11.5 
Tertiary endpoints 
 
Evaluation of CMI parameters in terms of frequencies of: 
 
Antigen-specific IFN- secreting cells upon in vitro stimulation at Day 1 and Visits 9, 11, 
12, and 15. 
 
B-memory cells reactive with the H1 stalk domain and a wild-type H1N1pdm09 virus at 
Day 1 and Visits 10, 11, 13, and 15. 
 
Plasmablasts reactive with the H1 stalk domain and a wild-type H1N1pdm09 virus at 
Visits 9 and 12. 
 
Levels of HI antibody to chimeric vaccine strains. The following aggregate variable will be 
calculated with 95% CI: 
 
Seropositivity rates and GMTs at Day 1 and Visits 10, 11, 13, and 15. 
 
Seroprotection rate at each time point listed above. 
 
Seroconversion rate at Day 1 and Visits 10, 11, 13, and 15. 
 
MGI from Day 1 to each subsequent time point listed above. 
 
Evaluation of the anti-H3 stalk response by ELISA pre-and post-vaccination. Levels of anti-N1 
NA antibody by ELISA at Day 1 and Visits 10, 11, 13, and 15. 

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 
Assessment of the in vivo protective effect of the anti-stalk antibodies when transferring Day 1, 
Visit 13 and Visit 15 pooled serum from a subset of subjects of each vaccine groups to mice 
subsequently challenged with cH6/1N5, or with current H1N1pdm09-like virus recommended 
by the World Health Organization, using the following endpoints: 
 
Survival over 14 days post-challenge (day of death/euthanasia for weight loss > 25% 
baseline body weight) in groups of mice/serum pool/per vaccine group/time point. 
 
Mean weight loss (change from baseline over 14 days post-challenge) in groups of 
mice/serum pool/vaccine group/time point. 
 
Lung virus titer in plaque-forming units (pfu)/g (log10 fold change [Day 1 minus Visit 13]), 
within challenge group. 
11.6 
Sample size  
In this study in which subjects must consent to participate as either inpatient subjects or outpatient 
subjects for Dose 1 prior to randomization and finding out to which regimen they will be assigned 
(LAIV-IIV vs IIV-IIV), we assume drop-out is possible between randomization and receipt of 
Dose 1, especially for subjects randomized to the major commitment of staying in the inpatient 
clinic. While such drop-out could occur equally in any of the three LAIV-IIV (or placebo) treatment 
arms, since Group 1 is our primary interest and for cost control, we over-randomized that group 
by 5 subjects. Admittedly, loss from Group 2 could lower the power in that group as well. We hope 
that drop-outs will be minimal in both groups. We also assume drop-out is possible between 
Dose 1 and primary immunogenicity sampling at Visit 13. The following Table 22 summarizes our 
assumptions, which are applied in the subsequent sample size and power tables. 
Table 23  Assumed losses of evaluable subjects from randomization until immunogenicity 
analyses at Visit 13 
Study 
Arm 
Planned 
sample 
size per 
Group 
Number of 
subjects assumed 
lost between 
randomization and 
receipt of Dose 1 
Evaluable 
subjects for 
safety analyses 
post- 
Dose 1 
Number of subjects 
assumed lost between 
Dose 1 and primary 
immunogenicity 
readouts at Visit 13 
Evaluable subjects 
for primary 
immunogenicity 
analyses at Visit 13 
Group 1 
20 
3 
17 
1 
16 
Group 2 
15 
2 
13 
1 
12 
Group 3 
5 
1 
4 
1 
3 
Group 4 
15 
0 
15 
1 
14 
Group 5 
10 
0 
10 
1 
9 
 

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11.6.1 Descriptive objectives 
11.6.1.1 
Safety 
The primary objectives of the study are to assess the safety of the investigational LAIV and IIVs 
28 days after each dose. Because Groups 1 and 2 will receive the same study LAIV at Dose 1, 
data for the period post-Dose 1 will be pooled for these groups. 
Table 24 shows the true proportions associated with a 90% probability to observe an event in 30 
LAIV recipients (e.g., SAE, pIMD) post-Dose 1. 
Table 24 
True proportions associated with a 90% probability to observe a certain 
number of adverse events pooled LAIV groups (30 subjects) 
True 
proportion 
Number of adverse events observed 
with > 90% probability 
0.074 
> 0 
0.124 
> 1 
0.168 
> 2 
0.209 
> 3 
Table 25 shows the true proportions associated with a 90% probability to observe an event in 15 
IIV recipients (e.g., SAE, pIMD) post-Dose 1. 
Table 25 
True proportions associated with a 90% probability to observe a certain 
number of adverse events within an IIV group (15 subjects) 
True 
proportion 
Number of adverse events observed 
with > 90% probability 
0.142 
> 0 
0.236 
> 1 
0.317 
> 2 
0.393 
> 3 
Table 26 illustrates the 95% CI for different possible numbers of AEs among all LAIV recipients 
post-Dose 1. 
 
 

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Table 26 
2-sided 95% exact confidence intervals for the true adverse event rate at 
different possible observed adverse event rates (30 subjects) 
Observed number 
of adverse events 
Observed adverse 
event proportion 
95% Exact Confidence Interval 
Lower Limit 
Upper Limit 
0 
0.000 
0.000 
0.116 
1 
0.033 
0.001 
0.172 
2 
0.067 
0.008 
0.221 
3 
0.100 
0.021 
0.265 
4 
0.133 
0.038 
0.307 
5 
0.167 
0.056 
0.347 
10 
0.333 
0.173 
0.528 
15 
0.500 
0.313 
0.687 
20 
0.667 
0.472 
0.827 
Table 27 illustrates the 95% CI for different possible numbers of AEs post-receipt of study IIV 
post-Dose 1. 
Table 27 
2-sided 95% exact confidence intervals for the true adverse event rate at 
different possible observed adverse event rates (15 subjects) 
Observed number 
of adverse events 
Observed adverse 
event proportion 
95% Exact Confidence Interval 
Lower Limit 
Upper Limit 
0 
0.000 
0.000 
0.218 
1 
0.067 
0.002 
0.320 
2 
0.133 
0.017 
0.405 
3 
0.200 
0.043 
0.481 
4 
0.267 
0.078 
0.551 
5 
0.333 
0.118 
0.616 
10 
0.667 
0.384 
0.882 
 
11.6.1.2 
Immunogenicity 
Table 28 presents the 95% CI for different possible rates of immunological response all LAIV 
subjects post-Dose 2. 
Table 28 
2-sided 95% exact confidence intervals for the true immunological response 
rate at different possible observed response rates (28 evaluable subjects) 
Observed number 
of responses 
Observed response 
proportion 
95% Exact Confidence Interval 
Lower Limit 
Upper Limit 
10 
0.357 
0.186 
0.559 
15 
0.536 
0.339 
0.725 
20 
0.714 
0.513 
0.868 
25 
0.893 
0.718 
0.977 

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Table 29 presents the 95% CI for different possible rates of immunological response among 
Group 1 LAIV-IIV subjects post-Dose 2. 
Table 29 
2-sided 95% exact confidence intervals for the true immunological response 
rate at different possible observed response rates (16 evaluable subjects) 
Observed number 
of responses 
Observed response 
proportion 
95% Exact Confidence Interval 
Lower Limit 
Upper Limit 
5 
0.313 
0.110 
0.587 
7 
0.438 
0.198 
0.701 
10 
0.625 
0.354 
0.848 
13 
0.813 
0.544 
0.960 
Table 30 presents the 95% CI for different possible rates of immunological response among IIV-
IIV subjects post-Dose 2. 
Table 30 
2-sided 95% exact confidence intervals for the true immunological response 
rate at different possible observed response rates (14 evaluable subjects) 
Observed number 
of responses 
Observed response 
proportion 
95% Exact Confidence Interval 
Lower Limit 
Upper Limit 
5 
0.357 
0.128 
0.649 
7 
0.500 
0.230 
0.770 
10 
0.714 
0.419 
0.916 
13 
0.929 
0.661 
0.998 
11.7 
Comparative objectives 
Secondary objectives include comparisons of the immunogenicity post-Dose two between LAIV-
IIV and IIV-IIV groups (Group 1 vs Group 4). These comparisons are purely descriptive with the 
aim to characterize the differences in immunogenicity between groups. For example, the ratio of 
GMTs in the LAIV-IIV and IIV-IIV groups will be compared. Table 31 illustrates the power to detect 
various fold increase in GMT ratios between treatment groups. 
Table 31 
Power to detect fold increases in GMT ratios for different values of alpha (type 
I error) assuming a standard deviation of 0.4* in the log10 titer values in both 
comparison groups (14** evaluable subjects per group) 
One Sided Alpha 
Fold Increase 
2.0 
2.5 
3.0 
3.5 
4.0 
.025 
48% 
72% 
86% 
93% 
97% 
.05 
62% 
82% 
92% 
97% 
99% 
.10 
75% 
90% 
97% 
99% 
100% 
*The assumed standard deviation is unpublished but is based on data from the study: Nachbagauer R, et al. J Virol; 
2014 25 
**For simplicity, we assume equivalent numbers of subjects (n=14) per group, as the power table is purely illustrative. 

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11.8 
Analysis sets 
11.9 
Exposed set 
The Exposed Set (ES) will include all subjects with at least one vaccine administration 
documented: 
 
A safety analysis based on the ES will include all vaccinated subjects. 
 
An immunogenicity analysis based on the ES will include all vaccinated subjects for whom 
immunogenicity results are available. 
The total vaccinated cohort (TVC) analyses will be performed per treatment actually administered. 
11.10 Per-protocol set 
The Per-Protocol set will be adapted by time point to include all eligible subjects’ data up to the 
time of important protocol deviation, namely: 
 
Dose of study vaccine not according to protocol procedures and to their random assignment. 
 
Randomization code broken. 
 
Non-compliance with the procedures and intervals defined in the protocol (refer to Appendix 1). 
 
Intake of concomitant medication/product/vaccination leading to elimination from the Per-
Protocol analysis. 
 
Occurrence of medical condition leading to elimination from the Per-Protocol analysis (refer 
to Section 5.9) 
11.11 Statistical analyses 
All analyses will be based on data pooled from both sites. However, because of the multi-center 
nature of this study with randomization stratified by site, sub-analyses by site will also be 
conducted. 
11.11.1 Analysis of demographics 
Demographic characteristics (age at study vaccination in years, gender, ethnicity, history of 
influenza vaccination since the 2014/2015 season) and withdrawal status will be summarized by 
group in the TVC, using descriptive statistics: 
 
Frequency tables will be generated for categorical variables such as gender. 
 
Mean, median, standard deviation will be provided for continuous data such as age. 

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11.11.2 Analysis of safety 
The analysis will be performed on the ES. 
All analyses will be descriptive. Data will be presented by dose, overall/dose and overall/subject. 
Outputs will be presented by study group. Analyses will be repeated pooling LAIV groups (for 
post-Dose 1 events collected prior to Visit 11). 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at least one 
general AE (solicited and unsolicited) and with any AE during the solicited follow-up period will be 
tabulated with exact 95% CI. The same calculations will be performed for AEs rated as grade 3. 
The percentage of subjects reporting each individual solicited local and general AE during the 
solicited follow-up period will be tabulated with exact 95% CI. The same tabulation will be 
performed for grade 3 AEs and for AEs with relationship to vaccination. 
The verbatim reports of unsolicited AEs will be reviewed by a physician and the signs and AEs 
will be coded according to MedDRA. The percentage of subjects with at least one report of 
unsolicited AE classified by MedDRA and reported up to 28 days after vaccination will be 
tabulated with exact 95% CI. The same tabulation will be performed for grade 3 unsolicited AEs 
and for unsolicited AEs with a relationship to vaccination. 
At each hematology/biochemistry sampling time point, by study group, individual hematological 
and biochemical values will be presented as number of subjects out of range (above and below 
normal range) and tabulated by toxicity grading (refer to Appendix 2). In addition, changes from 
baseline (median/interquartile range) will be presented. 
SAEs, LC-ILIs, MAEs, and pIMDs will be described in detail. Withdrawals due to AEs/SAEs will 
also be summarized. 
11.11.3 Analysis of immunogenicity 
The analysis of immunogenicity will be performed primarily on the Per-Protocol set. If 10% or 
more of the vaccinated subjects are eliminated from the Per-Protocol set, a second analysis will 
be performed on the TVC. 
11.11.3.1 
Within group assessment 
11.11.3.1.1 Humoral and mucosal immunogenicity assessment 
For each study group, at each time point at which the tests are done and results are available, for 
each humoral immunity parameter, the following analyses will be performed: 
 
Seropositivity rates and GMTs, with exact 95% CI. 
 
MGI from Day 1, with 95% CI. 

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 
Percentage of subjects with at least 4-fold increase from Day 1, with exact 95% CI. 
 
Percentage of subjects with at least 10-fold increase from Day 1, with exact 95% CI. 
 
Distribution of antibody titers using reverse cumulative distribution curves (RCCs). 
The correlation between anti-H1 stalk ELISA and anti-H1 stalk MN assay results will be explored. 
11.11.3.1.2 CMI assessment 
For each study group, at each time point where a blood sample result is available, the frequency 
of antigen specific IFN- secreting cells, B-memory cells, and plasmablasts will be summarized 
using descriptive statistics. 
11.11.3.2 
Between group assessment 
GMT ratios and their 2-sided 95% CI will be computed after fitting an ANCOVA model on the log10 
transformation of ELISA/MN titers, including vaccine group as fixed effect and the pre-vaccination 
titer as covariate. 
Differences in percentage of subjects with a four-fold increase from baseline and their 95% CIs 
will be calculated. 
The assessment time points will be described in the Statistical Analysis Plan, but generally 
speaking, the results 4 weeks post-booster (or second IIV dose) will be compared. 
The following group ratios/differences will be provided: 
 
Evaluation of the proof of principle: 
 
Dose 1: LAIV and Dose 2: IIV + AS03A versus Dose 1: IIV + AS03A and Dose 2: IIV + AS03A. 
 
Dose 1: LAIV and Dose 2: IIV versus Dose 1: IIV + AS03A and Dose 2: IIV + AS03A. 
 
Pooled Dose 1: LAIV and Dose 2: IIV groups versus Dose 1: IIV + AS03A and Dose 2: IIV + AS03A 
(only if results suggest AS03A did increase immune responses post-boost in the LAIV-IIV groups). 
 
Assessment of the adjuvant system: 
 
Dose 1: LAIV and Dose 2: IIV + AS03A versus Dose 1: LAIV and Dose 2: IIV. 
Additional ratios/differences, such as versus placebo groups, will be considered at the time of 
analysis. 

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11.12 Interpretation of analyses 
For humoral and mucosal immune responses, it is expected that for some assays 100% of 
subjects will already be seropositive at baseline. Thus, while seropositive rates will be calculated 
for each assay at each time point, GMTs, MGIs, and percentages of subjects with fold increases 
from baseline will be most meaningful.  
Generally, emphasis will be placed on the following assays for interpretation of immunologic 
responses in the descending order:  
 
Anti-H1 HA-stalk IgG by ELISA (using cH6/1 antigen) 
 
Serum neutralizing antibodies by microneutralization (using cH6/1N5 virus) 
 
ADCC assay 
 
Anti-H1 HA-stalk secretory IgA by ELISA (using cH6/1 antigen) 
 
Proportion of stalk-specific memory B cells by ELISPOT (stimulated by cH6/1 antigen) 
Comparative analyses will be descriptive with the aim to characterize the difference in 
reactogenicity/immunogenicity between groups. 
11.13 Conduct of analysis 
11.13.1 Sequence of analyses 
Staged analyses will be done. Excluding any IDMC analyses, the analyses will be performed in a 
stepwise manner: 
 
Interim analyses will be performed when safety, reactogenicity, and immunogenicity (including 
at least H1 anti-stalk ELISA) data from all subjects are available up to Visit 13. 
 
A final analysis of all data will be performed when data up to study conclusion are available. 
This analysis will be reported in a Study Report. 
11.13.2 Statistical considerations for interim analyses 
The decision to pursue development will be based on the final assessment of Visit 13 data 
performed at the first analysis. 
No statistical adjustment will be made for the interim analyses, which are intended to provide final 
outputs related to the different endpoints and time points in a phased manner. 
At the time of the interim analysis, PATH will neither have access to the individual treatment 
assignments, nor to the unblinded safety report, but will be provided with aggregated 
immunogenicity results per group in order to allow strategic decisions for the future of the project. 

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12 QUALITY ASSURANCE AND QUALITY CONTROL 
The study will be conducted in accordance with procedures identified in the protocol and staff will 
be guided by procedural activities detailed in SOPs. 
Site monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet ICH-GCP, sponsor standards, and regulatory guidelines, and that the study 
is conducted in accordance with the protocol and sponsor SOPs. 
12.1 
General considerations 
The study will be conducted in full compliance with the protocol and ICH-GCP to provide public 
assurance that the rights, safety, and well-being of trial subjects are protected, and that the clinical 
trial data are credible. To ensure quality and standardization, the site will develop SOPs for key 
protocol procedures and conduct the study guided by the study Manual of Procedures or other 
written guidelines. The site will also develop routine operational checks to verify that critical 
protocol requirements and procedures are executed correctly and completely at the time the work 
is being performed. Prior to the initiation of the study, the Sponsor and Emmes will conduct 
training on the protocol and SOPs for the study staff, including mock runs of study visits/walk-
throughs with study staff. 
12.2 
External monitoring 
To ensure that the study is conducted in accordance with ICH-GCP and regulatory requirements, 
monitoring responsibilities will be provided by Emmes. A site initiation visit will be conducted prior 
to beginning the study, and monitoring will be conducted at initiation, during, and at closeout of 
the study. During the course of the study, monitors will visit the clinical site at intervals to verify 
compliance to the protocol; completeness, accuracy, and consistency of the data and study 
product accountability; and adherence to ICH-GCP and applicable regulations. As needed and 
when appropriate, the monitors will also provide clarifications and additional training to help the 
site resolve issues identified during the monitoring visit. As appropriate and informed by risk 
assessment, remote centralized monitoring activities may be considered in place of or to 
supplement onsite monitoring. These may include analysis of data quality (e.g., missing or 
inconsistent data), identification of data trends not easily detected by onsite monitoring, and 
performance metrics (e.g., screening or withdrawal rates, eligibility violations, timeliness, and 
accuracy of data submission).  
The extent and frequencies of the monitoring visits will be described in a separate monitoring plan 
developed prior to study initiation. The investigator will be notified in advance of scheduled 
monitoring visits. The monitors should have access to all trial related sites, subject medical 
records, study product accountability, and other study-related records needed to conduct 
monitoring activities. Emmes will share the findings of the monitoring visit, including any corrective 
actions, with the site investigator and PATH. The site PI and the monitors must cooperate to 

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ensure that any problems detected in the course of these monitoring visits are resolved in a 
predefined timeframe. 
To ensure the quality of clinical data for all subjects, a clinical data management review will be 
performed on subject data received by Emmes. During this review, subject data will be checked 
for consistency, omissions, and any apparent discrepancies. In addition, the data will be reviewed 
for adherence to the protocol and ICH-GCP. To resolve any questions arising from the clinical 
data management review process, data queries and/or site notifications will be sent to the site for 
resolution as soon as possible and within the time frame described in the monitoring plan; all 
queries must be resolved prior to database lock. 
Essential documents must be filed in the site study file on an ongoing basis and be available for 
review by Emmes.  
12.3 
Independent auditing 
Sponsor representatives may audit the study to ensure that study procedures and data collected 
comply with the protocol and applicable SOPs at the clinical site and that data are correct and 
complete. The site PIs will permit auditors (employees of the Sponsor or employee of a company 
designated by PATH) to verify source data validation of the regularly monitored clinical study. The 
auditors will compare the entries in the eCRFs with the source data and evaluate the study site 
for its adherence to the clinical study protocol and ICH-GCP guidelines and applicable regulatory 
requirements. 
12.4 
Regulatory agency auditing 
The site PIs must be aware that regulatory authorities may wish to inspect the site records to 
verify the validity and integrity of the study data and protection of human research subjects. The 
site PIs will notify PATH within 24 hours following contact by a regulatory authority. The site PIs 
must make the relevant records available for inspection and will be available to respond to 
reasonable requests and audit queries made by authorized representatives of regulatory 
agencies. The site PIs will provide PATH with copies of all correspondence that may affect the 
review of the current study or his qualification as an investigator in clinical studies conducted by 
PATH. PATH will provide any needed assistance in responding to regulatory audits or 
correspondence. 
13 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) 
13.1 
Ethical standards 
This study will be conducted in accordance with the ethical principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, as 
drafted by the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research and in conformity with ICH-GCP, 45 CFR Part 46 and 21 CFR 50.  

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13.2 
Ethical review 
This study will be conducted under the auspices of the following ethics authorities at these 
institutions: CCHMC IRB, ISMMS IRB, Duke University Health System IRB, and PATH. The 
intention will be to identify one site IRB to serve as the central IRB of record.  
The investigators and Sponsor are responsible for obtaining approval from the IRB or record prior 
to enrollment of the first subject. The committee will review and approve the protocol, informed 
consent form, and any recruitment materials (advertising or informational material); including any 
modifications to these documents prior to, or during the study. All changes to the protocol or 
informed consent form must be reviewed and approved prior to implementation, except where 
necessary to eliminate apparent immediate hazard to study subjects. The investigators and 
Sponsor are also responsible for obtaining continuing review throughout the duration of the study 
in accordance with existing regulations.  
13.3 
Recruitment 
Participants will be recruited from the local community. The target population will reflect the 
community at large at each of the participating study sites. Estimated time to complete enrollment 
in this trial is approximately 2 months. Information regarding this trial may be provided to potential 
subjects who have previously participated in vaccine trials conducted at the participating study 
sites. Other forms and/or mechanisms of recruitment may also be used. The local IRB will approve 
all materials prior to use. Careful recruitment and communication about all aspects of the study 
will be critical to ensuring eligible subjects who eventually enroll and participate in the trial are 
committed to participate for the full length of the study. 
13.4 
Informed consent process 
Prior to any study related screening, informed consent will be obtained from each subject. The 
site PI or designee will fully inform the subject about the aims, procedures, potential risks, and 
potential benefits of the study. The subject will be given the written, IRB approved ICF, allowed 
ample time to read the consent form, encouraged to ask questions about the study, have the 
questions answered and then be given time to decide if s/he would like to participate in the study. 
It will be emphasized that participation is voluntary, and that the subject has the right to decline 
to participate or subsequently withdraw from the study at any time without prejudice. 
The site PIs or designees must obtain the subject’s voluntary, signed and dated ICF (or, if the 
subject is unable to sign, independently witnessed and documented) before any study-related 
procedures are performed. Study staff must document the informed consent process. The 
original, signed ICF must be kept in the site study file. A copy of the informed consent document 
will be given to the subjects for their records. Prior to any study vaccination activities, subjects 
must take a written exam about the study and pass with 70% of answers correct. 

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For the study extension, the site PI or designee will fully inform the subject about the additional 
visit. The site PIs or designees must obtain the subject’s voluntary, signed and dated addendum 
to the ICF (or, if the subject is unable to sign, independently witnessed and documented) before 
any study-related procedures are performed 
13.5 
Participant confidentiality  
Every effort will be made to protect subject privacy and confidentiality. Personal identifiers will not 
be included in any study reports. All study records will be kept confidential to the extent provided 
by national laws. Medical records containing identifying information will be made available for 
review when the study is monitored by PATH or an authorized regulatory agency. Direct access 
may include examining, analyzing, verifying, and reproducing any records and reports that are 
important in the evaluation of the study. 
All study-related information will be stored securely at the study site. All subject information will 
be stored in locked file cabinets in areas with access limited to study staff. Data collection, 
process, and administrative forms, and other reports will be identified only by a coded number to 
maintain subject confidentiality. All local databases will be secured with password-protected 
access systems. Forms, lists, logbooks, appointment books, and any other listings that link 
subject ID numbers to other identifying information will be stored in a separate, locked file in an 
area with limited access. Subjects’ study information will not be released without their written 
permission, except as necessary for monitoring, or as required/permitted by law/regulatory 
authorities. 
13.6 
Reimbursement 
Pending IRB approval, subjects will be compensated for their time and effort in this study, and be 
reimbursed for travel to study visits. The study ICF and addendum will state the plan for 
reimbursement. Participants will not be charged for study injections, research clinic visits, 
research-related examinations, or research-related laboratory tests. Subject payments will be 
suitable to the requirements of the protocol and site. Payments will also be designed to be ethically 
acceptable and ensure retention of subjects in this relatively complicated and demanding trial.  
13.7 
Compensation for research related Injury 
Subjects will be instructed that if they experience any illness they should contact study staff as 
soon as possible. Subjects will be encouraged to be evaluated at the study clinic, if possible. If 
subjects seek medical care outside the study clinic, they should inform the health care provider(s) 
of their participation in this study, provide the health care provider(s) with contact information for 
the investigator, and separately contact the investigator to inform the investigator of the medically 
attended illness. There are limited funds available to the study for care of study-related injury. 
Although the investigators and Sponsor will make every effort to cover the costs of any study-
related injury, full coverage cannot be guaranteed, and uncovered costs may fall on subjects 
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necessary for any research related injury. Subjects will be informed that there are limited funds to 
cover SRI care costs and that there is the possibility that they may ultimately be responsible for 
at least some of the cost of care (See Financing and Insurance, Section 14). 
14 FINANCING AND INSURANCE 
The trial is supported by a grant from the Bill & Melinda Gates Foundation to the Icahn School of 
Medicine at Mt. Sinai, New York. PATH, the study sponsor, is a sub-recipient under this grant. 
PATH maintains clinical trial and liability insurance with a limited rider for medical coverage for 
research-related injury. Institutional authorities will make the decision to invoke that additional 
coverage on an individual case basis. 
15 PUBLICATION POLICY 
A Clinical Study Report comprised of text and results tables reflecting all safety and 
immunogenicity data will be generated. The clinical study report (CSR) will be reviewed, approved 
and signed by the Protocol Chair. The CSR will be compliant with ICH-GCP guidelines. 
All data, documents, any recordings and information transferred by PATH to any contractor or 
obtained or prepared by any contractor, his consultants or persons associated by contractual 
relationships with any contractor during the trials, belong to PATH. 
All confidential information communicated to the Principal Investigator by PATH, ISMMS, 
University of Chicago, Neomed, or GSK Biologicals shall be kept strictly confidential by him/her 
or any other person connected with the study and shall not be disclosed, either orally or in written 
form, by him/her or such person to any third party without prior written consent of the organization 
of which the information is the exclusive property. 
Following completion of the CSR, the investigators, working with PATH, ISMMS, University of 
Chicago, and GSK representatives, are expected to publish the results of this research in peer-
reviewed scientific journal(s) and make the data publicly available. In no way may PATH prohibit 
the public dissemination of the results of this trial; details of the publication plan are specified in 
the Agreement between PATH and the investigator’s institution(s). Within any presentation or 
publication, confidentiality of individual subjects will be maintained, with identification by subject 
code number and initials, if applicable.  
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a trials-registration policy as a condition for publication. This policy requires that all clinical trials 
be registered in a public trials registry. It will be the responsibility of PATH representatives to 
register this trial in an acceptable registry. ICMJE authorship criteria will be strictly followed for 
publication of any manuscript(s) arising from this trial.  
 

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APPENDIX 2 FDA SEVERITY GRADING TABLES FOR HEMATOLOGIC 
AND BIOCHEMICAL PARAMETERS 
Only those parameters that will be assessed as part of the study have been maintained in 
the tables below: 
 
 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
ALT, AST increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
ULN = upper limit of the normal range. 
*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. 
**The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory 
abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a Grade 3 parameter 
(125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new seizure associated with the low 
sodium value. 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) change from 
baseline value - gm/dL 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) change from 
baseline value - gm/dL 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm
3 
10 800 – 15 000 
15 001 – 20 000 
20 001 – 25 000 
> 25 000 
WBC Decrease - cell/mm
3 
2 500 – 3 500 
1 500 – 2 499 
1 000 – 1 499 
< 1 000 
Lymphocytes Decrease - cell/mm
3 
750 – 1 000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - cell/mm
3 
1 500 – 2 000 
1 000 – 1 499 
500 – 999 
< 500 
Eosinophils - cell/mm
3 
650 – 1 500 
1 501 – 5 000 
> 5 000 
Hyper-eosinophilic 
Platelets Decreased - cell/mm
3 
125 000 – 
140 000 
100 000 – 
124 000 
25 000 – 99 000 
< 25 000 
*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. 
 
REFERENCE for Appendix 2: 
FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (September 2007)